Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([N:19]3[C:23](=[O:24])[C:22]4=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]4[C:20]3=[O:29])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][CH2:39][CH2:40]Br.O>CN(C)C=O>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:40][CH2:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[C:10](=[O:18])[CH:9]([N:19]3[C:20](=[O:29])[C:21]4=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]4[C:23]3=[O:24])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1CCOC1CCCCO1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a solution of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepine-2-one (1.90 g) in N,N-dimethylformamide (30 ml) was added sodium hydride (62% suspension in mineral oil; 0.20 g) gradually with stirring under cooling in an ice-bath (<3° C.). The mixture was stirred for 10 minutes under the same conditions. To the resultant mixture was added 2-[(tetrahydropyran-2-yl)oxy]ethyl bromide (1.60 g) in one portion. The mixture was stirred at ambient temperature for one hour and at 45° C. for 4.5 hours and allowed to stand overnight. The resultant reaction mixture was poured into water and extracted with ethyl acetate twice. The extract was washed with water and dried over magnesium sulfate. Removal of the solvent gave light yellow powder, which was washed with a mixture of ethyl acetate and diethyl ether and collected by filtration to afford a mixture (1.48 g) of (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-{2-((RS)-2-tetrahydropyranyloxy)ethyl} 2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-{2-((SR)-2-tetrahydropyranyloxy)ethyl)-2H-1, 4-benzodiazepine-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)([CH3:24])[C:17]=2[CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:35]=[C:36]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([C:25]4[O:26][CH:27]=[CH:28][CH:29]=4)([CH3:24])[C:17]=3[CH:30]=2)=[CH:10][CH:11]=[C:12]1[C:36]#[N:35])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(c1ccco1)OCC(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccco1)OCC(=O)N2

Procedure:
tert-Butyl-2-cyano-5-[5-(2-furyl)-5-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-1-carboxylate was prepared from tert-butyl-2-[5-(2-furyl)-5-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl]-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate generally according to the cyanation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.17 (s, 1H), 7.71 (d, J=1.46 Hz, 1H), 7.34 (dd, J=1.93, 8.34, Hz, 1H), 7.28 (d, J=3.79 Hz, 1H), 7.21 (d, J=8.42 Hz, 1H), 7.16 (d, J=1.94 Hz, 1H), 6.44-6.41 (m, 2H), 6.24 (d, J=3.18 Hz, 1H), 4.13 (d, J=16.14 Hz, 1H), 4.01 (d, J=16.11 Hz, 1H), 1.89 (s, 3H), 1.38 (s, 9H); MS (ES) m/z 434 ([M+H]+, 100%)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[CH:23]=[CH:22][N:21](S(C5C=CC=CC=5)(=O)=O)[CH:20]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2].[OH-].[Na+].O1CCOCC1>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[CH:23]=[CH:22][NH:21][CH:20]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:34])[C:5]([C:35]([OH:37])=[O:36])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccn(S(=O)(=O)c5ccccc5)c4)C3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc[nH]c4)C3)cc21
Temperature: 100 °C
Yield: 82.2 %

Procedure:
A mixture of 299 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid 3 ml of 1N sodium hydroxide and 10 ml of dioxane was heated at 100° C. for 4 hours, then allowed to cool and neutralized to pH 7 with 10% acetic acid. The solvents were evaporated until a solid formed. This solid was collected, washed with water, methanol and ether and dried, giving 180 mg of the desired product, mp 220° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH:32]=[O:33])[CH3:31])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[C:37]2[CH:47]=[CH:46][CH:45]=[CH:44][C:38]=2[S:39][C:40]=1[C:41](Cl)=[O:42]>>[C:1]([O:5][C:6](=[O:34])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:41]([C:40]2[S:39][C:38]3[CH:44]=[CH:45][CH:46]=[CH:47][C:37]=3[C:36]=2[Cl:35])=[O:42])[CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH:32]=[O:33])[CH3:31])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: CN(C=O)c1ccc(-c2ccc(F)c(CNC3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1
Product: CN(C=O)c1ccc(-c2ccc(F)c(CN(C(=O)c3sc4ccccc4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)cc1

Procedure:
The title compound was prepared from amine (261) (270 mg, 0.58 mmol) and 3-chlorobenzo[b]thiophene-2-carbonyl chloride (150 mg, 0.63 mmol) following Method D.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19]([C:18]1[C:17]([CH3:24])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)CCc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(CCC(C)(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(3,3-dimethylbutyl)benzonitrile (Example 21b) and ethyl 3-oxobutanoate as a white solid (95%). 1H NMR (400 MHz, DMSO-do) δ 0.93 (s, 9H), 1.32 (t, J=7.2 Hz, 3H), 1.42-1.46 (m, 1H), 2.55 (s, 3H), 3.11-3.15 (m, 2H), 4.33 (q, J=7.2 Hz, 2H), 7.12 (s, 2H), 7.19-7.21 (m, 1H), 7.46-7.52 (m, 2H). MS 315 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](O)=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5]=1[CH2:24][CH2:25][CH3:26])(=[O:3])[CH3:2].O[N:28]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O.C(OCC)(=O)C.CO>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH2:28])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:5]=1[CH2:24][CH2:25][CH3:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(C(C)=O)c2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(C(C)=O)c2ccc(C(N)=O)cc2n1Cc1ccccc1Cl
Temperature: 2 °C
Reaction time: 14 h
Yield: 90.8 %

Procedure:
To a solution of 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylic acid (74 mg) in dimethylformamide (2 ml) were added 1-hydroxybenzotriazole (38 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg) and 3N methanol solution of ammonia (0.5 ml). After stirred at 2° C. for 14 hours, the resulting mixture was diluted with ethyl acetate. The organic phase was washed successively with 1N hydrochloric acid, water, aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with isopropyl ether to give 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxamide (67 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL), and the solution was added with benzylamine (0.011 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) followed by stirring at room temperature for 16 hours. The reaction mixture was added with 3 mol/L aquous sodium hydroxide solution, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate. The mixture was added with aldehyde resin and stirred at room temperature for 16 hours. The resin was filtered off and the solvent of the filtrate was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was filtered through a column filled with SCX (positive-ion-exchange resin). The resulting SCX was washed with 7 mol/L ammonia-methanol solution and the solvent of the filtrate was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(benzylaminomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13]N>>[NH2:10][CH2:11][CH2:12][CH2:13][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCN
Reactant: NC(=O)c1ccccc1
Product: NCCCNC(=O)c1ccccc1
Temperature: 150 °C
Yield: 33.4 %

Procedure:
Benzamide (25 g, 0.20 mol) and 1,3-diaminopropane (45.9 g, 0.60 mol) were combined in a Parr vessel and heated to 150° C. for 15 hours. The vessel was cooled and the reaction mixture was concentrated under vacuum to remove excess diamine. The residue was dissolved in water (500 mL) and concentrated hydrochloric acid was added to adjust the pH to <1. The resulting precipitate (starting benzamide and diacylated product) was removed by filtration. The filtrate was washed with dichloromethane. The aqueous layer was made strongly basic by the addition of 50% sodium hydroxide and then it was extracted with dichloromethane (4×300 mL). The extracts were combined, washed with brine (300 mL), dried over sodium sulfate and then concentrated under vacuum to provide 11.9 g of N-(3-aminopropyl)benzamide as an oil.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][N:3]=1.[N:13]1(C(OC(C)(C)C)=O)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CN(C=O)C>[C:7]1([N:6]2[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:3][N:4]=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: c1ccc(-n2nnnc2N2CCNCC2)cc1

Procedure:
Preparation took place by reacting 5-chloro-1-phenyl-1H-tetrazole with tert-butyl piperazine-1-carboxylate in DMF at 40° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[H][H]>>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: [H][H]
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
By means of a centrifugal pump, a circulation was pumped through the main reactor at a rate of about 500 g/h at a feed of L-isopulegol of 24.5 g/h (total amount 588 g) with a purity of 99.9% by weight and 99.8% ee. The hydrogen pressure was kept constant at 40 bar. The main reactor was operated at a temperature of 85° C. and the postreactor at 75° C. All pipelines were provided with electrical trace heating to prevent the crystallization of the enantiomerically pure L-menthol (m.p. 44° C.). This gave L-menthol in an amount of 597 g, corresponding to a rate of 24.9 g/h. The L-menthol obtained in this way (99.8% ee) was analyzed by gas chromatography. The chemical purity of the L-menthol discharge is listed in Table 1.
Reaction SMILES: [F:1][C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1.Cl.[NH:26]1[CH2:29][CH:28]([C:30]2[NH:34][N:33]=[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[N:31]=2)[CH2:27]1>>[F:1][C:2]1[N:6]2[CH:7]=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][N:26]4[CH2:27][CH:28]([C:30]5[N:31]=[C:32]([C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=6)[NH:33][N:34]=5)[CH2:29]4)=[CH:13][CH:12]=3)=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: O=Cc1ccc(-c2nc3ncc(F)n3cc2-c2ccccc2)cc1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Agent: Cl
Product: Fc1cnc2nc(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)c(-c3ccccc3)cn12
Yield: 57.6 %

Procedure:
This compound was prepared in analogy by reacting 90 mg (0.28 mmol) 4-(3-fluoro-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde with 93 mg (0.34 mmol) 2-(5-azetidine-3-yl-[1,2,4]triazol-3-yl)-pyridine hydrochloride salt according to the procedure in example 1. After four and a half hours the reaction mixture was worked up and purified in the usual way as described in example 1. 81 mg of the desired product were obtained.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1.CN(C)C=O>[C:1]1([CH2:11][CH2:12][CH2:13][C:14]([Cl:19])=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCc1cccc2ccccc12
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)CCCc1cccc2ccccc12
Temperature: 70 °C

Procedure:
0.37 g of 4-Naphthalen-1-yl-butyric acid was dissolved in 5.0 ml of toluene, and 0.35 ml of thionyl chloride and 1 drop of dimethylformamide were added, followed by heating at 70° C. for 30 minutes. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give a crude 4-naphthalen-1-yl-butyryl chloride. To the resulting crude 4-naphthalen-1-yl-butyryl chloride was added 2.3 ml of a toluene solution of 0.40 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]piperazine, followed by stirring at room temperature for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate solution and, after extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Wako-gel C-200, chloroform:methanol=10:1) to give 0.58 g of 1-[2-(4-fluorophenyl)-2-(4-methylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyryl)piperazine as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][OH:21].C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>CCO.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H]2CO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.8 %

Procedure:
A solution of 10.0 g (50.2 mmol) of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester and 6.00 ml=6.15 g (60.2 mmol) of (S)-(−)-pyrrolidin-2-yl-methanol in 100.0 ml of EtOH was treated with 100.0 ml of 1,2-dichloroethane, followed by 7.53 ml (60.2 mmol) of borane-pyridine complex (8 molar). Then, 7.46 ml=7.84 g (130.5 mmol) of acetic acid was added to this solution. After stirring at RT for 16 hours, the reaction mixture was poured into crashed ice; then, the pH was adjusted to 9-10 with sodium carbonate solution and the mixture was extracted twice with EtOAc; the combined organic phases were washed with water, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 10.4 g (73%) of the title compound as light yellow oil. MS: 285.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]([CH2:22][C:23]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=4)[N:27]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH:26]=3)=O)[C:19]([OH:21])=[O:20])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C1(=O)OC(=O)C=C1.C(N1C2C(=CC=CC=2)C(C(CC(C2C3C(=CC=CC=3)N(CC)C=2C)=O)C(O)=O)=C1C)C>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:18]3[CH:22]=[C:23]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[CH:26]=4)[O:20][C:19]3=[O:21])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(C(=O)O)c1cn(Cc2ccccc2)c2cc(F)ccc12)c1cn(Cc2ccccc2)c2cc(F)ccc12
Agent: CCn1c(C)c(C(=O)CC(C(=O)O)c2c(C)n(CC)c3ccccc23)c2ccccc21
Agent: O=C1C=CC(=O)O1
Product: O=C1OC(c2cn(Cc3ccccc3)c3cc(F)ccc23)=CC1c1cn(Cc2ccccc2)c2cc(F)ccc12

Procedure:
Following a procedure similar to that described above in part A of this example except that 2,4-bis(6-fluoro-1-benzyl-3-indolyl)-4-oxobutanoic acid prepared by interaction of maleic anhydride and 6-fluoro-1-fluoro-1-benzylindole by a procedure similar to that described in Example 3, part A is used in place of 2,4-bis-(1-ethyl-2-methyl-3-indolyl)-4-oxobutanoic acid, there is obtained 3,5-bis(6-fluoro-1-benzyl-3-indolyl)-2(3H)-furanone (Formula II: R=C6H5CH2 ; R1 =H; Y=6-F).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][C:3]=1[NH2:10].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.[CH3:62][S-:63].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:63][CH3:62])=[CH:4][C:3]=1[NH2:10]
Reactant: Nc1cc(I)c(Cl)cc1Br
Reactant: C[S-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cc(N)c(Br)cc1Cl
Temperature: 80 °C
Yield: 50.6 %

Procedure:
To a solution of 2-bromo-4-chloro-5-iodo-phenylamine (0.573 g, 1.72 mmol) in dioxane (10 ml) was added Pd2(dba)3 (0.197 g, 0.2155 mmol), Xantphos (0.249 g, 0.431 mmol), Hunig base (0.60 ml, 3.448 mmol) and sodium thiomethoxide (0.133 g, 1.72 mmol). The mixture was heated at 80° C. for 6 hours. The mixture was cooled to room temperature and pH2 buffer was added. The mixture was extracted with EtOAc, and the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the residue by flash chromatography (hex:EtOAc/7:3) gave 2-bromo-4-chloro-5-methylsulfanyl-phenylamine (0.22 g, 50%) as an oil.
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH2:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](O)=[O:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C@@H:33]([CH3:36])[C@@H:32]([C:37](=[O:38])[NH:22][CH2:21][C:19]2[N:20]=[C:15]3[CH:14]=[CH:13][N:12]([S:2]([C:5]4[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=4)(=[O:3])=[O:4])[C:16]3=[N:17][CH:18]=2)[CH2:31]1)=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CN)cnc32)cc1
Reactant: C[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
To a slurry of (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanamine hydrochloride (34.0 g, 100 mmol, Example #5, Step C), (3R,4R)-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (24.43 g, 100 mmol) and HATU (38.2 g, 100 mmol) in DCM (700 mL) was added DIEA (52.6 mL, 301 mmol). The reaction was stirred at ambient temperature for about 45 min. The reaction was washed with saturated aqueous NaHCO3 (300 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered then concd in vacuo. The resulting residue was purified by chromatography on silica gel (330 g) using 33-100% EtOAc in heptane to give (3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (53 g, 100%) as a pale-yellow foam: LC/MS (Table 1, Method b) Rt=2.40 min; MS m/z: 528 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH2:34][C:35](=[O:41])[NH:36]2>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:35](=[O:41])[NH:36]2
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4c(F)cccc4F)c32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 84.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-2-[4-(2,6-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 20 (52 mg, yield 84.7%) as a yellow solid.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[F:16][CH:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1>>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:5]([O:7][CH:17]([F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:19]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: FC(Br)c1cccc(Oc2ccccc2)c1
Reactant: COc1ccc(C(C(=O)O)C(C)C)cc1
Product: COc1ccc(C(C(=O)OC(F)c2cccc(Oc3ccccc3)c2)C(C)C)cc1

Procedure:
This compound was prepared from α-isopropyl-(4-methoxyphenyl)acetic acid and α-fluoro-3-phenoxybenzylbromide following the procedure described in Example 2 Method B. The product, a colourless oil, was characterised by pmr spectroscopy. Chemical shift δ ppm (solvent CDCl3): 0.72(3H, d, J=6Hz, CH3); 1.06(3H, d of d, J=6Hz and J=2Hz, CH3); about 2.25(1H, m, --CH(CH3)2); 3.17(1H, d, J=10Hz, CH); 3.76(3H, s, CH3O); 7.18(1H, d of d, J=56Hz and J=2Hz, CHF); about 7.2(13H, m, aromatic protons).