Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[CH3:31][O:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[S:40](Cl)(=[O:42])=[O:41]>>[CH3:31][O:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[S:40]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23])(=[O:41])=[O:42]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Product: COc1cc(C)ccc1S(=O)(=O)Nc1ccc(N2CCNCC2)cc1NS(=O)(=O)c1ccccc1

Procedure:
2-Methoxy-4-methyl-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2-methoxy-4-methylbenzenesulfonylchloride (53 mg, 0.239 mmol) according to general method 3 to give 80 mg of a purple solid. MS (posES-FIA) m/z=Found: 517.2; Calcd 517.15; 1H NMR δ 7.67-7.37 (m, 6H), 7.10-7.04 (m, 2H), 6.97-6.74 (m, 2H), 6.30 (d, 1H), 4.06 (s, 3H), 3.26-3.09 (m, 8H), 2.37 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=1.Br[CH2:17][C:18]1[S:19][C:20]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:21]=2[N:22]=1.[Cl-].[NH4+]>CN(C)C=O>[F:27][C:24]1[CH:25]=[CH:26][C:20]2[S:19][C:18]([CH2:17][O:3][C:4]3[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[C:6]([CH3:15])[CH:5]=3)=[N:22][C:21]=2[CH:23]=1
Reactant: COC(=O)Nc1ccc(O)cc1C
Reactant: Fc1ccc2sc(CBr)nc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(OCc2nc3cc(F)ccc3s2)cc1C
Reaction time: 0.08 h
Yield: 67.2 %

Procedure:
54.6 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 204.9 mg of methyl N-(4-hydroxy-2-methylphenyl)carbamate [prepared as described in Example 15(a) above] in 5 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 5 minutes, and then 366.2 mg of 2-bromomethyl-5-fluorobenzothiazole [prepared as described in step (a) above] were added. The temperature of the resulting mixture was elevated to room temperature and the mixture was stirred for 1.5 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent to give 263.3 mg (yield 65%) of the title compound as a solid having a melting point of 165° to 168° C.
Reaction SMILES: [F:1][C:2]1[C:12]([SH:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C(=O)N(Cl)C(=O)C1.[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([CH:27]=[C:28]([CH:40]3[CH2:42][CH2:41]3)[N:29]2[C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=2)=[CH:25][CH:24]=1>C(Cl)Cl.O>[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:13][C:12]3[C:2]([F:1])=[C:3]([CH:9]=[CH:10][CH:11]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:28]([CH:40]3[CH2:42][CH2:41]3)[N:29]2[C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cccc(S)c1F
Reactant: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a stirred solution of ethyl 2-fluoro-3-mercaptobenzoate 6 (2.8 g, 14.0 mmol) in CH2Cl2 (30 mL) under inert atmosphere was added NCS (1.9 g, 14.0 mmol) at RT and allowed to stir for 2 h. To this, compound 5 (3.9 g, 12.8 mmol) in CH2Cl2 (10 mL) was added at RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2×80 mL). The combined organic extracts were washed with water (2×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified by triturating with n-pentane (2×50 mL) to afford 7 (5.2 g, 81%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.66-7.7.60 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4, 6.5 Hz, 1H), 6.93 (t, J=8.4 Hz, 1H), 6.79-6.75 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.26 (q, J=7.6 Hz, 2H), 1.74-1.68 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 1.41 (t, J=7.6 Hz, 3H), 1.08-1.04 (m, 2H), 0.89-0.84 (m, 2H); MS (ESI): m/z 502.5 (M+H+); HPLC: 97.5%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.44 min; ACN: 0.025% TFA (aq); 0.5 mL/min.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[N:10]([CH2:18][CH3:19])[C:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=3[N:17]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:18]([N:10]1[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]=[C:9]1[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1)[CH3:19]
Reactant: OB(O)c1ccccc1
Reactant: CCn1c(-c2nc(Br)cnc2N)nc2cnccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCn1c(-c2nc(-c3ccccc3)cnc2N)nc2cnccc21
Reaction time: 0.08 h
Yield: 23.7 %

Procedure:
5-Bromo-3-(1-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)pyrazin-2-amine (0.038 g, 0.12 mmol) (see Example 2), phenyl boronic acid (0.034 g, 0.27 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.009 g, 0.012 mmol), potassium carbonate (0.045 g, 0.32 mmol), and an 8:1 mixture of acetonitrile:water (3 mL) were combined and subjected to 150° C. for 5 minutes in a SmithSynthesizer microwave. The resulting heterogeneous, black mixture was filtered through a celite pad, which was then washed with ethyl acetate and water. The mixture is extracted into ethyl acetate (×3) and washed with water and saturated sodium chloride. The combined organic layers are dried over magnesium sulfate, filtered and concentrated. The residue is purified on silica, eluting with 2.5% methanol in chloroform to afford the title compound (0.009 g, 23%).
Reaction SMILES: C(Cl)CCl.[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)=[CH:8][CH:7]=1.[CH:17]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][NH:30][CH3:31])=[CH:21]1)([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.O.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:5][C:6]1[N:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([N:30]([CH2:29][C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]([CH:17]([CH3:19])[CH3:18])[CH:21]=2)[CH3:31])=[O:16])=[CH:8][CH:7]=1
Reactant: CNCc1cn(C(C)C)c2ccccc12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: CC(C)n1cc(CN(C)C(=O)/C=C/c2ccc(N)nc2)c2ccccc21
Reaction time: 8 h
Yield: 58.6 %

Procedure:
EDC (0.51 g, 2.64 mmole) was added to a solution of (E)-3-(6-aminopyridin-3-yl)acrylic acid (0.43 g, 2.64 mmole), 1-isopropyl-3-(methylaminomethyl)indole (0.49 g, 2.40 mmole), HOBt.H2O (0.36 g, 2.64 mmole) and diisopropylethylamine (0.84 mL 4.80 mmole) in DMF (40 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4. Flash chromatography on silica gel (10% MeOH/CHCl3) gave the title compound (0.49 g, 58%) as a yellow solid after drying in vacuo: MS (ES) m/e 349 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[O:42]([C@:50]([C@@H:58]([CH:60]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[OH:61])[OH:59])([OH:57])[C:51]([F:56])([F:55])[C:52](O)=[O:53])[Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>O1CCCC1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:52]([C:51]([F:56])([F:55])[C@@:50]([O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])([C@@H:58]([CH:60]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[OH:61])[OH:59])[OH:57])=[O:53]
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)O
Reactant: Clc1ncnc2nc[nH]c12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)n1cnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 34.3 %

Procedure:
To a solution of 0.77 g (5.0 mmol) of 6-chloro-purine in 50 ml of tetrahydrofuran was added 1.31 g (5.0 mmol) of triphenylphosphine and 0.87 g (5.0 mmol) of diethyl azodicarboxylate. To this solution was added a solution of 1.99 g (5.0 mmol) of 3,5-bis(t-butyldimethylsiloxy)-1-hydroxy-2-desoxy-2,2-difluororibose in tetrahydrofuran. The reaction mixture was stirred at room temperature for approximately 60 hours and an additional 0.66 g (1.7 mmol) of 3,5-bis(t-butyldimethylsiloxy)-1-hydroxy-2-desoxy-2,2-difluororibose was added to the reaction mixture. The mixture was stirred for an additional 6 hours at room temperature. The solvent was evaporated under vacuum and the residue was stirred in a small amount of diethyl ether overnight. The precipitated solid was removed by vacuum filtration and the filtrate was concentrated under vacuum to dryness. The residue was chromatographed over 70 g of silica and eluted with chloroform. Fractions containing the major component were combined and the solvent was evaporated therefrom to provide 1.0 g of 1-(6-chloro-9H-purin-9-yl)-3,5-bis(t-butyldimethylsiloxy)-2-desoxy-2,2-difluororibose. The structure of the product was verified by NMR. Mass spec.=477 [534-(t-butyl)]
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:12][O:13][C:14](=[O:16])[N:15]=2)[CH:6]=1.[F:19][C:20]([F:33])([F:32])[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28]Cl)=[O:26])=[CH:23][CH:22]=1.[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]([F:32])([F:33])[C:21]1[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][N:15]2[C:14](=[O:16])[O:13][N:12]=[C:11]2[C:7]2[CH:6]=[C:5]([C:4]([F:3])([F:17])[F:18])[CH:10]=[CH:9][N:8]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(OCCl)c1ccc(C(F)(F)F)cc1
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(OCn1c(-c2cc(C(F)(F)F)ccn2)noc1=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.8 %

Procedure:
Into 2 ml of N,N-dimethylformamide was suspended 0.07 g of sodium hydride (60% oily), and 0.3 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one was added at room temperature. After stirring for 15 minutes, 0.33 g of chloromethyl 4-trifluoromethylbenzoate was added, and the mixture was stirred at 70° C. for 4 hours. The reaction solution was allowed to cool to room temperature, and poured into an aqueous saturated ammonium chloride solution, followed by extraction with ethyl acetate three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.1 g of [3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-on-4-yl]methyl 4-trifluoromethylbenzoate (present compound (43)).
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)=[CH:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)C.[Li+].[OH-]>>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[N:9]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:8]=[C:7]([CH:6]=[C:5]([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:4]([OH:35])=[O:3])[CH:11]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(=O)C(=Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(-n2nc(C=C(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 4 h
Yield: 70.9 %

Procedure:
To a stirred solution containing 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1-H-pyrazol-3-yl]-2-m-tolyl-acrylic acid ethyl ester (Step B, 50 mg, 0.10 mmol) was added 2 mL LiOH (2 M). After 4 h at 50° C., the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography with 5:95 MeOH/CH2Cl2 to afford 34 mg (72.3%) of the title compound. HPLC: Rt=10.65 (Method A). MS (ES+): mass calculated for C26H20Cl2N2O3, 478.09; m/z found 479.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.35 (t, J=8.0 Hz, 1H), 7.28-7.23 (m, 3H), 7.15-7.11 (m, 3H), 7.09 (d, J=2.0 Hz, 1H), 6.88-6.86 (m, 2H), 6.77 (dd, J=8.3, 2.0 Hz, 1H), 5.45 (s, 1H), 3.82 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[C:48]([F:68])=[CH:49][C:50]([F:67])=[C:51]([NH:53][C:54](=[O:66])[C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([C:64]#[N:65])([CH3:63])[CH3:62])[CH:56]=2)[CH:52]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:64]([C:61]([C:57]1[CH:56]=[C:55]([CH:60]=[CH:59][CH:58]=1)[C:54]([NH:53][C:51]1[C:50]([F:67])=[CH:49][C:48]([F:68])=[C:47]([NH:46][C:10]([C:8]2[S:7][C:3]3=[N:4][CH:5]=[CH:6][N:1]=[C:2]3[CH:9]=2)=[O:12])[CH:52]=1)=[O:66])([CH3:63])[CH3:62])#[N:65]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(N)c(F)cc2F)c1
Reactant: O=C(O)c1cc2nccnc2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(NC(=O)c3cc4nccnc4s3)c(F)cc2F)c1
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
A mixture of thieno[2,3-b]pyrazine-6-carboxylic acid (57.1 mg, 0.317 mmol), HATU (145 mg, 0.381 mmol) and DIPEA (0.105 mL, 0.634 mmol) in DMF (3 mL) was stirred for 15 min. N-(5-amino-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide 73 (100 mg, 0.317 mmol) was added and stirred for 2 h at 80° C. Citric acid solution (3%) was added and the resulting precipitate was collected. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2,4-difluorophenyl)thieno[2,3-b]pyrazine-6-carboxamide 74 (31 mg, 20%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 7.61 (m, 2H), 7.79 (m, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.10 (t, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 10.35 (s, 1H), 10.80 (br s, 1H). (m/z)=478 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:15]([CH2:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:7][CH:8]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C(O)C>[CH2:17]([S:15]([C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([NH2:12])[C:2]([NH2:1])=[CH:3]2)=[CH:8][CH:7]=1)=[O:16])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CS(=O)c1ccc2cc([N+](=O)[O-])c(N)cc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CS(=O)c1ccc2cc(N)c(N)cc2c1

Procedure:
To 0.025 mole of the 2-amino-7-isobutylsulfinyl-3-nitronaphthalene in 100 ml of 95% ethanol is added a solution of 3.4 equivalents of sodium hydrosulfite (Na2S2O4) in a solution of 100 ml of water and 15 ml concentrated (28%) ammonium hydroxide. The mixture is refluxed for 5 minutes and an amount of hydrosulfite solution equal to 10% of the original is added to the refluxing mixture. TLC (silica gel, ether) indicates consumption of starting material. The mixture is concentrated to one-half its original volume under vacuum and the residual mixture extracted with two 150 ml portions of chloroform. The combined chloroform extracts are dried (Na2SO4), filtered, and evaporated to dryness to yield the crude title compound which is used without further purification in Example 10.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=O)=[CH:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[S:56]1[CH:57]=[CH:58][N:59]=[C:55]1[NH:54][C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:17]
Reactant: CSc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid (275 mg, 1.10 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (585 mg, 1.32 mmol) in methylene chloride (5 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.44 mL, 2.54 mmol). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was treated with 2-aminothiazole (254 mg, 2.54 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was partitioned between water (40 mL) and ethyl acetate (40 mL) and was treated with a 1N aqueous hydrochloric acid solution (25 mL). The layers were shaken and separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (155 mg, 42%) as light yellow solid: mp 172-176° C.; (ES)+-HRMS m/e calcd for C16H17N3OS2 (M+Na)+ 354.0705, found 354.0709.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18](O)=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[Na+].[OH-].[NH4+:29]>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]([NH2:29])=[O:19])[C:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1c(=O)n(Cc2ccccc2)c2ccccc21
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: NC(=O)Cn1c(=O)n(Cc2ccccc2)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 1.55 g. (0.005 mole) of 3-benzyl-2-oxo-1-benzimidazolineacetic acid and 10 ml. of thionyl chloride dissolved in 300 ml. of chloroform is refluxed for a period of approximately 2.5-4 hours. After cooling to room temperature (~25° C.), the reaction mixture is slowly poured into a solution consisting of 4.5 g. of sodium hydroxide dissolved in 100 ml. of ammonium hydroxide. The resulting chloroform layer is then separated and subsequently evaporated to near dryness while under reduced pressure to give a residual solid. Recrystallization of the latter material from ethanol-water then yields pure 3-benzyl-2-oxo-1-benzimidazolineacetamide in fine crystalline form.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-oxo-cyclohexanecarboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClCC1[O:46][C:47]([CH3:50])=[N:48][N:49]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[O:46][C:47]([CH3:50])=[N:48][N:49]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nnc(CCl)o1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as colorless gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: [NH:1]([C:8]1[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[Na]>>[C:22]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: OCCCCCCOc1ccc(Nc2ccccc2)cc1
Reactant: CCCCCCCC(=O)OC
Agent: CC(C)[O-]
Agent: [Al+3]
Agent: [Na]
Product: CCCCCCCC(=O)OCCCCCCOc1ccc(Nc2ccccc2)cc1

Procedure:
Following the method of Example 1, a mixture of 28.5 g. of 6-(p-anilinophenoxy)hexanol, 47.5 g. of methyl octanoate, 0.3 g. of aluminum isopropylate and a small chip of sodium metal (about 0.1 g.) was heated at 160°-170° C. for a total of 9 hours. The reaction mixture was then cooled and recrystallized from 2-propanol to afford the ester, 6-(p-anilinophenoxy)hexyl octanoate as a crystalline solid, m.p. 42°-43° C.