Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:7][C:6]2[CH:8]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Br)cc1

Procedure:
Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-bromo-benzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH2:12]([O:14][C:15]([C@:17]1([F:37])[C@@H:22]2[C@H:18]1[CH2:19][C@@H:20]([OH:36])[C@@:21]2([N:33]=[N+:34]=[N-:35])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[O:16])[CH3:13].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:12]([O:14][C:15]([C@:17]1([F:37])[C@@H:22]2[C@H:18]1[CH2:19][C@@H:20]([O:36][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)[C@@:21]2([N:33]=[N+:34]=[N-:35])[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])=[O:16])[CH3:13]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OC(=O)c3ccc(Cl)c(Cl)c3)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Temperature: 25 °C
Reaction time: 28 h
Yield: 99.9 %

Procedure:
234 mg of 3,4-dichlorobenzoyl chloride was added to 202 mg of (1R,2R,3R,5R,6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester dissolved in 3.7 mL of pyridine, and the mixture was stirred for 28 hours at room temperature, under a nitrogen atmosphere. After 100 mL of ethyl acetate was added to the reaction solution, this ethyl acetate solution was washed with a saturated aqueous solution of copper sulfate and with water, and then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=10:1), thereby yielding 298 mg of (1R,2R,3R,5R,6R)-2-azido-3-(3,4-dichlorobenzoyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])[CH:6]=[CH:5]2.[H-].[Na+].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[CH3:21][S:22]([O:18][C:12]([C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[N:8]=1)([CH3:17])[C:13]([F:15])([F:14])[F:16])(=[O:24])=[O:23]
Reactant: CC(O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)(c1ccc2cc(Br)ccc2n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 6-Bromo-quinolin-2-yl-1,1,1-trifluoropropan-2-ol (5.06 g, 15.8 mmol) in THF (50 ml) was added sodium hydride (1.26 g, 31.6 mmol) portionwise at 0° C. and the mixture was stirred at room temperature for 2 hour. A solution of methanesulfonyl chloride (3.62 g, 31.6 mmol) in THF (10 ml) was added there at 0°. Then the reaction mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated sodium bicarbonate aqueous solution, and the product was extracted with ethyl acetate which was dried over sodium sulfate. Then, filtration, evaporation, purification through silica gel column chromatography eluting with hexane/ethyl acetate (15:1 to 5:1) furnished the title compound (6.29 g, 84% yield) as a white solid. 1H NMR (300 MHz, CDCl3) ppm 2.45 (3H, s), 3.24 (3H, s), 7.81-7.86 (2H, m), 7.96-8.05 (2H, m), 8.17 (1H, d, J=8.8 Hz). MS (ESI): m/z 397, 399 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:3][C:4]1[N:9]2[N:10]=[CH:11][CH:12]=[C:8]2[N:7]=[C:6]([S:13][CH3:14])[C:5]=1[C:15]#[N:16])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSc1nc2ccnn2c(O)c1C#N
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc2ccnn2c(OCc2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
80 mg of sodium hydride (60%) was added to 400 mg of 7-hydroxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 6 ml of DMF, followed by stirring at room temperature for about 10 minutes, and then 350 mg of benzyl bromide was added thereto, followed by stirring at about 50° C. overnight. After completion of the reaction, the reaction mixture was cooled to room temperature, about 50 ml of water was added thereto, and the precipitated crystals were collected by filtration, washed with water and dried to obtain crude crystals. The crude crystals were purified by silica gel column chromatography to obtain 490 mg of 7-benzyloxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compound No. 51) having a melting point of 194° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)=[N:4][C:3]=1[C:20]1[CH:21]=[CH:22][C:23]([S:26]([CH3:27])=[O:33])=[CH:24][CH:25]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc2Br)cc1
Solvent: ClCCl
Product: CS(=O)c1ccc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
tert-Butyl 4-{5-bromo-4-[4-(methylsulfanyl)phenyl]-1,3-oxazol-2-yl}piperidine-1-carboxylate (705 mg, 1.55 mmol) was dissolved in methylene chloride (15.5 nit) under argon atmosphere. 3-Chloroperoxybenzoic acid (383 mg, 1.55 mL) was dissolved in methylene chloride (3.1 mL) and added via syringe to the stirring solution. The resulting solution was stirred at 25° C. for 1 hour. The solution was then diluted with methylene chloride (15 mL) and washed with saturated sodium bicarbonate followed by brine. The organics were dried over sodium sulfate and concentrated in vacuo to yield 680 mg of the desired product as colorless oil. LCMS (M+1)=469.40
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].C([O-])(=O)C.[NH4+].C(O)(=O)C.[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:6]([O:5][P:4]([C:3]([C:1]#[N:2])=[CH:27][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:11])[O:8][CH2:9][CH3:10])[CH3:7]
Reactant: Cc1ccccc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C(C#N)=CC1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of diethyl cyanomethylphosphonate (32.6 g, 184 mmol), ammonium acetate (6.0 g, 78 mmol), acetic acid (6 mL) in toluene (120 mL) was added cyclohexanecarboxyaldehyde (21 g, 174 mmol). The reaction mixture was stirred at room temperature for two days and then heated at 100° C. for 3 hours. After cooling, the reaction mixture washed with saturated sodium bicarbonate solution three times, with brine one time and then dried over magnesium sulfate. The reaction mixture was filtered and concentrated to yield a residue. The residue was purified by Kugelrohr distillation to yield [1-cyano-2-(cyclohexyl)-vinyl]-phosphonic acid diethyl ester as a light brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28]>>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([S:6]([CH:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]#[N:28])[C:4]([O:3][CH2:1][CH3:2])=[O:20])(=[O:7])=[O:8])=[CH:14][CH:13]=1)[C:17]#[C:18][CH3:19]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: N#CCCCCCBr
Product: CC#CCOc1ccc(S(=O)(=O)C(CCCCCC#N)C(=O)OCC)cc1
Yield: 60 %

Procedure:
Ethyl 2-{[4-(2-butynyloxy)phenyl]sulfonyl}-7-cyanoheptanoate was prepared according to the general method as outlined in example 1 (step 4), starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (10 g, 33.8 mmol) and 6-bromohexanenitrile (4.48 ml, 33.8 mmol); 7.9 g white solid. mp 63° C.; Yield 60%; MS (EI): 391.4 (M+H)+
Reaction SMILES: [CH:1]1([C:7](=[O:13])[C:8]([O:10]CC)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Na+].Cl>CO>[CH:1]1([C:7](=[O:13])[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=O)C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(=O)C1CCCCC1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of ethyl cyclohexyloxoacetate (46 g) in MeOH (25 mL) was added water (60 mL) and NaOH (50% 20 mL) at 0-15° C. The reaction mixture was heated to 60° C. for 1.5 h. The reaction mixture was cooled with ice-water bath, and acidified with 15% HCl till pH 1. The mixture was extracted with ethyl acetate (2×250 mL). The extracts were washed with brine, dried with sodium sulfate. The drying agent was removed by filtration and the solvent was removed to give a low melting solid (39 g, 99%). 1H NMR: δ 1.15-1.40 (m, 5H,), 1.62-1.96 (m, 5H). 3.20 (m, 1H), 9.4 (s, 1H). 13C-NMR δ, 25.93, 25.76, 27.89, 45.04, 160.90, 198.29.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][Br:32])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-nitrophenyl)methanol (2.0 g, 8.65 mmol) and triphenylphosphine (4.5 g, 17.3 mmol) were combined in tetrahydrofuran (40 mL) and cooled to 0° C. N-Bromosuccinimide (3.2 g, 18.2 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 2.2 g (84%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 8.27 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 4.45 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCOC(=O)C(C)(C)C)CC1
Temperature: 60 °C

Procedure:
To 4-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (480 mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol, 55-65% in mineral oil) and the mixture was warmed to 60° C. for 2 h. The mixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir over night and then poured into water and the mixture was extracted with ether. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by Flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield 4-[2-(2,2-dimethylpropionyloxy)ethyl]-piperidine-1-carboxylic acid tert-butyl ester as an oil, which was deprotected in CH2Cl2/TFA, employing the standard procedure. This yielded the crude title compound as an oil (94 mg, 0.44 mmol, 34%), which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[C:25]([O:27][CH:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH:24]=[CH:23][C:21]=1[NH:22][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Cn1cc(-c2cccc3cnc(Cl)cc23)cn1
Reactant: COc1cc(OC2CCN(C)CC2)ccc1N
Product: COc1cc(OC2CCN(C)CC2)ccc1Nc1cc2c(-c3cnn(C)c3)cccc2cn1
Yield: 5 %

Procedure:
The title compound was prepared according to Method 3 (Example 27) using 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7) and 2-methoxy-4-(1-methylpiperidin-4-yloxy)aniline at 100° C. for 3 hours. The reaction mixture was concentrated onto silica gel in vacuo and purified by silica gel column chromatography eluting with 0-100% EtOAc in cyclohexane followed by 0-10% MeOH in CH2Cl2 and finally eluting with 10% 1M NH3/MeOH in DCM to afford the title compound (5 mg, 5%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16].C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-:16])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [O-][n+]1ccccc1SCc1ccccc1F
Solvent: ClC(Cl)Cl
Product: O=S(Cc1ccccc1F)c1cccc[n+]1[O-]

Procedure:
The procedure employed is identical to that of Example 68 using 5.7 gm (0.024 mol) 2-(2-fluorophenylmethylthio)pyridine N-oxide in 50 ml of chloroform with 4.8 gm (0.024 mol) MCPBA in 75 ml chloroform.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([N:16]1[CH:23]2[CH:18]([CH2:19][CH2:20][NH:21][CH2:22]2)[CH2:17]1)=[O:15].Cl[C:31]1[CH:40]=[N:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:8]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([N:16]1[CH:23]2[CH:18]([CH2:19][CH2:20][N:21]([C:31]3[CH:40]=[N:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]=3)[CH2:22]2)[CH2:17]1)=[O:15]
Reactant: Clc1cnc2ccccc2n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CCNCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=C(c1ccccc1-c1ccccc1)N1CC2CCN(c3cnc4ccccc4n3)CC21
Temperature: 80 °C
Reaction time: 18 h
Yield: 40.4 %

Procedure:
A mixture of trifluoro acetic acid salt of biphenyl-2-yl-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-methanone (Intermediate 3, 122.0 mg, 0.3 mmol), 2-chloro quinoxaline (60.0 mg, 0.36 mmol), K2CO3 (166 mg, 4 mmol) in DMF (7 mL) was stirred at 80° C. for 18 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and water (120 mL). The organic layers were washed with water (2×30 mL), combined, dried (Na2SO4), filtered and concentrated. The crude residue was purified on HPLC (basic system) to yield the title compound (51 mg, 40%). MS (ESI) mass calcd. for C27H24N4O, 420.51; m/z found, 421 [M+H]+. 1H NMR (CDCl3): 8.44 (s, 0.55H), 8.17 (s, 0.45H), 7.97-7.87 (m, 1H), 7.76-7.71 (m, 0.5H), 7.65-7.50 (m, 2H), 7.48-7.30 (m, 7H), 7.09-6.94 (m, 2H), 7.20-7.12 (m, 0.5H), 4.78-4.49 (m, 1H), 4.02-3.78 (m, 1H), 3.76-3.58 (m, 2H), 3.55-3.48 (m, 0.5H), 3.32-3.23 (m, 0.5H), 3.15-2.97 (m, 1H), 2.74-2.39 (m, 1H), 2.12-1.54 (m, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[F:9][C:10]([F:37])([F:36])[C:11]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:33]([N:32]([CH2:31][C:11]([OH:30])([CH2:12][NH:13][C:14]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10]([F:37])([F:36])[F:9])[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH2:34][CH3:35]
Reactant: CCCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F
Reactant: O=C(O)c1cccs1
Product: CCCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccccc1)C(F)(F)F)C(=O)c1cccs1

Procedure:
Prepared similarly to Example 11 from 2-thiophenecarboxylic acid and 1,1,1-trifluoro-3-[(6-methyl-1-phenyl-1H-indazol-4-yl)amino]-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)[CH2:6]1)=[N+]=[N-].[C:18]([OH:21])(=S)[CH3:19]>>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][NH:1][C:18](=[O:21])[CH3:19])[O:9][C:8]2=[O:10])=[N:12][CH:13]=1
Reactant: CC(O)=S
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Product: CC(=O)NC[C@H]1CN(c2ccc(Br)cn2)C(=O)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
(5R)-5-(Azidomethyl)-3-(5-bromopyrid-2-yl)-1,3-oxazolidin-2-one (5.60 g, 18.7 mM) was dissolved in thioacetic acid (10 ml) to give a yellow solution. The solution was degassed and stirred at room temperature for 20 hours. The thick slurry was concentrated and the desired product was crystallized from acetone (100 ml) to give the product as a light yellow solid (3.25 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][C:26](=[O:45])[C:27]([CH3:44])([C:29]1[CH:30]=[N:31][CH:32]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)[CH3:28]>>[CH3:24][O:25][C:26](=[O:45])[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:34]=1)([CH3:44])[CH3:28]
Reactant: COC(=O)C(C)(C)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COC(=O)C(C)(C)c1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 0.215 mmol) and 2-methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-propionic acid methyl ester (Stage 229.1.1, 0.279 mmol) to give the title compound as a brown solid. (HPLC: tR 2.28 min (Method A); M+H=471 MS-ES)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][CH:3]=1.I.CS[C:15](=[NH:28])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:25][C:24]([F:26])([F:27])[O:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]2[NH:28][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:22][CH:21]=1
Reactant: CSC(=N)Nc1ccc(OC(F)(F)F)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(-c2nnc(Nc3ccc(OC(F)(F)F)cc3)[nH]2)cc1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
4-hydroxybenzoic acid hydrazide (0.643 g, 4.23 mmol) and S-methyl N-[4-(trifluoromethoxy)phenyl]isothiourea hydroiodide (1.6 g, 4.23 mmol) were suspended in 10 mL of anhydrous pyridine. The reaction mixture was refluxed for 24 hours, during which time it changed color from yellow into orange-red. Then it was cooled down to ambient temperature and poured with stirring into 150 mL of ice-water. The formed white solid was collected, washed thoroughly with water and dried in air. The resulting residue was purified by silica gel chromatography using Isco column with 10% to 100% gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a pinkish solid (575.2 mg). Yield 40.4
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:15])([F:14])[C:7]1[N:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([C:33](OC)=[O:34])[CH:27]=2>C1(C)C=CC=CC=1>[F:15][C:6]([F:5])([F:14])[C:7]1[N:12]=[CH:11][C:10]([NH:13][C:33]([C:28]2[CH:27]=[C:26]3[C:31]([CH:32]=[C:24]([C:18]4[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=4[Cl:16])[NH:25]3)=[CH:30][CH:29]=2)=[O:34])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To 4 mL of ice-cold toluene was added 0.28 mL of 2 M trimethylaluminum in toluene then 6-trifluoromethyl-pyridin-3-ylamine (84 mg, 0.5 mmol) was added in one portion and the yellow solution was stirred for 30 min. To this was added a solution of methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate (150 mg, 0.47 mmol) in toluene (5 mL) dropwise and the resulting solution was heated at 100° C. for 18 h. A second aliquot of trimethylaluminum was added and the mixture heated another 18 h, after which it was cooled to ambient temperature, quenched with 1N HCl. Water was added and the mixture was extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed using methylene chloride then 20% EtOAc/methylene chloride as eluent to give 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid (6-trifluoromethylpyridin-3-yl)-amide as a purple glass. MS (m/z) 449.9 (M+1); retention time=1.63 min (Method 10).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[NH3:25]>CN(C=O)C>[NH2:25][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: N
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N
Yield: 85.2 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28 in 30 ml of DMF was stirred at room temperature while NH3 was bubbled in. Reaction was monitored by GC. The residue was kugelrohr distilled at 80 Pa, pot temperature 106° C., giving 4.17 g (85.2%) of product as a yellow solid; mp 69°-70° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([C:5]1[CH:6]=[C:1]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-c2ccncn2)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(-c2ccncn2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of 4-phenylpyrimidine (10 g, 64 mmol) and conc. H2SO4 (33 ml) was added to a mixture of conc. H2SO4 (22 ml) and conc. HNO3 (16 ml) at 0° C. The resulting mixture was stirred at 0° C. for 2 hr, poured onto crushed ice, and extracted with CH2Cl2. The extract was washed with a 5% aqueous NaHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with isopropanol and the precipitate was filtered off and dried under reduced pressure to give (57) (6.4 g, 50%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:17]O>>[CH3:17][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([OH:1])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)c(O)c1

Procedure:
To a solution of 3-hydroxy-4-methyl-benzoic acid (5 g, 32.8 mmol) in MeOH (100 mL) cc H2SO4 (1 mL) is added. The solution is refluxed for 14 h, then concentrated to about 30 mL and poured into water. The aqueous layer is extracted with ether (50 mL×4) and the combined organic extracts are neutralized with a saturated aqueous solution of NaHCO3 (50 mL×2), washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound as a white powder. TLC, Rf (hexane/AcOEt 2:1 )=0.55. 1H-NMR (CDCl3, 300 MHz): δ=2.3 (s, 3H), 3.9 (s, 3H), 7.15 (d, 1H), 7.5 (d, 1H), 7.6 (s, 1H) ppm.