Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[C:9]([CH3:22])=[C:10]([CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:9]([CH3:22])=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: Cc1c(C=CCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(CCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 79.5 %

Procedure:
5.425 g of 6-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-hex-5-enoic acid dissolved in 100 ml of ethanol in the presence of 110 mg of platinum oxide had hydrogen pased therethrough and then the catalyst was filtered off. The filtrate was evaporated to dryness and the residue was taken up in ether. The solution was treated with activated carbon, filtered and evaporated to dryness. The residue was crystallized from a 1:1 isopropyl ether-petroleum ether mixture to obtain 4.34 g of 6-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-hexanoic acid melting at 82° C.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N:7]2.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[Br:1][C:2]1[C:11]([C@H:12]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:23])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:24])=[N+:7]2[O-:30]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C)ccc2c1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2c(ccc(C)[n+]2[O-])c1Br
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of (S)-ethyl 2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyacetate (5H) (500 mg, 1.27 mmol) in dichloromethane (13 mL) at 0° C. was added 3-chloroperoxybenzoic acid (269 mg, 77%, 1.21 mmol) and the reaction mixture was allowed to slowly warm to room temperature over 3 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes and methanol/ethyl acetate) to give a yellow oil (497 mg, 95%). LCMS-ESI+ (m/z): [M]+ calcd for C19H2413rNO4: 410.3;
Reaction SMILES: [O:1]([CH3:11])[C@@H:2]1[O:8][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4].C(N(CC)CC)C.[C:19]([Si:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:23]([CH:9]([OH:10])[C@H:7]1[O:8][C@@H:2]([O:1][CH3:11])[C@H:3]([OH:4])[C@@H:5]1[OH:6])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CO[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](C(O)[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.8 %

Procedure:
To a mixture of methyl β-D-ribofuranoside (Sigma Chemical Co., 460 mg, 2.8 mmol) and anhydrous methylene chloride (20 ml) were added triethylamine (0.468 ml, 3.36 mmol), t-butyldiphenylchlorosilane (0.9 ml, 3.46 mmol), and DMAP (13.7 mg, 0.112 mmol) successively at room temperature. The reaction mixture was stirred for 18 h at room temperature under nitrogen. The reaction mixture was washed with water (20 ml), saturated ammonium chloride (20 ml), and brine (20 ml), dried over anhydrous MgSO4, filtered, and concentrated to dryness. The residue was separated by silica gel column chromatography (CHCl3 --MeOH, 50:1) to yield 1-O-methyl 5-(t-butyldiphenylsilyl)-β-D-ribofuranoside [Rf =0.48 (CHCl3 --MeOH, 10:1), 618 mg, 54.8%] as a thick syrup. 1H NMR (DMSO-d6) d 0.96 (s, 9H, t-Bu), 3.22 (s, 3H, --OCH3), 3.61 (dd, J=11.0 and 5.3 Hz, 1H), 3.74 (d, J=4.4 Hz, 1H), 3.81 (dd, J=11.0 and 2.7 Hz, 1H), 3.90 (m, 1H), 4.00 (m, 1H), 4.68 (s, 1H, H-1'), 4.84 (br s, 1H, exchangeable with D2O, OH), 5.05 (br s, 1H, exchangeable with D2O, OH), 7.45 and 7.67 (m, 10H, Ph2). Anal. Calcd for C22H30O5Si: C, 65.64; H, 7.51; Found: C, 65.73; H, 7.55.
Reaction SMILES: [C:1]1([NH:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[C:13]([NH2:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:17]1([C:22](N)=[NH:23])C=CC=N1.C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[C:1]1([NH:7][C:8]2[S:12][N:11]=[N:10][C:9]=2[CH2:13][NH:15][C:22]([NH2:23])=[NH:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1nnsc1Nc1ccccc1
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: N=C(N)NCc1nnsc1Nc1ccccc1
Temperature: 80 °C

Procedure:
To a 2 mL pyridine solution of 5-phenylamino-[1,2,3]thiadiazole-4-carboxylic acid amide (50 mg, 0.24 mmole), was added the powder of 1H-pyrazole-1-carboxamidine hydrochloride (235 mg, 1.59 mmole) and diisopropyl ethylamine (234 mg, 1.8 mmole). Then the mixture was heated to about 80° C. The reaction mixture was cooled to room temperature for 4 hours and the solvent was then evaporated. The residue was loaded onto a preparative TLC plate and eluted sequentially with neat CH2Cl2 and CH2Cl2:MeOH (4:1). A 94 mg of crude product was collected, which was further purified by another preparative TLC (silica gel, CH2Cl2:MeOH:H2O=3.6:0.4:0.06). The title compound was obtained in 40 mg (66%). 1H NMR (ppm, CDCl3): 9.33 (br. t, 1H), 8.01 (br. s, 1H), 7.63-7.82 (m, 2H), 7.20-7.40 (m, 3H), 6.37 (br. s, 2H), 6.08 (br. s, 1H), 4.41 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@@H:5]([CH2:7][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH2:9])[CH2:4][O:3]1.[F:15][C:16]1[C:21]([F:22])=[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])[C:19]([NH2:32])=[C:18]([O:33][CH3:34])[CH:17]=1>N1C=CC=CC=1>[F:22][C:21]1[C:20]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=2[F:31])=[C:19]([NH:32][S:10]([C:8]([CH2:7][C@H:5]2[CH2:4][O:3][C:2]([CH3:14])([CH3:1])[O:6]2)=[CH2:9])(=[O:12])=[O:11])[C:18]([O:33][CH3:34])=[CH:17][C:16]=1[F:15]
Reactant: C=C(C[C@H]1COC(C)(C)O1)S(=O)(=O)Cl
Reactant: COc1cc(F)c(F)c(Nc2ccc(I)cc2F)c1N
Solvent: c1ccncc1
Product: C=C(C[C@H]1COC(C)(C)O1)S(=O)(=O)Nc1c(OC)cc(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(S)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)prop-1-ene-2-sulfonyl chloride (1 eq) is dissolved in pyridine and 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)-3-methoxybenzene-1,2-diamine (1 eq) added. The solution is stirred at 100° C. for 2 hours and then partitioned with water and ethyl acetate. The organic layer is washed with brine, dried (MgSO4), concentrated under reduced pressure and purified by flash column chromatography on silica (30% ethyl acetate/hexanes eluant).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:36][CH2:37][CH3:38])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CCCBr
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: CCCOc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with propyl bromide
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][C:13]([CH3:18])=[CH:14][C:15](Cl)=[O:16].C(N(CC)CC)C>C(OCC)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:15](=[O:16])[CH:14]=[C:13]([CH3:18])[CH3:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C

Procedure:
To a chilled solution of 4-tert-butylphenol (15 g, 100 mmol) and 11.12 mL of 3-methylbut-2-enoyl chloride in 200 mL of diethyl ether at 0° C. was added 13.9 mL of triethylamine by addition funnel. The reaction mixture was warmed to room temperature and stirred until TLC indicated the reaction was complete. The reaction mixture was then filtered through diatomaceous earth, and the diethyl ether layer was washed two times with water, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to leave 23 g of 3-methylbut-2-enoic acid 4-tert-butylphenyl ester as a brown oil that partially crystallized upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:31])([F:30])[F:29])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1.[CH3:35][NH2:36]>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:36][CH3:35])=[O:7])=[CH:4][C:3]=1[C:11]1[O:15][N:14]=[C:13]([CH2:16][N:17]2[C:25]3[C:20](=[C:21]([C:28]([F:30])([F:29])[F:31])[C:22]([C:26]#[N:27])=[CH:23][CH:24]=3)[CH:19]=[C:18]2[CH2:32][CH2:33][CH3:34])[N:12]=1
Reactant: CN
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)Cl)ccc2Cl)n1
Solvent: C1CCOC1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(=O)NC)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
A round bottom flask was mixed with 4-chloro-3-(3-{[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]methyl}-1,2,4-oxadiazol-5-yl)benzoyl chloride (Example 295B) (0.037 g, 0.07 mmol) and 1.0M MeNH2 in THF (10.0 mL). The mixture was stirred at rt for 2 h and concentrated to dryness. The resulting solid was crystallized with Et2O, filtered in vacuo and dried under high vacuum to afford a pure solid (0.022 g, 59% yield): MS (ES) m/z 501 (M+).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])[CH:14]=[CH:13][C:12]=1[Cl:30])(=[O:10])=[O:9].Cl[C:32]1C=CC(N2C(=O)C=C(C(F)(F)F)N(C)C2=O)=CC=1S(Cl)(=O)=O.COCCN.IC>CN(C)C=O>[CH3:3][O:4][CH2:5][CH2:6][N:7]([CH3:32])[S:8]([C:11]1[CH:16]=[C:15]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[N:19]([CH3:28])[C:18]2=[O:29])[CH:14]=[CH:13][C:12]=1[Cl:30])(=[O:10])=[O:9]
Reactant: COCCNS(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)c1=O
Agent: COCCN
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COCCN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred slurry of 0.2 g of a 60% dispersion of sodium hydride in mineral oil and 30 ml of N,N-dimethylformamide (DMF) cooled to 5° C. was added 1.95 g of N-(2-methoxyethyl)-2-chloro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl)benzenesulfonamide (Compound #52) prepared according to the procedure set forth above Process B using 2-chloro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)pyrimidinyl)benzenesulfonyl chloride and 2-methoxyethylamine After stirring for 1 hour at 5° C. 0.6 ml of iodomethane was added to the reaction mixture. After stirring at room temperature for 16 hours, the mixture was concentrated using a rotary evaporator. The resulting gummy residue was treated several times with water until a solid had formed. The solid was recrystallized from ethanol to give 1.3 g of the title compound as a white crystalline solid, m.p. 108°-110° C. Spectral data for this compound is found in Table I.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[H-].[Na+].Cl[CH2:15][C:16]1[CH:32]=[CH:31][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[O:21])=[CH:18][CH:17]=1.[I-].[Na+]>C1COCC1.CN(C=O)C>[CH3:30][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:32][CH:31]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reaction time: 0.67 h
Yield: 77.6 %

Procedure:
In an atmosphere of argon, phthalimide (150 mg, 1.0 mmol) was dissolved in THF (10 ml) to which was subsequently added sodium hydride (44 mg, 60%, 1.1 mmol) at room temperature. After 40 minutes of stirring at the same temperature, to this was added a DMF solution (5 ml) containing 4-chloromethyl-N-(2-methoxyphenyl)benzamide (276 mg, 1.0 mmol) and a catalytically effective amount of sodium iodide. After 2 hours of stirring at 80° C. and subsequent removal of the solvent by evaporation, the resulting residue was mixed with water (10 ml) and extracted with an ethyl acetate-methylene chloride (1:2) mixture solution. The resulting organic layer was washed with water and saturated brine and dried on anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation, and the resulting residue was subjected to a silica gel column chromatography (methylene chloride-ether:hexane=2:1) and then washed with ether to obtain 300 mg (77.6%) of the title compound in the form of colorless solid.
Reaction SMILES: O[N:2]=[C:3]([CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)C(O)=O.O>C(OC(=O)C)(=O)C>[C:13]1([C:11]2[CH:12]=[C:8]([CH2:7][C:3]#[N:2])[S:9][CH:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C(Cc1cc(-c2ccccc2)cs1)=NO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CCc1cc(-c2ccccc2)cs1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
2-(Hydroxyimino)-3-(4-phenylthiophen-2-yl)propanoic acid (0.8 g, 3.1 mmol) was heated in acetic anhydride (5 mL) for 1.5 h. The reaction mixture was cooled to room temperature and treated with water. The product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford 2-(4-phenylthiophen-2-yl)acetonitrile (0.45 g, yield 73%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.57-7.53 (m, 2H), 7.43-7.39 (m, 2H), 7.37-7.36 (m, 2H), 7.34-7.30 (m, 1H), 3.96 (s, 2H).
Reaction SMILES: [Na].[CH3:2][CH:3]([SH:6])[CH2:4][CH3:5].Cl[C:8]1[C:16]2[NH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[N:13][C:12]=2[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][C:9]=1[N+:24]([O-:26])=[O:25].O>C(O)C>[CH:3]([S:6][C:8]1[C:16]2[NH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[N:13][C:12]=2[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][C:9]=1[N+:24]([O-:26])=[O:25])([CH2:4][CH3:5])[CH3:2]
Reactant: CCC(C)S
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c2c1Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCC(C)Sc1c([N+](=O)[O-])cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
In 200 milliliters of ethanol, 1 gram of sodium (0.04 mole) was reacted with 3.6 grams of 2-butanethiol (0.04 mole). The mixture was stirred for one-half hour. Then 4-chloro-5,7-dinitro-2-trifluoromethylbenzimidazole (6.2 grams; 0.02 mole) was added, and the resulting reaction mixture was stirred overnight, poured into water, acidified, and filtered to separate the desired 4-sec-butylthio-5,7-dinitro-2-trifluoromethylbenzimidazole. It was recrystallized twice from a mixture of benzene and an aliphatic hydrocarbon fraction boiling at 60°-80° C., m.p., 111°-15° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12](O)=[O:13])[CH:8]=[C:7]2[OH:15].[Cl-].[NH4+].C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([NH2:21])=[O:13])[CH:8]=[C:7]2[OH:15]
Reactant: COc1ccc2c(O)cc(C(=O)O)nc2c1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc2c(O)cc(C(N)=O)nc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Chloro-4-hydroxy-7-methoxy-quinoline-2-carboxylic acid (115 mg, 0.45 mmol) and ammoniumchloride (36 mg, 0.68 mmol) were dissolved in DMF (4 mL). HATU (342 mg, 0.9 mmol) and NMM (159 mg, 1.58 mmol) were added and the mixture was stirred at r.t. overnight. An additional amount of ammoniumchloride (72 mg, 13.5 mmol) was added and heated to 53° C. for 18 h. The reaction mixture was cooled to r.t. and concentrated to give 8-chloro-4-hydroxy-7-methoxy-quinoline-2-carboxylic acid amide as a yellow solid.
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH3:47][CH:48]([O:50][CH2:51][CH2:52][CH2:53][NH2:54])[CH3:49].[BH3-]C#N.[Na+]>>[CH3:47][CH:48]([O:50][CH2:51][CH2:52][CH2:53][NH:54][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)[CH3:49]
Reactant: CC(C)OCCCN
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)OCCCNCc1ccc(B(O)O)s1
Yield: 36.5 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), {3-[(1-methylethyl)oxy]propyl}amine (38 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid. The crude {5-[({3-[(1-methylethyl)oxy]propyl}amino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). After purification on an Agilent MDAP twice as shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, the impure title compound was washed with a 20:4:1 mixture of hexanes/EtOAc/MeOH (2.5 mL) to give 7.6 mg of the title compound (9%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:14][C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1)=[O:16]>>[F:27][C:22]1[CH:21]=[C:20]([CH:18]2[CH2:19][CH:17]2[C:15]([OH:16])=[O:14])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1CC1c1ccc(O)c(F)c1
Reactant: CCCSc1ncccc1CCl
Product: CCCSc1ncccc1COc1ccc(C2CC2C(=O)O)cc1F
Yield: 48 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.016 g, 0.08 mmol) obtained in Step C of Preparation Example 14 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.017 g, 0.08 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.014 g, 48%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[C-:17]#[N:18].[Na+].O>CN(C)C=O>[C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:17]#[N:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCCCCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCCCc1ccccc1
Yield: 949.6 %

Procedure:
A stirred solution of 15.0 grams (0.0062 mole) of 1- methylsulfonyloxy-5-phenylpentane and 9.1 grams (0.190 mole) of sodium cyanide in 150 mL of N,N-dimethylformamide was heated at 50° C. to 55° C. for about 60 hours. After this time the reaction mixture was poured into 400 mL of water. The mixture was extracted with three 250 mL portions of diethyl ether. The combined extracts were then washed with three 200 mL portions of water and 200 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.2 grams of 6-phenylhexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.CC1(C)COB([C:26]2[CH:27]=[C:28]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[C:29]([O:31][CH3:32])=[O:30])OC1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(Cl)Cl>[CH3:17][CH:16]([S:13]([NH:12][C@@H:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][C:26]3[CH:27]=[C:28]([CH:33]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:35]=3)[C:29]([O:31][CH3:32])=[O:30])[CH:4]=2)[CH2:8]1)(=[O:15])=[O:14])[CH3:18]
Reactant: COC(=O)c1cc(B2OCC(C)(C)CO2)cc(C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CCl)cc2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1cc(Cc2ccc3c(c2)C[C@@H](NS(=O)(=O)C(C)C)C3)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 31.8 %

Procedure:
To (S)-N-(5-(chloromethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.160 mmol, 46 mg) in THF (1 mL) was added methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(trifluoromethyl)benzoate (0.160 mmol, 50.5 mg), Bromo(N-succinimidyl)bis-(triphenylphosphine)palladium(II) (7.99 μmol, 6.46 mg) and sodium carbonate (1.000 mmol, 0.5 mL). The reaction was heated to 100° C. for 10 minutes by microwave irradiation before diluting with DCM and filtering through a hydrophobic frit. The solvent was removed in vacuo before redissolving in MeCN (500 μL) and purifying by reverse phase preparative chromatography to give (S)-methyl 3-((2-(1-methylethylsulfonamido)-2,3-dihydro-1H-inden-5-yl)methyl)-5-(trifluoromethyl)benzoate (23.2 mg, 31.9%). MS (ESI): m/z [M+H]+ 456.0