Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC/C=[C:7]1\[CH2:8][N:9]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10][CH2:11][CH:12]\1[O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=O)C.[O:28]=[O+][O-]>ClCCl>[C:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH:12]([O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:15])[CH3:16])[C:7](=[O:28])[CH2:8]1)=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: O=[O+][O-]
Reactant: CC(=O)OC/C=C1\CN(C(=O)OC(C)(C)C)CCC1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C(=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of (E)-3-(2-acetoxyethylidene)-1-(t-butoxycarbonyl)-4-(t-butyldimethylsilyloxy)piperidine (9.9 g) in dichloromethane (100 ml) was introduced gaseous ozone at −78° C. for 2 hours. After the excess ozone was removed by bubbling nitrogen gas for 1 hour, triphenylphosphine (13 g) was added at the same temperature. The resulting mixture was stirred at room temperature for one hour, and concentrated in vacuo. The residue was purified by chromatography on silica gel using a mixture of hexane, ethyl acetate and dichloromethane (5:1:1 to 1:1:1) as the eluent to afford the title compound as a light yellow oil (4.6 g, yield: 56%).
Reaction SMILES: [N+](=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N-].[S:13]1[C@H:24]2[CH2:25][C@@H:26]([OH:37])[C@H:27](/[CH:28]=[CH:29]/[C@@H:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:23]2[CH2:22][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].CO>C(Cl)Cl>[CH2:3]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[S:13][C@H:24]2[CH2:25][C@@H:26]([OH:37])[C@H:27](/[CH:28]=[CH:29]/[C@@H:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:23]2[CH2:22]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)O)S[C@H]2C[C@H]1O
Reactant: CCCCCCCCCC=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCOC(=O)CCCCC1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]2S1

Procedure:
An ethereal solution of diazodecane was added dropwise to a solution of 100 mg of (13E)-(6RS,9α,11α,15S)-6,9-epithio-11,15-dihydroxyprost-13-enoic acid (prepared as described in Example 2) in 5 ml of methylene chloride at room temperature with stirring until the starting material was not detected by thin layer chromatography on silica gel using a 2% v/v solution of methanol in ethyl acetate as developing solvent. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:1) as eluent to give 109 mg of the title compound having the following physical characteristics:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:19].[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][O:13][CH:10]1[CH2:11][CH2:12][C:7]2([CH2:6][C:5](=[O:19])[C:4]3[C:16](=[CH:17][CH:18]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]#[N:21])[CH:3]=3)[O:15]2)[CH2:8][CH2:9]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC1CCC2(CC1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 100 °C
Yield: 62.2 %

Procedure:
In a μwave vial was placed 6-bromo-4′-methoxyspiro[chroman-2,1′-cyclohexan]-4-one (48 mg, 0.148 mmol), 3-cyanobenzeneboronic acid (28 mg, 0.191 mmol), PdCl2(PPh3)2 (10 mg, 0.014 mmol) and cesium carbonate (121 mg, 0.371 mmol). This solid mixture was dissolved in a Dioxane/water mixture (2.0 mL, 6:1 ratio, respectively). The solution was purged with a N2 stream for 20 seconds. The vessel was placed in the μwave and heated to 100° C. for 5 minutes. After that time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (10 mL) and water (10 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane (5 mL). The combined organic phases were washed with water, brine, dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4′-methoxy-4-oxospiro[chroman-2,1′-cyclohexane]-6-yl)benzonitrile (32 mg, 0.092 mmol, 62% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:21]([O:23]CC)=[O:22])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][N:3]=1.O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([C:6](=[O:26])[C:7]([C:21]([OH:23])=[O:22])=[CH:8][N:9]2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2c(Cl)c(Cl)ncc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(Cl)c(Cl)ncc2c1=O
Temperature: 0 °C

Procedure:
8.6 g (0.022 mol) of ethyl 7,8-dichloro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylate are heated at reflux in a mixture of 29 ml of acetic acid, 29 ml of water and 2.9 ml of concentrated sulphuric acid for two hours. The cooled mixture is put into ice-water, and the product is isolated and washed with water.
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C@H:12]1[O:17][C@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=3)[CH:21]=2)([O:18][CH3:19])[C@H:15]([OH:40])[C@@H:14]([OH:41])[C@@H:13]1[OH:42])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:6]([Si:3]([CH3:5])([CH3:4])[O:10][CH2:11][C@@H:12]1[C@@H:13]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@H:14]([O:41][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:15]([O:40][CH2:16][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@:16]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=3)[CH:21]=2)([O:18][CH3:19])[O:17]1)([CH3:8])([CH3:9])[CH3:7]
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a suspension of sodium hydride (1.90 g, 47.4 mmol, 60% dispersion in Mineral oil) in anhydrous tetrahydrofuran (50 mL) was added a solution of (2S,3R,4S,5S,6R)-6-[[tert-butyl (dimethyl)silyl]oxymethyl]-2-[4-chloro-3-[[4-(2,2,2-trifluoro ethoxy)phenyl]methyl]phenyl]-2-methoxy-tetrahy dropyran-3,4,5-triol 17f (4.8 g, 7.91 mmol) in anhydrous tetrahydrofuran (50 mL) slowly at 0° C. The mixture was stirred at 0° C. for 1 hour and warmed to room temperature. Then benzyl bromide (5.6 mL, 47.4 mmol) and tetrabutylammonium iodide (0.3 g, 0.79 mmol) were added in turn. The mixture was warmed up to 40° C. and further stirred for 12 hours. The reaction mixture was quenched with water (50 mL) and partitioned. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with saturated brine (80 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 17g as orange-yellow oil (1.6 g, 23.0%). This material was not further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:18]=3[N:14]2[CH2:13][CH2:12]1)[C:5]([OH:7])=O.[NH4+].O[N:31]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[C:18]=3[N:14]2[CH2:13][CH2:12]1)[C:5]([NH2:31])=[O:7]
Reactant: On1nnc2ccccc21
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3-chloro-4-[8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl]benzoic acid (45.4 mg, 0.109 mmol) in N,N-dimethylformamide (1.0 mL) were added 1-hydroxy-1H-benzotriazole ammonium salt (21.4 mg, 0.141 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (22.9 mg, 0.119 mmol). The reaction mixture was stirred at room temperature for 8 hr. The reaction mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2), aqueous saturated sodium hydrogen carbonate (×1) and brine (×1), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless solid (36.4 mg, 0.0872 mmol, 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21](O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOC(C)=O>CO.CC(O)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][N:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(C(O)c2ccccc2)cn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccccc2)cn1
Reaction time: 6 h
Yield: 60.5 %

Procedure:
To product from step 2 (50 mg, 0.13 mM) was added Pd/C 10% (40 mg, wt) in MeOH/AcOH (1.5 ml, 6:4) and stirred under H2 (H2 balloon, atm pr) for 6 h. 10% NaOH (5 mL) was added to quench the reaction. EtOAc was added and the mixture was filtered and dried down to give the title compound (29 mg, 83%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])/[CH:21]=[CH:22]/OCC)=[CH:15][CH:14]=3)=[N:6][C:5]=2[C:4]([CH2:27][CH2:28][CH3:29])=[N:3]1.N>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][C:13]3[CH:18]=[C:17]4[C:16](=[CH:15][CH:14]=3)[NH:19][C:20](=[O:26])[CH:21]=[CH:22]4)=[N:6][C:5]=2[C:4]([CH2:27][CH2:28][CH3:29])=[N:3]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(=O)/C=C/OCC)cc3)nc12
Agent: N
Agent: O=S(=O)(O)O
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc4[nH]c(=O)ccc4c3)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
Concentrated sulphuric acid (10 ml) was added to N-{4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl]phenyl}-(E)-3-ethoxy-2-propenamide (980 mg, 0.00248 mol) and the reaction stirred at room temperature for 4 hours. The mixture was then poured carefully onto ice and basified with 0.880 aqueous ammonia solution. The resulting precipitate was filtered and then triturated with boiling acetic acid/water to give the title compound (460 mg), m.p.>300° C.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:7]([O:8][CH2:9][C:10](OCC)=[O:11])=[C:6]([CH3:18])[CH:5]=1.O1CCCC1.C(O)C>O>[Br:3][C:4]1[CH:5]=[C:6]([CH3:18])[C:7]([O:8][CH2:9][CH2:10][OH:11])=[C:15]([CH3:17])[CH:16]=1
Reactant: CCOC(=O)COc1c(C)cc(Br)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1OCCO
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
Sodium borohydride (0.21 g) was added to a mixture of ethyl (4-bromo-2,6-dimethylphenoxy)acetate (0.78 g), tetrahydrofuran (5 mL) and ethanol (5 mL), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent:ethyl acetate/n-hexane=1/2) to afford the title compound (0.65 g).
Reaction SMILES: C[O:2][C:3](=[O:36])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Na+]>CO>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:36])=[O:2])=[CH:5][N:6]=2)=[O:35])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(-c3cccc4ccccc34)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(-c3cccc4ccccc34)cc2)nc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 25B-a, 45 mg, 0.094 mmol) in methanol (500 μL) was treated with a 1N aqueous sodium hydroxide solution (188 μL, 0.188 mmol). The reaction mixture was heated under reflux for 1 h and then allowed to cool to 25° C. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 15/1 methylene chloride/methanol) afforded 6-[3-cyclopentyl-2-(4-naphthalen-1-yl-phenyl)-propionylamino]-nicotinic acid (15 mg, 34%) as a pale yellow solid: mp 155-158° C.; FAB-HRMS m/e calcd for C30H28N2O3 (M+H)+ 465.2178, found 465.2169.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12]>[OH-].[Na+].CCOCC>[CH2:1]([NH:8][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCl
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: C[Si](C)(C)CNCc1ccccc1
Temperature: 200 °C
Yield: 74.3 %

Procedure:
Benzylamine (51.5 g, 480 mmol) was added to (chloromethyl)trimethylsilane (19.64 g, 160 mmol) and heated at 200° C. for 2 hours. The reaction mixture was diluted with 1 N sodium hydroxide solution and ether and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure to afford 23.00 g of N-benzyl-N-trimethylsilanylmethyl-amine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]([N:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52](OC3C=CC([N+]([O-])=O)=CC=3)=[O:53])[CH2:47][CH2:46]2)=[O:44])=[O:34])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[O:19]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][O:42][C:43]([N:45]2[CH2:50][CH2:49][CH:48]([O:51][C:52](=[O:53])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:47][CH2:46]2)=[O:44])=[O:34])=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Reactant: NCCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCCCCOC(=O)N1CCC(OC(=O)NCCCCc2ccccc2)CC1)Oc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of 4-phenylbutylamine (610 μl, 3.86 mmol) and triethylamine (2.24 mL, 16.1 mmol) in 30 mL of methylene chloride was added under nitrogen dropwise to a solution of the carbonate prepared in Example 5 (2.0 g, 3.22 mmol) in 30 mL of methylene chloride at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature overnight. An additional 204 μl (1.29 mmol) of 4-phenylbutylamine and 180 μl (1.29 mmol) of triethylamine were added and the reaction stirred at room temperature for approximately 7 hours. The reaction was extracted one time with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 2.02 g of a crystalline solid. Purification of the solid on silica gel (230-400 mesh) using 5%-20% ethyl acetate-methylene chloride as the eluent gave 1.43 g (70%) of the title compounds as a white crystalline solid, mp 84°-86° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH2:32][C:33](=[O:39])[NH:34]2>>[F:22][C:23]1[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[C:32](=[CH:20][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[C:7](=[O:19])[C:6]=3[C:2]=1[CH3:1])[C:33](=[O:39])[NH:34]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 33.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.3%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=[C:13](Cl)OC(Cl)(Cl)Cl>O1CCOCC1.CN(C)C=O.CO.CN(C)C1C=CN=CC=1.C(=O)(O)[O-].[Na+].[Cl-].[NH4+]>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cccc(C)c1N
Temperature: 60 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (25.0 g, 165 mmol) in p-dioxane (43 mL) under a nitrogen atmosphere was added diphosgene (20 mL, 165 mmol) and the resulting solution was stirred at 60° C. overnight. After cooling to room temperature, the mixture was filtered and the precipitate was rinsed with hexanes and dried in vacuo to afford 28.49 g of an off white solid. Without further characterization, this material was suspended in dry dimethylformamide (320 mL) and methanol (11.7 mL). 4-Dimethylaminopyridine (3.9 g) was added to this suspension and the resulting solution was stirred at 60° C. for 2 days. The cooled reaction mixture was diluted with saturated sodium bicarbonate solution and saturated ammonium chloride solution and extracted three times with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to yield the title compound of Step A (25.40 g) as an oil. 1H NMR (CDCl3): δ 7.73 (d, 1H), 7.10 (d, 1H), 6.52 (dd,1H), 5.85 (br s,2H), 3.80 (s,3H), 2.07 (s,3H). This material was used in Step B without further characterization.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[O:17])[NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)[CH3:2].[Br:19]Br>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([Br:19])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:17])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cccc2cccnc12
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1ccc(Br)c2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of the product from Example 81 (20 g, 82 mmol) in 200 mL acetic acid was treated with a solution of bromine (15.7 g, 0.198 mol) in 50 mL of acetic acid and stirred at room temperature for 1 hour. The solid was collected by filtration and washed with ether to give the title compound (23.5 g, 69% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14](=[O:38])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][NH:29]C(OC(C)(C)C)=O)=[O:22])=[C:17]([Cl:37])[CH:16]=3)[CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14](=[O:38])[C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[CH2:28][NH2:29])=[O:22])=[C:17]([Cl:37])[CH:16]=3)[CH2:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)butyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.06 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C24H27Cl2N5O2 (488.42); mass spectrum: (M+H)+=488/490/492 (chlorine isotope).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1.O>O1CCCC1>[Cl:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(SCCCCl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(SCCCCl)cc1
Reaction time: 0.75 h
Yield: 85.3 %

Procedure:
5 g of lithium aluminum hydride are suspended in 200 ml of tetrahydrofuran, and a solution of 31.9 g of methyl 4-(3-chloro-propylthio)benzoate in 200 ml of tetrahydrofuran is added thereto at 5° to 15° C. The mixture is stirred at the same temperature for 45 minutes. Water is added to the mixture at a temperature of below 20° C., and insoluble materials are filtered off. The filtrate is concentrated under reduced pressure to remove solvent, and the residue is distilled under reduced pressure. 24.1 g of 4-(3-chloropropylthio)benzylalcohol are obtained as an oil. Yild: 85%.