Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)[CH:11]=1.[C:25]1(S(OCCC)(=O)=O)[CH:30]=CC=C[CH:26]=1>CN(C)C=O.O>[CH2:6]([O:5][C:3]([CH2:2][S:1][CH2:26][CH2:25][CH2:30][C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]([C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:17]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)CS
Reactant: c1cncc(-n2ccc3ccccc32)c1
Reactant: CCCOS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSCCCc1cn(-c2cccnc2)c2ccccc12
Reaction time: 15 h

Procedure:
A solution of 0.36 g of ethyl mercaptoacetate in 20 ml of dimethylformamide is treated with 0.145 g of a 50% oil dispersion of sodium hydride at room temperature under nitrogen for 15 minutes. A solution of 1.13 g of N-(3-pyridyl)indole-3-propyl benzenesulfonate in 5 ml of dimethylformamide is added at room temperature. The reaction mixture is stirred for 15 hours, diluted with 100 ml of water and extracted 4 times with 50 ml of ethyl ether. The organic extracts are washed with 50 ml of water and 20 ml of cold 1N hydrochloric acid. The acid phase is extracted with ether and brought to pH=8.5 with 50% sodium hydroxide solution. The aqueous phase is extracted with chloroform (3×30 ml). The chloroform extract is dried over potassium carbonate and evaporated to yield 3-[3-(ethoxycarbonylmethylthio)propyl]-N-(3-pyridyl)indole; IR (CH2Cl2) 1725 cm-1.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[C:13]1[C:18]([C:19](=[O:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:26])[N:16]=[C:15]2[S:27][C:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:14]=12)[CH:3]=[CH2:4].[BH4-].[Na+]>C(O)C>[CH2:2]([O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[C:13]1[C:18]([CH:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:26])[N:16]=[C:15]2[S:27][C:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[C:14]=12)[CH:3]=[CH2:4]
Reactant: C=CCOc1cc(C)ccc1-c1c(C(=O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C=CCOc1cc(C)ccc1-c1c(C(O)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
To a stirred solution of ethyl {4-[2-(allyloxy)-4-methylphenyl]-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl}(oxo)acetate hydrochloride salt (Step 6, 1.1 g, 2.56 mmol) in ethanol (20 mL) was added sodium borohydride (145 mg, 3.84 mmol), and the reaction was stirred at room temperature for 5 minutes. The reaction was concentrated in vacuo, and the residue was partitioned between ethyl acetate (20 mL) and hydrochloric acid (aqueous, 1 N, 30 mL). The organic layer was separated, washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to give a mixture of diastereoisomers of the title compound as a pale orange gum, 1.1 g, in a 91% yield. LCMS (2 min acidic) 1.53 min 52-81% pure by UV, ES+/AP+ 452. 1HNMR (400 MHz, CDCl3 δ ppm 1.17-1.21 (m, 3H), 1.53-1.64 (m, 2H), 1.71-1.87 (m, 4H), 2.43 (s, 3H), 2.63 (s, 3H), 2.81 (t, 2H), 4.08-4.22 (m, 2H), 4.47-4.51 (m, 2H), 5.08-5.17 (m, 2H), 5.18 (s, 1H), 5.86 (m, 1H), 6.79 (s, 1H), 6.81-6.85 (m, 1H), 7.02 (d, 1H).
Reaction SMILES: OCC[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](NC)=[C:9](C(=O)C)[CH:8]=[CH:7]2.C(#N)CC#N>N1C=CC=CC=1>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CNc1c(C(C)=O)ccc2cc(CCO)ccc12
Solvent: c1ccncc1
Solvent: N#CCC#N
Product: c1ccc2ccccc2c1
Temperature: 95 °C

Procedure:
To a solution of 201 mg (0.83 mmol) of 1-(6-2-hydroxyethyl-methylamino-2-naphthyl)-1-ethanone in pyridine (6 mL), malononitrile (236 mg, 3.6 mmol) was added and the mixture was heated at 95° C. for 24 hours. The solvent was removed in vacuo, and the residue was chromatographed by radial chromatography (4 mm SiO2 1% MeOH/CH2Cl2) to give 150 mg (73%) of 2-(1,1-dicyanopropen-2-yl)-6-2-hydroxyethyl)-methyl-amino)-naphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14]([C:20]#[C:19][C:21]4[CH:22]=[CH:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Fc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Product: Nc1ccc(C#Cc2cnc3c(F)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-fluoro-3-iodo-imidazo[1,2-a]pyridine (example C.30 step 2) (300 mg, 0.8 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (114 mg, 0.8 mmol) according to general procedure II. Obtained as a light brown solid (170 mg, 58%). MS (ISP) 363.2 [(M+H)+], 365 [(M+2+H)+]; mp 259° C.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].C[Li].[CH2:7]([O:14][C:15]([NH:17][C@@H:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][C@@H:19]1[NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:36](O)(=O)C>O1CCCC1.C(OCC)C>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]1[CH2:23][CH2:22][C:21]([OH:24])([CH3:36])[CH2:20][C@@H:19]1[NH:25][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)O
Reactant: O=C1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Anhydrous cerium chloride (6.4 g) was suspended in tetrahydrofuran (50 ml), and the suspension was cooled to −78° C. in an argon atmosphere. A methyllithium solution (1.14N diethyl ether solution, 22.5 ml) was added to the suspension, and the mixture was stirred at −78° C. for 30 minutes. A tetrahydrofuran solution (50 ml) of (±)-cis-N1,N2-bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine (3.0 g) was added dropwise at −78° C., and the mixture was stirred for 30 minutes. The reaction mixture was poured into a 3% aqueous solution (100 ml) of acetic acid, and diethyl ether (50 ml) was added to stir the mixture at room temperature for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified twice by medium-pressure column chromatography on silica gel (methanol:chloroform=0:100-1:19) to obtain the title compound (Stereoisomer A) (780 mg) as a colorless foamy compound and the title compound (Stereoisomer B) (1.1 g) as white powder.
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][CH2:20]3)=[C:15]([CH3:30])[CH:14]=2)=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:23]([O:22][C:19]1([C:16]2[CH:17]=[CH:18][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:31])=[O:3])=[CH:10][CH:9]=3)=[CH:14][C:15]=2[CH3:30])[CH2:21][CH2:20]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
Using General Procedure I; a solution of ethyl4-[4-(1-benzyloxycyclopropyl)-3-methyl-phenylethynyl]-benzoate (Compound 79, 68.0 mg, 0.17 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (360.0 mg, 9.0 mmols, 3.0 mL of a 3N aqueous solution) and stirred overnight at room temperature. Work-up afforded 48.0 mg (76%) of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[CH:33]=[C:32]([CH3:34])[NH:31][C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:45](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:26]=[C:27]5[CH:33]=[C:32]([CH3:34])[N:31]([CH3:45])[C:28]5=[N:29][CH:30]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5[nH]c(C)cc5c4)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4cnc5c(c4)cc(C)n5C)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridine-4-yl)benzo[d]thiazol-6-yl)acetate (100 mg, 0.16 mmol) in DMF (5 mL) was added cesium carbonate (68 mg, 0.208 mmol). The reaction solution was stirred at room temperature for 5 minutes, iodomethane (30 mg, 0.208 mmol) was added. The reaction solution was stirred for 30 minutes and quenched with water. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C36H35ClN4O3S: 639.2 (M+H+); Found: 639.3 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9])(=[O:3])[NH2:2].Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22].C(N(CC)CC)C>C(#N)C>[OH2:3].[ClH:9].[C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7](=[O:10])[CH2:8][N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[C:20]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH2:24][CH2:25]1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccccc1NC(=O)CCl
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1OC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCN(CC(=O)Nc3ccccc3C(N)=O)CC2)cc1OC
Product: O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
5.00 Grams of o-carbamoyl-α-chloroacetanilide, 8.09 g of 3,4-dimethoxybenzoylpiperazine monohydrochloride, 8.31 g of triethylamine and 30 g of acetonitrile were mixed together and the mixture was stirred at 50° C. for 5 hours. Then the reaction mixture was ice-cooled, and the crystals formed were removed by filtration and the filtrate obtained was concentrated to dryness. The residue obtained was extracted with chloroform--1N sodium hydroxide aqueous solution, and the chloroform layer was washed with water, dried then chloroform was removed by distillation. The residue obtained was purified by a silica gel column chromatography and the desired product was converted into a hydrochloride by using hydrochloric acid-ethanol, then recrystallized from water-acetone to obtain 7.43 g of o-carbamoyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride monohydrate in the form of colorless needle-like crystals. Melting point: 122.0°-125.0° C. (decomposed).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:53])([CH3:52])[C@H:42]([N:46]1[CH2:50][CH2:49][NH:48][C:47]1=[O:51])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH3:40][C:41]([CH3:53])([CH3:52])[C@H:42]([N:46]1[CH2:50][CH2:49][NH:48][C:47]1=[O:51])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: CC(C)(C)[C@@H](C(=O)O)N1CCNC1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCNC1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.6 %

Procedure:
A solution of the product of Example 1H (0.020 g, 0.038 mmol) in tetrahydrofuran (0.40 mL) was treated with the product from Example 160B (0.0075 g, 0.038 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 12 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with 50% acetone in dichloromethane to give the title compound (0.020 g, 74% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.86 (s, 9 H), 1.33-1.56 (m, 2 H), 2.55-2.72 (m, 4 H), 2.82 (dd, J=5.9, 12.9 Hz, 1 H), 2.89-2.56 (m, 1 H), 3.08 (q, J=8.8 Hz, 1 H), 3.24-3.28 (m, 1 H), 3.50-3.57 (m, 4 H), 3.83 (d, J=9.6 Hz, 1 H), 3.87-3.94 (m, 1 H), 3.97 (s, 1 H), 4.14-4.20 (m, 1H), 4.42 (d, J=7.4 Hz, 1 H), 6.29 (s, 1 H), 6.88 (d, J=9.6 Hz, 1 H), 7.09-7.25 (m, 7 H), 7.30-7.34 (m, 1 H), 7.44 (d, J=9.6 Hz, 1 H), 7.83-7.97 (m, 5 H), 8.62 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:17][CH2:18][CH3:19]>>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(N2CCNCC2)ccc1F
Reactant: CCCI
Product: CCCN1CCN(c2ccc(F)c(C#N)c2)CC1

Procedure:
Beginning with 2-fluoro-5-piperazin-1-yl-benzo-nitrile and 1-iodopropane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 247 (M+, 25), 218 (bp), 175 (28), 147 (33), 70 (65).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH2:19][C:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21]=1.[Br:39][C:40]1[S:41][C:42]([C:45](O)=[O:46])=[CH:43][N:44]=1>CN(C=O)C.CCOC(C)=O>[Br:39][C:40]1[S:41][C:42]([C:45]([NH:19][C:20]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[N:22]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21]=2)=[O:46])=[CH:43][N:44]=1
Reactant: CC(C)(C)OC(=O)n1nc(N)cc1-c1ccc(F)cc1
Reactant: O=C(O)c1cnc(Br)s1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2cnc(Br)s2)cc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
2-Chloro-1-methylpyridinium iodide (0.84 g, 3.3 mmol), DIPEA (0.78 mL, 4.4 mmol) and tert-butyl 3-amino-5-(4-fluorophenyl)-1H-pyrazole-1-carboxylate (0.5 g, 2.2 mmol) were added to a solution of 2-bromothiazole-5-carboxylic acid (0.45 g, 2.2 mmol) in DMF (6 mL). The resulting solution was stirred at RT till completion of the reaction. Then the mixture was diluted with AcOEt, washed with water, dried with Na2SO4 and concentrated. The crude product was purified by column (50%-100% AcOEt/PE gradient), yielding tert-butyl 3-(2-bromothiazole-5-carboxamido)-5-(4-fluorophenyl)-1H-pyrazole-1-carboxylate (160 mg, 20%) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C@H:2]([CH2:7][OH:8])[C@@H:3]([CH3:4])[CH2:5][CH3:6])(=[O:25])=[O:24]
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reaction time: 12 h

Procedure:
To a solution of (S) isoleucinol (23 mg, 0.2 mmol) in THF (3 mL) was added triethylamine (46 μL, 0.24 mmol) and 2-bromobenzenesulfonyl chloride (51 mg, 0.2 mmol). The solution was stirred for 8 to 16 hours, then concentrated. The residue was dissolved in MeOH (1.5 mL) and purified by semi-preparative RP-HPLC using the following conditions:
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=1)#[CH:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[N:20][OH:21])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]2[CH:2]=[C:1]([C:3]3[C:4]([NH2:10])=[N:5][C:6]([NH2:9])=[CH:7][CH:8]=3)[O:21][N:20]=2)=[CH:16][CH:17]=1
Reactant: ON=C(Cl)Cc1ccc(Br)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Br)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridine-2,6-diamine (50 mg, 0.376 mmol) described in Manufacturing Example 13-1-3 and 4-bromophenyl acetohydroximoyl chloride (150 mg, 0.602 mmol) described in Manufacturing Example 207-1-3 was added triethylamine (131 μL, 0.94 mmol), which was stirred for 2 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH is silica gel column chromatography (ethyl acetate:heptane=1:1, then ethyl acetate) to obtain the title compound (85 mg, 66%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:36][C:37]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:38]=1[NH2:39]>O1CCCC1.ClCCl>[CH3:36][C:37]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][C:38]=1[NH:39][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:9]2[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:19][CH:20]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(Nc2nc(-c3ccccc3)c3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.2 %

Procedure:
To a solution of 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride (1.56 g, 4.35 mmol) and Hunig's base (1.3 mL, 7.5 mmol) in tetrahydrofuran (50 mL) and dichloromethane (10 mL) was added 2-methyl-5-nitroaniline (726 mg, 4.78 mmol), and the reaction was allowed to stir at rt overnight. The mixture was concentrated on a rotary evaporator and purified by flash column chromatography to give N-(2-methyl-5-nitrophenyl)-4-[(4-phenylquinazolin-2-yl)amino]benzamide (522 mg, 58%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.46 (s, 1H), 10.03 (s, 1H), 8.49 (d, 1H), 8.27 (d, 2H), 8.10 (d, 3H), 7.80 (m, 5H), 7.73 (m, 3H), 7.66 (d, 1H), 7.50 (dt, 1H), 2.50 (s, 3H). MS (EI) for C28H21N5O3: 476.0 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([NH:30][C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)[CH2:18][N:19]2C(=O)C3C(=CC=CC=3)C2=O)=[C:11]([N+:39]([O-:41])=[O:40])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:19][CH2:18][CH:17]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:35]#[N:36])=[CH:37][CH:38]=1)[C:12]1[CH:13]=[C:14]([O:15][CH3:16])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[N+:39]([O-:41])=[O:40]
Reactant: COc1cc(C(CN2C(=O)c3ccccc3C2=O)Nc2ccc(C#N)cc2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C(CN)Nc2ccc(C#N)cc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
4-[1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-benzonitrile (2.7 g, 5 mmoles) was dissolved in ethanol (100 ml) and hydrazine hydrate (0.65 ml, 20 mmoles) added. The reaction was heated to 60° C. for 3 hours then at room temperature for 48 hours. The solids that precipitated were filtered off and the residue submitted to flash chromatography to yield 4-[2-Amino-1-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-ethylamino]-benzonitrile (1.5 g). 1HNMR(CDCl3): 7.75 (s, 1H), 7.3-7.5 (m, 7H), 7.05 (s, 1H), 6.45 (d, 2H), 5.80 (bs, 1H), 5.32 (m, 1H), 5.19 (s, 2H), 3.81 (s, 3H), 3.25 (dd, 1H), 3.0 (dd, 1H), 1.65 (bs, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O(C(O)C)C>[C:1]1([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:14]=[C:15]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=Cc1ccccc1
Agent: COC(C)O
Product: c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 25 °C
Yield: 37 %

Procedure:
N1-phenylbenzene-1,2-diamine (4.15 g, 22 mmol) and benzaldehyde (2.1 g, 20 mmol) were mixed with methoxylethanol (60 ml) in a three-neck flask. The mixture was heated up to reflux for 48 hours. After cooled to room temperature, the solvent was evaporated. The residue was purified by column chromatography using dichloromethane to 5% of ethyl acetate in dichloromethane as eluent. 2 g of desired product was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.[OH-].[K+].[CH3:11]I.O>C(O)C>[CH3:11][N:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1
Reactant: CI
Reactant: OCCc1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(CCO)cn1

Procedure:
To a solution cooled (0° C.) of 2-(1H-pyrazol-4-yl)ethanol (93 g, 0.83 mol) and potassium hydroxide (48.8 g, 0.87 mol) in absolute ethanol (9.25 L) was added methyl iodide (178 g, 1.25 mol) dropwise. The mixture was allowed to react for 30 min, at which time it was poured into water (400 mL) and extracted with diethyl ether (4×100 mL). The combined organic layers were dried (Na2SO4), filtered, concentrated in vacuo, and purified by vacuum distillation to afford the title compound.
Reaction SMILES: [N:1]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:2]1[C:3]([N:5]([CH3:12])[CH2:6][C:7]([O:9]CC)=[O:8])=[O:4].O[Li].O>O1CCOCC1.O>[N:1]1([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:2]1[C:3]([N:5]([CH3:12])[CH2:6][C:7]([OH:9])=[O:8])=[O:4]
Reactant: CCOC(=O)CN(C)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CN(CC(=O)O)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Reaction time: 12 h
Yield: 90.1 %

Procedure:
To a solution of Cbz-D-hPro-N(Me)Gly-OEt (6 g, 16.6 mmol) in p-dioxane (200 mL) was added a solution of LiOH.H2O (2.78 g, 66.2 mmol) in water (100 mL) with vigorous stirring. After stirring for 12 hours, the solution was concentrated to a volume of 50 mL, diluted with water (100 mL), and extracted twice with diethyl ether (200 mL). The aqueous phase was adjusted to pH 2 with 5N aqueous HCl and extracted three times with ethyl acetate (150 mL). The combined ethyl acetate extracts were dried with MgSO4, filtered, and concentrated to give a white solid (5 g, 91%).