Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=[CH:2][O:3][CH3:4])[CH2:32][CH2:31]1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC=C1CCC(C)(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methoxymethyl triphenylphosphonium chloride (35.5 g, 0.104 mol) in THF (400 mL) at 0° C. was added n-BuLi (33.1 mL of a 2.8M solution in hexanes; 0.095 mol). The mixture was stirred at 0° C. for 30 min., cooled to −78° C. and a solution of 4,4-dimethyl cyclohexanone (10.0 g, 0.079 mol) in THF (100 mL) was added, dropwise. After 1 hr at −78° C. the mixture was slowly warmed to 0° C., diluted with satd ammonium chloride (400 mL) and ethyl acetate (100 mL) and stirred at room temperature for 48 hr. Layers were separated and the aqueous phase was extracted with ethyl acetate. Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with hexanes, solids were removed by filtration and the filtrated was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL), PS-TsNHNH2 (8 g; ca. 3.7 mmol/g) and acetic acid (2 drops) were added and the mixture was stirred at room temperature for 24 hr. Resin was removed by filtration and washed (CH2Cl2, MeOH, CH2Cl2). Combined filtrate/washings were concentrated in vacuo, affording (4,4-dimethyl cyclohexylidene)methyl methyl ether as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (s, 6H); 1.27 (m, 5H); 1.95 (m, 2H); 2.18 (m, 2H); 3.52 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:12]([SH:15])[NH:13][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][CH2:30]Br>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:12]3[S:15][CH2:29][CH2:30][N:13]3[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: BrCCBr
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
5-(3-Nitro-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol (298 mg, 1.0 mmol) was dissolved in dry DMF (12.5 mL) under nitrogen atmosphere. Solid potassium carbonate (690 mg, 5 mmol, 5 eq) was added followed by 1,2-dibromoethane (0.086 mL, 1 mmol, 1 eq) and the suspension was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate (60 mL) and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. 280 mg of 6-(3-nitro-phenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazole were obtained as an off-white solid (87%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(CC)CC.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a mixture of N-methylpiperizine (1.00 g, 10 mmol) and Et3N (2.1 mL, 15 mmol) in CH2Cl2 (50 mL) at rt was added 4-bromobenzoyl chloride (2.195 g, 10 mmol) in one portion. The reaction was heated to reflux briefly and cooled. The resulting mixture was stirred O/N at rt. The reaction was quenched with H2O (30 mL) and sat. NaHCO3 (10 mL), separated and dried (Na2SO4). Evaporation of solvents afforded the title compound as a pale yellowish white solid (2.69 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 3.70-3.20 (m, 4H), 2.40-2.15 (m, 7H; s, 3H at 2.18 ppm and m, 4H overlapping); MS ESI 283.0 [M+H]+, calcd. for [C12H15BrN2O+H]+ 283.0.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[NH2:2].S(=O)(=O)(O)[OH:14].OO>>[C:1]([NH:4][C:5](=[O:12])[CH2:6][CH2:7][CH2:8][C:9]([O:11][OH:14])=[O:10])(=[O:3])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)NC(=O)CCCC(=O)O
Agent: OO
Product: NC(=O)NC(=O)CCCC(=O)OO

Procedure:
87 g (0.5 mol) of N-(carbamoyl)glutaramic acid, 175 g of sulfuric acid and 102 g (1.5 mol) of hydrogen peroxide (50% strength by weight) are reacted and worked up as described in Example 3.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.ClC(Cl)C.[C:26](Cl)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:21][CH2:20][C:13]1[N:14]([CH2:15][C:16]([OH:18])([CH3:17])[CH3:19])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1)(=[O:28])[CH3:27]
Reactant: CC(C)(O)Cn1c(CO)nc2c(N)nc3ccccc3c21
Reactant: CC(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O

Procedure:
To a round-bottomed flask with stir bar was added 1-(4-amino-2-hydroxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (1 g, 3.5 mmol) followed by dichloroethane (20 mL) and pyridine (3 mL). To the stirred suspension was added acetyl chloride (0.27 mL, 1.1 equivalents) and the reaction was stirred at ambient temperature for 30 min. The solvent was evaporated under reduced pressure to afford a solid. The product was isolated by two purifications by prep HPLC (ISCO Combiflash Separation System, Biotage Si 40+M column, eluted with a gradient of 0-7% methanol in dichloromethane with 1% ammonium hydroxide) to provide [4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methyl acetate as an off white solid (130 mg), mp 203-205° C.; MS (ESI) m/z 329 (M+H); Anal. Calcd for C17H20N4O3.0.25CH4O: C, 61.59; H, 6.29; N, 16.66. Found C, 61.24; H, 6.22; N, 16.97.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=3)[CH2:3]1.[OH-].[Na+].Cl>CO.O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][CH:11]=3)[CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CC[C@@H](O)C3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CC[C@@H](O)C3)nc2c1
Reaction time: 0.1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of (R)-methyl 3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (147.4 mg, 0.42 mmol, 1.00 equiv) in methanol (15 mL). This was followed by the dropwise addition of a solution of sodium hydroxide (84.5 mg, 2.11 mmol, 5.00 equiv) in water (2 mL) with stirring. The resulting solution was stirred overnight at 50° C. in an oil bath. The pH value of the solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-1): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, water with 0.05% TFA and CH3CN (20% CH3CN up to 50% in 6 min, up to 100% in 1 min, down to 20% in 1 min); Detector, UV 220 254 nm. This resulted in 35 mg (24%) of (R)-3-(3-hydroxypyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]#[N:25])=[N:14]1.N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[C:16]([S:19][C:20]([F:23])([F:21])[F:22])[C:15]([C:24]#[N:25])=[N:14]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)C(=O)Oc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 20 h
Yield: 28.6 %

Procedure:
To the solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole (7.00 g, 16.6 mmol) and pyridine (4.91 g, 62.1 mmol) in 1,2-dichloroethane at room temperature was added trimethylacetyl chloride (4.37 g, 36.2 mmol) dropwise. Ice bath was used to maintain the temperature of the reaction. After 20 hr at room temperature, the organic layer was washed five times with aqueous KHSO4 till the aqueous solution was at pH 1. The organic layer was then dried (MgSO4) and concentrated to give a solid residue. Upon chromatographic purification via silica gel column of the solid residue, after trituration with pentane, a off-white solid (2.403 g, 28.6% yield, 97.0% HPLC purity) was provided as the desired product, m. p. 82-83 C.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[O:18])=[CH:12][CH:11]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C(=S)=S>[CH3:8][S:7][C:1]1[CH:6]=[CH:5][C:4]([C:17](=[O:18])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a stirred solution of thioanisole (380 mL, 3.2 mol) and 4-fluorophenylacetyl chloride (300 g, 1.6 mol) in carbon disulfide (1.2 L), cooled to 5° C., was added anhydrous aluminum chloride portionwise at such a rate that the internal temperature did not rise above 15° C. The reaction was stirred at room temperature for 16 hours. The solution was cautiously poured into 2 L of ice and water. The aqueous solution was extracted with methylene chloride (6×150 mL), the combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was dissolved in 800 mL of ether and cooled to 0° C. whereupon crystals of pure product formed which were isolated by filtration on a Buchner funnel and air dried to provide the ketone (199.6 g, 48%): mp 135°-138° C. 1H NMR (CDCl3 /TMS) 300 MHz 8.00 (d, J=8.7 Hz, 2H), 7.40-7.30 (m, 4H), 7.13-7.03 (m, 2H), 4.34 (s, 2H), 2.56 (s, 3H). Mass spectrum M+ =260.
Reaction SMILES: [CH2:1]([C:4]([P:10]([OH:13])([OH:12])=[O:11])([P:6]([OH:9])([OH:8])=[O:7])[OH:5])[CH2:2]N.C[CH2:15][N:16](CC)CC>O>[CH2:2]([CH2:15][NH2:16])[CH2:1][C:4]([P:10]([OH:13])([OH:12])=[O:11])([P:6]([OH:9])([OH:8])=[O:7])[OH:5]
Reactant: NCCC(O)(P(=O)(O)O)P(=O)(O)O
Reactant: CCN(CC)CC
Solvent: O
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The NHS ester (0.35 g, 0.62 mmol) was dissolved in H2O (30 mL), and pamidronate (0.52 g, 2.23 mmol) and Et3N (1.7 mL, 12.4 mmol) were added. The reaction solution was stirred for 24 h at room temperature. Subsequently, the H2O was removed in the vacuum. The product obtained was purified by means of HPLC.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.[CH2:21]=[O:22].[Na+].[Cl-]>C1COCC1>[CH3:12][O:13][C:14]1[N:15]=[C:16]([CH2:20][CH2:21][OH:22])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(C)n1
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(CCO)n1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37 %

Procedure:
1.6M n-Butyllithium/hexane solution (282 mL, 451.96 mmol) was added dropwise to a solution of 2-methoxy-6-methylpyridine (50.60 g, 410.87 mmol) in THF (625 mL) over 1 hr at −78° C. under argon atmosphere. The reaction mixture was stirred at −78° C. for 45 min, paraformaldehyde (49.3 g, 1643.49 mmol) was added thereto at −78° C., and the mixture was stirred vigorously at room temperature for 3.5 hr. The reaction mixture was poured into ice water (1000 mL), and NaCl was added thereto to give a saturated solution. The saturated solution was extracted with a mixed solvent of ethyl acetate/THF (3:1) (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 8→50% ethyl acetate/hexane) to give 2-(6-methoxypyridin-2-yl)ethanol (23.22 g, 152 mmol, 37%) as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13]([C:15]2[CH:34]=[CH:33][C:18]3[N:19]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:20]([CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C1COCC1.[OH-].[Na+].Cl>C(O)C>[CH2:29]([CH:28]([N:19]1[C:18]2[CH:33]=[CH:34][C:15]([C:13]([NH:12][C:5]3([C:3]([OH:4])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)=[O:14])=[CH:16][C:17]=2[N:21]=[C:20]1[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:31][CH3:32])[CH3:30]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)NC3(C(=O)OC)CCCCCC3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)NC3(C(=O)O)CCCCCC3)ccc21
Temperature: 25 °C
Yield: 25.7 %

Procedure:
400 mg of 1-{[1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-cycloheptanecarboxylic acid methyl ester were dissolved in 4 ml ethanol and 2 ml THF and 4 ml of 2 M aqueous sodium hydroxide solution were added. After stirring at room temperature over night, the reaction mixture was brought to pH 3 by addition of 2 M aqueous hydrochloric acid and extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulphate and concentrated to yield 100 mg (26%) of 1-{[1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-cycloheptanecarboxylic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16])[CH:4]=[CH2:5].[C:17]1([OH:23])C=CC=[CH:19][CH:18]=1.S(C1C=CC(C)=CC=1)(OC[C@@H]1OC1)(=O)=O>>[CH2:3]([O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:19][CH:18]1[CH2:17][O:23]1)[CH:4]=[CH2:5]
Reactant: Oc1ccccc1
Reactant: C=CCOc1cc([N+](=O)[O-])ccc1O
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Product: C=CCOc1cc([N+](=O)[O-])ccc1OCC1CO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
20 g (0.50 mole) of 60% NaH/mineral oil was placed in a two liter flask and washed with 500 mL of hexane. 1 L of DMF was added, followed by 77 g (0.40 mole) of the 2-allyloxy-4-nitrophenol prepared in the previous step. Addition of the phenol was performed in portions under argon. After stirring the mixture for 30 minutes at room temperature under argon, 108 g (0.48 moles) of (R)-glycidyl tosylate was added and the mixture heated at 70-75° C. under nitrogen overnight. Upon cooling, the DMF was removed in vacuum and replaced with one liter of methylene chloride. This was washed with 500 mL portions of 2 N HCl, saturated sodium bicarbonate and saturated brine and dried over sodium sulfate. The mixture was filtered, concentrated to an oil in vacuum and column chromatographed on silica gel using 1:1 hexane/methylene chloride as eluant. This gave 43 g of product contaminated with traces of the two starting materials, followed by 21 g of pure product as a pale yellow solid. The impure material was recrystallized from 1.2 L of 10% ethyl acetate/hexane to give 34 g of pure (homogeneous on silica gel tic with 1:1 hexane/methylene chloride) (R)-2-(2-allyloxy-4-nitrophenoxymethyl)-oxirane (m.p. 64° C.).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH:14][S:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)(=[O:25])=[O:24])[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cc(OC(F)(F)F)cc2cccnc12
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cc(OC(F)(F)F)cc2cccnc12)c1ccccn1
Yield: 56.4 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-trifluoromethoxy-quinolin-8-ylamine (Intermediate 46) (110 mg, 0.48 mmol), pyridine-2-sulfonyl chloride (Intermediate 18) (102 mg, 0.57 mmol), pyridine (0.08 ml, 0.96 mmol), DMAP (cat.) and DCM (5 ml) gave the title compound (100 mg, 56%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH:12]=[C:11]([OH:16])[CH2:10]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11](=[O:16])[C:12](=[C:17]([OH:19])[CH3:18])[C:13](=[O:15])[CH2:14]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1C=C(O)CC(c2ccc(F)cc2Br)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)=C1C(=O)CC(c2ccc(F)cc2Br)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 500 mL recovery flask was added 5-(2-bromo-4-fluorophenyl)-3-hydroxycyclohex-2-enone (1D) (14.3 g, 50.1 mmol, 1.0 eq.), CH2Cl2 (200 mL), acetic anhydride (6.65 g, 65.2 mmol, 1.3 eq.), Et3N (15.22 g, 150 mmol, 3.0 eq.), and DMAP (catalytic amount). The reaction mixture was stirred overnight at room temperature. Monitoring by LC/MS judged the reaction to be complete. The reaction mixture was concentrated and purified via column chromatography (gradient 70% CH2Cl2/Hex to 100% CH2Cl2) to yield the product as light yellow foam which later became an oil (3.55 g, 22%). The crude material was used in the next step without further purification. ESI-MS: m/z 327.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(Cl)Cl.CO>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:21][CH:20]=1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Reactant: COc1ccc(N)cc1
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Nc2nnc(Cc3ccncc3)c(C)c2C)cc1

Procedure:
The compound is prepared from 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.129 g para-methoxyaniline in the manner described in Example 82A. Title compound is obtained after FC in CH2Cl2/Methanol 19/1. 1H-NMR (250 MHz, CDCl3): δ=8.45 (d, 2H); 7.45 (d, 2H); 7.10 (d, 2H); 6.85 (d, 2H); 6.05 (s, wide, 1H); 4.25 (s, 2H); 3.80 (s, 3H); 2.30 (s, 3H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 321 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[OH:20].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CS(C)=O.O>[Br:1][C:2]1[C:3]([O:20][C:14]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=2[F:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Oc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 67.8 %

Procedure:
5-bromo-6-chloronicotinic acid (3 g, 12.69 mmol), 2,4-difluorophenol (3.30 g, 25.4 mmol) and cesium carbonate (16.54 g, 50.8 mmol) were combined in DMSO (25.4 mL), heated at 100° C. for 6 hours, cooled, diluted with 150 mL of iced water and the pH was adjusted to pH 3 with 12M HCl. The resulting solid was collected by filtration, washed with cold water and dried to constant mass to afford the title compound (2.84 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:12]1(C(OC(C)(C)C)=O)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(O)C(N)(CO)CO>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: NC(CO)(CO)CO
Solvent: ClC(Cl)Cl
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Reaction time: 3 h
Yield: 109.4 %

Procedure:
3,4-Dichlorophenylisocyanate (3.43 g) and tert-butyl piperazine-1-carboxylate (3.40 g) were stirred for 18 hours in chloroform (20 ml) at room temperature. Trisamine resin (1 g) was added and the mixture stirred for 3 hours, then filtered off. Trifluoroacetic acid (10 ml) was added to the filtrate and this mixture was stirred for two hours. The reaction mixture was concentrated in vacuo and the resulting oil separated between ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo to give the title compound (5.47 g).
Reaction SMILES: NC1C=CC(C2C=NN(CCCO)C=2)=CC=1C(N(CC)CC)=O.[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:30]=1.Br[C:45]1[C:46]([Cl:54])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=1>>[NH2:24][C:25]1[C:26]([C:40]([NH:42][CH3:43])=[O:41])=[N:27][C:28]([C:45]2[C:46]([Cl:54])=[N:47][N:48]([CH2:50][CH2:51][CH2:52][OH:53])[CH:49]=2)=[CH:29][CH:30]=1
Reactant: OCCCn1cc(Br)c(Cl)n1
Reactant: CNC(=O)c1nc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Product: CNC(=O)c1nc(-c2cn(CCCO)nc2Cl)ccc1N
Yield: 51.7 %

Procedure:
Prepared analogously to Compound 3C using 3-amino-N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (Compound 48D, 631.2 mg, 2.28 mmol) and 3-(4-bromo-3-chloro-pyrazol-1-yl)-propan-1-ol (Compound 49E, 600 mg, 2.51 mmol) to afford 365 mg of the title compound 52%. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 4.23 (t, J=6.9 Hz, 2H), 3.56 (t, J=6.1 Hz, 2H), 2.94 (s, 3H), 2.07 (t, J=6.4 Hz, 2H). MS (ESI): m/z=310.20/312.23 [M+H]+. UPLC: tR=min (UPLC-TOF: polar—2 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1>ClCCCl>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([N:1]2[CH:23]=[CH:27][CH:26]=[CH:25]2)=[CH:7][CH:6]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc(-c2ccccc2)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2ccc(-n3cccc3)cc2)cc1
Temperature: 75 °C
Yield: 61.8 %

Procedure:
To a solution of 4-aminobiphenyl (1.0 g, 5.9 mmol) in 1,2-dichloroethane (20 mL) was added TFA (0.46 ml, 5.9 mmol). To the resultant suspension of the TFA salt was added 2,5-dimethoxy-tetrahydrofuran (0.92 mL, 7.1 mmol). The suspension was heated at 75° C. for 17 hours. The mixture was allowed to cool, partitioned between EtOAc and 1 M pH 7 phosphate buffer, and the aqueousueous layer was extracted again with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to a crude residue, which was purified via flash column chromatography with 10-25% CH2Cl2/hex gradient eluent. The purified material was triturated with MTBE/hex to give 800 mg(62%) of N-biphenyl-4-yl-1H-pyrrole as an off-white solid, mp190-2° C. 1H NMR: δ 7.65 (d, 2H, J=8.5 Hz), 7.61 (d, 2H, J=7.0 Hz), 7.48-7.43 (m, 4H), 7.36 (t, 1H, J=7.0 Hz), 7.14 (t, 2H, J=2.0 Hz), 6.37 (t, 2H, J=2.0 Hz). Anal. Calculated for C16H13N: C, 87.63; H, 5.98; N, 6.39. Found: C, 87.48; H, 6.01; N, 6.30.