Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3(O)[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.CCO.COCCN(S(F)(F)[F:44])CCOC>C(Cl)Cl.O>[F:44][C:24]1([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:25][CH2:26][S:27][CH2:28][CH2:29]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCSCC3)s2)c1
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(F)CCSCC3)s2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
To a solution of the product of Step 1 (250 mg, 0.552 mmol) in CH2Cl2 (5 ml) were added EtOH (0.05 mL) and Deoxo-fluor (0.509 ml, 2.76 mmol). The reaction was stirred at room temperature for 30 minutes, diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Column chromatography on silica (gradient elution, 0 to 25% EtOAc in hexanes) afforded the title compound (0.186 g, 0.409 mmol, 74% yield) as a pale yellow foam. MS ESI: [M+H]+ m/z 455.0. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.83 (d, J=4.9, 1H), 8.10 (d, J=2.7, 1H), 8.03 (bs, 1H), 7.47 (bs, 1H), 7.28 (d, J=4.9, 1H), 7.20 (bs, 1H), 2.94-2.89 (m, 2H), 2.69-2.66 (m, 2H), 2.39-2.75 (m, 7H). rhSYK activity=++.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[Cl:17][C:18]1[CH:19]=[C:20]([C:26]([F:29])([F:28])[F:27])[C:21]([NH2:25])=[C:22]([NH2:24])[CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]([C:26]([F:27])([F:28])[F:29])[C:21]2[NH:25][C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)=[N:24][C:22]=2[CH:23]=1
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1N
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4cc(Cl)cc(C(F)(F)F)c4[nH]3)cc2)S1

Procedure:
6-Chloro-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]-4-(trifluoromethyl)benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 5-chloro-3-trifluoromethyl-1,2-phenylenediamine by following General Procedure 2.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=O)[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(O)C.O1CCCC1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=O.C([N:42](CC)CC)C>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:42][C:34]([C:33]([O:37][CH2:38][CH3:39])=[O:36])=[CH:16][CH:15]=3)[CH2:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)C=O
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc(C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (500 mg) in a mixed solvent of ethanol (15 mL) and tetrahydrofuran (5 mL) were added ethyl glyoxylate (polymer type, 47% toluene solution) (623 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (43 mg) and triethylamine (86 μL), and the mixture was heated under reflux under argon atmosphere for 30% min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in acetic acid (5 mL), ammonium acetate (1.7 g) was added, and the mixture was stirred at 110° C. for 30 min. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (210 mg, yield 34%) was obtained as a pale-yellow amorphous solid from a fraction eluted with hexane-ethyl acetate (1:1, volume ratio). MS: 432 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][CH3:23])[C:4](=[O:15])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](N(CC)CC)[CH3:31].[CH2:37](Br)C=C>ClCCl.C(O)C>[CH3:2][N:3]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]([CH3:37])[CH2:23][CH:30]=[CH2:31])[C:4](=[O:15])[CH2:5][C:6]1[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CN[C@@H]1CCCC[C@H]1N(C)C(=O)Cc1cccc2sccc12
Reactant: C=CCBr
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: C=CCN(C)[C@@H]1CCCC[C@H]1N(C)C(=O)Cc1cccc2sccc12
Reaction time: 6 h
Yield: 67 %

Procedure:
A solution of trans-(±)-N-methyl-N-[2-(methylamino)cyclohexyl]benzo[b]thiophene-4-acetamide monohydrochloride (400 mg, 1.13 mmol) in dichloromethane (10 ml) was treated with aqueous potassium carbonate (30 ml) to liberate the parent amine. This oil was dissolved in ethanol (10 ml), dichloromethane (1 ml) and triethylamine (0.3 ml, 2.2 mmol) and treated with allyl bromide (257 mg, 2.1 mmol). This mixture was stirred in an oil bath at 50°-60° C. for six hours, concentrated in vacuo and partitioned between 10% aqueous potassium carbonate and dichloromethane. The organic fractions furnished an oil which after silica gel chromatography (100:1 ethyl acetate-triethylamine) gave trans-(±)-N-methyl-N-(2-[methyl(2-propenyl)amino]cyclohexyl)benzo[b]thiophene-4-acetamide (270 mg, 67%); δH (CDCl3) 6.0-4.3 (3H, m); Vmax (liquid film) 1637 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:39]=[CH:38][C:21]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])=[CH:38][CH:39]=2)=[N:6][C:7]=1[C:8]1[N:9]=[C:10]2[CH2:16][CH:15]=[C:14]([CH3:17])[CH:13]=[C:11]2[N:12]=1
Reactant: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)[nH]c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1=CCC2=NC(c3nc(-c4ccc(C(=O)N5CCCNCC5)cc4)cnc3N)=NC2=C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.5 %

Procedure:
tert-butyl 4-[4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]benzoyl]-1,4-diazepane-1-carboxylate (117 mg, 0.2218 mmol) was dissolved in DCM (3 mL) and the mixture was cooled to 0° C. TFA (3 mL, 38.94 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for a further 2 hours. Solvents were evaporated and the residue was dissolved in a mixture of MeCN and water (5 mL/5 mL) and submitted to Genevac evaporation to yield the product (119 mg, 99% Yield).
Reaction SMILES: Cl.Cl.C([O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C@H:12]3[NH:23][CH2:22][CH2:21][C@@:18]4([C:19]=2[CH:20]=1)[C@@:13]3([O:24]C(=O)C)[CH2:14][CH2:15][CH2:16][CH2:17]4)(=O)C.Cl.C([O:32][C:33]1[CH:34]=[CH:35][C:36]2[CH2:37][C@H:38]3[NH:49][CH2:48][CH2:47][C@@:44]4([C:45]=2[CH:46]=1)[C@@:39]3([O:51]C(=O)C)[CH2:40][CH2:41][C:42](=[O:50])[CH2:43]4)(=O)C>>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH2:11][C@H:12]3[NH:23][CH2:22][CH2:21][C@@:18]4([C:19]=2[CH:20]=1)[C@@:13]3([OH:24])[CH2:14][CH2:15][CH2:16][CH2:17]4.[OH:32][C:33]1[CH:34]=[CH:35][C:36]2[CH2:37][C@H:38]3[NH:49][CH2:48][CH2:47][C@@:44]4([C:45]=2[CH:46]=1)[C@@:39]3([OH:51])[CH2:40][CH2:41][C:42](=[O:50])[CH2:43]4
Reactant: CC(=O)Oc1ccc2c(c1)[C@@]13CCCC[C@@]1(OC(C)=O)[C@@H](C2)NCC3
Reactant: CC(=O)Oc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC(C)=O)CCC(=O)C3
Agent: Cl
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3)C1
Product: Oc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3

Procedure:
In accordance with the above procedure, but where in place of 3,14-diacetylnoroxymorphone (4a) there is subjected to the acid hydrolysis 3,14-diacetoxymorphinan hydrochloride (4e) or 3,14-diacetoxy-6-oxomorphinan hydrochloride (4f) there are obtained the corresponding 3,14-dihydroxymorphinan (5e) and 3,14-dihydroxy-6-oxomorphinan (5f).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[N:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][CH:16]=[C:4]2[CH2:3]1.[Cl:17]N1C(=O)CCC1=O>CN(C)C=O>[Cl:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[N:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: CN1Cc2cncn2-c2cccnc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)ncn2-c2cccnc2C1=O
Reaction time: 0.5 h

Procedure:
0.56 g (2.6 mmol) of 4,5-dihydro-5-methyl-6H-imidazo[1,5-a]pyrido[2,3-f][1,4]diazepin-6-one and 0.35 g (2.6 mmol) of N-chlorosuccinimide are treated with 10 ml of dimethylformamide and the mixture is stirred at 90°-100° for 30 minutes. After evaporation to dryness, the residue is chromatographed on silica gel using chloroform containing 4% methanol for the elution. After recrystallization from ethyl acetate, there is obtained 3-chloro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a]pyrido[2,3-f][1,4]diazepin-6-one of melting point 247°-248°.
Reaction SMILES: C(O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].P(Cl)(Cl)(Cl)=O.P(OP(O)(O)=O)(O)(O)=[O:21].[CH-:29]1C=[CH:32][CH:31]=[CH:30]1.[CH-:34]1[CH:38]=[CH:37][CH:36]=[CH:35]1.[Fe+2:39].C(N([CH2:45][CH3:46])CC)C>C(Cl)Cl>[C-:46]1([C:45]([CH:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2])[C:10]([OH:12])=[O:11])=[O:21])[CH:32]=[CH:31][CH:30]=[CH:29]1.[CH-:34]1[CH:38]=[CH:37][CH:36]=[CH:35]1.[Fe+2:39]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: O=P(O)(O)OP(=O)(O)O
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCC(C(=O)O)C(=O)[c-]1cccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
0.67 g of sebacic acid, 1.0 ml of triethylamine and 2 ml of phosphorus oxychloride with 40 ml of methylene chloride were added and stirred at 0° C. for 30 minutes, and then 60 ml of pyrophosphoric acid and 6.0 g of ferrocene were added, and the resulting mixture was heat-refluxed. Subsequently, the same procedure as in Example 7 was conducted, to obtain a ferrocenoylnonanoic acid in an amount of 2.22 g and in a yield of 60.0%.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11].C([O-])(O)=[O:15].[Na+].ClCC1C=NC=CC=1C(F)(F)F.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[Cl:2][CH2:3][C:4]1[CH:5]=[N+:6]([O-:15])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:11])[F:12]
Reactant: O=C([O-])O
Reactant: FC(F)(F)c1ccncc1CCl
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(C(F)(F)F)c(CCl)c1
Reaction time: 29 h

Procedure:
3-Chloromethyl-4-trifluoromethylpyridine hydrochloride (204 mg, 0.88 mmol) from step 2 above was dissolved in CHCl3 (50 mL) and treated with saturated aqueous NaHCO3. The organic layer was removed, dried (Na2SO4), and concentrated to give the free pyridine. This 3-chloromethyl-4-(trifluoromethyl)pyridine was dissolved in CHCl3 (10 mL) and MCPBA was added (0.19 g of 80% MCPBA by weight; 0.88 mmol). After 29 h, the solution was extracted with saturated aqueous NaHCO3 (10 mL), dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography eluting with EtOAc. 3-Chloromethyl-4-trifluoromethylpyridine-N-oxide was obtained as a solid (TLC: Rf = 0.35 (EtOAc); FAB MS m/z 212 (M+ +H)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O:13]C)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O([Si](C)(C)C)[K:26]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O-:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2].[K+:26]
Reactant: COC(=O)C(CN(C(=O)OC(C)(C)C)C(C)C)c1ccc(Cl)cc1
Reactant: C[Si](C)(C)O[K]
Solvent: C1CCOC1
Product: CC(C)N(CC(C(=O)[O-])c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Product: [K+]
Reaction time: 8 h
Yield: 104.7 %

Procedure:
Methyl 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate (133 g, 374 mmol) was dissolved in THF (1.0 L) and treated with KOTMS (56.0 g, 392 mmol) at room temperature. The mixture was allowed to stir overnight to completion by LCMS analysis of the crude. The mixture was concentrated in vacuo to afford a wet foam, which was allowed to dry under vacuum overnight to afford potassium 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoate as a white solid (148.7 g, 105%). LC/MS (APCI+) m/z 242.1 [M−Boc−K]+.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19])[CH:14]=O.S(Cl)(Cl)=O>CC(O)C>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]2=[O:9])[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19]
Reactant: O=C1CC(=O)NC(=O)N1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)C(=O)N1
Reaction time: 100 h

Procedure:
To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde in 20 ml of 2-propanol was gradually added 5.0 ml of thionyl chloride. The mixture was stirred for 100 h at room tempererature. The product was filtered, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44%) , mp 269°-272° C.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O:5][CH3:6])=[O:4].[Cl:17][C:18]1[CH:19]=[CH:20][C:21](O)=[C:22]([C:24](=[O:27])[CH2:25][CH3:26])[CH:23]=1.[OH-].[K+].Cl>ClCCl.N1C=CC=CC=1.O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:13][C:12]([C:11]3[CH:15]=[CH:16][C:8]([CH2:7][P:3](=[O:4])([O:5][CH3:6])[O:2][CH3:1])=[CH:9][CH:10]=3)=[C:25]([CH3:26])[C:24](=[O:27])[C:22]=2[CH:23]=1
Reactant: CCC(=O)c1cc(Cl)ccc1O
Reactant: COP(=O)(Cc1ccc(C(=O)Cl)cc1)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COP(=O)(Cc1ccc(-c2oc3ccc(Cl)cc3c(=O)c2C)cc1)OC
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A 39.4 g quantity of 4-[(dimethoxyphosphoryl)methyl]benzoyl chloride was dissolved in 150 ml of dry dichloromethane. Then 150 ml of a pyridine solution containing 27.7 g of 5'-chloro-2'-hydroxypropiophenone was slowly added dropwise to the reaction mixture with stirring under ice-cooling, and the stirring was continued at room temperature for 10 hours. After addition of 150 ml of water, the reaction mixture was extracted with chloroform. The chloroform layer was washed serially with 300 ml of a 10% aqueous HCl solution and 200 ml of water and dried over Glauber's salt. The solvent was distilled off under reduced pressure, and the residue thus obtained was dissolved in 150 ml of pyridine. A 14.0 g quantity of potassium hydroxide was added to the solution with stirring at room temperature, and the mixture was heated at 50° C. with stirring for 2 hours. After addition of 300 ml of a 10% aqueous HCl solution, the reaction mixture was extracted with chloroform. The chloroform layer was washed with 100 ml of water and dried over Glauber's salt. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography (eluent: chloroform:ethyl acetate=1:1). The resulting crude crystals were recrystallized from dichloromethane-n-hexane to provide 3.9 g of the title compound as colorless crystals. Table 1 shows the structure and physical property of the compound obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:23]([CH3:37])[C:24]([NH:26][CH2:27][C:28]2[NH:32][N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:29]=2)=[O:25])[CH:15]=[CH:16][C:17]=1[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([CH:23]([CH3:37])[C:24]([NH:26][CH2:27][C:28]2[N:32]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:31]=[C:30]([C:33]([F:36])([F:34])[F:35])[CH:29]=2)=[O:25])[CH:15]=[CH:16][C:17]=1[CH2:18][S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CC(C(=O)NCc1cc(C(F)(F)F)n[nH]1)c1ccc(CS(C)(=O)=O)c(F)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1ccc(F)cc1)c1ccc(CS(C)(=O)=O)c(F)c1
Reaction time: 8 h
Yield: 74.6 %

Procedure:
4-Fluorophenylboronic acid (41 mg, 0.295 mmol), 2-(3-fluoro-4-(methylsulfonylmethyl)phenyl)-N-((3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)propanamide (60 mg, 0.147 mmol) and copper(II)-acetate (0.021 mL, 0.221 mmol) were added to DCM (2.2 mL). At room temperature was added pyridine (0.238 mL, 2.946 mmol) and the mixture was stirred for overnight. The reaction mixture was concentrated in vacuo, the solid obtained was purified by CC (eluent: cyclohexane/ethyl acetate (1:2)) to afford 2-[3-fluoro-4-(methylsulfonyl-methyl)-phenyl]-N-[[2-(4-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide (55 mg, 75%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)O[CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[C:27]#[N:28].[NH2:32][OH:33].[OH2:34]>CS(C)=O>[OH:33][N:32]=[C:27]([C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:34][CH2:11]3)[C:2]2=[O:1])[CH:25]=1)[NH2:28]
Reactant: O
Reactant: N#Cc1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Reactant: NO
Solvent: CS(C)=O
Product: NC(=NO)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (0.40 g, 0.98 mmol) in dimethyl sulfoxide (10 mL) was added hydroxylamine (50% w/w solution in water, 0.66 mL, 10.7 mmol). The reaction was stirred at 80° C. for 3 h and allowed to cool to ambient temperature. Water was added, causing a precipitate to be deposited. The solid was collected by filtration and washed with water to afford N′-hydroxy-3-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzenecarboximidamide (0.40 g, 93%): 1H NMR (300 MHz, CDCl3) δ 7.98 (br s, 1H), 7.64 (s, 2H), 7.43-7.38 (m, 4H), 7.15-7.11 (m, 2H), 7.01-6.96 (m, 1H), 6.79 (s, 1H), 6.67-6.64 (m, 1H), 6.49 (s, 1H), 5.33-5.28 (m, 1H), 4.96-4.58 (m, 3H), 4.19-4.16 (m, 4H); MS (ES+) m/z 444.0 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26](O)=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:32][C:33](=[O:43])[C@@H:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[C:15]([C:26]([NH:42][C@@H:34]([CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]([OH:32])=[O:43])=[O:27])[N:16]=[C:17]3[CH2:20][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)cc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Product: CC(C)(C)c1ccc(Oc2ccc3cc(C(=O)N[C@@H](Cc4ccccc4)C(=O)O)nc(CC4CCCC4)c3c2)cc1
Yield: 89.6 %

Procedure:
50 mg (0.12 mmol) of 7-(4-tert-butyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 419) was reacted with (2S)-amino-3-phenyl propionic acid methyl ester (24.4 mg, 0.13 mmol) as described in general procedure A. The resulting ester was hydrolyzed as described in general procedure C to afford 59.2 mg of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[C:8]([CH:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:12](OC)=[O:13])(=O)[CH3:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:6]=[C:5]2[N:7]=[C:8]([CH3:9])[C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:12]([OH:13])[N:4]2[N:3]=1
Reactant: COC(=O)CC(C(C)=O)C(=O)OC
Reactant: Nc1cc(Br)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: COC(=O)Cc1c(C)nc2cc(Br)nn2c1O
Yield: 54.2 %

Procedure:
To a solution of 3-bromo-1H-pyrazol-5-amine (0.2 g, 1.235 mmol) and dimethyl 2-acetylsuccinate (0.697 g, 3.70 mmol) in xylene (10 mL) was added p-toluenesulfonic acid monohydrate (2 mg, 10.51 mmol). The reaction mixture was heated at reflux under a Dean-Stark trap for 8 h. The solid was filtered and washed with hexanes to afford the title compound (0.201 g, 54.2%). 1H NMR (400 MHz, MeOD) δ ppm 2.37 (3H, s), 3.65 (2H, s), 3.71 (3H, s), 6.20 (1H, s).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]1[CH2:19][CH2:18][C@H:17]([OH:20])[C@H:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1O.C(O)(=O)/C=C/C(O)=O>C1C=CC=CC=1.CCOCC.C(O)C>[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[O:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][C@H:16]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Reactant: Oc1ccccc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)/C=C/C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: c1ccccc1
Product: CN1CC[C@@H](Oc2ccccc2F)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4.79 g of diethyl azodicarboxylate in 125 ml of benzene is added dropwise under a nitrogen atmosphere at 5°-10° C. over a 90 minute period to a mixture of 4.78 g of cis-1-methyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 3.08 g of 2-fluorophenol and 125 ml of dry benzene. After the addition, the mixture is stirred for 18 hours at room temperature, then filtered, and the solid waste is washed well with hexane. The filtrate is concentrated in vacuo to an oil which is stirred 18 hours with hexane. A gummy solid is filtered off, washed with hexane, and the filtrate concentrated in vacuo to an oil. This material is taken up in ether and extracted with 2 N HCl solution. The acid extracts are extracted with dichloromethane. The dichloromethane extracts are washed with 10% by weight of aqueous NaOH solution, then with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to afford and oil. The oil is chromatographed on silica gel, using acetone as solvent. A purified free base is obtained as an oil. This material is dissolved in 75 ml of ether and treated dropwise with a solution of 1.44 g of fumaric acid in a mixture of 25 ml of absolute ethanol and 50 ml of ether. Scratching of the resulting solution causes crystallization to occur. The solid is filtered, washed with ether, and dried to afford a colorless solid of trans-4-(2-fluorophenoxy)-1-methyl-3-phenylpiperidine furmarate hemihydrate, m.p. partially melts 149°, 161°-167° C. Recrystallization from ethyl acetate affords the product having mp s 154, 156° C., dec.