Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:22][C@@H:23]([CH2:36][NH2:37])[CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1>>[OH:22][C@H:23]([CH2:24][O:25][C:26]1[C:34]2[NH:33][C:32](=[O:35])[NH:31][C:30]=2[CH:29]=[CH:28][CH:27]=1)[CH2:36][NH:37][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 73 as a pale yellowish solid; mp 173-175° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.45-1.60 (m, 2H), 1.90-2.15 (m, 2H), 2.10-2.95 (m, 5H), 3.03 (brd, J=10.5 Hz, 1H), 3.26 (dd, J=14.1, 3.8 Hz, 1H), 3.68 (brd, J=12.4 Hz, 2H), 3.95-4.05 (m, 3H), 4.51 (dd, J=10.0, 4.0 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.75-6.95 (m, 3H), 7.05 (d, J=8.7 Hz, 2H), 11.60 (s, 1H), 11.85 (brs, 1H); MS (ES) m/z: 512.0 (MH+); HRMS Calcd. for C25H30N5O5S (MH+): 512.1968. Found: 512.1982.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[CH:15]=3)[N:10](C(=O)C(F)(F)F)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[OH:30].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[OH2:45]>C(Cl)Cl>[CH:18]1([S:17]([C:14]2[CH:15]=[C:16]3[C:6]4([CH2:7][CH2:8][N:4]([C:1](=[O:3])[CH3:2])[CH2:5]4)[CH2:9][NH:10][C:11]3=[CH:12][CH:13]=2)(=[O:30])=[O:45])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O
Reactant: O=C([O-])O
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(SC3CCCC3)cc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N1CCC2(CNc3ccc(S(=O)(=O)C4CCCC4)cc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
1-(1′-Acetyl-5-(cyclopentylthio)spiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (13 mg, 0.032 mmol) was dissolved in methylene chloride (1 mL). Thereafter, sodium hydrogen carbonate (8 mg, 0.096 mmol) was added to the above obtained solution, and then, under cooling on ice, m-chloroperbenzoic acid (11 mg, 0.064 mmol) was further added thereto. The thus obtained mixture was stirred at room temperature for 1 hour. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and brine, and was then dried over anhydrous magnesium sulfate, followed by concentration in vacuo. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1). The obtained colorless oily product was dissolved in methanol (1 mL). A saturated solution of ammonium-methanol (0.5 mL) was added to the above obtained solution, and the thus obtained mixture was then stirred at room temperature for 15 minutes. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain 1-(5-(cyclopentylsulfonyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)ethanone (2 mg, 17%) in the form of a colorless oily product.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:19][NH:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C([O-])(O)=O.[Na+]>[CH3:19][N:20]([CH3:21])[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)C1CCc2cc(NC(=O)OC(C)(C)C)ccc21
Yield: 54.3 %

Procedure:
To a solution of tert-butyl (1-oxo-2,3-dihydro-1H-inden-5-yl)carbamate (371 mg, 1.5 mmol) in dimethylamine (2.0 M solution in THF, 5 mL, 10 mmol) was added sodium triacetoxyborohydride (636 mg, 3.0 mmol). The resultant suspension was stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (225 mg, 54%) as an off-white solid. ESI MS m/z 277 [C16H24N2O2+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:10](=[O:32])[NH:11][C:12]3[C:17]([C:18]=2[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[O:26]C)=[CH:16][C:15]([C:28]([F:31])([F:30])[F:29])=[CH:14][CH:13]=3)=[CH:4][CH:3]=1.N[C:34]1C=CC(SC2C(=O)NC3C(C=2C2C=C(Cl)C=CC=2O)=CC(C(F)(F)F)=CC=3)=C[CH:35]=1.[S:64](Cl)(Cl)(=[O:66])=[O:65]>N1C=CC=CC=1.C(Cl)Cl>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([OH:26])=[C:19]([C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:28]([F:30])([F:31])[F:29])[CH:16]=3)[NH:11][C:10](=[O:32])[C:9]=2[S:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:64]([CH2:34][CH3:35])(=[O:66])=[O:65])=[CH:7][CH:6]=2)[CH:24]=1
Reactant: Nc1ccc(Sc2c(-c3cc(Cl)ccc3O)c3cc(C(F)(F)F)ccc3[nH]c2=O)cc1
Reactant: COc1ccc(Cl)cc1-c1c(Sc2ccc(N)cc2)c(=O)[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(Sc2c(-c3cc(Cl)ccc3O)c3cc(C(F)(F)F)ccc3[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(4-Amino-phenylsulfanyl)-4-(5-chloro-2-methoxy-phenyl)-6-trifluoromethyl-1H-quinolin-2-one or 3-(4-Amino-phenylsulfanyl)-4-(5-chloro-2-hydroxy-phenyl)-6-trifluoromethyl-1H-quinolin-2-one (49.0 mg, 103 μmol, 1 eq) in pyridine (50 μL) and methylene chloride (500 μL) was added the appropriate sulfonyl chloride (422 μmol, 4.1 eq), and the mixture stirred overnight at room temperature, or at 80° C. in the absense of methylene chloride for difficult cases. The pyridine was removed in vacuo, and 4 N NaOH was added. The suspension was diluted with water, washed with chloroform, and adjusted to pH 5 with 1 M HCl. The product was extracted into a mixture of EtOAc and methylene chloride, dried with Magnesium sulfate, and concentrated in vacuo. Final purification was effected by reverse phase HPLC to afford pure Ib. 1H NMR (300 MHz, CDCl3) δ 11.04 (s, 1H), 8.90 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.43 (s, 1H), 7.40–7.30 (m, 2H), 7.30–7.24 (m, 3H), 7.11 (d, J=2.5 Hz, 1H), 6.98 (d, J=8.7 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 2.99 (q, J=7.4 Hz, 2H), 1.21 (t, J=7.4 Hz, 3H); LCMS (M+H) 555, RT=3.177 (Method 1).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:9]=[CH:8]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][Cl:34]>CN(C=O)C.O.CCOCC>[Cl:34][CH2:33][CH2:32][CH2:31][O:14][C:13]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:6][C:5]=1[O:4][C:3]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:2]=1[F:1]
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(O)cc21
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(OCCCCl)cc21
Temperature: 80 °C

Procedure:
To a solution of 5-(2,4-difluorophenoxy)-1-isobutyl-1H-indazol-6-ol (0.015 g, 0.05 mmol) in DMF (1 mL) was added Cs2CO3. The reaction mixture was stirred for 30 minutes before the addition of 1-bromo-3-chloropropane (0.01 g, 0.08 mmol) and then was heated to 80° C. for 25 hours. After cooling the mixture to room temperature, the reaction mixture was diluted with water and ether and the layers separated. The aqueous layer was extracted with ether and the combined organic layers were washed with 1N NaOH, water, and brine. The crude mixture was dried over Na2SO4 and concentrated under reduced pressure to afford the product with a small impurity. The crude mixture was used in the next reaction without further purification.
Reaction SMILES: [O:1]([CH:8]([CH3:12])[C:9](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O1CCOCC1>[O:1]([CH:8]([C:9]1[S:16][C:15]([NH2:17])=[N:14][N:13]=1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: CC(Oc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(Oc1ccccc1)c1nnc(N)s1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
A 1,000 milliliter, 3-neck flask equipped with a Claisen adaptor, paddle stirrer, thermometer, addition funnel and condenser, was charged with 100 grams (0.602 moles) of 2-phenoxypropanoic acid, (54.8 grams, 0.602 mole) of thiosemicarbazide and 300 ml. of dioxane. The slurry was heated to 85° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 was slowly added (for 70 minutes) while maintaining the temperature within 90°-95° C., and then stirred for an additional 20 minutes. It was refluxed for 105 minutes and cooled. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), leaving a viscous residue to which 400 ml of water was added and the residue emulsified. A 50 percent solution of NaOH was added until the pH of the solution was 10, and a solid precipitate formed. The solid precipitate was filtered off, washed with water, air dried, then dried in a vacuum oven at 60° C. to a granular grey solid which was recrystallized from H2O/ethanol mixture, filtered and then dried in a vacuum oven at 60° C. to white needles of 5-(1-phenoxyethyl)-2-amino- 1,3,4-thiadiazole. (Melting point 157°-167° C.).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]3[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[OH:30].[Na+].[CH2:34]([O:36][C:37]([CH2:39][N:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[C:41]1[C:49](Cl)=[O:50])=[O:38])[CH3:35]>C(Cl)(Cl)Cl>[Br:1][C:2]1[N:6]([C:7]2[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:8]=2[C:9](=[O:30])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]([CH2:11][NH:10][C:49]([C:41]2[N:40]([CH2:39][C:37]([O:36][CH2:34][CH3:35])=[O:38])[C:48]3[C:43]([CH:42]=2)=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:50])=[N:4][N:3]=1
Reactant: O=C([O-])O
Reactant: CCc1cc2c(s1)-n1c(Br)nnc1CN=C2c1ccccc1Cl
Reactant: CCOC(=O)Cn1c(C(=O)Cl)cc2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc(Br)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
9-Bromo-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine is added to 2M sulfuric acid, and the mixture is stirred at 80° C. overnight. Sodium hydrogencarbonate is added to the reaction mixture to make the mixture alkaline. Chloroform and 1-ethoxycarbonylmethylindole-2-carbonyl chloride are added, and the mixture is stirred at room temperature for 2 hours to give ethyl 2-(3-bromo-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-5-ylmethylcarbamoyl)indole-1-acetate.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1>CN(C)C=O>[CH3:23][N:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[C:18]1[CH2:17][N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: c1ccc(Nc2ccccn2)nc1
Reactant: Cn1c(CCl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CN(c2ccccn2)c2ccccn2)nc2ccccc21

Procedure:
To a flask were added 1.1 g of 2,2′-dipyridylamine and 25 ml of N,N-dimethylformamide. To this mixture were added 0.32 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 10 C for ten minutes, 1.2 g of 2-(chloromethyl)-1-methyl-1H-benzimidazole in 5 ml of N,N-dimethylformamide were added. The reaction mixture was stirred at 22 C for several hours, and then quenched with 40 ml water. The product was extracted with 50 ml ethyl acetate, and then extracted with 30 ml of 1M hydrochloric acid, and basified with 3M sodium hydroxide. Following extraction with 20 ml ethyl acetate, the product was purified by silica gel chromatography using 33% ethyl acetate, 62% hexane, and 5% methanol, resulting in an oil which crystallized on standing. After drying, 0.6 g of a yellow solid remained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])[C:34](=[O:54])[CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][NH:42][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][C:51](O)=[O:52])=[O:44].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:51](=[O:52])[CH2:50][O:49][CH2:48][CH2:47][O:46][CH2:45][C:43](=[O:44])[NH:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][C:34](=[O:54])[CH:33]([OH:32])[CH:55]([OH:62])[CH:56]([OH:61])[CH:57]([OH:60])[CH2:58][OH:59])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(O)COCCOCC(=O)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCC(=O)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)NCCOCCOCC(=O)C(O)C(O)C(O)C(O)CO

Procedure:
30 is prepared similarly to 18 starting from 68 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one 76 mg of [2-({2-[2-(3,4,5,6,7-pentahydroxy-2-oxoheptyloxy)ethoxy]ethylcarbamoyl}methoxy)ethoxy]acetic acid (27, 62 μl of diisopropylcarbodiimide and 44 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 30: C43H55F2N3O14 (875.93) MS (ESI) 876 (M+H)
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][N:8]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:34]=[CH:33][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([CH:31]=O)=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[C:19]([C:35]([F:38])([F:37])[F:36])[CH:18]=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][N:8]1[C:12](=[O:13])/[C:11](=[CH:31]/[C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:22]([CH2:21][C:20]2[CH:33]=[CH:34][C:17]([Cl:16])=[CH:18][C:19]=2[C:35]([F:38])([F:36])[F:37])[N:23]=[CH:24]3)/[S:10][C:9]1=[O:14])([CH3:4])([CH3:2])[CH3:3].[NH2:7][N:8]1[C:12](=[O:13])/[C:11](=[CH:31]/[C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:22]([CH2:21][C:20]2[CH:33]=[CH:34][C:17]([Cl:16])=[CH:18][C:19]=2[C:35]([F:38])([F:36])[F:37])[N:23]=[CH:24]3)/[S:10][C:9]1=[O:14]
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NN1C(=O)CSC1=O
Product: CC(C)(C)OC(=O)NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: NN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}carbamic acid tert-butyl ester was prepared from (2,4-dioxothiazolidin-3-yl)carbamic acid tert-butyl ester and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F1. The Boc group was removed by TFA/DCM following General Procedure M to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH2:19])[CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.[C:20](O)(=[O:23])[CH2:21][CH3:22].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:11]([O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: CCC(=O)O
Reactant: COc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(=O)N[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2OC)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 116 %

Procedure:
Under nitrogen, the cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.383 mmol) obtained in Example 583 was suspended in N,N-dimethylformamide (2 ml), and propionic acid (31 μl, 0.421 mmol) and triethylamine (107 μl, 0.765 mmol) were added thereto, followed by adding thereto 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide mono-hydrochloride (81 mg, 0.421 mmol) and 1-hydroxybenzotriazole (57 mg, 0.421 mmol). The resulting mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate (three times). The combined ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/0, 100/2) to obtain N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]propanamide (141 mg, yield 116%) as light-yellow tar.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>[Ni].ClCCl.CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCS(=O)CC2)cc1
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(CN2CCS(=O)CC2)cc1

Procedure:
1.2 g of Raney nickel are added to a solution of 3.9 g (15 mmol) of 4-(4-nitrophenylmethyl)-thiomorpholine-1-oxide in 10 ml of dichloromethane and 40 ml of methanol. The mixture is hydrogenated under a hydrogen atmosphere. The product is obtained by chromatography on silica gel (dichloromethane/methanol=9:1).
Reaction SMILES: Cl.C(O)C.[Br:5][C:6]1[C:7]([Cl:17])=[C:8]([N+:14]([O-])=O)[CH:9]=[C:10]([F:13])[C:11]=1[Cl:12]>O.[Fe]>[Br:5][C:6]1[C:7]([Cl:17])=[C:8]([CH:9]=[C:10]([F:13])[C:11]=1[Cl:12])[NH2:14]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c(Br)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(Cl)c(Br)c1Cl
Yield: 72.2 %

Procedure:
To a suspension of iron powder (135.4 g) in water (140 ml), with vigorous stirring at 50°-60° C., was slowly added concentrated hydrochloric acid (18 ml). After ethanol (350 ml) was mixed, 3-bromo-2,4-dichloro-5-fluoronitrobenzene (218.8 g) was added portionwise to the suspension at 52°-76° C. during an hour. After stirring for 75 minutes at the same temperature, the hot reaction mixture was filtered after adding benzene (500 ml) and the insoluble material was successively washed with hot ethanol (100 ml) and benzene (200 ml). The filtrate and washings were combined. The organic layers were washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was recrystallized from ethanol-water to give the title compound (141.6 g) as light brown needles, mp 126°-129.5° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH2:45][CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH2:45][CH3:46])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(CC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(CC)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C. for 30 min, 4′-[(4-butyl-2-ethyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.0 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.54 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.68 g, 60%) as a solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:16][S:17][CH3:18])([OH:15])[CH:11]([C:19]2([CH3:27])[O:26][CH:20]2[CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH:10]1[O:28][CH3:29])=[O:7])=[O:4].[CH3:30][I:31]>C(#N)C>[I-:31].[Cl:1][CH2:2][C:3]([NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:16][S+:17]([CH3:30])[CH3:18])([OH:15])[CH:11]([C:19]2([CH3:27])[O:26][CH:20]2[CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[CH:10]1[O:28][CH3:29])=[O:7])=[O:4]
Reactant: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reactant: CI
Solvent: CC#N
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(C[S+](C)C)C1C1(C)OC1CC=C(C)C
Product: [I-]
Reaction time: 8 h
Yield: 100 %

Procedure:
In acetonitrile (2 ml) was dissolved 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (500 mg). To the solution was added methyl iodide (0.82 ml), and the mixture was stirred for 8 hours. The solvent was distilled off under reduced pressure. The residue was pulverized by the addition of ether to afford 4-O-(N-chloroacetylcarbamoyl)- 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-dimethylsulfoniomethyl-1,4-cyclohexanediol iodide (701 mg: yield 100%) as pale yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:35][C:34]2[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Reactant: Fc1cccc(CBr)c1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(Cc2cccc(F)c2)c1=O

Procedure:
This compound was prepared from 6-fluoro-6-chloro-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (82) and 3-fluorobenzyl bromide according to General Procedure B. Yield 207 mg (37%), MP 186° C.; 1H-NMR (DMSO-d6): δ 1.28 (t, J=7.2 Hz, 3H), 3.16 (m, 4H), 3.92 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.24 (s, 2H), 7.07 (m, 3H), 7.15 (dd, J=3.6, 5.2 Hz, 1H), 7.30 (m, 1H), 7.47 (dd, J=1.2, 3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.29 (d, J=2.8 Hz, 1H), 8.73 (d, J=2.8 Hz, 1H); EIMS: 555 (M+1). Anal. (C27H24ClFN4O4S) C, H, N.