Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:9]([C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][N:12]1[C:17](OCC1C=CC(OC(F)F)=CC=1)=[O:18])C.I[CH2:32][CH2:33][CH3:34].[F:35][C:36]1[CH:43]=[C:42]([OH:44])[CH:41]=[C:40]([F:45])[C:37]=1[CH2:38][OH:39]>>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:9][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][N:12]1[C:17]([O:39][CH2:38][C:37]1[C:36]([F:35])=[CH:43][C:42]([O:44][CH2:32][CH2:33][CH3:34])=[CH:41][C:40]=1[F:45])=[O:18]
Reactant: CCCI
Reactant: CC[C@@H]1CNCCN1C(=O)OCc1ccc(OC(F)F)cc1
Reactant: OCc1c(F)cc(O)cc1F
Agent: O=C(O)/C=C/C(=O)O
Product: CCCOc1cc(F)c(COC(=O)N2CCNC[C@H]2C)c(F)c1

Procedure:
(R)-2,6-Difluoro-4-propoxybenzyl 2-methylpiperazine-1-carboxylate fumarate was prepared from (R) 1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine, 1-iodopropane and 2,6-difluoro-4-hydroxybenzyl alcohol according to the methods described for Examples 54 and 96 to give the product as a white solid (19.2%); melting point 193.9–194.0° C.; NMR δH (400 MHz, DMSO-d6) 0.958(3H, t, J 7.5 Hz), 1.140(3H, d, J 7.0 Hz), 1.715(2H, m), 2.817(2H, m), 2.982(2H, m), 3.687(2H, m), 4.097(1H, bs), 5.027(2H, q, J 11.0 Hz), 6.573(2H, s) and 6.773(2H, d, J 10.0 Hz).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:39])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([S:27]([CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[Cl:38])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[NH:13][C:12]=1[CH3:40])=O.[NH:41]1[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]1>>[Cl:38][C:32]1[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=1[CH2:30][S:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:39])/[C:18]/2=[CH:17]\[C:14]1[NH:13][C:12]([CH3:40])=[C:11]([C:9]([N:41]2[CH2:46][CH2:45][CH:44]([OH:47])[CH2:43][CH2:42]2)=[O:8])[C:15]=1[CH3:16])(=[O:29])=[O:28]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)ON1C(=O)CCC1=O
Reactant: OC1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1CCC(O)CC1
Yield: 25.5 %

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (120 mg, 0.2 mmol) was condensed with piperidin-4-ol (21 mg, 0.2 mmol) to give 30 mg the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=[N:4][CH:5]=[C:6](/[CH:8]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[ClH:29]>O1CCOCC1.CCO>[ClH:1].[ClH:29].[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][C:3]=1[NH:16][C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1
Reactant: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (2.34 g) and 4N hydrogen chloride in dioxane solution (11 ml) in EtOH (10 ml) was stirred at ambient temperature for 4 hours. IPE (100 ml) was added to a reaction mixture and the precipitate was collected by filtration to give ethyl (2Z)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (1.95 g).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH:32]([CH3:34])C)[C:11]([N:13]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:35](OC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=C(NC(OC(C)(C)C)=O)C=1)C.C(OC(=O)CN(C(=O)[C@@H](NC(=O)C1C=CC=CC=1)C(C)C)CC1C=CC=[C:81]([S:85](C)(=[O:87])=[O:86])C=1)C>>[C:1]([NH:9][C@@H:10]([CH2:32][CH2:34][CH3:35])[C:11]([N:13]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([S:85]([CH3:81])(=[O:87])=[O:86])[CH:31]=1)[CH2:14][C:15]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][C:20]([OH:22])=[O:21])=[O:16])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1ccccc1
Reactant: CCOC(=O)CN(Cc1cccc(NC(=O)OC(C)(C)C)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Reactant: CCOC(=O)CN(Cc1cccc(S(C)(=O)=O)c1)C(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Product: CCC[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@H](C=O)CC(=O)O)Cc1cccc(S(C)(=O)=O)c1

Procedure:
Compound 745 was prepared by a method similar to the method used to prepare compound 706, except compound 703 was replaced with compound 744. 1H NMR (CD3OD) δ 8.29 (m), 8.02 (m), 7.82-7.69 (m), 7.51-7.32 (m), 7.29-7.01 (m), 6.98 (d), 4.94-4.38 (m), 4.36 (d), 4.34 (d), 4.30-4.13 (m), 4.04 (d), 3.31-3.19 (m), 2.88-2.77 (m), 2.64-2.48 (m), 2.44-2.32 (m), 2.21 (m), 1.00-0.83 (m). ##STR124##
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[N:4][CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])[S:28]([C:21]2[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:20]=2[F:19])(=[O:30])=[O:29])=[N:4][CH:3]=1
Reactant: COc1ccc(CNc2ncc(Cl)s2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Product: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1

Procedure:
Prepared according to Preparation 333 using 5-chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208) and 2,4,5-trifluorobenzenesulfonyl chloride. Purification using ISCO™ (12 g SiO2) eluting with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) afforded the title compound as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](O)=[O:26])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:26])[N:35]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:36][CH3:37])=[CH:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: CCNCc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)Cc1cnc(CNC(=O)OC(C)(C)C)c2cc(OC)c(OC)cc12

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with benzyl-ethyl-amine to give 84 mg of {4-[(Benzyl-ethyl-carbamoyl)-methyl]-6,7-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C28H35N3O5+H 494.6; found 494.1.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21](O)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C([O:42][C:43](=[O:50])[C:44]1([CH2:49][CH2:48][CH2:47][CH2:46]1)[NH2:45])C1C=CC=CC=1.C(N1CCOCC1)C>ClCCl.CN(C)C=O>[CH:16]1([C:21]([NH:45][C:44]2([C:43]([OH:42])=[O:50])[CH2:46][CH2:47][CH2:48][CH2:49]2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)C1CCCC1
Reactant: NC1(C(=O)OCc2ccccc2)CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)CCCC1)C1CCCC1
Temperature: 0 °C

Procedure:
A cool solution of 15 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to a solution of 15 mmoles of cyclopentanecarboxylic acid in dichloromethane at -5° C. 15 mmoles of cycloleucine benzyl ester toluenesulfonate salt in dimethylformamide (DMF), which is neutralized with N-ethyl morpholine, is then added. The reaction mixture is stirred at 0° C. initially and then at room temperature until the reaction is completed as judged by TLC. Dicyclohexylurea is removed by filtration and 50 ml of ethyl acetate is added to the filtrate. The organic phase is washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator. The residue is crystallized from isopropanol and hexane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39]([NH2:42])[CH2:40][CH3:41].[O:43]=[C:44]1[N:48](P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:26])[F:28])=[N:20][C:21]([C:22](=[O:24])[NH:42][CH2:39][CH2:40][CH3:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH:17]([C:44](=[O:43])[NH2:48])[N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([CH2:39][CH2:40][CH3:41])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Product: CCCc1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (190 mg, 0.345 mmol) was dissolved in 10 mL of dichloromethane, and propylamine (163 mg, 2.76 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (176 mg, 0.69 mmol) and triethylamine (105 mg, 1.04 mmol) were then added to the solution. The reaction mixture was stirred at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-propyl-carbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 44a (70 mg, yield 34.3%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:21](=[O:22])[N:20]([C:23]3[CH:36]=[CH:35][C:26]([O:27][C:28]([CH3:34])([CH3:33])[C:29](OC)=[O:30])=[CH:25][CH:24]=3)[C:19]([CH3:37])=[N:18][C:17]=2[CH2:38][CH2:39][CH3:40])=[C:11]([F:41])[CH:10]=1)#[N:2].[BH4-].[Li+].C(OCC)(=O)C.O>O1CCCC1>[F:41][C:11]1[CH:10]=[C:9]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:14]=[CH:13][C:12]=1[CH2:15][C:16]1[C:21](=[O:22])[N:20]([C:23]2[CH:36]=[CH:35][C:26]([O:27][C:28]([CH3:33])([CH3:34])[CH2:29][OH:30])=[CH:25][CH:24]=2)[C:19]([CH3:37])=[N:18][C:17]=1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 24 h
Yield: 43.2 %

Procedure:
To a solution of methyl 2-{4-[5-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate (1.00 g) in tetrahydrofuran (11 mL) was added lithium tetrahydroborate (0.056 g), and the mixture was stirred for 24 hr. Ethyl acetate and water were added, to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.41 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][CH2:34][CH:35]([OH:37])[CH3:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(O)CN
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNCC(C)O)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 1-amino-2-propanol (Eastman Kodak) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H34N6O5SF [(M+H)+]525.2290, observed 525.2295.
Reaction SMILES: [F:1][C:2]([F:33])([CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(C(C)C)CC)(C)C.[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[F:33][C:2]([F:1])([CH2:29][CH2:30][CH2:31][CH3:32])[CH:3]([OH:28])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[CH2:9][C@H:8]([OH:18])[C@@H:7]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:26]
Reactant: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1
Reactant: BrCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCCC(=O)OCc2ccccc2)[C@@H](O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 99.1 %

Procedure:
To the crude 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanoic acid (17) (132.1 mmol) in acetonitrile (315 ml), diisopropyl ethylamine (69.0 ml, 369 mmol) and benzyl bromide (47.1 ml, 369 mmol) were added and the mixture was stirred for 14 hours at room temperature. The reaction mixture was concentrated under reduced pressure, ethyl acetate (366 ml) and water (280 ml) were added to the residue and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (224 ml). The organic layers were combined and washed with 1N-hydrochloric acid (336 ml), saturated sodium bicarbonate water (336 ml) and saturated aqueous sodium chloride (336 ml). After drying with anhydrous magnesium sulfate (51 g), the solution was concentrated under reduced pressure. The concentration residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2400 g; ethyl acetate:hexane=1:2) to give benzyl 7-[(1R,2R,3R,5S)-2-(4,4-difluoro-3-hydroxyoctyl)-5-hydroxy-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (18) (74.44 g; 130.9 mmol; yield: 99.1%) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:7][CH2:8]2)=[CH:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CCCCCN2CCCCC2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-chlorophenyl chloroformate were reacted, followed by treatment with piperidine to give trans-Methyl-[4-(5-piperidin-1-yl-pentyl)-cyclohexyl]-carbamic acid 4-chloro-phenyl ester, MS: 421 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:18][C:15]1[N:14]=[CH:13][N:12]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=3[C:8](=[O:17])[N:9]([CH3:16])[CH2:10][C:11]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CN1Cc2cncn2-c2cccc(Cl)c2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(Br)ncn2-c2cccc(Cl)c2C1=O

Procedure:
12.38 g (50 mmol) of 7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 40 minutes with 9.80 g (55 mmol) of N-bromosuccinimide in 80 ml of N,N-dimethylformamide. The reaction mixture was poured into 800 ml of water and the suspension obtained was filtered. The filter residue was rinsed with water and taken up in methylene chloride. The organic phase was dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and recrystallization from ethyl acetate and hexane there was obtained 3-bromo-7-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 178°-179°.
Reaction SMILES: B.C1COCC1.C([O:9][C:10](=O)[CH2:11][C:12]1(O)[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13]1=O)C.O1CCCC1.C(OCC)(=O)C>O>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[Cl:22])[NH:14][CH:13]=[C:12]2[CH2:11][CH2:10][OH:9]
Reactant: CCOC(=O)CC1(O)C(=O)Nc2cc(Cl)c(Cl)cc21
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OCCc1c[nH]c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 57 h
Yield: 60 %

Procedure:
A 1 M borane/THF solution (28.0 ml. 28.0 mmol) was added to a solution of the (5,6-dichloro-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetic acid ethyl ester just prepared (2.13 g, 7.0 mmol), in abs. tetrahydrofuran (15 ml), in an ice bath in the course of 15 min. The reaction mixture was stirred at room temperature for 57 h and, for working up, was added to a mixture of ethyl acetate (50 ml) and water (50 ml), while stirring. The phases were separated and the aqueous phase was extracted with ethyl acetate (2×30 ml). The organic phases were combined, dried and concentrated. The crude indole was obtained as a yellow oil (1.9 g) by this procedure. Purification by chromatography [silica gel G (80 g); ethyl acetate/cyclohexane 1:2 (2 l)] gave the desired 2-(5,6-dichloro-1H-indol-3-yl)ethanol (Ind-83) as a beige-coloured solid in a yield of 60% (0.96 g) (m.p. 65-67° C.).
Reaction SMILES: [Cl-].CC(C)([O-])C.[K+].[CH:8]([CH:10]1[CH2:15][CH2:14][CH:13]([CH:16]2[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[CH2:9].O.C1[CH2:29][O:28][CH2:27]C1>>[CH3:27][O:28][CH:29]=[CH:22][CH:19]1[CH2:18][CH2:17][CH:16]([CH:13]2[CH2:12][CH2:11][CH:10]([CH:8]=[CH2:9])[CH2:15][CH2:14]2)[CH2:21][CH2:20]1
Reactant: C1CCOC1
Reactant: C=CC1CCC(C2CCC(C=O)CC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: C=CC1CCC(C2CCC(C=COC)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methoxymethyltryphenylphosphonium chloride (17.9 g) was suspended in THF (150 mL), to which THF solution (150 mL) of potassium tert-butoxide was then added dropwise at −20° C., followed by stirring at that temperature for 0.5 hour. To the resulting mixture, THF solution (100 mL) of 4′-Vinyl-bicyclohexyl-4-carbaldehyde (9.0 g) was added dropwise at −20° C., followed by stirring at that temperature for further 1 hour, and then the temperature of the system was gradually increased to room temperature. To the resulting solution, water (300 mL) was added, followed by extracting with toluene. The organic layer was washed with water and concentrated in about 300 mL under reduced pressure, and then the resulting solution was poured into 1000 mL of n-heptane with vigorous stirring. The resulting suspension was filtered under reduced pressure, and then the filtrate was concentrated under reduced pressure. The resulting colorless yellow residue was purified by silica gel column chromatography to obtain 4-(2-methoxy-vinyl)-4′-vinylbicyclohexyl (8.9 g) in a colorless yellow oily form.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8].C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][Si:18]([C:21]#[C:22][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[C:7]#[N:8])([CH3:20])[CH3:19]
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cncc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cncc(C#N)c1
Temperature: 25 °C
Yield: 109.3 %

Procedure:
Combine 5-bromonicotinonitrile (10.0 g, 53.0 mmol), bis(triphenylphosphine)palladium (II) dichloride (1.86 g, 2.65 mmol), copper (I) iodide (1.04 g, 5.46 mmol) and triethylamine (50 mL, 359 mmol) in a sealed tube under nitrogen and treat with (trimethylsilyl)acetylene (8.00 mL, 56.75 mmol). Stir the resultant black reaction mixture at 70° C. for 1.7 h and cool to room temperature. Dilute the reaction mixture with ethyl acetate and wash with a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Dissolve the residue in dichloromethane and filter through a pad of diatomaceous earth/silica gel. Wash with 80:20 dichloromethane:ethyl acetate. Concentrate the filtrate to give 11.6 g of the title compound as a brownish-tan solid. This material contains minor impurities, which do not have an adverse effect on subsequent chemistry (see PREPARATION 4). The crude material is purified by silica gel chromatography, eluting with 95:5 to 85:15 hexanes:ethyl acetate to give the title compound.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13](O)=O)=O)C1C=CC=CC=1.NC1C=CC=CC=1O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][C:26]=1[NH2:37].C(OC(NCC(N[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C1)=O)=O)(C)(C)C.C(OC([NH:72][CH2:73][C@@H:74]1[CH2:78][N:77](C(OC(C)(C)C)=O)[C@@H:76]([C:86]([OH:88])=O)[CH2:75]1)=O)(C)(C)C>>[NH2:72][CH2:73][C@@H:74]1[CH2:78][NH:77][C@@H:76]([C:86]([NH:11][CH2:12][C:13]2[NH:37][C:26]3[CH:27]=[C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:29]=[CH:30][C:25]=3[N:24]=2)=[O:88])[CH2:75]1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nc1ccc(-c2ccccc2)cc1N
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: Nc1ccccc1O
Product: NC[C@@H]1CN[C@@H](C(=O)NCc2nc3ccc(-c4ccccc4)cc3[nH]2)C1

Procedure:
This compound was prepared as in Compound M77, replacing N-(Benzyloxycarbonyl)-D-homophenylalanine with N-(Benzyloxycarbonyl)glycine, 2-aminophenol with 1,2-diamino-4-phenylbenzene and trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline with trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-D-proline.