Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[N:18]3[CH2:19][CH2:20][CH2:21][C:17]3=[CH:16][N:15]=2)[CH2:9]1.C(N(CC)CC)C.Cl[C:30]1[N:35]=[C:34]([NH2:36])[C:33]([N+:37]([O-:39])=[O:38])=[CH:32][CH:31]=1>C(#N)C>[CH:16]1[N:15]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:30]3[N:35]=[C:34]([NH2:36])[C:33]([N+:37]([O-:39])=[O:38])=[CH:32][CH:31]=3)[CH2:9]2)[N:18]2[CH2:19][CH2:20][CH2:21][C:17]=12
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: c1nc(C2CCCNC2)n2c1CCC2
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc(N2CCCC(c3ncc4n3CCC4)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 3-(piperidin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole trifluoroacetate salt (94 mg) in anhydrous acetonitrile (1.1 mL) at 10° C. was added triethylamine (130 μL, 0.93 mmol). Then 6-chloro-3-nitropyridin-2-amine (39 mg, 0.2 mmol) was added. The reaction mixture was shaken at 80° C. for 2 h and then for 18 h at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (3 mL). The mixture was washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (0-10% methanol in dichloromethane) to afford 6-(3-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)piperidin-1-yl)-3-nitropyridin-2-amine as a yellow oil (60 mg, 82%). MS (ES+) (M+H) 329.2; LCMS retention time: 1.61 minutes (Method L).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)O)[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3].[Cl-:23]>ClCCl>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[Cl:23])[CH:8]=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1cccc(C(O)c2cccc(CC(C)C)c2)c1
Reactant: [Cl-]
Solvent: ClCCl
Product: CC(C)Cc1cccc(C(Cl)c2cccc(CC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of bis(3-isobutylphenyl)methanol (2.87 g) and oxaly chloride (1 ml) in dichloromethane (10 ml) was stirred at 25° C. for 2 hours. After evaporation of the solvent, the oily residue was distilled to give bis(3-isobutylphenyl)chloromethane (2.45 g) as pale yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1.[CH3:17][C:18]1[N:23]=[C:22]([SH:24])[N:21]=[C:20]([OH:25])[CH:19]=1.C(N(CC)CC)C.ClCCl>C(O)C>[CH2:15]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[N:7]=[CH:8][C:3]([CH2:2][S:24][C:22]3[N:21]=[C:20]([OH:25])[CH:19]=[C:18]([CH3:17])[N:23]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)[CH3:16]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCN1CCN(c2ccc(CBr)cn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCN1CCN(c2ccc(CSc3nc(C)cc(O)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
To a suspension of 1-[5-(bromomethyl)pyridin-2-yl]-4-ethylpiperazine (3.85 g, 13.54 mmol) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.25 g, 8.86 mmol) in anhydrous ethanol at 0° C. was added triethylamine (5.47 g, 54.18 mmol). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was purified by column chromatography using 0-15% methanol:dichloromethane to provide (2-({[6-(4-ethylpiperazin-1-yl)pyridin-3-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol as a white solid (1.82 g, 39% yield); 1H NMR (400 MHz, DMSO-d6): δ 0.99 (t, 3H), 2.18 (s, 3H), 2.31 (q, 2H), 2.56 (m, 4H), 3.42 (m, 4H), 4.23 (s, 2H), 6.01 (bs, 1H), 6.78 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 8.14 (s, 1H); LRMS (ES+) m/z 345.6.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:5]2=[N:15][CH:16]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18](=[O:19])[N:4]2[CH:3]=1.[Cl-].[NH4+].C(Cl)(Cl)Cl.CO>O.C(O)C.[Fe]>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH3:1])=[CH:3][N:4]3[C:18](=[O:19])[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][N:15]=[C:5]32)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc2c3cc([N+](=O)[O-])ccc3c(C)cn2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2c3cc(N)ccc3c(C)cn2c1=O
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a stirred mixture of ethyl 7-methyl-10-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (140 mg) and iron powder (90 mg) in a mixture of water (0.5 ml) and ethanol (13 ml) was added a solution of ammonium chloride (90 mg) in water (0.5 ml) under refluxing. After refluxing for 1 hour and 50 minutes, ammonium chloride (28 mg) in water (0.5 ml) and iron (50 mg) was added, and then the mixture was stirred for additional 1 hour. The reaction mixture was filtered and the residue on a filter was washed with hot ethanol. The filtrate was concentrated in vacuo and then treated with dilute sodium hydrogen carbonate solution to give crude product. Chromatography on silica gel with chloroform-methanol gave pure ethyl 10-amino-7-methyl-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (100 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.Cl.[CH3:11][C:12]1([CH3:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C.O>[Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([N:15]2[CH2:16][CH2:17][CH2:18][C:12]([CH3:19])([CH3:11])[CH2:13][CH2:14]2)=[O:9])[CH:3]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: CC1(C)CCCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)CCCN(C(=O)c2csc(Br)c2)CC1
Reaction time: 8 h
Yield: 71.9 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid (0.5 g, 2.42 mmol), 4,4-dimethyl-azepane hydrochloride (0.475 g, 2.91 mmol), triethylamine (1.01 mL, 7.25 mmol) and HATU (1.20 g, 3.16 mmol) were dissolved in acetonitrile (10 mL) and the resulting mixture stirred overnight. The mixture was diluted with water and extracted with DCM (×2). The organics were dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on a silica II cartridge, eluting with 10-25% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give (5-bromo-thiophen-3-yl)-(4,4-dimethyl-azepan-1-yl)methanone (0.55 g).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[CH3:18][C:16]([CH3:19])([O:15][C:13]([NH:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:14])[CH3:17]
Reactant: COC(=O)C1(CCNC(=O)OC(C)(C)C)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC1(C(=O)O)CCCC1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 1-[2-[[(1,1-dimethylethoxy)carbonyl]amino]ethyl]cyclopentane carboxylic acid methyl ester (10.6 g, 39.0 mmol) in THF/MeOH (3:1, 40 mL) was added a solution of LiOH (4.20 g, 98.0 mmol) in water (10 mL). The mixture was stirred for 2.5 h at 50° C. and then cooled to room temperature. The reaction mixture was poured into a round bottom flask and concentrated in vacuo. The mixture was diluted with H2O (60 mL) and acidified with 1M HCl. The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organic layer was dried over MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography, using hexane-ethyl acetate (3:1), afforded 5.80 g (58%) as a white powder. HR MS (C13H23NO4): Calcd mass, 258.1705. Obs mass, 258.1700 [(M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][N:24]1[CH:31]=[CH:30][C:28](=[O:29])[NH:27][C:25]1=[O:26].C(N(CC)CC)C.ClCCl>C(O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:27]2[C:28](=[O:29])[CH:30]=[CH:31][N:24]([CH3:23])[C:25]2=[O:26])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Cn1ccc(=O)[nH]c1=O
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1ccc(=O)n(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c1=O
Reaction time: 8 h

Procedure:
The mixture of 30 mg of (2S)-2-(t-butoxycarbonylamino)-3-[4-(dihydroxy boranyl)phenyl]propionic acid, 25 mg of 1-methyluracil, 27 mg of copper acetate(II), 40 mg of triethylamine and 4 ml of dichloromethane were stirred overnight. The reaction solvent was diluted by ethanol and filtered by Celite filtration. The residual material obtained by concentrating the filtrate was dilluted by 1N sodium hydroxide and washed with ethyl acetate. After making the water layer acidic by hydrochloric acid, the solution was extracted with ethyl acetate, washed with saturated NaCl aqueous solution, dried with magnesium sulfate and the solvent was removed to obtain a crude material of (2S)-2-(t-butoxycarbonylamino)-3-[4-(1-methyluracil-3-yl)phenyl]propionic acid. This crude material was diluted by 5 ml of ethanol and hexane solution including 2M trimethylsilyldiazomethane was added to give methyl ester. The reaction solvent was concentrated and purified by silica gel chromatography (ethyl acetate-ethanol) to obtain the title compound (7 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])(O)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)=O.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22][CH3:23])[CH3:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(OC)c(C(C)(O)COCCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1ccc(OC)c(C(C)COCCc2ccccc2)c1
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of 2-(2,5-dimethoxyphenyl)-2-hydroxypropyl 2-phenylethyl ether (550 mg., 1.74 mM) in pyridine (2 ml.) is added dropwise phosphorous oxychloride (477 ml., 5.22 mM). The reaction is allowed to warm to 20° C. over a 1.5 hour period. It is then stirred for 1.5 hours at 20° C. and then added to ether (150 ml.) and 15% sodium carbonate (100 ml.). The organic phase is separated and washed with 15% sodium carbonate (3×50 ml.), dried over magnesium sulfate and evaporated to an oil. The oil is dissolved in absolute ethanol (15 ml.), 10% palladium-on-carbon (100 mg.) added and the mixture stirred under one atmosphere of hydrogen gas. When hydrogen uptake ceases, the reaction is filtered through diatomaceous earth and the filtrate evaporated to an oil. The oil is purified via preparative layer chromatography on silica gel plates, eluting with 6:1 pentane: ether to yield 2-(2,5-dimethoxyphenyl)propyl 2-phenylethyl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=O)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[CH3:30][O:31][NH2:32]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][C:24]2=[N:32][O:31][CH3:30])[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2=O)C(=O)Nc2cnccn2)cc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: CON=C1CCCC1CC(C(=O)Nc1cnccn1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 32, 99.5 mg, 0.23 mmol) in pyridine (0.69 mL) and methanol (0.69 mL) at 25° C. was treated with methoxyamine hydrochloride (30 mg, 0.35 mmol). The reaction mixture was heated under reflux for 12 h. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (75 mL) and was washed with a 1N aqueous sodium hydroxide solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(2-methoxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (92.7 mg, 87.2%) as a white wax: mp 74-76° C.; FAB-HRMS m/e calcd for C20H23ClN4O4S (M+Na)+ 473.1021. found 473.1024.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[F:22]>>[F:15][C:16]1[CH:17]=[C:18]([C:2]2[C:3]([C:4]([OH:6])=[O:5])=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccc(F)c(F)c2)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example B25 from 2-Iodo-5-methanesulfonyl-benzoic acid (example B19(b)) and 3,4-difluoro-benzeneboronic acid. Light brown solid. MS (m/e): 311.1 ([M−H], 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[Mg+2].[Cl-].[Cl-].[K+].[CH3:30][O:31][C:32](=[O:37])[CH2:33]C([O-])=O>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9](=[O:11])[CH2:33][C:32]([O:31][CH3:30])=[O:37])=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)[O-]
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)C(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
To a solution of 2-(4-chlorophenyl)-2-methylpropanoic acid (200 mg, 1.01 mmol) in THF (20 mL) was added CDI (172 mg, 1.06 mmol) at rt. The reaction mixture was stirred at rt for 2 h. Added MgCl2 (105 mg, 1.11 mmol) and 3-methoxy-3-oxopropanoic acid potassium salt (173 mg, 1.11 mmol) at rt. The mixture was stirred at 60° C. overnight. Dilute with ethyl acetate (100 mL), washed with 0.5 N HCl (20 mL×2) and brine (50 mL), dried over Na2SO4, filtered, concentrated, purified by flash column chromatography to give the title compound (60 mg, 23%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.51 (6H, s), 3.28 (2H, s), 3.67 (3H, s), 7.20-7.30 (2H, m), 7.34-7.37 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.Cl[CH2:16][CH2:17][CH2:18][S:19](Cl)(=[O:21])=[O:20]>>[O:20]=[S:19]1(=[O:21])[CH2:18][CH2:17][CH2:16][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)CCCCl
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1[N+](=O)[O-]

Procedure:
Using methyl 4-amino-2-nitrobenzoate (750 mg) and 3-chloropropane-1-sulfonyl chloride (0.61 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (967 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:35][CH3:36])=[C:21]([C:23]([CH3:34])([CH3:33])[CH2:24][C:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=O)[CH:22]=1.C(O)(=O)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:35][CH3:36])=[C:21]([C:23]([CH3:33])([CH3:34])[CH2:24][C:25]([C:28]([F:30])([F:31])[F:29])([OH:32])[CH:26]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:13])[F:14])=[N:7]3)[CH:22]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2nc(C(F)(F)F)ccc12
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(F)(F)F)ccc12)C(F)(F)F

Procedure:
Analogously to Example 37, 250 mg (1.18 mmol) of 5-amino-2-(trifluoromethyl)quinoline is reacted with 438 mg (1.42 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1.30 ml of concentrated acetic acid in 20 ml of toluene. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 500 mg (84% of theory) of the product is obtained.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](I)=[C:11]([F:16])[CH:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.[Cu]I>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]2)=[C:11]([F:16])[CH:10]=1
Reactant: O=Cc1c[nH]cn1
Reactant: Fc1cc(Cl)ccc1I
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: O=Cc1cn(-c2ccc(Cl)cc2F)cn1
Temperature: 110 °C
Yield: 69.7 %

Procedure:
To 1H-imidazole-4-carbaldehyde (2.56 g, 26.6 mmol), 4-chloro-2-fluoro-1-iodobenzene (0.739 g, 2.88 mmol) and Cs2CO3 (1.564 g, 4.80 mmol) in DMF (50 mL) was added copper(I) iodide (0.023 g, 0.120 mmol) and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (0.068 g, 0.480 mmol). The reaction was heated to 110° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered, and washed with EtOAc (100 mL). The organic was washed with water (2×30 mL) and brine (30 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromotography to give 1-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carbaldehyde (451 mg), to which was added (S)-2-methylpropane-2-sulfinamide (0.29 g, 2.4 mmol), CuSO4 (0.638 g, 4 mmol) and DCE (10 mL). The reaction was heated to 65° C. for 18 hours. The reaction was cooled to rt, filtered and concentrated to give (S,E)-N-((1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)methylene)-2-methylpropane-2-sulfinamide, to which was added DCM (20 mL). The reaction mixture was cooled to −70° C. and methylmagnesium bromide (1.33 ml, 4 mmol) was added dropwise to the solution. The reaction was stirred for two hours and the cold bath was then removed, and the reaction was allowed to warm to rt and stir for 30 minutes. The reaction was cooled to 0° C. and HCl (1M) was added cautiously to quench until aqueous pH=8. The phases were separated and the aqueous layer was extracted with DCM (2×30 mL). Combined organic was dried (Na2SO4) and concentrated to give (S)—N—((S)-1-(1-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)ethyl)-2-methylpropane-2-sulfinamide (130 mg), which was then dissolved in MeOH (5 mL) and HCl (0.5 mL, 4M) was added. The reaction was stirred for one hour and concentrated to give product (100 mg). LCMS m/z 240.1 (M+H)+; Rt-0.50 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13]OS(C)(=O)=O)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.ClCCl.CO>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:10][CH:11]=[CH2:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1c[nH]cn1
Reactant: C=CCC(COS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: CO
Solvent: ClCCl
Product: C=CCC(Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Yield: 70.3 %

Procedure:
4-(3,4-Dichlorophenyl)-5-(methanesulphonyloxy)pent-1-ene (5.4 g) (see Preparation 23) and imidazole (3.6 g) were dissolved in anhydrous acetonitrile (40 ml) and the mixture heated under reflux for 100 hours. The solvent was removed under reduced pressure, the residue dissolved in dichloromethane and the solvent removed under reduced pressure. The residue was dissolved in dichloromethane (100 ml) and washed with sufficient aqueous sodium carbonate solution to ensure that the aqueous phase reached pH14. The two phases were separated and the aqueous phase extracted with dichloromethane (100 ml). The organic phases were combined and the solvent removed under reduced pressure to give a residue which was chrornatographed on silica gel eluting with a solvent gradient of 100:0 changing to 98:2, by volume, dichloromethane:methanol, to give 4-(3,4-dichlorophenyl)-5-(imidazol-1-yl)pent-1-ene (3.45 g) as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[F:23][C:24]1[C:29]([C:30](Cl)=[O:31])=[C:28]([F:33])[C:27]([F:34])=[C:26]([F:35])[C:25]=1[F:36]>O1CCCC1>[F:23][C:24]1[C:25]([F:36])=[C:26]([F:35])[C:27]([F:34])=[C:28]([F:33])[C:29]=1[C:30]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:31]
Reactant: O=C(Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3c(F)c(F)c(F)c(F)c3F)c2)CC1
Reaction time: 0.17 h
Yield: 107.5 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in tetrahydrofuran (2 mL) was allowed to stand for 10 min. Pentafluorobenzoyl chloride (33 μL, 0.229 mmol) was added to the reaction mixture. The reaction mixture was mixed for 2 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 51 mg (>100%) of the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[N:15]=[C:14]([CH3:19])[C:13]=1[CH2:20][OH:21].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[C:13]([CH:20]=[O:21])=[C:14]([CH3:19])[N:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: Cc1nc(Cl)cc(Cl)c1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)cc(Cl)c1C=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A dry flask was charged with DCM (59.9 mL) and oxalyl chloride (3.15 mL, 35.9 mmol) and cooled to −78° C. Dimethyl sulfoxide (3.40 mL, 47.9 mmol) was added and the reaction was stirred for 30 min. A solution of (4,6-dichloro-2-methylpyridin-3-yl)methanol (4.60 g, 23.95 mmol) in DCM (2 mL) was then added. The reaction was stirred for 30 min then triethylamine (6.74 mL, 71.9 mmol) was added and the reaction mixture was stirred at −78° C. for 30 min. The reaction was warmed to 0° C. and stirred for 1 h. The reaction was then quenched with sodium bicarbonate, diluted with water, and the aqueous layer extracted with EtOAc. The organic phase was washed with sat. sodium bicarbonate, dried over MgSO4, filtered, and concentrated in vacuo to afford 4,6-dichloro-2-methylnicotinaldehyde, which was carried onto the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 10.60 (s, 1H), 7.37 (s, 1H), 2.80 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:15]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1

Procedure:
4-(bromomethyl)benzoic acid was coupled to 4-chloro-3-(pyridin-2-yl)aniline as described in general procedure E to yield 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide.