Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24]([SH:26])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:28]=[CH:27][C:22]3[NH:23][C:24]([S:26][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc3[nH]c(S)nc3c2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CSc1nc2cc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
A mixture of 5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1H-benzimidazole-2-thiol obtained in Example 27 (750 mg), tert-butyl bromoacetate (429 mg), potassium carbonate (415 mg), and N,N-dimethylformamide (5 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 90:10-50:50 hexane/ethyl acetate) to provide the title compound (785 mg, 81%) as an amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:22]([O-:24])=[O:23])=[CH:4][C:5]([Cl:21])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:25][N:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH3:27].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN(C1C=CN=CC=1)C.ClCCCl.N1CCCCC1>[Cl:21][C:5]1[CH:4]=[C:3]([N+:22]([O-:24])=[O:23])[C:2]([NH:1][C:32](=[O:33])[C:31]2[CH:30]=[CH:29][C:28]([N:26]([CH3:25])[CH3:27])=[CH:36][CH:35]=2)=[CH:7][C:6]=1[N:8]1[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: C1CCNCC1
Product: CN(C)c1ccc(C(=O)Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cc2[N+](=O)[O-])cc1
Temperature: 85 °C
Yield: 70.9 %

Procedure:
A mixture of tert-butyl 4-(5-amino-2-chloro-4-nitrophenyl)piperazine-1-carboxylate (1.2 g, 3.36 mmol), 4-(N,N-dimethylamino)benzoyl chloride (803 mg, 4.37 mmol), BEMP (1846 mg, 6.73 mmol), and DMAP (411 mg, 3.36 mmol) in DCE (Volume: 15 ml) was heated at 85° C. foe 4 h. Cooled down and treated with a few drops of piperidine for 1 h. After the solvent was removed and mixture was diluted with MeOH, a orange precipitate formed. Filtration and washing with MeOH gave tert-butyl 4-(2-chloro-5-(4-(dimethylamino)benzamido)-4-nitrophenyl)piperazine-1-carboxylate (1.2 g, 2.381 mmol, 70.8% yield). 1H-NMR (CDCl3, 500 MHz): δ11.53 (1H, s), 8.82 (1H, s), 8.31 (1H, s), 7.89 (2H, d, J=8.85 Hz), 6.74 (1H, d, J=8.85 Hz), 3.64 (4H, m), 3.27 (4H, m), 3.09 (6H, s), 1.50 (9H, s).
Reaction SMILES: [C:1]([O:4]C(=O)C)(=O)[CH3:2].[CH2:8]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:24](OC(C)(C)C)=O>C1(C)C=CC=CC=1>[C:1]([N:20]1[C:19]2[C:18](=[CH:17][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:22][CH:21]=2)[CH:23]=[N:24]1)(=[O:4])[CH3:2]
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(OCc2ccccc2)ccc1N
Solvent: Cc1ccccc1
Product: CC(=O)n1ncc2cc(OCc3ccccc3)ccc21
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
1-Acetyl-5-benzyloxy-1H-indazole can be obtained in the following way: 0.8 ml of acetic anhydride is run into a solution of 500 mg of 4-benzyloxy-2-methylaniline in 3 ml of toluene and the reaction medium is heated at a temperature in the region of 90° C. for 1 hour. 0.55 ml of tert-butyl nitrite is run in dropwise into this solution at approximately 90° C. Heating is continued for 1 hour 30 minutes and then the reaction medium is cooled to a temperature in the region of 20° C. and concentrated to dryness under reduced pressure. The solid residue is taken up with 5 ml of chloroform and the organic phase is washed with 4 ml of a 5% aqueous potassium carbonate solution, dried over magnesium sulfate, filtered and concentrated by evaporation under reduced pressure. The solid thus obtained is purified by chromatography on a silica column with a dichloromethane/cyclohexane (9/1 by volume) mixture as eluent. 467 mg of 1-acetyl-5-benzyloxy-1H-indazole are thus obtained in the form of a brown powder (Rf=0.54, silica gel thin layer chromatography, eluent: cyclohexane/dichloromethane (1/9 by volume)).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([O:14]CC)=[O:13])=[CH:9][NH:8][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.Cl>[OH-].[Na+].C(O)C>[O:1]=[C:2]1[C:11]2[C:10]([C:12]([OH:14])=[O:13])=[CH:9][NH:8][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)CCCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c[nH]c2c1C(=O)CCCC2

Procedure:
A mixture of ethyl 4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-carboxylate (3.48 g, 15.7 mmol ) and ammonium acetate (2.41 g, 31.3 mmol) in N,N-dimethylformamide (25 mL) was heated at 115° C. for 6 hours. The mixture was concentrated in vacuo, ice water was added, then extracted 2× with dichloromethane. The combined organic layers were washed with saturated aqueous sodium bicarbonate then brine, dried over sodium sulfate, filtered through a small pad of Silica gel (1:19 methyl alcohol/dichloromethane), and the filtrate concentrated in vacua to give ethyl 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylate (1.76 g). A solution of this ester in aqueous 5N sodium hydroxide (30 mL) and ethyl alcohol (6 mL) was heated at reflux for 1 hour, then cooled in an ice bath. The mixture was acidified with hydrochloric acid, and the precipitate collected, rinsed with water followed by diethyl ether and allowed to dry to give 4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid (1.17 g). m.p. 225-227° C.
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH:27]4[CH3:34])=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:37]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH:27]5[CH3:34])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:35][CH:36]=2)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC1C(=O)NS(=O)(=O)N1c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: CC1C(=O)NS(=O)(=O)N1c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-methyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-methyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:16][C:17]([O:19][CH:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:18])=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:41][S:42](Cl)(=[O:44])=[O:43].CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([NH:16][C:17]([O:19][CH:20]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[O:18])=[CH:11][C:12]([NH:15][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:13][CH:14]=2)=[O:7])=[CH:33][CH:34]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(NC(=O)c2ccc(Cl)cc2)c(NC(=O)OC(c2ccncc2)C2CCNCC2)c1
Reaction time: 16 h
Yield: 44.8 %

Procedure:
A solution of N1-(4-chlorobenzoyl)-N2-[1-(4-pyridyl)piperidin-4-ylmethoxycarbonyl)-1,2,4-benzenetriamine (40 mg, 0.08 mmol) in 5 mL of CH2Cl2 was treated with pyridine (1 mL) and methanesulfonyl chloride (0.008 mL, 0.09 mmol). After 16 h, the mixture was treated with MeOH (1 mL) and then concentrated. The residue was partitioned between EtOAc and NaOH (aq). The organic layer was dried (MgSO4), concentrated, and purified by chromatography (17:3 CH2Cl2:MeOH) affording 20 mg (40%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8]2[CH2:12][CH2:11][CH2:10][C:9]=2[C:13]2[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][CH:14]=2)[CH:7]=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1.[CH3:32][C:33](=O)[CH2:34][CH3:35]>CC(C)=O>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][O:20][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:9]3[CH2:10][CH2:11][CH2:12][C:8]=3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[O:22][CH2:32][C:33]3[CH:6]=[CH:7][C:2]([F:1])=[CH:35][CH:34]=3)[N:18]=2)=[O:21])=[CH:26][CH:25]=1
Reactant: CCC(C)=O
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(O)c1cccc(C2=C(c3cc(F)ccc3O)CCC2)n1
Solvent: CC(C)=O
Product: O=C(OCc1ccc(F)cc1)c1cccc(C2=C(c3cc(F)ccc3OCc3ccc(F)cc3)CCC2)n1

Procedure:
Prepared by general procedure 5 but using 6-{2-[5-fluoro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic acid instead of 6-{2-[5-chloro-2-(hydroxy)phenyl]cyclopent-1-enyl}pyridine-2-carboxylic acid, 4-fluorobenzyl bromide instead of 4-chlorobenzyl bromide and with acetone as solvent instead of 2-butanone.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=1>O1CCCC1>[CH3:15][C:13]1[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:14]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCN(C)CC2)nc1-c1ccc(C)cc1
Yield: 73 %

Procedure:
Methyl 2-(4-methyl-2-(4-methylpiperazin-1-yl)-6-p-tolylpyrimidin-5-yl)pentanoate was prepared according to the general method A starting from 1-methylpiperazine (0.132 mL; 1.18 mmol) and methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.098 g; 0.235 mmol) in tetrahydrofuran (2 mL). Purification by flash-chromatography on silica gel using a gradient of methanol (0-6%) in dichloromethane furnished 68 mg (74%) of the title compound as an oil. ESI/APCI(+): 397 (M+H)a). ESI/APCI(−): 395 (M−H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:18]1([C:24]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:26][O:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:26][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:25])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: c1ccc(C2(c3ccccc3)CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(O)(c2ccccc2)c2ccccc2)CCN(C)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido (4,3-b) indole (800 g, 4.0 mmol) in DMF (8 mL), sodium hydride [60% dispersion in oil] (480 mg, 12.0 mmol) was added and the reaction mixture stirred for 5 min. 2,2-Diphenyl oxirane (1.176 g, 6.0 mmol) was added dropwise at RT and reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice water and the compound extracted with EtOAc (3×200 mL). The organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum to obtain the crude product. The crude compound was crystallized in ether (50 mL) to obtain 950 mg of white solid product as the free base. 100 mg free base was converted to HCL salt. 1H NMR (DMSO, HCl salt) δ (ppm): 7.50 (d, 2H), 7.30 (m, 3H), 7.20 (m, 5H), 7.10 (s, 1H), 7.05 (d, 1H), 6.70 (d, 1H), 6.08 (bs, 1H), 4.80 (m, 2H), 4.50 (m, 1H), 4.18 (m, 1H), 3.18 (m, 2H), 2.82 (s, 3H), 2.80 (m, 2H), 2.30 (s, 3H).
Reaction SMILES: [BH4-].[Na+].OC(C(F)(F)F)=O.FC(F)(F)C(O)=O.CO[N:19]=[C:20]1[CH2:23][C@H:22]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:21]1[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>O1CCCC1>[CH3:41][C:38]([Si:35]([CH3:37])([CH3:36])[O:34][CH2:33][C@@H:21]1[C@@H:22]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:23][C@H:20]1[NH2:19])([CH3:39])[CH3:40]
Reactant: CON=C1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](N)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 186.3 g (4.9 mol) of sodium borohydride in 4 of tetrahydrofuran (THF) was added (over a 30 minute period 376 mL (4.9 mol) of trifluoroacetic acid TFA), with ice water cooling to maintain temperature below 15° C. [2R,3S]-2,3-bis(((1,1-Dimethylethyl)di-methylsilyl)oxymethyl)cyclobutanone-O-methyl oxime (400 g, 1.03 mol), from Step 2E, in 3 L of THF was added with ice water cooling to maintain the temperature below 20° C. After stirring the reaction mixture at ambient temperature overnight, it was concentrated, diluted with methylene chloride 3 L) and washed portionwise (with cooling with 400 mL of brine. After filtration, the layers of the filtrate were separated and the aqueous layer was washed with methylene chloride. The combined methylene chloride solution was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give crude title compound which was taken on to the next step without purification.
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])[CH2:2][CH:3]=[CH2:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C@:52]1([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[C:63]([CH:73]=[CH2:74])[CH:62]=2)[CH2:56][NH:55][C@H:54]([C:57]([O:59][CH3:60])=[O:58])[CH2:53]1>C(Cl)Cl>[CH2:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([N:55]1[CH2:56][C@:52]([O:51][CH3:50])([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[C:63]([CH:73]=[CH2:74])[CH:62]=2)[CH2:53][C@H:54]1[C:57]([O:59][CH3:60])=[O:58])=[O:12])=[O:7])[CH2:2][CH:3]=[CH2:4]
Reactant: C=Cc1cc([C@@]2(OC)CN[C@H](C(=O)OC)C2)ccc1-c1ccccc1
Reactant: C=CCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3)c(C=C)c2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
(S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoic acid (117 mg, 0.511 mmol), DIEA (0.179 mL, 1.022 mmol) and HATU (143 mg, 0.375 mmol) were added to a solution of (2S,4R)-methyl 4-methoxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (115 mg, 0.341 mmol) in DCM (4 mL). The reaction was stirred at r.t. overnight. The reaction was evaporated and purified by flash chromatography on the Biotage (0-40% EtOAc:Hex) to give (2S,4R)-methyl 1-((S)-2-((but-3-enyloxy)carbonylamino)-3,3-dimethylbutanoyl)-4-methoxy-4-(2-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (150 mg, 0.273 mmol, 80% yield) as a white foam. LCMS: rt=1.89 min. [M+Na]+=571; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH2:1]1[C:6](=O)[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:2]1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][N:21]=[CH:20]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][CH:6]3[CH2:5][CH2:4][N:3]([CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:2][CH2:1]3)=[CH:25][CH:24]=2)[CH:20]=[N:21]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCN(CCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(CCN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.5 %

Procedure:
1-(2-Phenethyl)-4-piperidone (142 mg), 5-aminoindazole (67 mg), and acetic acid (0.02 ml) were dissolved in methanol (1 ml), and a borane-pyridine complex (0.06 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC [chloroform/methanol] to give the title compound (104 mg, yield 65%).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:23]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[N:24]1([C:23]2[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCOC(=O)C1(NC(=O)c2ncccc2N2CCCCC2)Cc2ccccc2C1
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ncccc1N1CCCCC1
Reaction time: 38 h

Procedure:
A 100 mL round bottom flask which contains 2-[(3,4,5,6-Tetrahydro-2H-[1,3′]bipyridinyl-2′-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (360, 370 mg, 0.94 mmol) is charged with 1,4-dioxane (4 mL) and MeOH (4 mL). A stirring bar is added and stirring is initiated. After dissolution, water (2 mL) is added followed by LiOH monohydrate (100 mg, 2.38 mmol). After 38 h, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material has been completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 4 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.29, 84%).
Reaction SMILES: [CH3:1][C:2]1([CH:5]=O)[CH2:4][CH2:3]1.[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][OH:10].C[Si]([C:21]#[N:22])(C)C>CO>[OH:10][CH2:9][C@H:8]([NH:7][C@@H:5]([C:2]1([CH3:1])[CH2:3][CH2:4]1)[C:21]#[N:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[Si](C)(C)C#N
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CC1(C=O)CC1
Solvent: CO
Product: CC1([C@@H](C#N)N[C@@H](CO)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylcyclopropanecarbaldehyde in MeOH (20 mL) was added (R)-2-amino-2-phenylethanol (3.23 g, 23.54 mmol) at rt under N2 in 3 portions. The mixture was stirred at rt for 2 h and then cooled down with ice-water bath and added with trimethylsilyl cyanide (5.74 mL, 42.8 mmol) dropwise over 5 min. The mixture was stirred for 10 min, ice bath was removed and the reaction was stirred at rt overnight. The reaction mixture was concentrated and purified on a 40 g silica gel column (EtOAc/hexane: 0 to 100%) to afford (S)-2-((R)-2-hydroxy-1-phenylethylamino)-2-(1-methylcyclopropyl)acetonitrile. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.40-7.30 (m, 5H), 4.08 (dd, J=9.2, 4.1 Hz, 1H), 3.82 (dd, J=10.8, 4.0 Hz, 1H), 3.64 (t, J=10.0 Hz, 1H), 2.97 (s, 1H), 1.26 (s, 3H), 0.63-0.53 (m, 2H), 0.51-0.42 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.O([Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:14]1([S:11]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([NH2:1])[C:3]([NH:20][C@H:21]4[CH2:22][CH2:23][C@H:24]([O:27][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:25][CH2:26]4)=[C:4]3[CH:10]=[CH:9]2)(=[O:13])=[O:12])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Trans 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol (5.00 g, 13.0 mmol) was dissolved in DCM (50 mL) and 2,6-lutidine (6.0 mL, 51.8 mmol) was added. The mixture was cooled to 0° C. and tert-butyldimethylsilyl triflate (8.90 mL, 38.9 mmol) was added dropwise. The mixture was allowed to return to room temperature and stirred for 16 h. The mixture was concentrated under vacuum, then the residue was dissolved in methanol (10 mL). This mixture was stirred at room temperature for 90 min, then concentrated. The residue was suspended in water and extracted with DCM (×3). The combined organic extracts were washed sequentially with 10% aqueous citric acid, saturated aqueous NaHCO3 and brine, then dried (Na2SO4) and concentrated under vacuum. Purification by column chromatography on silica gel (gradient: DCM to 25% ethyl acetate in DCM) gave 3.09 g (48%) of trans 1-benzenesulfonyl-N*4*-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-1H-pyrrolo[2,3-b]pyridine-4,5-diamine. LCMS (Method B, ESI): RT=3.99 min, m+H=501.1; NMR (400 MHz, CDCl3) δ: 8.14 (d, 2H), 7.84 (s, 1H), 7.54 (m, 1H), 7.45 (m, 3H), 6.55 (d, 1H), 3.70 (m, 2H), 2.35-1.85 (m, 6H), 1.46 (m, 2H), 1.30 (m, 2H), 0.89 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.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>CN(C=O)C>[NH2:17][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][CH2:15][O:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:33](=[O:34])[C:30]3[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][N:31]=3)[CH:3]=[CH:4][C:5]=2[F:25])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Cl)cn4)ccc3F)OCC[C@H]2CS1
Yield: 48 %

Procedure:
A solution of (±)-tert-butyl (4aR,7aR)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate from step G of Preparation 1 (9 mg), 5-chloropicolinic acid (7 mg), HATU (14 mg), and DIEA (11 μL), in DMF (0.12 mL) was stirred at rt for 2 h, and the crude reaction mixture was subjected to preparative HPLC eluting with 0-100% B (A: 95% H2O/5% MeCN, 10 mM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 12 min period to give the title compound as a white foam (6 mg, 48%). 1H NMR (500 MHz, CDCl3) δ 9.87 (1H, s), 8.60 (1H, s), 8.26 (1H, d, J=8.5 Hz), 8.02 (1H, br d), 7.92 (1H, dd, J=2.0, 8.0 Hz), 7.72 (1H, m), 7.14 (1H, t, J=10.5 Hz), 4.20 (2H, m), 3.32 (1H, m), 3.02 (1H, m), 2.90 (1H, m), 2.40 (1H, m), 2.24 (1H, m), and 1.51 (9H, s). MS (M+H)+:505.3.