Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[N:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27](OC)[O:28]C)[CH:19]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:38])[N:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([CH:27]=[O:28])[CH:19]=2)[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)c1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(Oc2cccc(N(C(=O)OCc3ccccc3)C3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 42 h

Procedure:
Cyclohexyl-[3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenyl]-carbamic acid benzyl ester (0.0027 mol) was dissolved in THF (12 mL). Water (6 mL) and 12N HCl (3 mL) were added and the reaction mixture was stirred for 42 hours at room temperature. Water was added. This mixture was extracted with diisopropyl ether. The organic layer was separated, washed with a 10% aqueous NaHCO3 solution and then with water, dried (MgSO4) and filtered. The solvent was then evaporated to yield a residue that was used in the next reaction step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].IC.Cl[CH2:15]Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:15])=[CH:4][C:3]=1[F:9]
Reactant: ClCCl
Reactant: Fc1cc(S)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1ccc(Br)c(F)c1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 4-bromo-3-fluoro-benzenethiol (225 mg, 1.09 mmol) in tetrahydrofuran (3 ml) was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 52 mg, 1.31 mmol) was added and the mixture was stirred for 5 minutes. Iodomethane (78 μl, 1.25 mmol) was then added and the mixture was allowed to return to room temperature with stirring over 20 minutes. Dichloromethane (10 ml) was added and the reaction was quenched with 1 M aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water, dried (MgSO4), then concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, pentane:diethyl ether, gradient 100:0 to 90:10) to afford the title compound as a bright yellow oil (208 mg, 86%). 1H NMR (CDCl3, 400 MHz) 7.43 (1H, dd, J=8.4, 7.2), 7.00 (1H, dd, J=9.4, 2.3), 6.91 (1H, ddd, J=8.4, 2.1, 0.7), 2.48 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([S:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:11]([CH:22]([CH3:24])[CH3:23])[N:10]=[C:9]1[CH2:25]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:34]1C(SC2C=C(Cl)C=C(Cl)C=2)=C(C(C)C)N=C1CO)C1C=CC=CC=1>>[NH2:34][CH2:25][C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([S:13][C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)=[C:11]([CH:22]([CH3:23])[CH3:24])[N:10]=1
Reactant: CC(C)c1nc(CCl)n(Cc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1nc(CO)n(Cc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1
Product: CC(C)c1nc(CN)n(Cc2ccccc2)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
1-Benzyl-2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazole (28e)was synthesized from [1-benzyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-imidazol-2-yl]methanol by the same synthetic process as that for (28a)in Example 66, and without purification of this compound, 2-azidomethyl-1-benzyl-5-(3,5-dichlorophenylthio)-4-isopropylimidazole (29e)was obtained by the same synthetic process as that for (29a)in Example 66. Oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[OH:9]O.C=O>C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][N+:6]([O-:9])=[CH:5][CH:4]=1)[CH3:2]
Reactant: OO
Reactant: CCc1ccncc1
Agent: C=O
Solvent: CC(=O)O
Product: CCc1cc[n+]([O-])cc1
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of 4-ethylpyridine (10.7 g, 0.10 mol) in 35 ml of acetic acid heated at 95-100° C. is treated dropwise over a 18 min period with 30% hydrogen peroxide (28 ml). After 4 h, the excess hydrogen peroxide is decomposed by the portionwise addition of paraformaldehyde (10.0 g) at the previously maintained temperature until a negative starch iodide test is obtained. The reaction mixture is cooled and concentrated at reduced pressure. The residue is chromatographed with 325 g of silica gel packed and eluted initially with acetone-chloroform-methanol (3:6.7:0.3) and thereafter with an increasing methanol gradient to obtain 10.55 g (83%) of 4-Ethylpyridine-1-oxide.
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:16]([C:18]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:28]([OH:30])=O)[CH2:12]1)(=[O:10])=[O:9].[NH2:31][C@@H:32]([CH2:41][CH2:42][CH3:43])[C@H:33]([OH:40])[C:34]([NH:36][CH:37]1[CH2:39][CH2:38]1)=[O:35]>>[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:16]([C:18]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:28]([NH:31][C@@H:32]([CH2:41][CH2:42][CH3:43])[C:33](=[O:40])[C:34]([NH:36][CH:37]2[CH2:39][CH2:38]2)=[O:35])=[O:30])[CH2:12]1)(=[O:9])=[O:10]
Reactant: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(I)cc2)CC1
Reactant: CCC[C@H](N)[C@H](O)C(=O)NC1CC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=O)C1(c2ccc(I)cc2)CC1)C(=O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to Example 1, using (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[1-(4-iodo-phenyl)-cyclopropanecarbonyl]-pyrrolidine-2-carboxylic acid and (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide in step 1. MS (m/e)=726.09 [M+H+].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:21]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>C1COCC1>[C:40]([N:11]([CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[N:21]=1)(=[O:42])[CH3:41]
Reactant: c1cn(-c2nccc(N3CCCCC3CCNCc3ccc4c(c3)OCO4)n2)cn1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(CCC1CCCCN1c1ccnc(-n2ccnc2)n1)Cc1ccc2c(c1)OCO2
Reaction time: 16 h
Yield: 59.5 %

Procedure:
To THF (3 mL) was added N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (8 mg, 0.03 mmol), Hünig's base (8 mg, 0.06 mmol), and acetic anhydride (4 mg, 0.04 mmol). After stirring for 16 hours, the solvent was removed in vacuo and the residue was chromatographed (CH2Cl2/MeOH. 19/1) to give 8 mg (60%) of N-acetyl-N-[(1,3-benzodioxol-5-yl)methyl]-1-[2-(1H-imidazol-1-yl)pyrimidin-4-yl]piperidine-2-ethanamine (the compound of formula (Igg)): 1H NMR (CDCl3) δ 8.48 (s, 1), 8.08 (d, 1), 7.76 (s, 1), 7.09 (s, 1), 6.66 (m, 3), 6.33 (m, 1), 5.94 (s, 1), 5.91 (s, 1), 4.43 (m,3), 3.40 (m, 2), 2.11 (d, 3), 1.14 (m); MS: 450.0 (M+H)+.
Reaction SMILES: [CH:1]1([S:7]([CH2:10][CH2:11]O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH:10]([S:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:8])=[O:9])=[CH2:11]
Reactant: O=S(=O)(CCO)C1CCCCC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-cyclohexylsulfonylethanol (22 g) and triethylamine (30 ml) in methylene chloride (200 ml) was treated dropwise with a solution of methanesulfonyl chloride (15 ml) in methylene chloride (100 ml) at 10° C. After stirring for 2 h at room temperature the mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo leaving the product, cyclohexyl vinyl sulfone, as an oil (19 g).
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][C:7](=[CH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[C:6]1=[O:26])=[O:4].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][C:7](=[CH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[C:6]1=[O:26])=[O:4])(=[O:29])[CH3:28]
Reactant: CC(C)(C)c1cc(C=C2CCN(C(=O)NO)C2=O)cc(C(C)(C)C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)ONC(=O)N1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 0.1 %

Procedure:
N-(N-Hydroxycarbamoyl)-3-(3,5-di-tert-butyl-4-hydroxybenzylidene)pyrrolidin-2-one (Ia-4)(2 g, 5.55 mmole), acetic anhydride (680 mg, 6.66 mmole), and pyridine (10 ml) were reacted according to the same method as in Example 22, whereby 1.35 mg of the objective compound (Ia-17) was obtained in 60.5% yield.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>>[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3-trifluoromethyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.88-0.99 (m, 6H), 1.53-1.63 (m, 1H), 1.78 (ddd, J=13.82, 7.09, 6.97 Hz, 1H), 2.0-2.15 (m, 1H), 3.83 (t, J=7.70 Hz, 1H), 7.56-7.61 (m, 3H) 7.63-7.74 (m, 6H) 7.74-7.86 (m, 2H); Calcd for C26H22F6O2 (M+H) 481.44, Found 481.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1.OCC1NN=C(C2C=CC(C3N=C4N(CCC5CCOCC5)C(=O)NC4=NC=3)=CC=2)[N:35]=1>S(Cl)(Cl)=O>[NH2:35][CH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]4[N:20]([CH2:24][CH2:25][CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:21](=[O:23])[NH:22][C:17]4=[N:16][CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1
Reactant: O=c1[nH]c2ncc(-c3ccc(-c4n[nH]c(CCl)n4)cc3)nc2n1CCC1CCOCC1
Reactant: O=c1[nH]c2ncc(-c3ccc(-c4n[nH]c(CO)n4)cc3)nc2n1CCC1CCOCC1
Solvent: O=S(Cl)Cl
Product: NCc1nc(-c2ccc(-c3cnc4[nH]c(=O)n(CCC5CCOCC5)c4n3)cc2)n[nH]1
Yield: 81 %

Procedure:
6-(4-(5-(Chloromethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one. 6-(4-(5-(Hydroxymethyl)-1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo[4,5-b]pyrazin-2(3H)-one (0.130 g, 0.31 mmol) in thionyl chloride (2 mL) was stirred in a sealed tube at 80° C. for 1 h. The cooled reaction solvent was removed under reduced pressure. The resulting material was dried under vacuum at 50° C. to give the desired product (0.110 g, 81%) as a white solid. MS (ESI) m/z 440.0[M+1]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][CH:4]([C:15]([OH:17])=[O:16])[CH2:3]1>ClCCl>[O:1]=[C:2]1[N:6]([C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:8])[CH2:5][CH:4]([C:15]([O:17][C:4]([CH3:15])([CH3:5])[CH3:3])=[O:16])[CH2:3]1
Reactant: C[C@H](c1ccccc1)N1CC(C(=O)O)CC1=O
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1CC(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Yield: 64 %

Procedure:
To a suspension of 5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid produced by the method described in Culbertson T. P., Domagala J. M., Nichols J. F., Priebe S., and Skeean R. W., J. Med. Chem., 1987, 30, 1711-1715 (1165 g, 4.994 mol) in dichloromethane (10 L), O-tertiary butyl-N,N′-diisopropylurea (3020 g, 15.00 mol) was added at room temperature with stirring. When increase in the inner temperature and starting of refluxing were noted, the reaction system was cooled in an ice bath. After cooling the reaction mixture to room temperature, the mixture was stirred for 1 hour after removing the ice bath, and for another 3 hours while heating to 40° C. After starring the reaction mixture for another 1 hour with cooling in an ice bath, the insoluble content was removed, and the filtrate was dried under reduced pressure. The residue was purified by silica gel column chromatography (silica gel:4 kg; elusion by hexane:ethyl acetate, 3:1) to obtain 925.2 g (64%) of the title compound (a mixture of isomers at position 3) as a pale yellow syrup. Although separation of the diastereomers of position 3 of the pyrrolidine was easy, the diastereomers were used without separation since the subsequent step involved epimerization. 1H-NMR spectrum of the isomers aliquoted for evaluation purpose are shown below.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH:11]([CH2:20][CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([CH:11]1[C:12]2[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[NH:8][CH2:9][CH2:10]1)[CH3:21]
Reactant: CCC1CCN(C(=O)OC(C)(C)C)c2cc(OC)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC1CCNc2cc(OC)ccc21
Yield: 93.8 %

Procedure:
In a oven dried 250 mL r.b. flask equivuipped with a magnetic stir bar and a N2 gas inlet was dissolved (R/S)-1-t-butoxycarbonyl-4-ethyl-1,2,3,4-tetrahydro-7-methoxyquinoline (34.0 mg, 117 μmol) in dry CH2Cl2 (1 mL). To the stirred solution was added TFA (1.2 mL) at rt and was allowed to react for 2 h. The dark red solution was quenched with sat NaHCO3 solution (10 mL), extracted with CH2Cl2 (3×25 mL), washed with brine (50 mL), dried (Na2SO4) and concentrated in vacuo to afford 21 mg (95%) of the desired amine as a clear light yellow oil. Data for (R/S)-4-ethyl-1,2,3,4-tetrahydro-7-methoxyquinoline: Rf =0.1 (hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 6.92 (d, J=8.5, 1 H), 6.21 (dd, J=2.5, 8.2, 1 H), 6.03 (d, J=2.5, 1 H), 3.73 (s, 3 H), 3.27 (m, 2 H), 2.59 (m, 1 H), 1.86 (m, 1 H), 1.75 (m, 2 H), 1.48 (m, 1 H), 0.968 (t, J=7.4, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]([CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]1([C:10]2[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:28][C:29]4[CH:34]=[N:33][C:32]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:31][CH:30]=4)=[CH:26][CH:25]=3)[CH:11]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Reactant: ClCc1ccc(-c2ccccc2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CCc1cn(Cc2ccc(OCc3ccc(-c4ccccc4)nc3)cc2)cc1-c1ccccc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (600 mg), 5-chloromethyl-2-phenylpyridine (370 mg), potassium carbonate (450 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[4-phenyl-1-[4-(6-phenyl-3-pyridylmethoxy)benzyl]-3-pyrrolyl]propionic acid (820 mg, yield: 98%). This was recrystallized from acetone-hexane. Melting point: 185–186° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nccc2cnccc12
Product: Clc1nccc2cnccc12

Procedure:
1-Hydroxy-2,6-naphthyridine (550 mg) [prepared according to the method of Sakamoto, T. et al Chem. Pharm. Bull. 33, 626, (1985)] was stirred with phosphorous oxychloride (10 ml) at 110° for 5 h. The volatiles were removed in vacuo and the residue treated carefully with ice. After diluting with water (to ˜25 ml), solid NaHCO3 was added to effect neutralisation and the product extracted into EtOAc (2×80 ml). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the crude product chromatographed (SiO2; EtOAc) affording the title compound as a slightly yellow solid (420 mg, 68%). δH (CDCl3) 9.35 (1H, s), 8.82 (1H, d, J 5.9 Hz), 8.48 (1H, d, J 5.6 Hz), 8.00 (1H, d, J 5.9 Hz), 7.74 (1H, d, J 5.6 Hz); m/z (ES+, 70V) 165 and 167 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22](F)=[O:23])[CH:19]=[C:18]([Cl:25])[CH:17]=4)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27](=[CH2:30])[CH2:28][CH3:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(=[O:35])=[O:34].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([C:22]([N:39]5[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]5)=[O:23])[CH:19]=[C:18]([Cl:25])[CH:17]=4)[CH2:14][C:13](=[O:26])[NH:12][CH:11]3[C:27](=[CH2:30])[CH2:28][CH3:29])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)F)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(CC)C1NC(=O)CC(c2cc(Cl)cc(C(=O)N3CCN(S(C)(=O)=O)CC3)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 0.9 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chloro-5-fluorocarbonyl-phenyl)-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.16 g, 36 mmol) prepared in example 94a was reacted with N-methylsulfonylpiperazine (59 mg, 36 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (1 mg, 0.008 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-[3-chloro-5-(4-methanesulfonyl-piperazine-1-carbonyl)-phenyl]-2′-(1-methylene-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.2 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[C:16]([S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:25][CH3:26])(=[O:11])=[O:10].[Cl:27][C:28]1[CH:41]=[CH:40][C:31]2[S:32][C:33]([S:36](Cl)(=[O:38])=[O:37])=[C:34]([CH3:35])[C:30]=2[CH:29]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:26][O:25][C:13]1[CH:14]=[CH:15][C:16]([S:18]([C:21]([F:24])([F:22])[F:23])(=[O:20])=[O:19])=[CH:17][C:12]=1[S:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:36]([C:33]1[S:32][C:31]2[CH:40]=[CH:41][C:28]([Cl:27])=[CH:29][C:30]=2[C:34]=1[CH3:35])(=[O:38])=[O:37])(=[O:10])=[O:11]
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1sc2ccc(Cl)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of of N-(2-aminophenyl)-2-methoxy-5-trifluoromethanesulfonylbenzenesulfonamide (0.5 mmol, prepared as in Example A) in DCM (1 mL) and pyridine (1 mL), 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (0.55 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 202 mg of 5-chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-trifluoromethanesulfonyl-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.32 min, MS: 655.4 (M+1)+. 1H NMR (CDCl3, 400 MHz): δ 2.14 (s, 3H), 4.29 (s, 3H), 6.33 (bs, 1H), 6.54 (d, 1H), 6.98 (t, 1H), 7.24 (t, 1H), 7.35 (d, 1H), 7.45 (dd, 1H), 7.49 (dd, 1H), 7.70 (d, 1H), 7.75 (d, 1H), 8.14 (bs, 1H), 8.17 (dd, 1H), 8.31(d, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=3[CH:12]=2)[C:6]([N+:22]([O-])=O)=[CH:5][CH:4]=1>C(O)(=O)C.CCOC(C)=O.[Zn]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[S:17][C:13]=3[CH:12]=2)[C:6]([NH2:22])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCc2ccc3nc(SC)sc3c2)n1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(NCc2ccc3nc(SC)sc3c2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a mixture of 6-methoxy-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-3-nitropyridin-2-amine (431 mg, 1.19 mmol) from Step 5 of this Example in acetic acid (6 mL) was added zinc powder (235 mg, 3.57 mmol) slowly at 0° C. The reaction mixture was stirred at 0° C. for 20 min and then stirred at rt for 4 h. The resulting reaction mixture was diluted with 30 mL of EtOAc and filtered through a Celite pad. The filtrate was neutralized with saturated aq NaHCO3. The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of EtOAc-CH2Cl2 (1:3, v/v) as eluent to give 6-methoxy-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)pyridine-2,3-diamine as a brown oil (389 mg, 98%). LCMS (ESI) m/z 333 (M+H)+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
A mixture of 52.5 mmol 2-chlorobenzoxazol, 53.6 mmol piperazine-1-carboxylic acid tert-butyl ester and 63 mmol of potassium carbonate in 60 ml of acetonitrile was refluxed for 16 hours. The reaction mixture was conentrated, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated to yield the title compounds as a slightly orange solid. MS (m/e): 304.2 (M+H+)