Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Br:9][C:10]1[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][S:15]([C:13]2[S:14][C:10]([Br:9])=[CH:11][CH:12]=2)(=[O:17])=[O:16])[CH:4]=1
Reactant: NCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCc1cccnc1)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.6 %

Procedure:
To a stirred solution of 3-aminomethyl-pyridine (1.24 g, 11.5 mmol) in THF (8 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) dissolved in THF (8 ml) and triethylamine (0.59 ml, 4.21 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (dichloromethane/methanol) and crystallization from dichloromethane/hexane to yield the title compound (1.23 g, 97%) as a white solid. MS (ISN) 331.0 [(M−H)−], mp 125° C.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH3:19])[CH2:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1>CO>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:10]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([NH:18][CH3:19])[CH2:16][CH2:17]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNC1CCN(CC(c2cccc(Cl)c2)C2CCCCC2)CC1
Agent: Cl
Solvent: CO
Product: CNC1CCN(C[C@H](c2cccc(Cl)c2)C2CCCCC2)CC1

Procedure:
Racemic 1-[2-(3-chlorophenyl)-2-cyclohexylethyl]-N-methylpiperidin-4-amine (see Example 232) was dissolved in methanol at a concentration of approximately 50 mg/mL. The resulting solution was injected onto the Preparative High Performance Liquid Chromatography instrument. The baseline resolved enantiomers, using the conditions described below, were collected. The enantiomeric purity of each enantiomer was determined under the same HPLC conditions using a Chiralcel OD-H 5u, 250 mm×4.6 mm ID column at 1.0 mL/min flow rate using an HP 1100 HPLC (Agilent Technologies. Palo Alto, Calif., USA).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=C[CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C(=NC=CC=3)CC2)=[N:27]C(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[N:27][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCc3ncccc32)n1
Product: CCc1nc(NC2CCc3ncccc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting N-(3,6-diethylpyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 8.49, 7.67, 7.17, 5.77, 4.55, 3.21, 3.09, 2.85–2.75, 2.58, 1.97, 1.31–1.25; HRMS (FAB) calcd for C16H19BrN4+H 347.0872, found 347.0878.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][N:8](C(=O)C2C=CC(F)=CC=2)[CH:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=4)[CH:17]=[CH:18][C:19]=3[C:11]=2[CH2:10][CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1cc(-c3cccc(OC)c3)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1=CNCCc2c1[nH]c1cc(-c3cccc(OC)c3)ccc21
Temperature: 93 °C
Yield: 91.1 %

Procedure:
To a stirred solution of 3-(4-fluorobenzoyl)-8-(3-methoxyphenyl)-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester (48 mg, 0.10 mmol) in 2 mL of EtOH was added 0.30 mL of 1M Na2CO3 solution at ambient temperature. The reaction mixture was heated at 93° C. reflux under N2for 3.5 hours and samples monitored by LC-MS. The solution was diluted with DCM (10 mL), washed with brine. The aqueous phase was extracted with DCM (10 mL) twice. The combined organic phase was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatograph on silica gel, eluting with EtOAc-hexane (0-30%) to yield the title compound (33 mg) as a yellow solid; 1H-NMR (CDCl3): δ 10.46 (1H, s), 7.73 (1H, d), 7.47 (1H, d), 7.37 (1H, d), 7.26 (2H, m), 7.12 (1H, m), 7.00 (1H, m), 6.79 (1H, m), 5.25 (1H, s), 4.21(2H, m), 3.80 (3H, s), 3.55 (2H, m), 3.11 (2H, m), 1.26 (3H, t). MS (ESI): 363 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](O)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][NH2:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH:11]1[C:19]2[C:18](=[CH:17][C:16]([O:15][CH3:14])=[C:21]([O:22][CH3:23])[CH:20]=2)[CH2:24][CH2:25][NH:26]1
Reactant: O=C(O)CCc1cccc(F)c1F
Reactant: COc1ccc(CCN)cc1OC
Product: COc1cc2c(cc1OC)C(CCc1cccc(F)c1F)NCC2

Procedure:
The compound is prepared from 3-(2,3-difluoro-phenyl)-propionic acid and 2-(3,4-dimethoxy-phenyl)-ethylamine according to the method of example A8.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](Cl)=[C:4](Cl)[C:5]([F:8])([F:7])[F:6].[OH-].[Na+].[H][H]>O1CCCC1.[Pd]>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C(Cl)=C(Cl)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: FC(F)(F)CCC(F)(F)F
Yield: 48.2 %

Procedure:
To 1,1,1,4,4,4-hexafluoro-2,3-dichloro-2-butene (23.5 g, 0.1 mole) in 50 ml tetrahydrofuran were added sodium hydroxide (8.5 g) and as catalyst 5% by weight palladium on carbon (3 g). This mixture was hydrogenated with hydrogen at temperatures of 20 to 40° C. under pressures of 20 to 40 bar. The reaction mixture was worked up as in Example B, producing 8.0 g (75% of theory) of 1,1,1,4,4,4-hexafluorobutane.
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][CH:7]2[CH2:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]=12.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([N:16]=[C:4]2[N:8]3[C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=4[CH2:15][CH:7]3[CH2:6][S:5]2)[CH:18]=1
Reactant: Nc1cccnc1
Reactant: CSC1=[N+]2c3ccccc3CC2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: c1cncc(N=C2SCC3Cc4ccccc4N23)c1
Reaction time: 24 h
Yield: 76.5 %

Procedure:
(RS)-3-Methylthio-9,9a-dihydrothiazolo[3,4-a]indolium iodide (14.0 g) is added to a solution of 3-aminopyridine (4.5 g) in pyridine (150 cc). The suspension gradually passes into solution. After 24 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm Hg) at 50° C. The residue is dissolved in a mixture of methylene chloride (500 cc) and 2 N aqueous sodium hydroxide solution (150 cc). The organic phase is decanted, washed with water (200 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. The residue obtained is recrystallised from absolute ethanol (40 cc). (RS)-3-(Pyrid-3-ylimino)-9,9a-dihydrothiazolo[3,4-a]indole (8.2 g), melting at 131° C., is obtained.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[CH2:14][CH2:13][CH:12]([N:15]2[CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[NH:17][C:16]2=[O:26])[CH2:11][CH2:10]1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:23]1[CH:24]=[CH:25][C:18]2[NH:17][C:16](=[O:26])[N:15]([CH:12]3[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[CH2:21][CH2:20][C:19]=2[CH:22]=1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2CCN1C1CCNCC1

Procedure:
801 mg (6.0 mmol) N-chlorosuccinimide were added to 1.23 g (5.0 mmol) 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one in 10 mL carbon tetrachloride and the reaction mixture was refluxed for 3 days. The solvent was evaporated down using the rotary evaporator and the residue was purified by flash chromatography. The product fractions were combined and the solvent was eliminated using the rotary evaporator. For further purification the product fractions were purified by preparative HPLC. The product fractions were combined and evaporated to dryness using the rotary evaporator.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:15][O:16][C:17](=[O:43])[C:18]([O:21][C:22]1[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=1)[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:38])=[C:27]1[CH3:39])([CH3:20])[CH3:19]>>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:24]2[CH:23]=[C:22]([CH:42]=[CH:41][CH:40]=2)[O:21][C:18]([CH3:19])([CH3:20])[C:17]([O:16][CH3:15])=[O:43])[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH3:13])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)C(C)(C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: C[C@H](N)c1ccc(C(C)(C)C)cc1
Agent: Cl
Product: COC(=O)C(C)(C)Oc1cccc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4ccc(C(C)(C)C)cc4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(4-(tert-butyl)phenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the 1-(3-((1-methoxy-2-methyl-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:3]([NH:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:7]=1)=[O:4].CCN(C(C)C)C(C)C.Br[CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>CN(C=O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:10]([CH3:11])[N:9]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccnc(Cl)c2)cc1NC(=O)[C@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a 500 ml flask was added 2000 mg of (2S)-2-amino-N-(3-(2-chloropyridin-4-yl)-1-methyl-1H-pyrazol-5-yl)-3-phenylpropanamide 17.7.E, 50 ml of DMF, 1.4 ml of DIEA and the reaction was cooled to 0° C. To the reaction was then added 953 μl of tert-butyl bromoacetate and the reaction was stirred at 22° C. for 16 hours at which time the crude was partitioned between 800 ml EtAc, 2×200 ml of saturated brine, and 2×200 ml of water. (Note: no product observed in aqueous layer). The organic solvent was removed by rotary evaporation and the crude purified with a silica gel column (eluting with 50% EtAc in Hexane) to give 1.8 g of 17.8.A as a white solid.
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH2:13][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[N:10]2)=[CH:5][CH:4]=1.CCCCCC.[CH:39]([C:41]1[CH:42]=[C:43]([CH:47]([S:55][CH2:56][CH2:57][C:58](=[O:62])[N:59]([CH3:61])[CH3:60])[S:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH:44]=[CH:45][CH:46]=1)=O.C([O-])(=O)C.[NH4+]>C1COCC1>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[CH:39][C:41]3[CH:42]=[C:43]([CH:47]([S:55][CH2:56][CH2:57][C:58](=[O:62])[N:59]([CH3:61])[CH3:60])[S:48][CH2:49][CH2:50][C:51]([O:53][CH3:54])=[O:52])[CH:44]=[CH:45][CH:46]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=O)c1
Reactant: Clc1ccc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 7-chloroquinolin-2-ylmethyltriphenylphosphonium bromide (Example 4, Step 2) (809 mg, 1.56 mmol.) in THF (15 mL) at -78° C., was added a solution of n-Buli (1.6 M) in hexane (0.89 mL, 1.43 mmol.). The mixture was stirred for 0.5 hrs at -78° C. Then, (+)-methyl 5-(3-formylphenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoate (step 3) (480 mg, 1.3 mmol.) in THF (4 mL) was slowly added. The mixture was stirred for 0.5 hr at -78° C. and then warmed up to room temperature and stirred for an additional 2 hrs. A solution of 25% ammonium acetate was added, the mixture was extracted with ethyl acetate, and the extracts were washed with brine (3×), dried over sodium sulfate, filtered and evaporated to dryness. Purification by flash chromatography afforded the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([OH:24])[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:25]>CO>[NH2:25][C:2]1[C:11]2[N:12]=[C:13]([OH:24])[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: COc1ccc(Cn2c(O)nc3c(Cl)nc4ccccc4c32)cc1
Solvent: CO
Product: COc1ccc(Cn2c(O)nc3c(N)nc4ccccc4c32)cc1
Temperature: 150 °C

Procedure:
4-Chloro-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-ol (2.0 g, 5.9 mmol) and ammonia (30 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated at 150° C. for two days. An analysis by LC/MS indicated the reaction was incomplete, and the vessel was sealed and heated at 165° C. for three days. The volatiles were removed under reduced pressure, and the residue was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.5:9.5:90). The resulting white solid was mixed with acetonitrile, isolated by filtration, and dried overnight under vacuum to provide 4-amino-1-(4-methoxybenzyl)-1H-imidazo[4,5-c]quinolin-2-ol as a white solid, mp greater than 260° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([NH:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Reactant: NCCN1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2cccc(Cl)c2)nc2cccnc21)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.4 g, 0.0188 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.0188 mole) in anhydrous tetrahydrofuran (150 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 21/2 hours. The nitrogen flow was stopped and a solution of 1-(2-aminoethyl)piperidine (2.4 g, 0.0188 mole) in dry tetrahydrofuran (50 ml) was added. The solution was stirred at room temperature under nitrogen for 2 hours. The reaction mixture was concentrated in vacuo and the residue partitioned between methylene chloride (75 ml) in water (75 ml). The layers were separated and the aqueous portion washed with methylene chloride (25 ml). The organic layers were combined and washed with potassium bicarbonate solution (2×50 ml), water (25 ml), dried over sodium sulfate, and concentrated in vacuo. The residue (6.6 g) was recrystallized from isopropyl alcohol-isopropyl ether to give 3.5 g (47%). Recrystallization from isopropyl alcohol-isopropyl ether gave 2.5 g of cream colored solid, mp 114°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14](C(OC(C)(C)C)=O)[C@H:13]([C:23](=[O:30])[NH:24][C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)[CH2:12]1)(=[O:10])=[O:9]>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:23]([NH:24][C:25]2([C:28]#[N:29])[CH2:27][CH2:26]2)=[O:30])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1
Solvent: O=CO
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Yield: 85 %

Procedure:
The reaction of the amide 6H with formic acid yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide as a white foam (85%). MS ISP (m/e): 354.2 (100) [(M+H)]+.
Reaction SMILES: [CH:1](=O)[CH3:2].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:35])[C:11]2[O:17][C:16]3[C:18]([Cl:31])=[CH:19][C:20]([NH:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:33])(=[O:32])[C:12]=2[CH:34]=1)=[O:7].C(O)(C(F)(F)F)=O.C([BH3-])#N.[Na+]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:35])[C:11]2[O:17][C:16]3[C:18]([Cl:31])=[CH:19][C:20]([N:22]([CH2:1][CH3:2])[CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:21][C:15]=3[CH2:14][S:13](=[O:32])(=[O:33])[C:12]=2[CH:34]=1)=[O:7]
Reactant: CC=O
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCCC3)cc(Cl)c1O2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCN(CCN1CCCCC1)c1cc(Cl)c2c(c1)CS(=O)(=O)c1cc(C(=O)OC)cc(C)c1O2
Reaction time: 2 h

Procedure:
Acetaldehyde (0.151 g, 3.4 mmol) was added to a solution of Example 92k (0.330 g, 0.68 mmol) in MeOH (10 mL) at 0° C. TFA (0.08 g, 0.68 mmol) was then added and stirring continued for 2 h. The reaction mixture was brought to room temperature, treated with sodium cyanoborohydride (0.108 g, 1.7 mmol) and allowed to stir for 4 h. It was concentrated, treated with aqueous sodium bicarbonate solution, water and extracted ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography to obtain the title compound. Yield: 0.80 g, (51%); 1H NMR (CDCl3): δ 1.20 (t, 2H, CH2), 1.70 (t, 2H, CH2), 1.80 (t, 4H, 2CH2), 2.70 (s, 3H, CH3), 2.80 (s, 2H, CH2), 2.90 (m, 2H, CH2), 3.40 (q, 2H, CH2), 3.80 (t, 2H, CH2), 3.9 (s, 3H, OCH3), 4.8 (s, 2H, CH2), 6.8 (s, 2H, Ar), 8.10 (s, 1H, Ar), 8.4 (s, 1H, Ar); MS: m/e (ES−) 506 (M−1).
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:15].[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:16][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:15]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSC1C(=O)Nc2ccc([N+](=O)[O-])cc21
Solvent: ClC(Cl)Cl
Product: CSC1(Cl)C(=O)Nc2ccc([N+](=O)[O-])cc21

Procedure:
A solution of 3-methylthio-5-nitrooxindole (900 mg, 4 mmol) and N-chlorosuccinimide (600 mg, 4.5 mmol) in 50 ml of chloroform was stirred at room temperature for 1 hour and then evaporated to dryness in vacuo, yielding 3-chloro-3-methylthio-5-nitrooxindole. The residue was dissolved in 15 ml of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide powder (900 mg, 4.3 mmol) and boron trifluoride etherate (600 mg, 4.3 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. After stirring at room temperature for two hours, the reaction mixture was extracted with three 100-ml portions of chloroform. The chloroform layer was dried over anyhdrous magnesium sulfate, filtered and evaporated. The residue was recrystallized from 95 percent ethanol to give 5-nitroisatin (600 mg, 78%), mp 252°-254°
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23](Cl)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[C:23]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[NH:1][CH:2]=[CH:3][C:4]1=2)=[O:24])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Cl
Reactant: c1cc2c([nH]1)CCCCN2
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCCCc2[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of(S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (664 mg) in DCM (10 mL) at 0° C. was added oxalyl chloride (4.7 mmol), followed by one drop of DMF. After stirring at rt for 2 hours, the solvent was concentrated to give S) 2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester. To a solution of 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-b]azepine (350 mg, 2.6 mmol) was added TEA (362 μL) and (S)-2-chlorocarbonyl-pyrrolidine-1-carboxylic acid tert-butyl ester (dissolved in 10 mL of DCM). After stirring at rt for overnight, the reaction was diluted with DCM, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 410 mg of (S)-2-(5,6,7,8-tetrahydro-1H-pyrrolo[3,2-b]azepine-4-carbonyl)-pyrrolidine-1-carboxylic-acid tert-butyl ester as a light brown liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:3][C:4]=1[CH2:9][CH3:10]
Reactant: CCc1cc(Br)ccc1Cl
Reactant: NCCc1ccc(C(F)(F)F)cn1
Product: CCc1cc(NCCc2ccc(C(F)(F)F)cn2)ccc1Cl

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-chloro-3-ethyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 329.2 [M+H]+) was prepared from 4-bromo-1-chloro-2-ethylbenzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH2:20][CH2:19][C:11]3[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=3[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(=O)(O)[O-].[Na+]>CCO>[C:1]([C:5]1[S:6][C:7]2[CH2:20][CH2:19][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(C(C)(C)C)sc1CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1nc2c(s1)CCc1nc(N)sc1-2
Temperature: 25 °C

Procedure:
N-(7-tert-Butyl-4,5-dihydro-benzo[1,2-d;3,4-d′]bisthiazol-2-yl)-acetamide (Stage T.2, 225 mg, 0.732 mmol) was dissolved in EtOH (10 mL), HCl 36% (1.48 g, 14.64 mmol) was then added, and the RM heated to reflux. After 18 hours at reflux the RM was cooled to rt and adjusted to pH 8-9 by the addition of 5% aqueous sodium bicarbonate solution, extracted with EtOAc, and washed two times with H2O. The organic layer was dried over Na2SO4 and evaporated to give the title product (tR 4.408 min (Method F)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH2:28])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH3:23]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.536 g (10 mmol) of β-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.