Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([OH:21])=O)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:55][C:56]([F:60])([F:59])[CH2:57][NH2:58]>ClCCl>[C:10]([O:14][C:15](=[O:16])[NH:17][CH2:18][C:19](=[O:21])[NH:58][CH2:57][C:56]([F:60])([F:59])[F:55])([CH3:11])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NCC(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(F)(F)F
Reaction time: 24 h

Procedure:
DIPEA (15 ml) is added to a solution of N-(tert-butoxycarbonyl)glycine (5.0 g), PYBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, 16.3 g) and 2,2,2-trifluorethylamine (2.47 ml) in dichloromethane (48 ml). After 24 hours at room temperature, the reaction is quenched with water and extracted three times with dichloromethane. The combined organic phases are washed with HCl (2M), Na2CO3 (1M) and a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified by column chromatography (450 g) eluting with a mixture of ethyl acetate and hexane (2:3 to 3:2) to yield [(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (3.89 g).
Reaction SMILES: [N+](C1C=CC=CC=1N=NC1C=C(C)C=CC=1O)([O-])=[O:2].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[N:30]=[N:31][C:32]1[CH:37]=[C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=[C:34]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:33]=1O)([O-])=O>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]2=[N:20][N:31]([C:32]3[CH:37]=[C:36]([C:38]([CH3:40])([CH3:39])[CH3:41])[CH:35]=[C:34]([C:42]([CH3:45])([CH3:43])[CH3:44])[C:33]=3[OH:2])[N:30]=[C:24]2[CH:25]=1
Reactant: CC(C)(C)c1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1

Procedure:
When in Example 1, the 2-nitro-2'-hydroxy-5'-methylazobenzene is replaced by an equivalent amount of 2-nitro-5-chloro-2'-hydroxy-3',5'-di-tert-butylazobenzene, the above noted product is obtained.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[O:19][C:18]([CH3:24])([CH3:23])[CH2:17][C:16]3([CH3:26])[CH3:25])=[CH:7][CH:6]=1.[OH-].[Na+]>CO>[CH3:23][C:18]1([CH3:24])[CH2:17][C:16]([CH3:25])([CH3:26])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:27])=[O:2])=[CH:10][CH:9]=3)[CH:14]=2)[O:19]1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)cc3)ccc2O1
Temperature: 55 °C
Yield: 75.1 %

Procedure:
A solution of [4-(2,2,4,4-tetramethyl-chroman-6-yl-ethynyl) phenyl]acetic acid methyl ester (Compound 27, 0.047 g, 0.13 mmol) in 5 mL of methanol was treated with 1M sodium hydroxide solution (2 mL) and heated at 55° C. for 2 h. The volatiles were distilled off in vacuo and the residue was acidified with 10% hydrochloric acid and extracted with ethyl acetate (×2). The combined organic phase was washed with brine (×1), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue which was purified by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase to afford the title compound (0.034 g, 82%).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH3:39])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH3:39])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
75 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 78 mg of potassium carbonate were dissolved in 0.95 ml of water and 4.75 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.016 ml of methyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [BrH:1].[CH2:2]([NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>COCCOC>[Br:1][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=1
Reactant: Br
Reactant: C=CCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: COCCOC
Product: O=C(O)c1ccc(NCCCCCCCCCCCBr)cc1

Procedure:
Anhydrous hydrogen bromide is passed rapidly into a solution of 5 g. of 4-(10-undecenylamino)benzoic acid and 1 g. of dibenzoyl peroxide in 300 ml. of 1,2-dimethoxyethane for 1 hour. Partial evaporation of the solvent affords a crystalline solid which is separated by filtration and recrystallized from ether-petroleum ether to yield the product as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:11]([F:31])[CH:10]=1>>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([N:6]4[CH:2]([CH3:1])[CH2:3][CH2:4][C:5]4=[O:7])=[CH:10][C:11]=3[F:31])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3F)CC2)c(C)c1
Yield: 42 %

Procedure:
Using 5-methylpyrrolidin-2-one (54 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, the title compound (94 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:15]([Cl:35])=[CH:16][C:17]([F:34])=[C:18]([C:20]2[C:24]([C:25]([F:28])([F:27])[F:26])=[C:23]([C:29]([F:32])([F:31])[F:30])[N:22]([CH3:33])[N:21]=2)[CH:19]=1>O1CCCC1>[Cl:35][C:15]1[C:14]([N:13]([S:9]([CH3:8])(=[O:11])=[O:10])[S:9]([CH3:8])(=[O:11])=[O:10])=[CH:19][C:18]([C:20]2[C:24]([C:25]([F:26])([F:27])[F:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[N:22]([CH3:33])[N:21]=2)=[C:17]([F:34])[CH:16]=1
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1nc(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Reaction time: 16 h

Procedure:
1 g (10 mmol) of triethylamine and 0.8 g (6.6 mmol) of methanesulfonyl chloride were added in succession to a solution of 1.2 g (3.3 mmol) of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-4,5-di(trifluoromethyl)-1H-pyrazole in 30 ml of tetrahydrofuran. The reaction mixture was subsequently stirred for 16 hours, whereupon it was concentrated. The residue was treated with water and ethyl acetate. The organic phase which had been separated off was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and finally concentrated. Yield: quantitative.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]2[C:13](=O)[CH:12]3[CH2:15][CH2:16][N:9]2[CH2:10][CH2:11]3)[CH:2]=1.[CH2:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH2:17]=[C:13]1[CH:12]2[CH2:15][CH2:16][N:9]([CH2:10][CH2:11]2)[CH:8]1[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1C2CCN(CC2)C1Cc1cccnc1
Product: C=C1C2CCN(CC2)C1Cc1cccnc1

Procedure:
The saturated ketone intermediates, such as 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one, also present opportunities for derivatization. One example is the reaction with phosphorus ylids (Wittig and Homer-Emmons reagents) to give alkenes. These alkenes can subsequently be reduced to alkanes by catalytic hydrogenation, providing a means of producing 2-((heteroaryl)alkyl)-1-azabicycles with alkyl and substituted alkyl substituents at the 3-position of the azabicycle. Thus, by way of example, 2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-one reacts with methylenetriphenylphosphorane to give 3-methylene-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane. Hydrogenation of this alkene, for example, over palladium on carbon catalyst, yields 3-methyl-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane as predominantly the cis diastereomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cccc1Cl)n1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 72 h

Procedure:
2-(4-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (3.8 grams; 0.018 mole), toluene (50 ml) and triethylamine (2.8 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dichlorobenzoyl chloride (4.19 grams) dissolved in toluene (10 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 3 days. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate, is filtered and is stripped of solvent under reduced pressure. The residue is washed with a hexane-ether mixture to yield a brown solid. This solid is recrystallized from a benzene-hexane mixture to yield the desired product 2-(4-chlorophenyl)-4-(2,6-dichlorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione having a melting point of 112° to 116°C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH2:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([Li])CCC.CN([CH:19]=[O:20])C>C1COCC1.CCCCCC>[O:8]1[C:4]2[CH:3]=[C:2]([CH:19]=[O:20])[CH:10]=[CH:9][C:5]=2[CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)OCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To an cooled solution (−78° C. internal temp) of 1 g of 6-bromo-2,3-dihydro-1-benzofuran (prepared as described by Z. J. Song, M. Zhao, L. Frey, J. Li, L. Tan, C. Y. Chen, D. M. Tschaen, R. Tillyer, E. J. J. Grabowski, R. Volante, P. J. Reider, Y. Kato, S. Okada, T. Nemoto, H. Sato, A. Akao, T. Mase, Organic Letters, 2001, Vol. 3, No. 21, 3357-3360) in 20 mL of anhydrous THF was added 4 mL of 2.5 M n-butyllithium in hexane. After stirring 10 min at −78° C., 0.5 mL of anhydrous DMF was added and the mixture allowed to warm to −20° C., quenched with 20 mL of 3N HCl and extracted into 2×50 mL of ether. Combined extracts dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (0-20% ethyl acetate in hexanes) gave the product as white crystalline solid. MS (m+1)=149.1; 1H NMR (400 MHz, CDCl3) 9.9 (s, 1H), 7.4 (m, 2H), 7.3 (s, 1H), 4.62 (t, 2H), 3.28 (t, 4H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:29](=[N:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.C(O)C.[C].[Pd]>[C:42]([O:41][C:39]([NH:38][C:29]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([O:18][CH2:17][CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[CH:20][CH:21]=2)[CH2:26]1)=[N:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(C(=O)OCc4ccccc4)CC3)cc2C1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Yield: 207.7 %

Procedure:
4-[2-(N,N′-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-carboxylic acid benzyl ester (500 mg) was hydrogenated using 7.5% palladium carbon (150 mg) in a mixture of tetrahydrofuran (5 ml) and ethanol (100 ml) at 3 atm over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (815 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:14][CH3:15])([O-:3])=[O:2].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>C(Cl)CCl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:12])([CH3:11])[CH3:13])[CH:7]=[C:6]([N+:16]([O-:18])=[O:17])[C:5]=1[O:14][CH3:15])([O-:3])=[O:2]
Reactant: COc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
The recovered 2-nitro-4-tertbutylanisole is then again subjected to nitration. Specifically, the 2-nitro-4-tertbutylanisole intermediate is mixed with between 2-9 parts (by volume) organic solvent such as ethylene dichloride. Next is the cooling of the reaction mixture of 2-nitro-4-tertbutylanisole and organic solvent in an ice-water bath to a temperature below 5° C. This is followed by the adding of a mixture of 70% nitric acid and 98% sulfuric acid while maintaining a temperature below 10° C. Following the acid mixture addition, the cooling bath is removed and the temperature of the reaction mixture is increased to 50° C. and maintained there for 2-10 hours to produce 2,6-dinitro-4-tertbutylanisole and a 2,4-dinitrophenol byproduct.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].C1COCC1.[N:35]1([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1>CCOC(C)=O.CCCCCC>[O:29]=[C:4]1[C:3](=[CH:2][NH:47][C:44]2[CH:43]=[CH:42][C:41]([CH2:40][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:46][CH:45]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CN2CCCC2)cc1
Reactant: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccsc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CN3CCCC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 200 mg, 0.4945 mmol) and THF (5.0 mL). To the resulting solution was added 4-Pyrrolidin-1-ylmethyl-phenylamine (87.1 mg, 0.494 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜40 mL). The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (˜5 mL) to afford the title compound in 52% yield (0.144 g, 0.256 mmol).
Reaction SMILES: [Mg].CI.[CH2:4]([O:11][C:12]1[CH:21]=[CH:20]C(C(OC)=O)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl-].[NH4+].C[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH2:4]([O:11][C:12]1[CH:21]=[CH:20][C:27]([C:26]([OH:25])([CH3:29])[CH3:28])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(C)(C)C
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(O)c1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
Under argon 6.63 g of magnesium (273 mmol) was suspended in 15 mL of tert-butyl methyl ether. A solution of 38.68 g of methyl iodide (273 mmol) in 145 mL of tert-butyl methyl ether was added during 45 minutes under stirring while maintaining the temperature at 40° C. Then stirring was continued at 40° C. for 1.5 hours and then the mixture was cooled to room temperature. A solution of 30.0 g of methyl 4-benzyloxybenzoate (124 mmol) in 120 mL of tetrahydrofuran was then added during 1 hour. The temperature was kept at 20° C. After complete addition, the reaction mixture was heated to 42° C. and stirred 3 hours at this temperature. After cooling to room temperature, the reaction mixture was poured into a mixture of 300 mL of 10% aqueous ammonium chloride and 100 g of ice and extracted with ethyl acetate. The organic phases were washed with water and saturated aqueous sodium bicarbonate, combined, dried and evaporated to give the crude product as an oil which partially crystallised. The product was dissolved at 25° C. in diethyl ether. When crystals started to separate the solution was cooled to 18° C. After 30 minutes hexane was added. The suspension was then stirred for 1 hour at 5° C. The crystalline 2-(4-benzyloxy-phenyl)-propan-2-ol was collected on a filter and washed with hexane.
Reaction SMILES: [CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[CH:14])=[C:8]3[N:7]=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:5]=2)[CH2:3][CH2:2]1.Br[C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([C:4]2[N:9]3[N:10]=[CH:11][C:12]([C:13]#[C:14][C:26]4[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=4)=[C:8]3[N:7]=[C:6]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 7-cyclopropyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.7) (82 mg, 0.25 mmol) and 4-bromo-benzenesulfonamide (59 mg, 0.25 mmol) according to general procedure II. Obtained as a yellow solid (60 mg, 50%). MS (ISN) 480.9 [(M−H)−]; mp 228-230° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:12][CH2:11]1)=[O:8]
Reactant: CC(C)C(=O)Cl
Reactant: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To an ice cooled solution of 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 100 mg, 0.274 mmol) in dry DCM (5 mL) were added triethylamine (0.2 mL, 1.37 mmol) and isobutyryl chloride (0.035 mL, 0.33 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1.5 h), and quenched with saturated NaHCO3. The organic solution was evaporated to dryness and the oil obtained was purified by column chromatography using DCM/MeOH 95:5 as eluent. Further purification was carried out by treating a DCM solution of the obtained compound with trisamine scavenger (100 mg) for 2 h. The scavenger was filtered off, and the solvent evaporated to give 2-(2,4-dichlorophenoxy)-N-(1-isobutyrylpiperidin-4-yl)benzamide (93 mg, 77%) as a white solid. Rf: 0.15 (hexane/AcOEt 4:6), mp 51-54° C. LC/MS (APCI) tr=4.66 min, m/z 437.33 (66), 435.31 (M++H, 100). HPLC tr=2.39 min (97.97%) 1H NMR (270 MHz, CDCl3) δ 1.10 (6H, d, J=6.7 Hz, 2CH3), 1.36 (2H, m, CH2), 2.00 (2H, m, CH2), 2.78 (1H, hept, J=6.7 Hz, CHMe2), 2.80 (1H, m, ½CH2), 3.18 (1H, br t, ½CH2), 3.83 (1H, m, ½CH2), 4.19 (1H, m, CH), 4.44 (1H, m, ½CH2), 6.79 (1H, d, J=8.6 Hz, ArH), 6.87 (1H, d, J=8.7 Hz, ArH), 7.19-7.28 (2H, m, ArH), 7.35 (1H, br s, NH), 7.40 (1H, m, ArH), 7.50 (1H, d, J=2.5 Hz, ArH) and 8.17 (1H, dd, J=7.7, 1.7 Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.[CH2:30]([OH:33])[C:31]#[CH:32].ClCCl>C1COCC1.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:32]#[C:31][CH2:30][OH:33])[C:3]=12
Reactant: C#CCO
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ncnc2c1c(C#CCO)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Yield: 76.8 %

Procedure:
To a solution of Example 57a (0.180 g, 0.363 mmoles) in THF (5 ml), propargyl alcohol (0.051 g, 0.436 mmoles) diisopropylamine (0.31 ml, 1.81 mmoles), copper(I) iodide (7 mg, 0.036 mmoles) and) Tetrakis triphenylphosphine Palladium (0.042 g, 0.0363 mmoles) were added and the system is degassed for 30 min and heated to reflux for 4 h. The reaction mixture filtered through celite pad and washed with ethyl acetate. The filtrate was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.118 g, 77% yield). MP: 171-173° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.21(s, 1H), 8.06(dd, J=7.9, 1.6Hz, 1H), 7.77(m, 1H), 7.50(dt, J=8.0, 0.9Hz, 1H), 7.40-7.33(m, 6H), 5.43(s, 2H), 4.33(d, J=6.1z, 2H). Mass: 423.88(M+).
Reaction SMILES: OC(C(F)(F)F)=O.C1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:32]([O:34]C)=[O:33])=[CH:19][C:20]=3[N:21]3[C:27]=2[C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[NH:24][CH2:23][CH2:22]3)CCCCC1.C1(N=C=O)CCCC1>C(N(CC)CC)C.C(Cl)Cl>[CH:28]1[C:26]2[C:27]3[N:21]([C:20]4[CH:19]=[C:18]([C:32]([OH:34])=[O:33])[CH:17]=[CH:16][C:15]=4[CH:14]=3)[CH:22]=[CH:23][NH:24][C:25]=2[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNc1ccccc1-3
Agent: O=C=NC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)c1ccc2cc3n(c2c1)C=CNc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (13-cyclohexyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)-carboxylate TFA (80 mg, 0.17 mmol) in triethylamine (0.20 mL) and CH2Cl2 (5 mL) which had been stirred for 5 min. was added cyclopentyl isocyanate (0.20 mL, 1.77 mmol). The reaction solution was stirred overnight at rt, concentrated to dryness, dissolved into MeOH/THF (1:1, 3 mL) and treated with 1M aqueous NaOH (0.80 mL). The reaction mixture was stirred and heated at 80° C. with microwave irradiation for 15 min in a sealed tube. The clear solution was diluted with H2O (3 mL), neutralized with 1M aqueous HCl (0.80 mL) and concentrated to remove organic solvents. The solids were collected by filtration, washed with water and purified by preparative HPLC (MeOH/H2O with NH4OAc buffer) to yield 5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylic acid, 13-cyclohexyl-5-[(cyclopentylamino)carbonyl]-6,7-dihydro (8 mg, 0.02 mmol, 10%) as an off-white solid. 1HNMR (300 MHz, CD3OD) δ 8.14 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.72 (dd, J=8.4, 1.1 Hz, 1H), 7.68–7.59 (m, 3H), 7.52–7.46 (m, 1H), 4.79–4.60 (m, 2H), 4.05–3.46 (m, 3H), 3.06–2.92 (m, 1H), 2.14–1.25 (m, 18H). LCMS: m/e 472 (M+H)+, ret time 2.66 min, column A, 3 minute gradient.