Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH2:18][OH:19])[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[H][H].Cl>O.CO.[Pd]>[NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH:4]1[CH2:18][OH:19])[NH:11][C:10](=[O:16])[CH2:9][CH2:8]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2CO
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1cc2c(c3c1NC(=O)CC3)OC(CN)C2CO
Yield: 77.3 %

Procedure:
(2RS,3SR)-2-Aminomethyl-3-hydroxymethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (550.0 mg, 2.12 mmol) was dissolved in water (50 ml). To the solution, 10% palladium-on-carbon (500 mg) was added, followed by stirring at 80° C. for 2 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure, and the residue was dissolved in methanol. HCl--methanol solution was added thereto to convert the mixture to a hydrochloric acid salt. The salt was condensed, and recrystallized from methanol--ether. As a result, 430.1 mg of the title compound was obtained as colorless powdery crystals (78.2%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[OH-:10].[Na+:11]>O>[OH2:3].[OH2:10].[C:1]([O-:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[Na+:11]
Reactant: O=C(O)C[C@H](O)C(=O)O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C[C@H](O)C(=O)[O-]
Temperature: 10 °C
Reaction time: 4 h
Yield: 120.8 %

Procedure:
26.8 g (0.20 mole) of L-malic acid and 8.0 g (0.20 mole) of sodium hydroxide are dissolved in 200 ml of water. The solution (pH 4.1) is concentrated under reduced pressure to make the total weight thereof 60 g. The concentrated solution is cooled to 10° C., and the mixture obtained (i.e., the mixture of the concentrated solution and crystals precipitated) is stirred at the same temperature for 4 hours. After stirring, the mixture had a pH of 4.1. The crystalline precipitates are collected by filtration, washed with an aqueous 80% methanol solution, and dried at 35° C. in air for 16 hours. 23.2 g of monosodium L-malate dihydrate are obtained as crystals. The amounts of L-malic acid, sodium and water contained in the product are shown in Table 5. The results set forth in this table indicate that the product obtained is the pure crystals of monosodium L-malate dihydrate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.BrC[CH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][O:16]2)=[C:4]([Cl:11])[N:3]=1
Reactant: BrCCC1CCOCO1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(CC3CCOCO3)c2n1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
Equimolar amounts of 2-amino-6-chloropurine, 4-bromoethyl-1,3-dioxane (prepared according to Price C. C. J. Amer. Chem. Soc. 1950, 72, 5335-6) and anhydrous potassium carbonate were mixed in dry dimethyl formamide. After stirring for seven days at room temperature the mixture was filtered and the filtrate evaporated at reduced pressure. The residue was triturated with hot ethanol and undissolved material filtered off. The filtrate was evaporated to dryness and a yellow crystalline solid was obtained which was recrystallized from chloroform to give colourless rod-shaped crystalls. M.p. 169°-70° C. (uncorr.) UV Spectra (hydrochloric acid 0.01 mol/l): λmax (nm) 308, 245. UV spectra (ethanol): λmax (nm) 310, 247. M.S.: 11.2 a J., m/e (int): 271/269 (0.19/0.55), 226/224 (0.11/0.28) 212/210 (0.38/0.82) 171/169 (0.35/1.0)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:28]=1)([O-])=O>CO.C(OCC)(=O)C.[Pd]>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]3[O:11][C:7]4[CH:6]=[CH:5][C:4]([NH2:1])=[CH:28][C:8]=4[N:9]=3)=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc2oc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)nc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc2oc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)nc2c1
Reaction time: 4 h
Yield: 54.6 %

Procedure:
27 mg (0.0703 mmol) of 5-nitro-2-(4′-trifluoromethyl-[1,1′-biphenyl]-4-yl)benzo[d]oxazole was dissolved in methanol, and then, 10% Pd/C was added thereto to allow a catalytic reaction therebetween for 4 hours under hydrogen gas atmosphere. The reaction solution was diluted with ethyl acetate. Then, the diluted reaction solution was filtered with a celite pad, and then, was concentrated under reduced pressure. Afterwards, the filtered reaction solution was purified by using a silica gel column chromatography (ethyl acetate/normal-hexane at a volume ratio of 1:1) to obtain 13.6 mg (54.6%) of 2-(4′-trifluoromethyl-[1,1′-biphenyl]-4-yl)benzo[d]oxazole-5-amine (Derivative #8).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1>CCO>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Solvent: CCO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 0 °C
Yield: 70 %

Procedure:
Codeine, 5.0 g, and 0.117 g catalyst, Ru(P(C6H5)3)3Cl2, were dissolved in 25 ml EtOH. The mixture was flushed with nitrogen for 5 minutes. After refluxing under nitrogen for 2 hours the reaction mixture was cooled down to 0° C. and filtered. The collected crystals were washed twice with 5 ml each MeOH and dried in air for 1 hour to yield white crystals, 70% yield hydrocodone.
Reaction SMILES: C(=O)=O.[CH3:4][C:5]([CH3:7])=[CH2:6].[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[O:10].C(=O)([O-])O.[Na+]>CC(C)=O>[OH:10][C@H:9]([CH2:6][C:5]([CH3:7])=[CH2:4])[C:8]([O:12][CH3:13])=[O:11]
Reactant: C=C(C)C
Reactant: COC(=O)C=O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)=O
Product: C=C(C)C[C@@H](O)C(=O)OC
Yield: 69.4 %

Procedure:
The above-obtained solution was cooled to -70° C. in a bath of dry ice and acetone, subsequently 0.56 g (10 mmoles) of 2-methyl-l-propene was bubbled into the cooled solution, and then 88 mg (1 mmole) of methyl glyoxylate was added to the solution. Then, the mixture was allowed to react at -30° C. for 15 hours. Subsequently, 10 ml of an aqueous sodium hydrogencarbonate solution was added to terminate the reaction. The reaction mixture was filtered through Celite and extracted with two 20 ml portions of diethyl ether and two 20 ml portions of ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Thereafter, the solvents were distilled off, and hexane was added to the residue to crystallize binaphthol. The remaining solution was purified by means of silica gel column chromatography to obtain 0.10 g of methyl (R)-2-hydroxy-4-methyl-4-pentenoate. The yield was 72%.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[Cl:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1>CCCCCC.C(OCC)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:21]=[C:20]([S:24][CH3:25])[N:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CSc1nccc(Cl)n1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CSc1nc(Cl)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
31.3 ml 1.6M n-butyllithium in hexane are added at −70° C. to a solution of 11.25 g 4-bromo-benzotrifluorid in 50 ml diethylether. After stirring for 15 min. the solution is warmed to −30° C. and added to a −30° C. cold solution of 8.0 g 4-chloro-2-methylthio-pyrimidine in 50 ml ether. The mixture is stirred for 30 min. at −30° C. and another 30 min. at 0° C., then quenched with a mixture of 3.2 ml acetic acid, 0.5 ml water and 10 ml tetrahydrofuran (THF). Immediately after quenching, a solution of 11.8 g dichlorodicyanobenzoquinone (DDQ) in 50 ml THF is added and stirring is continued for 5 min. at room temperature. It is again cooled to 0° C. and 20 ml 10% aqueous sodium hydroxide are added. After stirring for 5 min. at 0° C. the organic layer is separated, dried and chromatographed to yield 10.3 g of the title compound (m.p. 93-96° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.O.[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[N:1]([C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:11])[F:12])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: N#Cc1ncc(N)cc1C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Temperature: 22 °C
Reaction time: 2 h

Procedure:
5-Amino-3-(trifluoromethyl)pyridine-2-carbonitrile 8 (1.141 g, 6.1 mmol) is mixed with chloroform (5 ml) and water (40 ml) to give a white suspension. Thiophosgene (0.701 ml, 9.15 mmol) is added and the reaction stirred for 2 hours at 22° C. to give a clear biphasic system. Chloroform (20 ml) is added and the phases are separated. The aqueous layer is extracted with chloroform (30 ml) and the combined organic is washed with saturated aqueous NaHCO3 and water, dried over MgSO4 and the solvent is removed under reduced pressure. The crude 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-carbonitrile 9 is dried under vacuum and used as such in the next step, for example, in the step described in Example 8 below.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Cl[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)c1ccc(-c2cccs2)nc1
Temperature: 25 °C
Yield: 290.5 %

Procedure:
2-thienylboronic acid (Lancaster Synthesis, Inc., 1.00 g, 7.81 mmmol), 2-chloro-5-trifluoromethylpyrdine (Adrich Chemical Co., 1.417 g, 7.81 mmol), tetrakistriphenylphosphine palladium(0) (Aldrich, 451 mg, 0.391 mmol), potassium carbonate (EM Science, 3.24 g, 23.4 mmol), water (20 mL), and dimethoxyethane (Aldrich, 20 mL) were allowed to stir at reflux for 20 hours under N2, after which time the mixture was cooled to room temperature and the organic and aqueous layers were separated. The aqueous layer was extracted with 3×50 mL of diethyl ether, and the combined organic fractions were dried with sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by silica gel flash chromatography with CH2Cl2/hexanes (1:1) as the eluent (product Rf=0.5), to afford the product as a white crystalline solid (yield=5.2 g, 73% isolated yield). 1H NMR (CDCl3, 296 K, 300 MHz): δ=7.73-7.57 (2H, m), 7.55 (1H, d, J=8.5 Hz), 7.34 (1H, d, J=4.8 Hz), 6.88 (1H, d, J=4.8 Hz) ppm. 19F NMR (CDCl3, 296K, 282 MHz) δ=−62.78 ppm. Intermediate bridged dimer,
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32]>C(#N)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=3[O:31][CH3:32])[CH2:3][CH2:2]2)=[N:8]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCCN1CCN(c2nsc3ccccc23)CC1
Yield: 38.7 %

Procedure:
A mixture of 3-(1-piperazinyl)-I,2-benzisothiazole (4.0 g, 18.2 mmol), 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (6.0 g, 20.0 mmol), K2 CO3 (3.0 g, 21.8 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 5 hours. Most of the solvent was removed in vacuo and the resultant gummy residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried with MgSO4, and concentrated to yield 7.8 g. Purification by preparative HPLC (Waters Associates Prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent) afforded 6.5 g of a damp, off-white solid. The product was recrystallized twice from toluene to provide 3.1 g (39%) of 1-[4-[4-[4-(1,2-benzisothiazol-3yl)-1-piperazinyl]butoxy]-3-methoxy-phenyl]ethanone as a white solid, m.p.=114°-116° C.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][S:6][C:7]1[N:8]=[C:9]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[N:17]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:16]=2)=[O:14])[S:10][CH:11]=1)C.[OH-].[Na+].Cl>CCO>[CH:26]1([CH2:25][N:17]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:15]([C:13]([NH:12][C:9]3[S:10][CH:11]=[C:7]([S:6][CH2:5][C:4]([OH:29])=[O:3])[N:8]=3)=[O:14])=[CH:16]2)[CH2:28][CH2:27]1
Reactant: CCOC(=O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CSc1csc(NC(=O)c2cn(CC3CC3)c3cc(F)ccc23)n1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
Following general procedure A using 6-fluoroindole and R5X=cyclopropyl-methylbromide {2-[(1-Cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid ethyl ester was obtained. Ester hydrolysis: 110 mg (0.25 mmol) {2-[(1-cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid ethyl ester was dissolved in EtOH (3 mL) and NaOH (254 μL, 4N) was introduced. The mixture was heated to 80° C. for 1 hour before it was cooled to room temperature and pH was adjusted to 2 using 1 N HCl, whereupon a white precipitate was formed. The product was filtered off and dried to give 85 mg {2-[(1-Cyclopropylmethyl-6-fluoro-1H-indole-3-carbonyl)-amino]-thiazol-4-ylsulfanyl}-acetic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][N:24]2[C:23](=[O:25])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:30])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc(OCc2ccccc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccc(OCc2ccccc2)cc1
Yield: 30.7 %

Procedure:
A solution of 1-benzyloxy-4-(3-bromopropyloxy)benzene (29.4 g) and potassium phthalimide (20.4 g) in dimethylformamide (150 ml) was stirred and heated on a steam bath for 17 hours under nitrogen. The solvent was distilled in vacuo and water (250 ml) was added to the residue. The mixture was extracted with dichloromethane and the extract dried over anhydrous potassium carbonate. The solvent was evaporated in vacuo and the residue was crystallized from ethanol-acetone to give 10.9 g (31%) of 1-benzyloxy-4-(3-phthalimidopropoxy)benzene, mp 143°-145°. A second crop which was obtained by concentrating the filtrate, weighed 9.2 g (26%), mp 137°-140°. The analysis of a sample, mp 141°-143°, from an earlier run was as follows:
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH2:10][CH3:11])[S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH3:3].[Cl:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][CH:25]=3)=[CH:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1>>[CH2:1]([N:4]([CH2:9][CH2:10][CH3:11])[S:5]([N:36]1[CH2:37][CH2:38][N:33]([S:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:17]3[C:16]4[C:21](=[CH:22][C:13]([Cl:12])=[CH:14][CH:15]=4)[N:20]=[CH:19][CH:18]=3)=[CH:25][CH:26]=2)(=[O:31])=[O:32])[CH2:34][CH2:35]1)(=[O:7])=[O:6])[CH2:2][CH3:3]
Reactant: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCNCC1
Reactant: CCCN(CCC)S(=O)(=O)Cl
Product: CCCN(CCC)S(=O)(=O)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1

Procedure:
In the manner given in Example 13 but using dipropylsulfamoyl chloride in place of dimethylsulfamoyl chloride and [[4-[[7-chloro-4-quinolinyl]-amino]phenyl]sulfonyl]piperazine in place of [[4-[(7-trifluoromethyl-4-quinolinyl)amino]phenyl]-sulfonyl]piperazine, 1-[(dipropylamino)sulfonyl]-4-[[4-[[7-chloro-4-quinolinyl]amino]phenyl]sulfonyl]-piperazine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:30]([C:29]4[CH:28]=[C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:24])=[O:25])[CH:35]=[CH:34][CH:33]=4)=[O:31])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Reactant: O=C(O)c1cccc(NS(=O)(=O)c2ccccn2)c1
Product: O=C(c1cccc(NS(=O)(=O)c2ccccn2)c1)N1CCN(c2nc3ccc(Cl)cc3s2)CC1

Procedure:
Compound 11 is prepared using synthesis method 2 using intermediates 3g and 5a (yield: 60%)
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:32]([NH2:34])[CH3:33].[BH4-].[Na+]>ClCCl.CO>[CH2:32]([NH:34][CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:26]=[CH:25][CH:24]=1)[CH3:33]
Reactant: CCN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol) in dichloromethane (0.5 mL) and methanol (0.5 mL) was added ethylamine (130 uL, 0.27 mmol). This mixture was stirred for 1 h at room temperature, and then sodium borohydride (10 mg, 0.27 mmol) was added. The reaction was stirred at ambient temperature overnight, and the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (13.2 mg, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:23])[CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>[Ni].CN(C)C=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:23])[CH:5]=1
Reactant: CSc1ccc2c(c1)C(=O)N(c1cc([N+](=O)[O-])ccc1C)C2=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)C(=O)N(c1cc(N)ccc1C)C2=O

Procedure:
The mixture of 6.0 g of N-(4-nitro-o-tolyl)-4methylmercaptophthalimide, 3.0 g of Raney nickel and 200 ml of ethyl acetate is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is diluted with dimethylformamide to solubilize any organic material, filtered and the filtrate evaporated. The residue is recrystallized from chloroform-diethyl ether to yield the N-(4-amino-o-tolyl)-4-methylmercaptophthalimide melting at 173°-177°. The starting material is prepared as follows: The mixture of 8.5 g of potassium methylsulfide, 21.2 g of diethyl 4-chlorophthalate and 100 ml of dimethylformamide is stirred at 100°-120° for one week. After cooling it is diluted with diethyl ether, the precipitate filtered off, the filtrate washed with 5% aqueous sodium hydroxide, water, dried and evaporated, to yield the diethyl 4-methylmercaptophthalate. The mixture of 18.2 g thereof and 100 ml of 30% aqueous ethanolic sodium hydroxide is refluxed for 21/2 hours and evaporated. The residue is acidified with concentrated hydrochloric acid and thoroughly extracted with diethyl ether. The extract is washed with water, dried, evaporated and the residue recrystallized from 30% aqueous methanol, to yield the 4-methylmercaptophthalic acid, m.p. 178°-181°. The mixture of 13.0 g thereof and 130 ml of acetic anhydride is refluxed for 3 hours and evaporated, to yield the 4-methylmercaptophthalic anhydride melting at 157°-160°. The mixture of 10.3 g thereof, 7.8 g of 4-nitro-o-toluidine and 100 ml of acetic acid is refluxed for 24 hours and evaporated. The residue is recrystallized from ethanol-ethyl acetate to yield the N-(4-nitro-o-tolyl)-4-methylmercaptophthalimide melting at 155°-157°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([C:16]2[NH:17][CH:18]=[CH:19][N:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[C:10]1([C:16]2[N:20]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[CH:19]=[CH:18][N:17]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(-n2ccnc2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
A mixture of 4-fluorobenzonitrile (3.63 g, 30 mmol), 2-phenylimidazole (3.72 g, 30 mmol) and anhydrous K2CO3 (4.15 g, 30 mmol) in dry DMSO (30 ml) was heated at 100° C. for 20 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into an ice-cold saturated aqueous NH4Cl (100 ml) solution and the whole extracted with Et2O (150 ml×2). The combined extracts was washed with water (100 ml), brine (80 ml), dried over MgSO4 and solvent removed under reduced pressure. The resultant residue was purified by column chromatography (SiO2 ; dichloromethane:ethyl acetate:ethanol=20:1:1) to afford title compound (3.61 g, 49%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][NH:24][CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:23][N:24]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc(CS[C@@H]2C[C@@H](CNCc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(CS[C@@H]2C[C@@H](CN(CC(=O)OC(C)(C)C)Cc3cc(F)ccc3F)N(C(=O)OC(C)(C)C)C2)cc1
Yield: 104.9 %

Procedure:
6.94 g (14.5 mmol) (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester were dissolved in 170 ml acetonitrile and treated with 3 ml (20.3 mmol, 1.4 eq) t-butyl bromoacetate and 18.6 g (134.9 mmol, 9.3 mmol) K2CO3 at RT for 2d. The solid was removed by filtration, and the organic phase was washed with water and brine, dried over Na2SO4 and evaporated, yielding 9.02 g (quant) (2S,4R)-2-[[tert-butoxycarbonylmethyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as orange oil, MS: 593 (MH+).