Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=1[C@@H:17]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:18][CH2:19][N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])C1C=CC=CC=1>[Pd].CO>[CH:24]([N:20]([CH:21]([CH3:23])[CH3:22])[CH2:19][CH2:18][C@@H:17]([C:10]1[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:9]=1[OH:8])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CO)ccc1O)C(C)C

Procedure:
(R)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol of formula (H) is reduced by using Pd/C in the presence of alcoholic solvents, preferably methanol to obtain (R)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxy methyl phenol of formula (I) which is recrystallized with mixture of ethyl acetate and hexane.
Reaction SMILES: Cl.[NH2:2]O.[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][C:10]([CH3:16])=[C:9]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:8]2=[O:25].O>N1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([C:8]2[O:25][N:2]=[C:10]([CH3:16])[C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:12]([OH:11])=[CH:13][C:14]=1[OH:15]
Reactant: COc1ccc(-c2c(C)oc3cc(O)c(Cl)cc3c2=O)cc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2c(C)noc2-c2cc(Cl)c(O)cc2O)cc1

Procedure:
Hydroxylamine hydrochloride (0.7 g, 10 mmol) was added to a suspension of 6-chloro-7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one [prepared analogously to Example 1, Step 2] (0.32 g, 1.0 mmol) in pyridine (4 ml) and the mixture heated under reflux for ˜6 hrs., to give a pale yellow solution. The solution was allowed to cool and water (20 ml) added. The mixture was extracted with diethyl ether (2×10 ml). The combined extracts were washed with water (2×20 ml) and saturated aqueous sodium chloride solution (10 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate/hexane (1:1), to give 4-chloro-6-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzene-1,3-diol as an off-white powder (0.103 g)
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:32])[C:15]1[C:20](Br)=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:16]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>COCCOC.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:12][O:13][C:14](=[O:32])[C:15]1[C:20]([CH:8]=[CH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][C:18]([F:22])=[C:17]([F:23])[C:16]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]
Reactant: COC(=O)c1c(Br)cc(F)c(F)c1Nc1ccccc1Cl
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1c(C=Cc2ccccc2)cc(F)c(F)c1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 16 h
Yield: 56.5 %

Procedure:
Pd(PPh3)4 (0.313 g, 0.271 mmol) and trans-2-phenylvinylboronic acid (1.105 g, 7.468 mmol) were added to a mixture of 6-bromo-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (2.00 g, 5.31 mmol) in 35 mL DME and 8 mL 2.0 M aqueous K2CO3 solution. The reaction mixture was heated under a N2 atmosphere to 90° C. and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water and the layers separated. The organic layer was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography gave 1.20 g (56%) clean desired product.
Reaction SMILES: C(N)(C)C.C1OC1C.[CH:9]([N:12]([CH2:17][CH:18]([OH:20])[CH3:19])[CH2:13][CH:14]([OH:16])[CH3:15])([CH3:11])[CH3:10]>>[CH:9]([N:12]1[CH2:17][CH:18]([CH3:19])[O:20][C:14]([CH3:15])([OH:16])[CH2:13]1)([CH3:11])[CH3:10]
Reactant: CC(O)CN(CC(C)O)C(C)C
Agent: CC1CO1
Solvent: CC(C)N
Product: CC1CN(C(C)C)CC(C)(O)O1
Yield: 32 %

Procedure:
Isopropylamine (11.8 g, 0.2 mol) and propylene oxide (34.8 g, 0.6 mol) were subjected to a reaction as described in Example 1 above, except that the reaction temperature was 165° C. A 32% yield of 4-isopropyl-2,6-dimethyl-2-hydroxymorpholine was obtained along with 50% of N-isopropyl-bis-(2-hydroxypropyl)amine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[C:19]([F:21])[CH:20]=[C:15]3[C:14]([C:22]3[N:23]=[N:24][C:25]([C:29]([CH3:35])([CH3:34])[C:30]([O:32]C)=O)=[C:26](O)[N:27]=3)=[N:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH3:36]>C(#N)C>[CH:6]1([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[C:19]([F:21])[CH:20]=[C:15]3[C:14]([C:22]3[N:23]=[N:24][C:25]4[C:29]([CH3:34])([CH3:35])[C:30](=[O:32])[NH:36][C:26]=4[N:27]=3)=[N:13]2)[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(CC3CCCC3)c3ncc(F)cc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5 ml (53.642 mmol) of phosphoryl chloride were added to 376 mg (0.863 mmol) of methyl 2-{3-[1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate, and the mixture was stirred at RT overnight. The reaction solution was diluted with 20 ml of dry acetonitrile and, with ice-cooling, slowly added dropwise to 83 ml of a 25% strength aqueous ammonia solution, and the mixture was stirred at RT overnight. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. The residue was triturated with DMF/methanol, filtered off with suction and dried under high vacuum. This gave 84 mg of the target compound (24% of theory).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]2[C:21]([CH2:24][C:25]([F:28])([F:27])[F:26])=[CH:22][N:23]=[C:9]12)(C)(C)C.FC(F)(F)C(O)=O.CN(C)C=O>ClCCl>[CH3:20][C@H:11]1[N:10]2[C:21]([CH2:24][C:25]([F:27])([F:26])[F:28])=[CH:22][N:23]=[C:9]2[C@@H:8]([NH2:7])[CH2:13][C@H:12]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H]1[C@H](c2ccccc2)C[C@H](NC(=O)OC(C)(C)C)c2ncc(CC(F)(F)F)n21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](c2ccccc2)C[C@H](N)c2ncc(CC(F)(F)F)n21
Reaction time: 1.5 h
Yield: 74 %

Procedure:
To a solution of tert-butyl[(5R,6S,8S)-5-methyl-6-phenyl-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-8-yl]carbamate (18.4 mg, 0.045 mmol) in dichloromethane (900 μL) was added trifluoroacetic acid (104 μL, 1.35 mmol). The mixture was stirred 90 min. N,N-dimethylformamide was added and the dichloromethane was removed under vacuum. The resulting mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid). Product containing fractions were treated with 1 M hydrochloric acid and concentrated to give the hydrochloride salt of the title compound (10.3 mg). MS 310.3 (M+1).
Reaction SMILES: II.[S:3]=[C:4]([C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[S:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=2)=[CH:13][CH:12]=1)[CH3:10])[CH2:5][C:6]([NH2:8])=[O:7].C([O-])([O-])=O.[K+].[K+].Cl>CCO.O>[F:24][C:23]([F:25])([F:26])[C:21]1[N:22]=[C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([C@H:9]([C:4]3[S:3][N:8]=[C:6]([OH:7])[CH:5]=3)[CH3:10])=[CH:16][CH:15]=2)[S:19][CH:20]=1
Reactant: C[C@@H](C(=S)CC(N)=O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Agent: Cl
Agent: II
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1cc(O)ns1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A solution of iodine (135 mg, 0.53 mmol) in EtOH (5 ml) was added dropwise to a cooled mixture (0-5° C.) of the intermediate 12b (150 mg, 0.40 mmol) and K2CO3 (212 mg, 1.53 mmol) in EtOH (5 ml). The reaction mixture was stirred for 24 h at room temperature. Water (10 ml) was added and pH adjusted to 3 by 1M HCl. The aqueous layer was extracted with EtOAc (3×10 ml); the collected organic extracts were dried over anhydrous Na2SO4 and, after solvent evaporation, the purification of the crude by flash chromatography (CH2Cl2/CH3OH 95:5) afforded 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]isothiazol-3-ol (12) (82 mg, 0.22 mmol) as a white solid (41%). [α]D=−31 (c=1; CH3OH); 1H-NMR (CDCl3): δ 10.60 (bs, 1H, OH), 9.15 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.00 (s, 1H), 5.50 (s, 1H), 3.80 (q, 1H, J=7 Hz), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:22])[C:16]=1[CH3:32].Cl.C(N=C=NCCCN(C)C)C.O[C:46]1[C:54]2[N:53]=N[NH:51][C:50]=2[CH:49]=[CH:48][CH:47]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:51][C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:54]=2[NH2:53])=[O:30])=[O:22])[C:16]=1[CH3:32]
Reactant: Oc1cccc2[nH]nnc12
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCCCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(Cl)cc32)c(C)c1C(=O)NCCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.9 %

Procedure:
6-(5-(((5-chloro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3 -carboxamido)-hexanoic acid (458 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (438 mg, 80% yield) as a red solid. LC-MS (m/z) 548 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 165 mg (0.55 mmole) 4-(1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester, 25 mg tetrabutylammonium hydrogen sulfate and 0.08 mL (0.6 mmole) benzenesulfonyl chloride in 2 mL 4 M sodium hydroxide and 5 mL toluene was stirred at room temperature for 2 hours. The mixture was diluted with 5 mL water and extracted with 25 mL ethyl acetate. The organic phase was washed with 5 mL water, 5 mL saturated sodium chloride, dried (magnesium sulfate) and concentrated. 4-(1-Benzenesulfonyl-1H-indol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester was isolated by recrystallization from ether/hexane, 223 mg, m.p. 143-144° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][NH:7][C:6]2=[N:10][CH:11]=[CH:12][C:5]=12.CI.[C:15](OCC)(=O)C>CN(C)C=O.O>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([CH3:15])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cn1ccc2c(Cl)ncnc21
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.4 g (12.5 mmol) of sodium hydride is added to 25 cm3 of dimethylformamide under an argon atmosphere at a temperature in the region of 20° C., and a solution of 1.8 g (11.7 mmol) of 4-chloropyrrolo[2,3-d]pyrimidine in 25 cm3 of dimethylformamide is then added dropwise over the course of 15 minutes. The reaction mixture is stirred at a temperature in the region of 20° C. for 1 hour, 1.12 cm3 (18 mmol) of methyl iodide are then added, and stirring is continued for 15 hours at a temperature in the region of 20° C. The reaction mixture is then poured into a mixture of 200 cm3 of ethyl acetate and 200 cm3 of water. The organic phase is separated out after the phases have settled, washed successively twice with 200 cm3 of water and 200 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa), giving 1.35 g of 4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine in the form of a brown powder. Mass spectrum (DCI): m/e 168 (MH+) (base peak).
Reaction SMILES: C(N)CN.C(C1OC(C)=NC=1Cl)C1C=CC=CC=1.[CH2:19]([C:26]1[O:30][CH:29]=[N:28][C:27]=1[CH2:31][NH:32][CH2:33][CH2:34][NH2:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:36][N:37]=[C:38]=[S:39]>>[CH3:36][NH:37][C:38]([NH:35][CH2:34][CH2:33][NH:32][CH2:31][C:27]1[N:28]=[CH:29][O:30][C:26]=1[CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:39]
Reactant: NCCNCc1ncoc1Cc1ccccc1
Reactant: CN=C=S
Agent: Cc1nc(Cl)c(Cc2ccccc2)o1
Solvent: NCCN
Product: CNC(=S)NCCNCc1ncoc1Cc1ccccc1

Procedure:
5-Benzyl-4-oxazolecarboxylic acid is converted to 5-benzyl-4-hydroxymethyl xazole by the procedure of Example 135. Treating this hydroxy ethyl compound with thionyl chlroide gives 5-benzyl-4-chloromethyloxazole. Reacting ethylenediamine with 5-benzyl-4-chloro-methyloxazole by the procedure of Example 34, then reacting the resulting N-(5-benzyl-4-oxazolylmethyl)ethylenediamine with methyl isothiocyanate by the procedure of Example 3(b) and chromatographing gives N-methyl-N'-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-((5-benzyl-4-oxazolyl)methylamino)ethyl]-N'-cyano-N"-methylguanidine.
Reaction SMILES: Br[C:2]1[C:3]([F:10])=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[F:8].[F:11][C:12]1[C:13](B2OC(C)(C)C(C)(C)O2)=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>>[NH2:9][C:4]1[C:3]([F:10])=[C:2]([C:13]2[C:14]([C:15]#[N:16])=[CH:17][CH:18]=[CH:19][C:12]=2[F:11])[C:7]([F:8])=[CH:6][CH:5]=1
Reactant: CC1(C)OB(c2c(F)cccc2C#N)OC1(C)C
Reactant: Nc1ccc(F)c(Br)c1F
Product: N#Cc1cccc(F)c1-c1c(F)ccc(N)c1F
Yield: 25 %

Procedure:
3-Bromo-2,4-difluorophenylamine and 3-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile were coupled together as described in Example 2 to give 3′-amino-6,2′,6′-trifluorobiphenyl-2-carbonitrile as an off-white solid (400 mg, 25%): δH (360 MHz, CDCl3) 6.88 (2H, s), 7.41-7.46 (1H, m), 7.50-7.56 (1H, m), 7.61 (1H, dd, J 7 and 1).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[Cl:8][CH2:9][C:10]([OH:12])=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:8][CH2:9][C:10]([O:7][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][C:10](=[O:12])[CH2:9][Cl:8])=[O:12]
Reactant: OCCOCCO
Reactant: O=C(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(CCl)OCCOCCOC(=O)CCl
Temperature: 25 °C
Yield: 90.1 %

Procedure:
In a 10-liter 4-neck round bottom flask equipped with a mechanical stirrer and Dean-Stark apparatus was added a solution of diethylene glycol (500 g), chloro acetic acid (980 g) and para-toluene sulphonic acid (25 g) in toluene (2.5 L). The solution was refluxed with stirring and azeotropic removal of water for 5 hours, and then cooled to room temperature. The toluene layer was washed with 5% sodium bicarbonate solution (3×1000 ml) and water (3 L). The toluene layer was dried over anhydrous sodium sulphate, filtered, and distilled to obtain chloro-acetic acid 2-[2-(2-chloro-acetoxy)-ethoxy]-ethyl ester (1.1 Kg) as light yellow oil. The product was characterized by 1H NMR (CDCl3) δ 3.75 (t, 2H, CH2), 4.12 (s, 2H, CH2), 4.36 (t, 2H, CH2)
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]2[CH:15]=[N:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]2[CH2:6][NH:5]1.[CH3:23]I.O>CN(C)C=O.C(O)(=O)C>[CH3:23][N:5]1[C:4](=[O:3])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]2[CH:15]=[N:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]2[CH2:6]1
Reactant: CCOC(=O)c1ncn2c1CNC(=O)c1ccccc1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
70 mg (1.6 mmol) of sodium hydride (55 percent oil dispersion) are suspended in 5 ml of dry dimethylformamide and treated with 135 mg (0.5 mmol) of ethyl 5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate. After completion of the gas evolution, 0.15 ml (2.3 mmol) of methyl iodide is added and the mixture is stirred at room temperature for 1 hour. The mixture is poured into ca 50 ml of water, neutralised with glacial acetic acid and extracted three times with ca 30 ml of chloroform each time. The combined chloroform phases are washed with ca 20 ml of water, dried over magnesium sulphate and evaporated. After column chromatography and recrystallisation from ethyl acetate, there is obtained ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 166°-167° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][C:3]=1[Cl:13].[OH-].[Na+]>CO>[NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:13]
Reactant: CCOC(=O)c1ccc(N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(C(=O)O)cc1Cl

Procedure:
The benzoate ester (2), 45.5 g (0.23 moles), was dissolved in 250 mL of hot MeOH and then 230 mL of 3N NaOH (3 equivalents, 0.69 moles) was added. The mixture was stirred at reflux for 5 hours. The solution was concentrated on a rotary evaporator at 80° C. to remove the MeOH and then the mixture was acidified to pH 2 with 3N HCl. The precipitated solids were filtered on a sintered glass funnel and washed with water. The product was homogeneous by TLC (Hexane: EtOAc, 4:1, Rf=0.1) and therefore was not further purified. The white solid was dried at 70° C. in a vacuum oven to give 38.1 (97%) of 4-amino-3 chlorobenzoic acid (3), mp 225-226° C. 1H NMR (DMSO d6) d 7.70 (d, 1H, J=0.9 Hz, ArH), 7.61-7.56 (dd, 1H, J=0.7 Hz, ArH), 6.78 (d, 1H, J=3.4 Hz, ArH), 6.15 (bs, 2H, NH2). IR (KBr) cm-1, 3515, 3410 (NH2, m), 1675, (C=O, s) 1640. MS(El) m/e 171 (M+), 173 (M+2). Anal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[C:34]([NH2:42])(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:42][C:34]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)=[O:41])=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1ccncc1
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)c2ccncc2)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and isonicotinamide, the title compound was obtained as crystals, melting at 184-185° C. (from ethyl acetate).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:39])[CH:32]([O:36][CH2:37][CH3:38])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:39])[CH:32]([O:36][CH2:37][CH3:38])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)C(OCC)C(=O)O
Product: CCOC(=O)C(OCC)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2-ethoxy-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Colorless oil (94%). MS: m/e=517(M+H+).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH:10]([CH3:13])[CH:11]=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].C(O)(=O)C.O.[NH2:20][NH2:21]>C(O)C>[CH3:9][O:8][C:6](=[O:7])[CH2:5][CH:4]1[CH:10]([CH3:13])[CH:11]=[N:21][NH:20][C:3]1=[O:2]
Reactant: COC(=O)CC(C(=O)OC)C(C)C=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)CC1C(=O)NN=CC1C
Temperature: 0 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To this 2-(1-methyl-2-oxo-ethyl)succinic acid dimethyl ester was added ethanol (13 L), which was cooled to 0° C. Acetic acid (1.2 kg, 20 mol) was added with maintaining the temperature. To the reaction mixture was added hydrazine hydrate (1.08 kg, 21.6 mol), which was warmed to room temperature and stirred for 16 h. Ethanol was removed by distillation under reduced pressure, methylene chloride was added to the residue, which was then extracted-dried-concentrated according to a conventional manner to give the title compound (2.80 kg, Yield: 51%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:12]([O:16][CH3:17])(=[O:15])C=C>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:16][CH3:17])=[O:15]
Reactant: C=CCCCCCCCCCl
Reactant: C=CC(=O)OC
Solvent: ClCCl
Product: COC(=O)/C=C/CCCCCCCCCl
Reaction time: 4 h
Yield: 85 %

Procedure:
To a flame-dried round-bottomed flask, evacuated and backfilled with nitrogen (3×), was added 10-chlorodecene (1 equiv, 16 mmol, 2.79 g), methyl acrylate (25 equiv, 395 mmol, 36 mL), and CH2Cl2 (140 mL). Grubbs 2 catalyst (0.031 equiv, 0.48 mmol, 416 mg) was dissolved in CH2Cl2 (15 mL) and added to the reaction mixture in one portion. The reaction was stirred for 4 h, concentrated in vacuo, and purified by flash column chromatography (3% EtOAc/Hex) to afford (E)-methyl 11-chloroundec-2-enoate (3.14 g, 13.6 mmol, 85%). TLC Rf=0.30 (5% EtOAc/Hex); 1HNMR (300 MHz): δ 6.99 (dt, 1H, J=15.6, 7.0 Hz), 5.84 (dt, 1H, J=15.7, 1.5 Hz), 3.75 (s, 3H), 3.55 (t, 2H, J=6.8 Hz), 2.22 (qd, 2H, J=7.3, 1.4 Hz), 1.72-1.85 (m, 2H), 1.26-1.55 (10H); 13CNMR (75 MHz): δ 167.2, 149.6, 120.9, 51.4, 45.1, 32.6, 32.2, 29.2, 29.0, 28.7, 27.9, 26.8; FTIR: 2928, 2856, 1722, 1657, 1435, 1270, 1195, 1174, 1041, 979, 720 cm−1; HRMS-ESI: calc. for C12H21ClNaO2 (M+Na)+: 255.1128. found: 255.1118.