Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19].C(OCC)(=O)C>CC(C)=O>[CH2:19]([O:10][C:8]1[CH:9]=[C:4]([C:2](=[O:3])[CH3:1])[CH:5]=[CH:6][CH:7]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C=CCOc1cccc(C(C)=O)c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
3-Hydroxyacetophenone (1.36 g, 10.0 mmol) was dissolved in acetone (50 mL), then added with potassium carbonate (2.76 g, 20.0 mmol) and allylbromide (1.27 mL, 15.0 mmol) at room temperature, and heated to reflux for 2 hours. The reaction solution was cooled to room temperature, added with ethyl acetate, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (n-hexane/ethyl acetate=10/1), and 1-(3-(allyloxy)phenyl)ethanone (1.76 g, 100%) was obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[S:17][C:16]([NH:18][C:19]3[CH:24]=[C:23]([C:25]#[C:26][CH2:27][O:28][CH3:29])[N:22]=[C:21]([CH3:30])[N:20]=3)=[N:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]>C1COCC1.CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[S:17][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[N:22]=[C:21]([CH3:30])[N:20]=3)=[N:15][CH:14]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(S(=O)(=O)c2cnc(Nc3cc(C#CCOC)nc(C)n3)s2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cccc(S(=O)(=O)c2cnc(Nc3cc(CCCOC)nc(C)n3)s2)c1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A mixture of [5-(3-Ethoxy-benzenesulfonyl)-thiazol-2-yl]-[6-(3-methoxy-prop-1-ynyl)-2-methyl-pyrimidin-4-yl]-amine (32.0 mg, 0.072 mol) and Pd—C (10%, 2.0 mg) in THF (1.00 mL) and EtOAc (1.00 mL) was stirred under H2 (70 psi, Parr) for 30 min. The reaction mixture was filtered through Celite using EtOAc (ca. 50 mL). The filtrate concentrated under reduced pressure to give the title compound (30 mg, 93%) as an off-white solid. LCMS (m/z): 449 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH2:14])[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.Cl[C:16]1[C:17]([N:22]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH2:24][CH2:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:25]1[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:22]([C:17]2[C:16]([NH:14][CH:7]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:23][CH2:24]1
Reactant: NC(c1cccnc1)c1cccnc1
Reactant: Clc1cccnc1N1CCOc2ccccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1cncc(C(Nc2cccnc2N2CCOc3ccccc32)c2cccnc2)c1

Procedure:
To a solution of (dipyridin-3-ylmethyl)amine (139 mg, 0.75 mmol) (prepared according to the procedure in German patent DE 2447258 (1976)) and 4-(3-chloropyridin-2-yl)-3,4-dihydro-2H-1,4-benzoxazine (183 mg, 0.75 mmol) in dry dioxane (1.5 mL) was added sodium t-butoxide (91 mg, 0.95 mmol), bis(tri-t-butylphosphine)palladium(0) (30 mg, 0.058 mmol). The vessel was sealed with a septum cap, degassed (3×), and heated at 100 C for 8 hours. The reaction was cooled and diluted with methylene chloride and washed with NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with a 20-90% acetone/hexane gradient to the title compound as a clear glass. 1H-NMR (500 MHz, CDCl3): δ 8.60 (2H, s), 8.56 (2H, d, J=4.4 Hz), 7.91 (1H, d, J=4.6 Hz), 7.54 (1H, d, J=7.8 Hz), 7.26 (1H, t, J=7.5 Hz), 6.97 (1H, dd, J=4.6, 7.8 Hz), 6.87 (1H, d, J=7.8 Hz), 6.77-6.81 (3H, m), 6.37 (1H, d, J=7.6 Hz); 5.57 (1H, d, J=4.4 Hz), 4.77 (1H, d, J=4.1 Hz), 4.40 (2H, t, J=4.4 Hz), 3.76 (2H, br s). m/e (m+1): 396.2
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)\[C:10]#[N:11])=[CH:4][C:3]=1[O:22][CH3:23].[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[OH:1][C:2]1[C:7]([N+:24]([O-:26])=[O:25])=[CH:6][C:5](/[CH:8]=[C:9](/[C:12]2[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)\[C:10]#[N:11])=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: COc1cc(/C=C(\C#N)c2ccc(C(F)(F)F)nc2)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(/C=C(\C#N)c2ccc(C(F)(F)F)nc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C

Procedure:
To a solution of (Z)-3-(4-hydroxy-3-methoxyphenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile (0.858 g, 2.68 mmol) in acetic acid (20 mL) was added 60% nitric acid (0.23 mL, 2.95 mmol) dropwise. The resulting mixture was allowed to stir at room temperature for thirty minutes then poured onto ice-water (100 mL). The yellow precipitate was filtered off, washed with water and dried. Recrystallisation from isopropanol afforded (Z)-3-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acrylonitrile as a yellow solid, 0.597 g, (61%).
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[O:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:32]2[O:33][C:34]([C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]3[CH:7]=[CH:8][C:9]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[CH:10][CH:11]=3)=[CH:35][CH:36]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1
Reactant: COc1cc(OC)cc(-c2ccco2)c1
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: COc1cc(OC)cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)c1

Procedure:
N,2-Dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide was coupled with 2-(3,5-dimethoxyphenyl)furan following the procedure of Example 12. 1-(5-(3,5-Dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone was isolated as a yellow oily foam (0.343 g, 62% yield). MS: m/z 438.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[S:11])[CH:6]=[CH:7][CH:8]=1.Br[CH:21](Br)[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:15][C:13]([N:12]=[C:10]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:18])([F:1])[F:19])[CH:4]=2)[CH2:22][CH2:21][S:11]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)NC(=S)Nc1cccc(C(F)(F)F)c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N=C1SCCN1c1cccc(C(F)(F)F)c1
Yield: 83.1 %

Procedure:
A solution of N-(3-trifluoromethylphenyl)-N'-ethoxycarbonylthiourea (1.8 g), dibromoethane (1.29 g) and anhydrous potassium carbonate (2.6 g) in acetone (20 ml) was refluxed for 5 hours. The solvent was removed by distillation, and the residue was extracted with diethyl ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from a mixture of hexane and ethanol to give 1.63 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazolidine. m.p., 75.8° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[Cl:15][CH2:16][CH2:17][CH2:18]I>CN(C=O)C>[Cl:15][CH2:16][CH2:17][CH2:18][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:14]=2)[CH:10]=[CH:11]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: ClCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2ccn(CCCCl)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.6 %

Procedure:
Sodium hydride (1.96 g, 49.337 mmol, 60% suspension in mineral oil) was treated with DMF (60 mL), followed by 6-nitroindole (6) (2.0 g, 12.334 mmol) in DMF (20 mL) over a period of 5 min at 0° C. After stirring for 15 min, the solution was treated with 1-chloro-3-iodopropane (3.9 mL, 37.002 mmol), the reaction was brought to room temperature and stirred for 3 h. The reaction was quenched with saturated brine (80 mL), water (80 mL) and cooled to 0° C. The solid was filtered off, washed with water (50-75 mL) and dried to obtain the crude product. The crude product was recrystallised from hot toluene (10 mL)/hexanes (5 mL) to obtain compound 148 (2.637 g, 90%) as solid. mp 85-87° C.; 1H-NMR (CDCl3) δ 2.28-2.36 (m, 2H), 3.46 (t, 2H, J=5.7 Hz), 4.45 (t, 2H, J=6.6 Hz), 6.62 (d, 1H, J=2.7 Hz), 7.43 (d, 1H, J=3.0 Hz), 7.66 (d, 1H, J=8.7 Hz), 8.02 (dd, 1H, J=1.8, 7.9 Hz), 8.36 (d, 1H, J=0.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[C:7]([CH3:17])=[N:6]1.[OH-].[K+:24]>C(O)C>[CH3:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O-:16])=[O:15])[CH:12]=2)[C:7]([CH3:17])=[N:6]1.[K+:24]
Reactant: Cc1cccc(C)c1Cn1nc(C)c2ccc(C(=O)O)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1Cn1nc(C)c2ccc(C(=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound [117](568 mg) in ethanol (20 mL) was added an aqueous solution of 1N-potassium hydroxide (1.93 mL) at room temperature, and then the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the titled compound (636 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:7]4[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=4)=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CC(=O)c1ccc(C(=O)O)s1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)s1
Temperature: 79 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
A dry 25 mL flask was charged with 5-Acetyl-thiophene-2-carboxylic acid (0.880 g, 5.15 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.01 g, 3.97 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 3 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo, and the crude residue was dissolved in EtOH (5 mL). The ethanolic solution was treated with 1M NaOH(aq) (2 mL) and stirred for 30 min. The basic solution was acidified to a pH of 1 with 1M HCl(aq) yielding a tan precipitate. The tan solids were filtered to afford the pure 5-Acetyl-thiophene-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (1.275 g, 3.05 mmol, 77%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][CH2:14][CH:15]([OH:17])[CH3:16]>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:13][CH2:14][CH:15]([OH:17])[CH3:16])[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:13][CH2:14][CH:15]([OH:17])[CH3:16])[CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1Cl
Reactant: CC(O)CN
Product: CC(O)CNc1cc(Cl)cc(NCC(C)O)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
0.2 mole (45.3 g) of 2,4,6-trichloronitrobenzene is added in small portions to 180 ml of 3-amino-2-propanol heated to 80° C., with stirring. The reaction is exothermic. After heating for 3 hours 30 minutes, the reaction mixture is poured into 180 ml of ice-cold water. The product expected precipitates. It is drained, washed to neutrality with water and then dried under vacuum in the presence of phosphorous pentoxide. After recrystallization from 96° ethanol, it melts at 170° C.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][C:13]([CH3:29])([C:26](=[O:28])[CH3:27])[CH2:14]OS(C1C=CC(C)=CC=1)(=O)=O.O>CO>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:14])[C:26](=[O:28])[CH3:27])=[CH:7][CH:6]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)C(C)(C)COc1ccc(Cl)cc1
Yield: 55.5 %

Procedure:
29.7 g (0.55 mole) of sodium methylate were dissolved in 500 ml of methanol, and 70.4 g (0.55 mol) of 4-chlorophenol were added, while stirring. After stirring the mixture for 10 minutes, the solvent was distilled off under reduced pressure and the residue was taken up in 100 ml of glycol. This solution was added to a solution of 135 g (0.5 mole) of 2,2-dimethyl-1-tosyloxy-butan-3-one in 200 ml of glycol. The reaction mixture was stirred at 100° to 120° C. for 48 hours, cooled and stirred into 2,000 ml of water. The mixture was extracted twice with 250 ml of diethyl ether each time and the combined organic phases were washed three times with 100 ml of water each time, once with 100 ml of 10% strength sodium hydroxide solution and once more with 100 ml of water, dried over sodium sulphate and distilled. 62.9 g (55.7% of theory) of 1-(4-chlorophenoxy)-2,2-dimethyl-butan-3-one of boiling point 135°-140° C./0.4 mm Hg were obtained.
Reaction SMILES: [C:1](=O)([O:21]N1C(=O)CCC1=O)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[NH:16][CH:17]3[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH:34]=1.C(N(CC)CC)C>ClCCl>[CH3:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)[CH:34]=1)[C:1](=[O:21])[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[NH:16][CH:17]3[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CNCc1cccc(-c2ccncc2)c1
Reactant: O=C(Oc1ccc(-c2ccc(C(=O)NC3CC3)cc2)cc1)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cccc(-c2ccncc2)c1)C(=O)Oc1ccc(-c2ccc(C(=O)NC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask was placed a solution of 4-[4-(cyclopropylcarbamoyl)phenyl]phenyl 2,5-dioxopyrrolidin-1-yl carbonate (600 mg, 1.52 mmol, 1.00 equiv) in dichloromethane (40 mL), N-methyl([[3-(pyridin-4-yl)phenyl]methyl])amine (301 mg, 1.52 mmol, 1.00 equiv) and triethylamine (153 mg, 1.51 mmol, 0.99 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with 2×20 mL of water and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product (650 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, uv 220 & 254 nm. The title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6](=[NH:10])[O:7][CH2:8][CH3:9])=[C:4]([F:13])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[F:14][C:15]([F:25])([F:26])[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([N:10]=[C:6]([O:7][CH2:8][CH3:9])[C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][C:4]=1[F:13])=[O:19]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CCOC(=N)c1ccc(Cl)cc1F
Product: CCOC(=NC(=O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1F

Procedure:
starting from ethyl 4-chloro-2-fluorobenzimidate and o-trifluoromethyl-benzoyl chloride there is obtained ethyl N-(o-trifluoromethyl-benzoyl)-2-fluoro-4-chlorobenzimidate and therefrom with methylhydrazine there is obtained 3-(4-chloro-2-fluorophenyl)-1-methyl-5-(o-trifluoromethyl-phenyl)-1H-1,2,4-triazole, m.p. 109.5°-112° C.;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27](O)=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH2:50]([NH:54][CH2:55][CH:56]([CH3:58])[CH3:57])[CH:51]([CH3:53])[CH3:52].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27](=[O:28])[N:54]([CH2:55][CH:56]([CH3:58])[CH3:57])[CH2:50][CH:51]([CH3:53])[CH3:52])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CNCC(C)C
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)O)c(Cl)cc3[nH]c2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)N(CC(C)C)CC(C)C)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 4-[2-(1-tert-butoxycarbonyl-piperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid (48 mg in 0.50 mL methylene chloride) was added 12 mg 1-hydroxybenzotriazole (HOBt) followed by 0.020 mL diisobutylamine, 0.025 mL triethylamine and 33 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and the mixture stirred at room temperature. After 22 hours, the mixture was diluted with methylene chloride and washed with 10% aqueous sodium bisulfate and brine. The organics were dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (chloroform:methanol, 97.5:2.5) to give the title compound (37 mg).
Reaction SMILES: CC([C:5]1[CH:6]=[C:7]([CH:10]=[C:11](C(C)(C)C)[C:12]=1OCOCCOC)[C:8]#[N:9])(C)C.C(N(CC)CC)C.N1C=CC=CC=1.[SH2:37]>>[C:7]1([C:8](=[S:37])[NH2:9])[CH:10]=[CH:11][CH:12]=[CH:5][CH:6]=1
Reactant: COCCOCOc1c(C(C)(C)C)cc(C#N)cc1C(C)(C)C
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ccccc1
Reaction time: 15 h

Procedure:
Into a solution containing 10.0 g (0.03 mole) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile, 5.7 ml (0.04 mole) of triethylamine and 14.2 ml (0.18 mole) of pyridine, hydrogen sulfide gas is bubbled over 15 hours. The mixture is poured into ice water (110 ml), and an oily precipitate solidifies upon standing at 0° C. for 15 hours. The solid is thoroughly washed with water and filtered. Recrystallization from ethyl acetate and hexane gives 7.9 g (71%) of analytically pure 3,5-bis(1,1-dimethylethyl)-4-[2-methoxyethoxy)methoxy]benzenecarbothioamide, mp 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH:19]=[CH:18][C:17]2[N:20]([C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)[N:21]=[N:22][C:16]=2[CH:15]1[CH3:29])=[O:13].C([O-])=O.[NH4+]>CO.[Pd].[C]>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][C:17]2[N:20]([C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)[N:21]=[N:22][C:16]=2[CH:15]1[CH3:29])=[O:13]
Reactant: CC1c2nnn(-c3cncnc3)c2C=CN1C(=O)c1cccc(C(F)(F)F)c1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC1c2nnn(-c3cncnc3)c2CCN1C(=O)c1cccc(C(F)(F)F)c1Cl
Yield: 102.6 %

Procedure:
A solution of (2-chloro-3-(trifluoromethyl)phenyl)(4-methyl-1-(pyrimidin-5-yl)-1H-[1,2,3]triazolo[4,5-c]pyridin-5(4H)-yl)methanone (237 mg, 0.56 mmol) in MeOH (12 ml) was treated with ammonium formate (147 mg, 2.3 mmol) and Pd/carbon (10 wt %, 20 mg) and the reaction was refluxed for 90 min. The reaction was filtered through celite and the filter cake washed with MeOH and concentrated to a crude solid which was re-suspended with CHCl3 and filtered to remove in-organic salts then purified on 40 g SiO2 with 0-60% EtOAc hexanes to provide 243 mg (22%) of desired product. MS (ESI) mass calcd. C18H14ClF3N6O, 422.09. m/z found, 423.1 [M+H]+. The enantiomers were separated by chiral SFC on (CHIRALPAK AD-H 5 μm 250×20 mm). Mobile phase (70% CO2, 30% EtOH).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([O:19]CC)=O)[N:8]=2)=[N:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Mg]Br>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])=[O:19])[N:8]=2)=[N:2]1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Reactant: COc1ccccc1[Mg]Br
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 17.1 %

Procedure:
To a suspension of ethyl 4-(1H-pyrazol-3-ylamino)quinazoline-2-carboxylate (0.110 g, 0.39 mmol) in THF (5 mL) under argon at −40° C. was added (2-methoxyphenyl)magnesium bromide (0.5 M solution in THF; 2.32 mL, 1.16 mmol). The mixture was stirred at −40° C. for 3 h and quenched with 0.5 N HCl (10 mL). The organic layer was separated. The aqueous layer was washed with 10% MeOH/CH2Cl2 (50 mL×2). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on preparative HPLC (Phenomenex phenylhexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O) to afford (4-(1H-pyrazol-3-ylamino)quinazolin-2-yl)(2-methoxyphenyl)methanone as a yellow solid (0.023 g, 17%). 1H NMR (300 MHz, DMSO-d6) δ 3.50 (s, 3H), 6.58 (s, 1H), 7.15 (m, 2H), 7.70-7.50 (m, 4H), 7.88 (m, 2H), 8.75 (d, 1H), 10.68 (s, 1H), 12.42 (s, 1H); LC-MS (ESI) m/z 346 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[CH:14][CH:13]=2)=[N:3]1.FC(F)(F)C(O)=O>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCOCCCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCCCc1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 64.6 %

Procedure:
tert-Butyl 3-{3-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-3-pyridyl]propoxy}propanoate (1.0 g, 2.3 mmol) and trifluoroacetic acid (4.0 ml) was stirred under ice cooling condition for 5 hrs. The reaction mixture was concentrated under reduced pressure, diluted with chloroform, washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography, eluted with ethyl acetate-methanol (20:1, v/v) and recrystallized from chloroform-ethyl acetate to give the titled compound (0.55 g, 66%).