Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1
Reactant: O=C1CCCCc2ccc(Br)cc21
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCCCc2ccc(Br)cc21

Procedure:
To a stirred solution of 1.91 g (8.0 mmol) of 3-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (J. Med. Chem. 2000, 43, 2049-2063) in 40 mL of ethanol under nitrogen cooled in an ice-bath was added 0.635 g (16.8 mmol, 2.1 equiv) of sodium borohydride. After three hours 32 mL of saturated sodium bicarbonate solution was added, and the mixture was concentrated under reduced pressure to remove the ethanol. The aqueous residue was diluted with 8 mL water and extracted with 2×80 mL of ethyl acetate. The combined extract was washed with 10 mL each of water and brine, dried over sodium sulfate, filtered, and concentrated to give product as a white crystalline solid. MS (m+1)=242.2; 1H NMR (400 MHz, CDCl3) 7.62 (s, 1H), 7.25 (m, 1H), 6.95 (d, 1H, J 8 Hz), 4.89 (d, 1H, J 9 Hz), 2.84 (m, 1H), 2.65 (d, 1H, J 12 Hz), 1.99 (m, 2H), 1.78 (m, 4H), 1.38 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])=O)=[CH:6][C:3]=1[C:4]#[N:5].N1([CH2:34][C:35]([NH2:37])=[O:36])C2C=CC=CC=2N=N1.[OH-].[Na+].Cl>CCO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH:22]([CH3:24])[CH3:23])[NH:37][C:35](=[O:36])[CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CC(C)COc1ccccc1C(=O)/C=C/c1ccc(F)c(C#N)c1
Reactant: NC(=O)Cn1nnc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)COc1ccccc1-c1cc(-c2ccc(F)c(C#N)c2)cc(=O)[nH]1
Temperature: 50 °C
Yield: 19.3 %

Procedure:
A mixture of (E)-2-fluoro-5-(3-(2-isobutoxyphenyl)-3-oxoprop-1-enyl)benzonitrile (324 mg, 1 mmol), commercially available 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetamide (176 mg, 1 mmol), and NaOH (80 mg) in 5 mL of EtOH was heated to 50° C. for 5 h. The reaction mixture was acidified with conc. HCl, concentrated and purified by preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate) to afford 2-fluoro-5-(6-{2-[(2-methylpropyl)oxy]phenyl}-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile (70 mg, 39%). 1H NMR (400 MHz, CDCl3): δ 7.90-7.80 (m, 2H), 7.78 (d, 1H), 7.46-7.33 (m, 2H), 7.13-7.03 (m, 2H), 6.62 (d, 2H), 3.85 (d, 2H), 2.21-2.14 (m, 1H), 1.06 (d, 6H). MS (EI) for C22H19FN2O2: 363 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]1=[O:9].[OH2:10]>>[O:8]=[C:7]([CH2:2][CH3:1])[CH2:6][CH2:5][CH2:4][C:3]([OH:9])=[O:10]
Reactant: O
Reactant: CC1C(=O)CCCC1=O
Product: CCC(=O)CCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A modification of the procedure of Ijima et al. Chem. Pharm. Bull. 19, 1053-5 (1971) was used. A solution of 2-methyl-1,3-cyclohexanedione (40 g, 0.317 mole, Aldrich) and Ba(OH)2.8H2O (360 g) in water (840 mL) was heated at reflux for 48 h. After standing overnight at room temperature and cooling to 0° C., the precipitated barium hydroxide was removed by suction filtration. CO2 gas (generated from Dry Ice) was bubbled through the filtrate to precipitate any remaining barium hydroxide as barium carbonate. The precipitate was removed by suction filtration, and water was removed in vacuum until crystallization started. The resulting mixture was acidified to pH 1 (conc. HCl) and extracted with OEt2 (3×300 mL). The extract was dried (Na2SO4) and stripped of solvent in vacuum giving 5-oxoheptanoic acid (Compound XXI) as a white solid (43.3-45.1 g, 95-99%, lit.112 69%): mp 48°-49.5° C. (lit.182 50° C.); IR (KBr pellet) cm-1 3000 (very br), 1725, 1710, 1690, 1460, 1435, 1420, 1380, 1340, 1280, 1210, 1120, 1085, 985, 910, 770, 685; 1H NMR (200 MHz, CDCl3) δ 10.2 (br, 1H), 2.51 (t, 7.1 Hz, 2H), 2.43 (q, 7.3 Hz, 2H), 2.40 (t, 7.1 Hz, 2H), 1.91 (rough pentet, 2H), 1.06 (t, 7.3 Hz, 3H); 13C NMR (22.5 MHz, CDCl3) δ 211.5, 178.6, 41.0, 36.0, 33.1, 18.7, 7.8; mass spectrum (16 eV) m/e (% base) 144 (M+, 4.1), 126 (61.3), 115 (88.8), 98 (40.0), 87 (40.1), 70 (21.3), 57 (100); TLC (OEt2, I2) Rf=0.37.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1Br.[CH2:15](Cl)Cl.C([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>O>[NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[CH3:15]
Reactant: CN1C(=O)CCc2cc(Br)c(N)cc21
Reactant: ClCCl
Agent: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc2c(cc1N)N(C)C(=O)CC2
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To 7-amino-6-bromo-1-methyl-3,4-dihydro-1H-quinolin-2-one 1 (57 mg, 0.615 mmol) dissolved in 4 ml degassed dioxane was added 50 mg (0.0615 mmol) PdCl2dppf.CH2Cl2, K2CO3 (255 mg 1.845 mmol), 400 ul H2O, and 86 ul (0.615 mmol) trimethylboroxine. The mixture was heated to 110° C. and stirred for 12 hours, then cooled and partitioned between ethyl acetate and brine. The organic layer was dried over MgSO4 filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with 75% ethyl acetate/hexanes, provided 75 mg of 7-amino-1,6-dimethyl-3,4-dihydro-1H-quinolin-2-one.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:10]([C:11](=[O:25])[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C:8]2[N:26]=[CH:27][N:28]([CH2:29][CH2:30][C:31]34[CH2:40][CH:35]5[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]5)[CH2:32]3)[CH2:38]4)[C:7]=2[CH2:6]1)=[O:4].[OH-].[Na+]>O1CCCC1CO>[C:31]12([CH2:30][CH2:29][N:28]3[C:7]4[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[N:10]([C:11](=[O:25])[CH:12]([C:13]5[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:9][C:8]=4[N:26]=[CH:27]3)[CH2:40][CH:35]3[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]3)[CH2:32]1)[CH2:38]2
Reactant: COC(=O)C1Cc2c(ncn2CCC23CC4CC(CC(C4)C2)C3)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: O=C(O)C1Cc2c(ncn2CCC23CC4CC(CC(C4)C2)C3)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 2.0 g methyl-1-(2-(1-adamantyl)ethyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo-[4,5-c]-pyridine-6-carboxylate in tetrahydrofuranmethanol (3:1, 20 mL) is treated at 25° C. with 4.1 mL 1N NaOH. After 6 hr the solution is evaporated, the residue is suspended in 10 mL water and treated with 4.1 mL 1N HCl. The resulting precipitate is collected by filtration and dried to afford a white solid, 1-(2-(1-adamantyl)ethyl)-5-diphenylacetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid. MS (FAB) 524 (M+1). mp 168°-175° C. or 187° to 200° C. dec.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)=[CH2:2].C(O)(=O)C.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>O>[CH:13]1([NH:16][CH2:2][CH2:1][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:15][CH2:14]1
Reactant: C=Cc1ccncc1
Reactant: NC1CC1
Solvent: CC(=O)O
Solvent: O
Product: c1cc(CCNC2CC2)ccn1

Procedure:
4-Vinyl pyridine (50 mmol), glacial acetic acid (3 ml), cyclopropylamine (4.28 g, 75 mmol) and water (12.8 ml) were heated at 50° C. for 22 hours. The crude reaction products partitioning, the organic phase was washed with water, brine and dried. Filtered and solvents removed under vacuum. The residue was further distilled under vacuum (Kugelrohr) and the product amine collected. NMR (CDCl3) 8.45 (m, 2H), 7.05 (m, 2H), 2.93 (m, 2H), 2.73 (m, 2H), 2.07 (m, 1H), 1.37 (m, 2H), 1.25 (m, 2H); m/z 163.17.
Reaction SMILES: C[Li].C(NC(C)C)(C)C.[CH2:10]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=1)[CH:11]([CH3:13])[CH3:12].Cl[Si:28]([CH3:31])([CH3:30])[CH3:29]>C(OCC)C>[CH2:24]([O:23][C:21]([O:22][Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:20]([CH3:26])[C:17]1[CH:16]=[CH:15][C:14]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:19][CH:18]=1)[CH3:25]
Reactant: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CCOC(O[Si](C)(C)C)=C(C)c1ccc(CC(C)C)cc1
Temperature: -70 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
Methyllithium in diethyl ether (0.25 mol, 140 ml of 1.8 M solution) was added dropwise to a solution of 27.6 g (0.27 mol) of diisopropylamine in 40 ml of diethyl ether. The reaction mixture was cooled to -70° C. and 37.5 g (0.16 mol) of ethyl 4-isobutyl-α-methylphenylacetate were added dropwise. The reaction mixture was warmed to 0° C. and 46 ml (0.36 mol) of chlorotrimethylsilane were added. The reaction mixture was stirred overnight at 25° C., filtered and then distilled to give 34.3 g (70% yield) of β-ethoxy-4-isobutyl-α-methyl-β-(trimethylsiloxy)-styrene as a colorless liquid, bp 129°-130° C. (0.4 mm). Anal. Calcd. for C18H30O2Si: C, 70.53; H, 9.87; Found: C, 70.38; H, 9.78.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:11])[N:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[OH:9].Cl[CH2:13][C:14](Cl)=[O:15].N1C=CC=CC=1.OS([O-])(=O)=O.[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.CC(=O)OCC.C(O)(C)C.O>[CH3:10][N:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:13][C:14](=[O:15])[NH:2][C:3]=2[C:4]1=[O:11]
Reactant: Cn1ccc(O)c(N)c1=O
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cn1ccc2c(c1=O)NC(=O)CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.7 %

Procedure:
To a solution of the title compound of Example 237, step 3 (1.6 g, 9.01 mmol, 1.00 Eq) in CH2Cl2 (150 mL) at 0° C. under N2 is added chloroacetyl chloride (0.75 mL, 9 mmol) dropwise. Pyridine (2.2 mL, 37 mmol) is then added, and the mixture was stirred for 5 h at room temperature. Saturated aqueous KHSO4 (100 mL) is added and the aqueous layer was extracted a total of three times with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and then acetone (200 mL) followed by cesium carbonate (14.6 g, 45 mmol) were added directly to the filtrate (250 mL). The mixture was then heated at 50° C. for 2 h. The volume was reduced and water was added. Extractive work up with 3:1 CH2Cl2: isopropanol followed by trituration with 1:2 EA/PE gave the title compound (400 mg, yield: 24.67%) as a yellow solid. 1H NMR: (CDCl3, 400 MHz) δ: 8.17-8.14 (br, 1H), 7.01 (d, J=7.2 Hz, 1H), 6.07 (d, J=7.2 Hz, 1H), 4.69 (s, 1H), 3.59 (s, 3H). LCMS: 181.0 (M+H)+
Reaction SMILES: C([O:3][C:4]([CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)=[O:9])=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16]/[C:17](=[C:24]2\[C:25](=[O:33])[NH:26][C:27]3[C:32]\2=[CH:31][CH:30]=[CH:29][CH:28]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:14][CH:15]=1)=[O:9])([OH:5])=[O:3]
Reactant: CCOC(=O)CNC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CNC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 8 from (Z)-3-[1-(3-ethoxycarbonylmethylaminocarbonyl-phenylamino)-1-phenyl-methylidene]-2-indolinone and sodium hydroxide solution in ethanol.
Reaction SMILES: P(=O)(O)(O)O.O.[Cl:7][C:8]1[C:17]([CH:18]=[CH:19][O:20]C)=[C:16]([Cl:22])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>O1CCOCC1>[Cl:7][C:8]1[C:17]([CH2:18][CH:19]=[O:20])=[C:16]([Cl:22])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC=Cc1c(Cl)ccc(C(=O)OC)c1Cl
Agent: O=P(O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(Cl)c(CC=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.7 %

Procedure:
6 ml of 85% strength phosphoric acid and 6 ml of H2O were added dropwise to 2.6 g (10 mmol) of methyl 2,4-dichloro-3-(2-methoxyethen-1-yl)benzoate in 80 ml of dioxane. The mixture was heated under reflux for 12 hours and then stirred at room temperature for 12 hours. The solvent was removed and the residue was taken up in ethyl acetate, washed with 10% strength sodium bicarbonate solution, dried and concentrated. The residue was chromatographed over silica gel (eluent: cyclohexane:ethyl acetate=9:1). 1.4 g (57% of theory) of methyl 2,4-dichloro-3-(2-oxoeth-1-yl)benzoate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:32]=[CH:31][C:15]3[N:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35][O:36][C:37](=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Br.O>CN(C)C=O>[CH3:35][O:36][C:37](=[O:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[C:12]1[CH:32]=[CH:31][C:15]2[N:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 mg of 4-chloro-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 8 mg of sodium hydride, and stirred for 30 minutes at 20° C. 70 mg of 7-bromoheptanoic acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:9][C:10]1[C:11](=[O:20])[C:12]([CH3:19])=[C:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].Cl.C(OCC)(=O)C>C1COCC1>[OH:20][C:11]1([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]([CH3:9])=[C:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:18])=[C:12]1[CH3:19]
Reactant: CCOC(=O)C[Zn]Br
Reactant: CC1=C(C)C(=O)C(C)=C(C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C(C)=C(C)C(=O)C(C)=C1C
Yield: 94 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.45 g (3.33 mmol) of 2,3,5,6-tetramethyl-1,4-benzoquinone in 4 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. for 1 hour. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After cooling, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 0.79 g of the desired product (yield 94%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH2:12].C12CC3CC(CC(C3)C1N=[C:24]=[O:25])C2.ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[N:12]=[C:24]=[O:25]
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: Cc1cccc(C(F)(F)F)c1N
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(C(F)(F)F)c1N=C=O

Procedure:
This compound was made from 2-methyl-6-trifluoromethyl-phenylamine in analogy to Eur. J. Med. Chem. 28 (1), 1993, 37-45 by treatment with bis-(trichloromethyl)-carbonate (627 mg) and triethylamine (1.58 mL) in DCM (16 mL). (2-Methyl-6-trifluoromethylphenyl)isocyanate was obtained as a colorless solid (1.17 g). 1H-NMR (δ, CDCl3): 7.49 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[N:4][CH:5]=[C:6]([NH2:8])[CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[Br:15][C:5]1[C:6]([NH2:8])=[CH:7][C:2]([Cl:1])=[C:3]([O:9][CH2:10][C:11]([F:13])([F:14])[F:12])[N:4]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1cc(Cl)c(OCC(F)(F)F)nc1Br
Yield: 100.2 %

Procedure:
3-Chloro-5-amino-2-(2,2,2-trifluoroethoxy)-pyridine (3.05 g) obtained in Step B was brominated with N-bromosuccinimide (2.4 g) in acetonitrile (68 ml) as described in Example 14, Step C to give 2-bromo-5-chloro-6-trifluoroethoxy-pyridin-3-yl-amine (4.12 g) as a red oil. MS (ES+) 305/307/309 (MH+); 346/348/350 (MH++CH3CN); 1H NMR (400 MHz, CDCl3) 3.80 (br s, 2H), 4.65 (q, 2H), 7.10 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:39]=[CH:38][C:18]([O:19][C:20]2[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:37])[N:28]([CH3:36])[CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:21]=2)=[CH:17][C:16]=1[F:40].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1.C(O)C>[F:40][C:16]1[CH:17]=[C:18]([CH:38]=[CH:39][C:15]=1[NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[S:13])[O:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:37])[N:28]([CH3:36])[CH:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[CH:21]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)c(F)c3)ncn2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)c(F)c3)ncn2)CC1
Reaction time: 4 h
Yield: 10 %

Procedure:
After adding a solution of 2-(4-fluorophenyl)acetyl isothiocyanate in toluene (0.2 M, 3.4 ml) to a solution of crude 3-[6-(4-amino-3-fluorophenoxy)pyrimidin-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea and (+)-10-camphorsulfonic acid (86.2 mg) in ethanol (2.5 ml) at room temperature, the mixture was stirred for 4 hours. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine in that order and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure, and diethyl ether (2.0 ml) was added to the resultant residue to precipitate crystals. The crystals were filtered and then subjected to aeration drying to provide the title compound (21.0 mg, 10%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][CH2:42]O)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([NH:40][CH2:41][CH2:42][O:23][C:22]([C:21]1[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:24])=[O:44])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCCNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and (2-hydroxyethyl)carbamic acid tert-butyl ester. A colorless powder (120 mg).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[Na]>C1COCC1>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[CH:17][CH:16]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: c1c[nH]cn1
Reactant: N#CCNC(=O)C1(NC(=O)c2ccc(CBr)cc2)CCCCC1
Agent: [Na]
Solvent: C1CCOC1
Product: N#CCNC(=O)C1(NC(=O)c2ccc(Cn3ccnc3)cc2)CCCCC1
Temperature: 25 °C

Procedure:
N-[1-(cyanomethyl-carbamoyl)-cyclohexyl]-4-bromomethyl-benzamide (0.34 mmol) is dissolved in THF (2 ml) and sodium-imidazol (0.41 mmol) is added and the reaction mixture stirred at RT over night. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated. The residue was suspended in diethylether and the solid filtered of. The crude product is purified by chromatography on silica using CH2Cl2/MeOH=9:1. The fractions containing the pure product were collected and evaporated. The residue was suspended in diethylether and the solid filtered of. A white powder with mp. 194-196° C., Rf=0.28 (CH2Cl2/MeOH=9:1) is obtained.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17]([O:9][CH2:8][CH:5]2[CH2:6][CH2:7][C:2]([F:10])([F:1])[CH2:3][CH2:4]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: OCC1CCC(F)(F)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCC(F)(F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above (4,4-difluorocyclohexyl)methanol was dissolved in 5 ml of pyridine. Thereto 2.2 g of p-toluenesulfonyl chloride was added at 0° C. and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with water, dilute hydrochloric acid and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.1 g of 4,4-difluorocyclohexylmethyl p-toluenesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.[I-].[Na+]>C1COCC1>[N:24]1([CH2:21][C:17]2[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=2)[C:14]([NH:13][CH2:12][CH2:11][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][CH:6]=2)=[O:23])[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: c1c[nH]cn1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(Cn2ccnc2)c1
Yield: 16.5 %

Procedure:
3-((1H-Imidazol-1-yl)methyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), imidazole (0.034 g; 0.5 mmol) and sodium iodide (0.090 g; 0.6 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 20 minutes. Flash chromatography on silica gel (eluent 0 to 10% methanol in dichloromethane) furnished 0.009 g (16%) of the title compound as a white solid.