Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([CH2:9][CH3:10])[CH:3]=1.C([Li])CCC.CN(C)[CH:18]=[O:19].Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:18]=[O:19])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CCc1cc(Br)ccc1I
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C=O
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of 4-bromo-2-ethyl-1-iodobenzene (75 g, 0.24 mol) in tetrahydrofuran (375 ml) at −75° C. is added n-butyl lithium (1.6 M in hexanes, 196 ml, 0.31 mol) dropwise, maintaining the temperature of the reaction mixture below −70° C. When the addition is complete the mixture is stirred at −75° C. for an additional 30 minutes and then N,N-dimethylformamide (70.7 g, 0.97 mol) is added dropwise. After the addition is complete the reaction is stirred at −75° C. for 2 hours, then allowed to warm to room temperature for 2 hours. The mixture is cooled in an ice bath and acidified with 0.5 N aqueous hydrochloric acid. The mixture is extracted with ethyl acetate (3×500 ml) and the organic fractions are combined, washed with brine, and dried over anhydrous sodium sulphate. The mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-bromo-2-ethylbenzaldehyde (48 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=2)[N:10]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:9]1=[O:38])([CH3:4])([CH3:3])[CH3:2].Br[C:41]1[CH:45]=[CH:44][S:43][CH:42]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:39])[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:41]3[CH:45]=[CH:44][S:43][CH:42]=3)[CH:15]=2)[N:10]([CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:9]1=[O:38])([CH3:3])([CH3:4])[CH3:2]
Reactant: Brc1ccsc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CC(NC(=O)OC(C)(C)C)C(=O)N2Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccsc3)ccc2N(Cc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
To a solution of 4A (25 mg, 0.043 mmol) in degas sed THF (2 mL) was added tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), K2C3 (18 mg, 0.13 mmol), and 3-bromothiophene (21 mg, 0.13 mmol). The resulting mixture was heated at 70° for 16 h under argon. After cooling to RT, the mixture was filtered through Celite®, rinsing with CH2Cl2. The filtrate was evaporated under vacuum and the resulting residue was chromatographed on silica gel eluted with EtOAc in hex ane to obtain the title compound (14.5 mg, somewhat impure).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH:3]=1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)(=[O:11])=[O:10])=[C:4]([CH:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[OH:31])[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(O)c2ccccc2Cl)cc1OC
Reaction time: 18 h
Yield: 43.9 %

Procedure:
To 0.152 g of the compound obtained in Example 5.1 dissolved in 5 ml of ethanol is added 0.036 g of sodium borohydride and the mixture is left for 18 hours at room temperature. The reaction medium is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is taken up in a minimum amount of ethyl acetate and the precipitate formed is filtered off and dried to give 0.067 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:11]([N:16]2[CH2:21][CH:20]=[C:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:9][C:10]1[C:11]([N:16]2[CH2:17][CH:18]=[C:19]([C:22]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:23])[CH2:20][CH2:21]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)cc1)C1=CCN(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloroaniline (13.2 g, 103 mmol), 3′-chloro-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylic acid (16.49 g, 69.1 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26.5 g, 1.38 mmol) were combined in dichloromethane (150 mL) and stirred overnight at ambient temperature. The mixture was diluted with dichloromethane (200 mL), washed with water (400 mL), 400 mL brine, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel using hexane:ethyl acetate (7:3) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.20 (dd, 1H), 7.70 (dd, 1H), 7.62 (s(br) 1H), 7.54 (d, 2H), 7.30 (d, 2H), 6.92 (dd, 1H), 6.76 (m, 1H), 4.16 (dd, 2H), 3.64 (dd, 2H), 2.66 (m, 2H) MS (ESI) 349 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([OH:29])[CH3:28].[CH3:30][O:31][C:32]([C:34]1[S:35][C:36]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[CH:37][C:38]=1O)=[O:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:30][O:31][C:32]([C:34]1[S:35][C:36]([N:40]2[CH:44]=[CH:43][N:42]=[CH:41]2)=[CH:37][C:38]=1[O:29][CH:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH3:28])=[O:33]
Reactant: CC(O)c1ccccc1Cl
Reactant: COC(=O)c1sc(-n2ccnc2)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(-n2ccnc2)cc1OC(C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Triphenyl phosphine (304 mg, 1.16 mmol, 1.3 Eq.), 1-(2-Chloro-phenyl)-ethanol (182 mg, 1.16 mmol, 1.3 Eq.) and 3-Hydroxy-5-imidazol-1-yl-thiophene-2-carboxylic acid methyl ester (200 mg, 0.89 mmol, 1.0 Eq.) in anhydrous THF (5 mL) were cooled to 0° C. under nitrogen. Diethyl azodicarboxylate (183 μL, 1.16 mmol, 1.3 Eq.) was added dropwise. The reaction was stirred at 0° C. for 30 minutes then warmed to ambient temperature for 3.5 hours. The solvent was removed in vacuo and the residue re-dissolved in DCM and absorbed onto SiO2. The crude product wad purified by column chromatography (75% EtOAc/petroleum ether) to give the sub-title compound as a light yellow foam (290 mg, 0.80 mmol, 84%); 1H NMR (400 MHz, d-6 DMSO) δ 1.60 (3H, d), 3.80 (3H, s), 5.90 (1H, q), 7.14 (1H, d), 7.31-7.37 (1H, m), 7.43-7.49 (3H, m), 7.74-7.78 (2H, m), 8.29 (1H, d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=1)[C:10]#N.O=[CH:24][C:25](=C)[CH3:26]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[CH:24]=[C:25]([CH3:26])[CH:10]=1
Reactant: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)cc1F
Reactant: C=C(C)C=O
Product: Cc1cc(-c2ccc(F)cc2F)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(2,4-difluorophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale brown powder (yield 32%), melting at 170-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>C1COCC1>[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:8][CH:9]=[CH:10][N:11]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)nccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reaction time: 1 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.546 g, 2.182 mmol) in THF (7 mL) was cooled in a dry ice-acetone bath for 5 minutes. Lithium bis(trimethylsilyl)amide (1M in THF) (2.381 ml, 2.381 mmol) was added dropwise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A suspension of 1-chloroisoquinoline-6-sulfonyl chloride (0.520 g, 1.984 mmol) in THF (5 mL) was added dropwise, then the cooling bath was removed. The reaction was stirred for one hour. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by silica gel chromatography on a 40 g silica column with 0 to 30% EtOAc/Heptane. The product containing fractions were combined and concentrated to afford a white solid. The solid was triturated with methanol and stirred for five minutes. The solution was filtered and the solids were washed with methanol. The solids were dried under a vacuum to afford 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. m/z (ESI) 498.1 (M+H)+.
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[NH2:9][CH2:10][CH2:11][C:12]#[N:13].C[O-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[C:20]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1>CO.C(#N)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:13][CH2:12][CH2:11][C:10]#[N:9])[CH:21]=[C:20]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:19]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: N#CCCN
Agent: C[O-]
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: N#CCCNc1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 3-aminopropanenitrile fumarate (147 mg, 0.74 mmol) and sodium methoxide (1.1 mL, 0.54 mmol) in MeOH (2 mL) was added dropwise to an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (64 mg, 0.25 mmol) in acetonitrile (2 mL). The mixture stirred at rt over night. The mixture was heated to 50° C. for 20 h. The reaction mixture was concentrated in vacuo and the crude was partitioned between EtOAc and 1M NaOH. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound, 29 mg (40%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[C:19]([CH:25]=O)=[N:20][CH:21]=[C:22]([CH3:24])[CH:23]=1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:16])[N:7]([CH:8]1[CH2:9][CH2:10]1)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:25][C:19]1[C:18]([CH3:17])=[CH:23][C:22]([CH3:24])=[CH:21][N:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CC(C)(C)OC(=O)N(CCCCN)C1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(CNCCCCN(C(=O)OC(C)(C)C)C2CC2)c(C)c1
Yield: 89 %

Procedure:
Using General Procedure B, (4-amino-butyl)-cyclopropylcarbamic acid tert-butyl ester and 3,5-dimethyl-pyridine-2-carbaldehyde in MeOH were reacted with NaBH4 to obtain cyclopropyl-{4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester as a colorless oil (0.217 g, 89%). 1H NMR (CDCl3) δ 0.52-0.58 (m, 2H), 0.68-0.74 (m, 2H), 1.44 (s, 9H), 1.53-1.65 (m, 4H), 2.26 (s, 6H), 2.45-2.50 (m, 1H), 2.70 (t, 2H, J=6.9 Hz), 3.19 (t, 2H, J=7.2 Hz), 3.82 (s, 2H), 7.23 (s, 1H), 8.20 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][S:11][CH3:12].ClN1C(=O)CCC1=O>C(Cl)Cl>[CH3:10][S:11]([CH3:12])=[N:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: CSC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(C)nc(N=S(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
To a solution of 12.3 g (0.10 mole) of 2-amino-4,6-dimethylpyrimidine and 8 ml (0.109 mole) of methylsulfide in 100 ml of methylene chloride at -20° C. was added dropwise a solution of 13.3 g (0.10 mole) of N-chlorosuccinimide in 300 ml of methylene chloride. After addition, the resulting solution was warmed to room temperature and was kept at room temperature for one hour with stirring. The solution was then washed with 400 ml of 2.5% sodium hydroxide aqueous solution and then 400 ml of water. This solution was dried over sodium sulfate and filtered. The filtrate was washed with ethyl ether, and dried under vacuum at ambient temperature to afford 4 g of the title compound as a white solid, m.p. 117°-120° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[CH:27]=[C:26]([CH2:28][NH2:29])[CH:25]=[C:24]([CH3:30])[N:23]=1>CCCCO>[CH3:21][C:22]1[CH:27]=[C:26]([CH2:28][NH:29][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:25]=[C:24]([CH3:30])[N:23]=1
Reactant: Cc1cc(CN)cc(C)n1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CNc2nc(F)nc3[nH]cnc23)cc(C)n1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.9 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (2,6-dimethylpyridin-4-yl)methanamine (0.54 g, 4 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient flash column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.5 g (63%); δH CDCl3, 250 MHz) 2.48 (6H, s, 2×CH3), 3.65-3.54 (2 H, m, NHCH2), 4.61 (1 H, s, br, NH), 7.32 (2 H, s, ArH), 7.84 (1 H, s, ArH)), 9.05 (1 H, s, br, NH); δC (CDCl3, 250 MHz) 159.2 (C), 156.62 (C), 156.61 (C), 155.46 (C), 146.92 (CH), 136.3 (C), 122.05 (2×CH), 119.48 (C), 41.6 (CH2), 18.06 (2×CH3)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:4]1[N:3]=[C:2]([N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:23][CH2:24]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(c2nc(-c3ccccc3O)nc3ccccc23)CC1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a suspension of 2-(4-chloroquinazolin-2-yl)phenol (2.0 g, 7.79 mmol) in CH2Cl2 (25 mL) at 0° C. under an N2 atmosphere, was added dropwise tert-butyl piperidin-4-ylcarbamate (2.08 g, 10.13 mmol) and triethylamine (2.20 mL, 15.8 mmol) in CH2Cl2 (10 mL). The reaction was stirred overnight, quenched with water and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to afford tert-butyl 1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate (3.27 g, 100%-solvent residue). LC/MS: m/z 421.3 (M+H)+ at 2.70 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C@@H:3]1[CH2:18][C:19](O)=[O:20].[N:22]1([CH:28]([C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C@H:36]([NH:40]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]3)[CH3:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=2)(=[O:9])=[O:10])[C@@H:3]1[CH2:18][C:19]([NH:40][C@H:36]1[C:37]2[C:32](=[CH:31][C:30]([CH:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH3:29])=[CH:39][CH:38]=2)[CH2:33][CH2:34][CH2:35]1)=[O:20]
Reactant: CC(c1ccc2c(c1)CCC[C@H]2NC(=O)OC(C)(C)C)N1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C=CNC(=O)[C@H]2CC(=O)N[C@@H]2CCCc3cc(C(C)N4CCCCC4)ccc32)cc1
Reaction time: 8 h

Procedure:
(R)-2-(3-Oxo-1-tosyl-1,2,3,4-tetrahydropyrazin-2-yl)acetic acid (140 mg) and (1R)-6-(1-(piperidin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-amine (122 mg, prepared in Example 12) are combined in 2 mL of DMF, then EDCI (112 mg) and HOBT (79 mg) are added and the mix is stirred under nitrogen overnight. Next the mix was quenched with sat. sodium bicarb., extracted with ethyl acetate, washed with brine, washed with water, dried with sodium sulfate, and concentrated. The compound was then purified on the varian using 10 to 90% acetonitrile in water to give the product. MS 551 (ESI, pos. ion).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[NH2:28][C:29]1[CH:30]=[C:31]([NH:35][C:36]([C@@H:38]2[CH2:42][CH2:41][CH2:40][N:39]2[CH3:43])=[O:37])[CH:32]=[CH:33][CH:34]=1>CN1C(=O)CCC1>[CH2:18]([NH:17][C:15]1[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=[C:11]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]([C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[CH3:43])=[O:37])[CH:30]=2)[N:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)c1cnc(On2nnc3ccccc32)nc1NCc1ccccc1
Reactant: CN1CCC[C@H]1C(=O)Nc1cccc(N)c1
Solvent: CN1CCCC1=O
Product: CN1CCC[C@H]1C(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCc3ccccc3)n2)c1
Temperature: 100 °C
Yield: 77 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-(benzylamino)pyrimidine-5-carboxamide (50 mg, 0.14 mmol) in NMP (1 mL) was added (S)-N-(3-aminophenyl)-1-methylpyrrolidine-2-carboxamide (33 mg, 0.152 mmol) and pTsO.RH2O (60 mg, 0.28 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, and purified by preparative HPLC to give of (S)-4-(benylamino)-2-(3-(1-methylpyrrolidine-2-carboxamido)phenylamino)pyrimidine-5-carboxamide (48 mg). MS found for C24H27N7O2 as (M+H)+ 446.5. λ=247.5.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH:33]([C:37]#[N:38])[C:34]([NH2:36])=[O:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:36][C:34](=[O:35])[CH:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:37]#[N:38]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: N#CC(N)C(N)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: N#CC(NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1)C(N)=O
Reaction time: 1 h
Yield: 28.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 20 mg, 0.046 mmol), (R/S)-2-amino-2-cyanoacetamide (4.59 mg, 0.046 mmol), 4-methylmorpholine (18.76 mg, 0.185 mmol), and HATU (22.92 mg, 0.060 mmol) were added to DMF (2 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.4 min) to provide N-(2-amino-1-cyano-2-oxoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (8 mg, 0.013 mmol, 28.6% yield) as a mixture of diastereomers. LCMS=513.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.28 (2 H, m), 7.50-7.80 (7 H, m), 5.40-5.63 (1 H, m), 5.27 (1 H, s); HPLC peak RT=9.2 min (Method A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH3:16])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H-].[CH2:19]([Al+]CC(C)C)C(C)C.COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([O:17][CH3:19])[C@H:4]([CH3:16])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: COC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: COC(OC)OC
Product: COC(OC)[C@H](C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of N-carbobenzyloxy-L-alanine methyl ester (41.0 g, 0.71 mol) in 300 ml anhydrous toluene at -78° C., under N2, was added dropwise a toluene solution of diisobutyl-aluminum hydride (25% wt. % soln., 234 ml, 0.345 mol) over 0.5 hour. After the addition was complete the mixture was stirred 0.75 hour and quenched with the dropwise addition of 2N HCl (350 ml). The solution was warmed to room temperature and extracted with ethyl acetate. The combined organic layers were washed with brine and dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 400 ml methanol and trimethylorthoformate (43 ml, 0.40 mol) and p-toluenesulfonic acid (0.723 g 3.8 mmol) was added. The mixture was stirred overnight and concentrated in vacuo to approximately 70% of the original volume. The residue was poured onto 800 ml of saturated NaHCO3. Ether and water were added. The aqueous layer was extracted with ether. The combined organic layers were washed with brine and dried (MgSO4) and concentrated in vacuo. Chromatography of the residue on HPLC using 30% ethyl acetate in hexanes as eluents provided the oily product N-carbobenzyloxy-L-alaninal dimethyl acetal.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([CH3:21])([CH3:20])[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>C(O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:11]([CH3:20])([CH3:21])[C:12]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc(C(c2ccccc2)C(C)(C)C(=O)Nc2nccs2)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(O)c1ccc(C(c2ccccc2)C(C)(C)C(=O)Nc2nccs2)cc1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of the title compound of Example 368 (20 mg, 0.053 mmol) in ethanol (1 ml) was added sodium borohydride (2 mg, 0.053 mmol) at ° C. The reaction mixture was stirred for 2 h. It was diluted with DCM and saturated aqueous NaHCO3. After separation, the organic extract was washed (brine), dried (MgSO4) and concentrated. The crude product was purified by silica gel flash chromatography using 0 to 50% ethyl acetate in heptane to afford the title compound of Example 371 as a white solid (18 mg, 89% yield). LC/MS (m/z) 381.19 [(M+1)+]; HPLC Rt: 3.246 min. 1H NMR (400 MHz, MeOD) δ ppm 7.36-7.40 (5H, m) 7.28-7.23 (4H, m) 7.20-7.16 (1H, m) 7.06 (1H, s) 4.79-4.75 (1H, m) 4.64 (1H, s) 1.4-1.39 (9H, m).