Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[CH2:23]([N:25]([CH2:34][CH3:35])[C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[CH3:24]>CN(C=O)C>[CH2:34]([N:25]([CH2:23][CH3:24])[C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:2][C:3]2[N:7]=[C:6]([CH:8]([CH3:22])[C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([F:21])[CH:10]=3)[O:5][N:4]=2)[CH2:32][CH2:33]1)=[O:27])[CH3:35]
Reactant: CCN(CC)C(=O)N1CCNCC1
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)N1CCN(Cc2noc(C(C)c3ccc(-c4ccccc4)c(F)c3)n2)CC1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A mixture of 2.14 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, 2.54 g of N,N-diethyl-1-piperazine carboxamide and 15 ml of dry DMF was heated at 100° C. for 2 hours. After cooling, the reaction mixture was poured into ice-water and extracted with diethyl ether. The organic phase was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed over silica gel using chloroform-methanol (50:1, v/v) to yield 2.43 g of 3-[4-(N,N-diethylcarbamoyl)piperazinomethyl]-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a light brown oil. To a solution of this product in ethanol was added equal mole of ethanolic hydrogen chloride and the mixture was concentrated to dryness under reduced pressure. Recrystallization of the residue from ethanol-diethyl ether gave colorless crystals, m.p. 181°-182° C.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)CCC(=O)O)cc1
Yield: 84.6 %

Procedure:
The title compound was prepared from anisole (11 g, 102 mmol) and succinic anhydride (i2 g, 120 m mol) in presence of anhydrous aluminum chloride (30 g) by the same method as described for 2 above to furnish 4-(4-methoxyphenyl)-4-oxo-butanoic acid in 84.6% yield, which on purification and crystallization from methanol/ethyl acetate (1:9) produced white crystals of 3, mp142–43° C., analyzed for C11,H12, O4 (found C64.21, H5.86; requires C63.45, H5.80%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]1[CH2:36][O:35][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH2:26][CH2:27]Br)[O:24]1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:27][CH2:26][C:25]3([O:24][CH2:23][CH2:36][O:35]3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCC1(c2ccccc2)OCCO1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCC2(c3ccccc3)OCCO2)CC1
Yield: 99.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (7.2 g) and 3,3-ethylenedioxy-3-phenylpropyl bromide (6.0 g) were reacted and treated in the same manner as in Example 172 to give 9.2 g of 4-amino-5-chloro-N-((1-(3,3-ethylenedioxy-3-phenylpropyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[N:10][C:9]=12)=[NH:4].[S:28]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](O)=O)(=[O:31])(=[O:30])[NH2:29]>>[F:17][C:14]([F:15])([F:16])[C:13]1[N:8]2[N:7]=[CH:6][C:5]([C:3]3[N:4]=[C:35]([C:34]4[CH:33]=[C:32]([S:28]([NH2:29])(=[O:31])=[O:30])[CH:40]=[CH:39][CH:38]=4)[O:1][N:2]=3)=[C:9]2[N:10]=[C:11]([C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH:12]=1
Reactant: N=C(NO)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Product: NS(=O)(=O)c1cccc(-c2nc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)no2)c1

Procedure:
The title compound was prepared from N-hydroxy-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxamidine (example B.1) (195 mg, 0.5 mmol) and commercially available 3-sulfamoyl-benzoic acid (101 mg, 0.5 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (144 mg, 52%). MS (ISN) 553.3 [(M−H)−]; mp 285° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:14])=[CH:15][CH:16]=2)=[CH:17][CH:18]=1
Reactant: NCC(=O)O
Reactant: O=C(O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: O=C(O)CNC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 98.8 %

Procedure:
A reaction similar to that described in Example 1 (1b) was conducted using 4-[4-(trifluoromethyl)phenoxy]benzoic acid (compound described in International Publication No. WO 04/14844, 7.06 g, 25.0 mmol) and glycine (1.88 g, 25.0 mmol) to give 8.38 g of the title compound (white powder, yield: 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:35])[O:14][CH2:15][C@@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:5]2.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45](O)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:20][CH2:19][CH2:18][CH2:17][C@H:16]([N:21]([CH3:34])[C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Cl:33])=[O:23])[CH2:15][O:14][C:13](=[O:35])[NH:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCN)COC(=O)Nc1cc2cc(F)ccc2cn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCCNC(=O)CNC(=O)OC(C)(C)C)COC(=O)Nc1cc2cc(F)ccc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
To a solution of (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (96 mg, 0.19 mmol), 2-(tert-butoxycarbonylamino)acetic acid (51 mg, 0.29 mmol) and HBTU (110 mg, 0.29 mmol) in DMF (1.0 mL) was added DIEA (63 □L, 0.38 mmol). The mixture was stirred at RT for 30 min. The mixture was filtered and the filtrate was purified by RP-HPLC using a mixture of acetonitrile and water to give (6-Fluoro-isoquinolin-3-yl)-carbamic acid (S)-5-(2-tert-butoxycarbonylamino-acetylamino)-2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-pentyl ester (105 mg, 83%). LRMS (M+Na+) m/z 663.2.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:23][CH2:22]1>>[CH:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:23][CH2:22]2)=[CH:7][CH:8]=1
Reactant: CCCCCCCCCCCCCCCN1CCC(CN)CC1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Product: CCCCCCCCCCCCCCCN1CCC(CNC[C@H](O)COc2cccc3[nH]c4ccccc4c23)CC1
Yield: 52.9 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.239 g, 1.0 mmol) and 4-aminomethyl-1-pentadecylpiperidine (0.650 g, 2.0 mmol) according to procedure used for Example 2 to give 0.298 g of the title compound as a white solid (mp-69-71° C., Et2O).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.[H-].[Na+].[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[CH2:35]Br)[CH:24]=[CH:23][C:22]=1[Cl:37])[CH3:17]>O1CCOCC1>[CH2:16]([O:18][C:19](=[O:38])[CH2:20][C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[CH2:35][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])[CH:24]=[CH:23][C:22]=1[Cl:37])[CH3:17]
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)ccc1Cl
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(4S,5R)-(−)-4-Methyl-5-phenyl-2-oxazolidinone (0.062 g, 0.35 mmol) was added to a vial containing sodium hydride (60% in mineral oil; 0.015 g, 0.38 mmol) in 1,4-dioxane (10 mL). After stirring for 30 minutes at room temperature, the mixture was added to a vial containing [5-(4-bromo-2-bromomethyl-phenoxy)-2-chloro-phenyl]-acetic acid ethyl ester (0.15 g, 0.32 mmol) at 10° C. The reaction was stirred at room temperature overnight, and then additional (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (0.062 g, 0.35 mmol), pretreated with sodium hydride (60% in mineral oil; 0.015 g, 0.38 mmol), was added and the reaction was stirred overnight. Once no starting material was observed by analytical LCMS, the mixture was carried forward to the hydrolysis step.
Reaction SMILES: [F:1][CH:2]1[CH2:5][NH:4][CH2:3]1.[CH3:6][N:7]([CH3:29])[C:8]1[N:28]=[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25](O)=[O:26])=[O:18])=[CH:15][N:10]2[N:9]=1>>[CH3:6][N:7]([CH3:29])[C:8]1[N:28]=[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]([C:19]3[N:23]([CH3:24])[N:22]=[CH:21][C:20]=3[C:25]([N:4]3[CH2:5][CH:2]([F:1])[CH2:3]3)=[O:26])=[O:18])=[CH:15][N:10]2[N:9]=1
Reactant: FC1CNC1
Reactant: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)N4CC(F)C4)cnn3C)cn2n1

Procedure:
Using 3-fluoro-azetidine and 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Light yellow solid (160 mg, 68%). MS: m/z=387 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][C:7](=[O:13])[CH:6]=2)([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2
Reactant: O=C1C=c2c([N+](=O)[O-])cccc2=N1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1cccc2c1CC(=O)N2

Procedure:
4.43 g (18.45 mmol) of methyl-(2,6-dinitrophenyl)-acetate is added in 38.8 ml of glacial acetic acid and 11 ml of water and mixed with 3.75 g of iron powder and stirred for four more hours. In this case, heating to 40 to 60° C. takes place. The reaction mixture is added to ice water, mixed with ethyl acetate and vigorously stirred for ten minutes. The mixture is filtered through a glass-fiber filter, the organic phase is separated, and the aqueous phase is extracted twice more with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off after the desiccant is filtered off. The residue is chromatographed on silica gel (mobile solvent methanol/dichloromethane). 2.38 g of 4-nitro-indol-2-one is isolated. The nitro compound is mixed again in glacial acetic acid/water with 2.7 g of iron powder, and the above-described cycle is passed through another time. 1.63 g of the desired amine is isolated.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[NH:11][C:10]2=[O:17])=[CH:5][CH:4]=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:10](=[O:17])[NH:11][C:12](=[O:16])[NH:13][C:14]2=[O:15])=[CH:7][CH:8]=1
Reactant: COc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1NC(=O)C(c2ccc(O)cc2)C(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103 %

Procedure:
To a suspension of 5-(4-methoxyphenyl)barbituric acid (222 mg) in 5 ml of methylene chloride, kept at -5/-10° C. and under nitrogen atmosphere, is dropped a solution of boron tribromide (473 μl) in 2 ml of methylene chloride. The stirring is continued for additional 2 hours at -5° C., then the temperature is brought to room temperature and stirring is continued for further 20 hours. The reaction mixture is again cooled to 0° C. with an ice bath and it is basified to pH=9-10 by adding dropwise 5% sodium hydroxide. The aqueous phase is separated, filtered through a celite plug, cooled with ice bath and acidified to pH=1 with 37% hydrochloric acid. A white solid separates which after 1 hour is separated by filtration and dried under vacuum at 60° C. to give 215 mg of the product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[N:14][O:15][CH2:16][C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.[C:30](Cl)(=[O:37])[O:31][CH2:32][CH2:33][CH2:34][CH2:35][Cl:36]>ClCCl>[CH3:1][N:2]1[C:6](/[C:7](=[N:14]\[O:15][CH2:16][C:17]2[N:22]=[C:21]([NH:23][C:30](=[O:37])[O:31][CH2:32][CH2:33][CH2:34][CH2:35][Cl:36])[CH:20]=[CH:19][CH:18]=2)/[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1C(=NOCc1cccc(N)n1)c1ccccc1
Reactant: O=C(Cl)OCCCCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnnc1/C(=N\OCc1cccc(NC(=O)OCCCCCl)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)-methyl]pyridin-2-amine (150 mg, 0.485 mmol) in dichloromethane (5 mL), was added pyridine (0.078 mL), 4-chlorobutyl carbonochloridate (166 mg, 0.970 mmol). The reaction mixture was stirred for 5 hours at room temperature, concentrated in vacuo, and then purified by silica gel chromatography to yield to 4-chlorobutyl {6-[({[(Z)-(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate [200 mg; 90% of purity; 84% of to theory; HPLC/MS: m/z=344 (M+H); log P(HCOOH)=3.67].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:12])[C:10]=1[Cl:11])[C:7](=[O:13])[C:6]([CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:14])[CH2:5]2.C(=O)([O-])[O-].Br[CH2:25][C:26]([O:28]CC)=[O:27]>CC(C)=O>[Cl:11][C:10]1[C:9]([Cl:12])=[C:8]2[C:4]([CH2:5][C:6]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)([CH3:14])[C:7]2=[O:13])=[CH:3][C:2]=1[NH:1][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CC1(C2CCCC2)Cc2cc(N)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(NCC(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 8 h
Yield: 15.7 %

Procedure:
A mixture of 5-amino-6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1H-inden-1-one (800 mg), postassium carbonate (440 mg), and ethyl bromoacetate (540 mg) in acetone (20 ml) is heated at reflux overnight. The reaction mixture is filtered, the acetone is distilled at reduced pressure and the residual oil is dissolved in a mixture of ethanol (5 ml) and methylene chloride (5 ml) and treated with 10 N sodium hydroxide (2 ml). The mixture is stirred overnight, the solvents are distilled at reduced pressure and the residue is treated with water, then filtered and acidified with hydrochloric acid and extracted with ethyl acetate. Evaporation of the ethyl acetate gives 150 mg of [(6,7-dichloro-2-cyclo-pentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)amino]acetic acid which melts at 199°-200° C. after recrystallization from chloroform-hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1ccccc1
Product: COc1ccc(-c2cc(Oc3ccccc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (160 mg, 0.490 mmol) and phenol were reacted as starting materials at 120° C. for 22 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless needles (133.1 mg, 70.7%). Melting point: 198.8-199.5° C. (ethyl acetate-hexane).
Reaction SMILES: C([O:8][C:9](=O)[NH:10][CH2:11][C:12](=[O:46])[NH:13][C@H:14]1[CH2:18][C@@H:17]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][C:22]([Cl:43])=[N:23][C:24]=3[NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([OH:44])[C@@H:15]1[OH:45])C1C=CC=CC=1>CCO>[Cl:43][C:22]1[N:21]=[C:20]2[C:25]([N:26]=[CH:27][N:19]2[C@@H:17]2[CH2:18][C@H:14]([N:13]3[C:12](=[O:46])[CH2:11][NH:10][C:9]3=[O:8])[C@@H:15]([OH:45])[C@H:16]2[OH:44])=[C:24]([NH:28][CH2:29][CH:30]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:23]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: O=C1CNC(=O)N1[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
({(1S,2R,3S,4R)-4-[2-Chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl)-carbamic acid benzyl ester (Intermediate UA) is dissolved in EtOH and purged with argon and Pd/C is added. The reaction mixture is placed under a positive pressure of H2(g) (0.35 Barr) at RT over night. The reaction mixture is filtered through celite and reduced in vacuo. Intermediate VA is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].O>CN(C=O)C>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(=O)OCC)c2)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(1H-indazol-5-yl)pyrimidine-4-carboxamide (Example 45, 350 mg; 1 mmol) in DMF (4 ml) was treated with potassium carbonate (140 mg; 1 mmol), and ethyl 2-bromoacetate (184 mg; 1.1 mmol). After stirring at RT for 18 hours the mixture was poured into water (20 ml) and stirred at RT for 30 minutes. The solid was removed by filtration and purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid, together with ethyl {5-[({6-[(cyclopropylmethyl)(propyl)amino]pyrimidin-4-yl}carbonyl)amino]-2H-indazol-2-yl}acetate (Example 120 below).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@H:34]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].I[CH2:49][CH3:50].COC(C)(C)C>CN(C)C=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][CH:34]([N:37]([CH2:49][CH3:50])[S:38]([CH3:41])(=[O:40])=[O:39])[CH2:33]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:44])[F:45])[CH:8]=1
Reactant: CCI
Reactant: Cc1cc(F)ccc1-c1cc(N2CC[C@H](NS(C)(=O)=O)C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CCN(C1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 150 mg (0.227 mmol) (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-methanesulfonylamino-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide in 1 ml dimethylformamide were added 14 mg (0.35 mmol) sodium hydride (60% dispersion in mineral oil). After stirring at room temperature for 30 min. 22 mg (0.27 mmol) iodoethane were added. The reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml tert-butyl methyl ether and washing with 20 ml water and with 10 ml of a saturated aqueous solution of sodium carbonate. The combined organic layers were dried over sodium sulfate, concentrated and purified by flash chromatography to give 86 mg (55%) of the title compound as an off-white foam.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=2)=[O:30])[C:3]1=[O:20]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-methylphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 207°-209° C.
Reaction SMILES: [CH2:1]([N:5]1[CH2:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]1=O)[CH2:2][CH2:3][CH3:4]>O1CCCC1>[CH2:1]([N:5]1[CH2:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1Cc2c([nH]c3ccccc23)C1=O
Solvent: C1CCOC1
Product: CCCCN1Cc2[nH]c3ccccc3c2C1

Procedure:
2-n-Butyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one, 20 g., in dry tetrahydrofuran, 400 ml., is added slowly to a slurry of LiAl H4, 14 g., in tetrahydrofuran, 250 ml. After refluxing twenty hours, the reaction mixture is hydrolyzed with 30 ml. of water, and filtered. After the solvent is removed, one obtains 20.1 g. of a reddish-brown solid. Recrystallization from methanol, 200 ml., gives 11 g. of the title compound, m.p. 151°-2°.