Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:22])[CH2:10][CH2:11][O:12][CH2:13][C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)=[O:15].C(N(CC)CC)C.[Cl:30][C:31]1[C:40]2[C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:37]=[CH:36][C:35]=2[CH:34]=[N:33][CH:32]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:8][N:9]([CH3:22])[CH2:10][CH2:11][O:12][CH2:13][C:14]([NH:16][C@H:17]1[CH2:21][CH2:20][N:19]([S:41]([C:39]2[C:40]3[C:31]([Cl:30])=[CH:32][N:33]=[CH:34][C:35]=3[CH:36]=[CH:37][CH:38]=2)(=[O:43])=[O:42])[CH2:18]1)=[O:15]
Reactant: CN(C)CCOCC(=O)N[C@H]1CCNC1
Reactant: O=S(=O)(Cl)c1cccc2cncc(Cl)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(C)CCOCC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
A solution of (S)-3-[2-[2-(Dimethylamino)ethoxy]acetyl]aminopyrrolidine trifluoroacetate (246 mg) prepared in Step F in dichloromethane (5 ml) was successively added with triethylamine (387 μl) and 4-chloro-5-isoquinolinesulfonyl chloride (145 mg) at 0° C., and the mixture was stirred at the same temperature for 45 minutes, and further stirred at room temperature for 15 minutes. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, and the organic layer was separated. The aqueous layer was extracted three times with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain the title compound (160 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15]Cl)[C@@H:10]([CH2:18][OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].CC(O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C@@H:10]([CH2:18][O:19][CH2:15][C:14]2=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)[C@@H](CO)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)COC[C@H]2C1
Yield: 90.8 %

Procedure:
To a solution of (R)-4-(2-chloro-acetyl)-3-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester (710 mg, 2.45 mmol) in THF (16 mL) at 0° C. was added potassium tert-butoxide (326 mg, 2.91 mmol). The resulting mixture was stirred for 75 min before the addition of AcOH (0.6 mL). The resulting mixture was partitioned between water and DCM and the aqueous layer extracted with further DCM. The combined organic fractions were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as a colourless oil (570 mg, 91%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C[O-].[Na+].[Cl:10][C:11]1[CH:28]=[CH:27][C:14]([C:15]([C:17]2[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[N+:23]=[N-:24])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1>C(O)C>[NH2:2][C:1]1[N:22]([CH2:21][C:20]2[CH:19]=[CH:18][C:17]([C:15](=[O:16])[C:14]3[CH:27]=[CH:28][C:11]([Cl:10])=[CH:12][CH:13]=3)=[CH:26][CH:25]=2)[N:23]=[N:24][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: [N-]=[N+]=NCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: N#CCC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1nnn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1N
Temperature: 25 °C
Yield: 11.2 %

Procedure:
To a suspension of 2-cyanoacetamide (527 mg, 6.27 mmol) in ethanol (20 ml) was added sodium methoxide (330 mg, 6.11 mmol). The mixture was refluxed 15 minutes, cooled slightly, and 4-(4-chlorobenzoyl)benzyl azide (1.24 g, 4.56 mmol) was added. The mixture was refluxed 2 hours, cooled to ambient temperature, and filtered. The filtrate was evaporated under vacuum and the residue was triturated with hot 19:1 (v/v) dichloromethane-methanol (50 ml) and filtered. The remaining solid was triturated with hot methanol (3 ml), filtered, and dried at 60° C. under vacuum to provide 182 mg (11%) of 5-amino-1-(4-[4-chlorobenzoyl]benzyl)-1,2,3-triazole-4-carboxamide, m.p. 229°-231° C.
Reaction SMILES: [CH:1](=[CH:10][C:11]([OH:13])=[O:12])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>[Br-].C([N+](CC)(CC)CC)C.O>[CH:1](=[CH:10][C:11]([O:13][CH2:14][CH:16]1[O:18][CH2:17]1)=[O:12])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: ClCC1CO1
Reactant: O=C(O)C=CC=Cc1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: O
Product: O=C(C=CC=Cc1ccccc1)OCC1CO1
Temperature: 110 °C

Procedure:
To 9.0 g of cinnamylideneacetic acid (manufactured by Lancaster) were added 3.5 g of tetraethylammonium bromide (manufactured by Wako Pure Chemical) and 100 ml of epichlorohydrin (manufactured by Wako Pure Chemical), the mixture was heated to reflux at 110° C. for 3 hours, 50 ml of distilled water was added thereto and an organic layer was separated and concentrated in vacuo at 80° C. to give 17.3 g of glycidyl cinnamylideneacetate. An epoxy equivalent of this glycidyl cinnamylideneacetate was 444.3.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[O:58]1[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59]1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:63]([C:60]3[CH:61]=[CH:62][O:58][CH:59]=3)(=[O:65])=[O:64])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: O=S(=O)(Cl)c1ccoc1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccoc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 3-furansulfonyl chloride (43 mg, 0.256 mmol), the title compound was obtained as a white solid (71 mg, 61% yield). MS (ESI): 474.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21](O)=[O:22])[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][CH:19]=[C:20]([C:21]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:22])[C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(Nc1c[nH]nc1-c1nc2c(C(=O)O)cccc2[nH]1)c1c(F)cccc1F
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2cccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.1 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-4-carboxylic acid (50 mg, 0.13 mmol), N-methylpiperazine (20 μl, 0.18 mmol), EDC (30 mg, 0.15 mmol) and HOBt (22 mg, 0.15 mmol) in DMF (5 ml) was stirred at ambient temperature for 18 h. The mixture was reduced in vacuo and the residue purified by flash column chromatography [SiO2, CH2Cl2/MeOH (95:5, 90:10)] to give 2,6-difluoro-N-{3-[4-(4-methyl-piperazine-1-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (14 mg) as a cream solid. (LC/MS: Rt 2.21, [M+H]+ 466).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[O:8]1[CH2:14][CH2:13][C:12]([C:15](Cl)=[O:16])=[CH:11][C:10]2[CH:18]=[CH:19][CH:20]=[CH:21][C:9]1=2>O1CCCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:15]([C:12]1[CH2:13][CH2:14][O:8][C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[CH:11]=1)=[O:16]
Reactant: O=C(Cl)C1=Cc2ccccc2OCC1
Reactant: Nc1ccccn1
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)C1=Cc2ccccc2OCC1

Procedure:
10 ml of 2-aminopyridine were dissolved in 10 ml thetrahydrofurane. 2,3-Dihydro-benzo[b]oxepine-4-carbonylchloride (1.1 mmol) dissolved in 2 ml tetrahydrofurane were added dropwise. The reaction mixture was quenched by water and extracted with diethylether. The diethylether phase was washed by 1 mol/l sodiumhydroxide and dried over sodiumsulfate. Evaporation of the solvent yielded 230 mg of crude product which was purified by preparative HPLC (Chromolith prep. RP18, Solvent A water:acetonitrile 90:10+0.1% formic acid, solvent B: water:acetonitrile 10:90+0.1% formic acid, flow: t=0 min 25 ml/min, t=1 min 50 ml/min, gradient: t=0 min 10% B, t=1 min 10% B, t=2 min 10% B, t=2.2 min 20% B, t=7.5 min 50% B, t=7.6 min 100% B, t=8.5 min 100% B). Form this 85 mg of 2,3-Dihydro-benzo[b]oxepine-4-carboxylic acid pyridin-2-ylamide. LC-MS 1.6 min, 267.2 (MH+) 1H-NMR: (DMSO-d6, 500 MHz) d [ppm] 10.358 (s, 1H), 8.370 (m, 1H, J=1 Hz), 8.109 (m, 1H, J=4 Hz), 7.815 (m, 1H, J=2.4 Hz), 7.474 (m, 1H, J=2.3 Hz), 7.392 (s, 1H), 7.277 (m, 1H, J=1.7 Hz), 7.140 (m, 1H, J=1.9 Hz), 7.068 (m, 1H, J=3.2 Hz), 6.983 (m, 1H, J=1.9 Hz), 4.259 (m, 2H, J=3.1 Hz), 2.985 (m, 2H, J=2.6 Hz)
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.B.CSC.[C:26]([O:30][C:31](=[O:52])[NH:32][C@H:33]1[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C:40](=[O:50])[CH:41]=[CH:42][C:43]2[CH:44]=[N:45][C:46]([CH3:49])=[N:47][CH:48]=2)[C:34]1=[O:51])([CH3:29])([CH3:28])[CH3:27].CO>ClCCl.C1COCC1>[C:26]([O:30][C:31](=[O:52])[NH:32][C@H:33]1[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][CH:40]([OH:50])[CH:41]=[CH:42][C:43]2[CH:44]=[N:45][C:46]([CH3:49])=[N:47][CH:48]=2)[C:34]1=[O:51])([CH3:27])([CH3:28])[CH3:29]
Reactant: Cc1ncc(C=CC(=O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ncc(C=CC(O)CN2C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]2C)cn1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of (S)-2-methyl-CBS-oxazaborolidine (6.4 mL, 1M in toluene) in dichloromethane (15 mL) was added a solution of borane-dimethylsulfide (0.64 mL, 10M) and the resulting solution was stirred at ambient temperature for 40 minutes. This solution was added to a stirred solution of 5-1 (800 mg, 2.14 mmol) in THF (30 mL) at −40° C. and the reaction mixture was stirred for 3 hours. Methanol (5 mL) was added and the reaction mixture was concentrated at reduced pressure. The residue was purified by flash column chromatography (silica gel, 9:1 ethyl acetate/methanol) to give 5-2 as a colorless oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]2)[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][N:4]=1.S(Cl)(Cl)=O.[CH3:26][CH:27]([NH2:29])[CH3:28]>C1COCC1.C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][C@H:10]2[CH2:11][CH2:12][C@H:13]([C:16]([NH:29][CH:27]([CH3:28])[CH3:26])=[O:18])[CH2:14][CH2:15]2)[C:6]([N+:19]([O-:21])=[O:20])=[CH:5][N:4]=1
Reactant: CC(C)N
Reactant: O=C(O)[C@H]1CC[C@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)NC(=O)[C@H]1CC[C@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
trans-4-(2-Chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid hydrochloride (0.500 g, 1.487 mmol) was suspended in THF (3 mL). Thionyl chloride (0.434 mL, 5.95 mmol) was added to the suspension, and the reaction mixture was stirred at 20° C. for 2 hours. The resulting mixture was concentrated in vacuo. The solid was resuspended in THF (5 mL) and then propan-2-amine (0.153 mL, 1.785 mmol) was added. The mixture was stirred at RT for 16 hours, and additional propan-2-amine (0.128 mL, 1.487 mmol) was added. Stirring at RT was continued for 1 hour. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3 and brine. The organic layer was concentrated in vacuo, and the residual material was purified via silica gel chromatography, eluting with 20-100% EtOAc in hexanes, to yield trans-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide as a yellow solid (0.312 g, 61.6% yield). MS m/z=341.0 [M+H], calc 340.81 for C15H21ClN4O3.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=1)=[O:19].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13][NH:15][C:16]2[CH:35]=[CH:34][CH:33]=[CH:32][C:17]=2[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[C:23]([C:28]([F:31])([F:29])[F:30])[CH:22]=2)=[O:19])=[CH:9][CH:8]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: COc1ccc(C=O)cn1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2ccccc2C(=O)Nc2ccc(Br)c(C(F)(F)F)c2)cn1
Reaction time: 16 h

Procedure:
Sodium cyanoborohydride (8.80 g of 95%, 133 mmol) is added in portions over 30 minutes to a stirred mixture of acetic acid (3.8 mL), 6-methoxy-3-pyridinecarboxaldehyde (Fluka, Buchs, Switzerland; 7.80 g, 57 mmol) and 2-amino-N-(4-bromo-3-trifluoromethylphenyl)-benzamide (step 1.2; 13.65 g, 38 mmol) in methanol (380 mL) at 25° C. The mixture is stirred for 16 hours. The solvent is evaporated under reduced pressure to give a residue which is treated with a saturated aqueous solution of sodium hydrogen carbonate (500 mL) and extracted with dichloromethane (3×150 mL). The combined extracts are dried (Na2SO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product that is purified by column chromatography on silica gel, eluent 5% ethyl acetate in dichloromethane and recrystallised from diethylether-hexane to give the title compound as a beige crystalline solid, m.p. 101–103° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8]/[CH:9]=[C:10](/[F:13])\[CH2:11]Br)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(Br)C=C>CN(C=O)C.O>[CH:15]1([NH:21][C:22]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:11]/[C:10](/[F:13])=[CH:9]\[CH2:8][NH:7][C:6](=[O:14])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:25][CH:24]=2)=[O:30])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC/C=C(/F)CBr
Reactant: O=C(NC1CCCCC1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC/C=C(/F)COc1ccc(C(=O)NC2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A stirred solution of (E)-tert-butyl-N-(3-fluoro-4-bromobut-2-enyl)carbamate (3.48 g, 13 mmol), N-cyclohexyl-4-hydroxybenzamide (3.55 g, 16.2 mmol) and potassium carbonate (2.76 g, 20 mmol) in DMF (10 mL) under nitrogen was heated at 60° C. for 3 hours at which time TLC analysis showed no remaining allyl bromide. The reaction mixture was allowed to cool and then water (50 mL) added, causing a white precipitate to form. Stirred for 30 minutes, then filtered, washing with water to remove any remaining DMF from the filtercake. The precipitate was then taken up into dichloromethane (150 mL), filtered to remove any insolubles and then washed with NaOH solution (2 M; 20 mL) and brine (20 mL). Dried over MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound as a white solid (4.23 g, 80%); 1H-NMR (400 MHz, CDCl3): δppm: 1.21-1.25 (3H, m), 1.40-1.46 (2H, m), 1.44 (9H, s), 1.61-1.69 (1H, m), 1.73-1.77 (2H, m), 2.01-2.05 (2H, m), 3.80 (2H, t, J 6.7 Hz), 3.96 (1H, m), 4.64 (1H, br s), 4.73 (2H, d, J 19.0 Hz), 5.46 (1H, dt J 18.9, 8.1 Hz), 5.81 (1H, br s), 6.96 (2H, d, J 8.3 Hz), 7.73 (2H, d, J 8.3 Hz).
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15]([C:17]([O:19]CC)=O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH:39][C:17]([C:15]3[S:16][C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH3:5])[CH2:11][CH2:10]4)=[CH:13][CH:14]=3)=[O:19])[NH:37][N:38]=2)[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCN(C)CC2)s1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.8 %

Procedure:
2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of ethyl 5-(4-methylpiperazin-1-yl)thiophene-2-carboxylate (0.254 g, 1 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. The reaction mixture was stirred at ambient temperature for 16 h and then heated at 65° C. for 24 h. Ethyl acetate (5 mL) was added to the reaction mixture followed by a solution of potassium sodium tartrate (5 mL, 20% aqueous). More ethyl acetate (50 mL) and water (25 mL) was added and the mixture was filtered through celite. The filtrate was transferred to a separating funnel and the aqueous layer removed. The ethyl acetate layer was washed with saturated brine and then dried over magnesium sulphate. After filtration the solvent was evaporated to give the crude product as a yellow solid. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.154 g, 33.8%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[O:18]=[C:16]([CH3:17])[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: CC(=O)CBr
Reactant: COC(=O)C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccc(OCC(C)=O)cc1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 16 g of methyl 4-hydroxycinnamate, 14.9 g of bromoacetone, 20 g of potassium carbonate and 150 ml of dimethylformamide, the title compound was obtained as crystals, melting at 117°-118° C. (after recrystallization from ethyl acetate).
Reaction SMILES: C(S[CH:5]([CH2:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.C(Cl)(Cl)(Cl)Cl.[SH:30][CH2:31][C:32]([OH:34])=[O:33]>C(O)C>[C:17]([CH2:16][CH:5]([S:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)SC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(O)CS
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: O=C(O)CSC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 72 h

Procedure:
To a suspension of 0.90 g. of 1-(3-benzoylacryloyl)-L-proline (prepared as described in Example 8) in 30 ml. of carbontetrachloride is added 0.28 ml. of mercaptoacetic acid. An additional 30 ml. of carbontetrachloride is added and the mixture stirred 3 days. The solvent is removed under vacuum. Carbontetrachloride (30 ml.) and 0.78 ml. of mercaptoacetic acid is added and the mixture stirred for 3 days. The solvent is removed and the residue chromatographed on a silica gel column with dichloromethane-methanol-acetic acid (90:10:2) as solvent. Fractions showing one spot by thin layer chromatography are combined to give 1.3 g. of clear gum. Placing the gum under high vacuum over night gives the product of the example as a glass, [α]D23° -31°±2(c, 0.534 ethanol).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:6]=1.[CH2:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:17][CH3:18]>>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([NH:1][S:25]([C:22]3[CH:23]=[CH:24][C:19]([CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=3)(=[O:27])=[O:26])[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)cc1

Procedure:
The title compound was prepared from 2-amino-4-(3-nitrophenyl)thiazole and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (41.5 mg) with purity >90%: MS (pos) m/z 404.1, (neg) m/z 402.2; HRMS m/z 403.0062 (calc. of monoisotopic mass for Cl18H17N3O4S2 gives 403.0060).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[C:22]([Cl:23])=[C:21]3[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:29])=[C:10]([N+:32]([O-])=O)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[NH4+].[Cl-]>CCOC(C)=O.[Zn]>[NH2:32][C:10]1[CH:9]=[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH:31]=[CH:30][C:11]=1[O:12][C:13]1[C:22]([Cl:23])=[C:21]2[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]2)=[CH:15][C:14]=1[Cl:29]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-])c2Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1N)c2Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A mixture of ethyl 7-(4-(tert-butoxycarbonyl)-2-nitrophenoxy)-6,8-dichlorochroman-4-carboxylate (61.593 g, 120.22 mmol), THF (500 ml), and saturated NH4Cl solution (500 ml) was purged with Argon for 10 minutes. Zn dust (78.612 g, 1202.2 mmol) was added and the mixture was stirred at ambient temperature for 1 hour under Argon atmosphere. The reaction was slightly exothermic. The mixture was diluted with EtOAc (500 ml) and filtered. The filtered solid was rinsed with EtOAc (250 ml). The filtrate was transferred to a 3 L separatory funnel. The layers were separated and the organic layer was washed with brine (250 ml). The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified on silica gel (EtOAc in hexanes gradient) to provide 45.6 g of the title compound as an oil (79%).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.Cl.Cl.[NH2:15][CH:16]([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:17]([NH:19][C:20]1([C:29]#[N:30])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]1)=[O:18]>>[C:29]([C:20]1([NH:19][C:17](=[O:18])[CH:16]([NH:15][C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[S:4](=[O:12])(=[O:11])[N:3]=2)[CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]1)#[N:30]
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC2CCCCC2)NC2=NS(=O)(=O)c3ccccc32)CC1

Procedure:
The title compound was prepared starting from 3-chloro-benzo[d]isothiazole 1,1-dioxide and 2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt according to the procedure from Example 81, except that the compound was further purified by HPLC using a 20×250 mm C18 reverse phase column with the method being 20% acetonitrile in water to acetonitrile. MS, m/z 486=M+1.