Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22](O)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:30][N:31]([CH:33]=O)[CH3:32]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([NH:19][C:13]4[CH:14]=[CH:25][C:10]([CH2:33][N:31]([CH3:30])[CH:32]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:11][CH:12]=4)=[O:23])=[CH:15][C:14]=3[CH:25]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In DMF (5 ml) was dissolved 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.2 g). To the solution was added, under ice-cooling, thionyl chloride (0.11 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (15 ml). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.15 g) and triethylamine (0.41 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-(4-ethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.25 g) as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)C(C)C)C.Cl[CH2:17][C:18](=[O:20])[CH3:19].[N:21]1([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[O:20]=[C:18]([CH3:19])[CH2:17][N:24]1[CH2:23][CH2:22][N:21]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[CH2:26][CH2:25]1
Reactant: CC(=O)CCl
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)CN1CCN(C(=O)OCc2ccccc2)CC1
Yield: 58.6 %

Procedure:
Potassium carbonate (1.27 g, 9.22 mmol), N-ethyldiisopropylamine (0.80 ml, 4.61 mmol), and chloroacetone (1.22 ml, 13.83 mmol) were added to a solution of benzyl piperazine-1-carboxylate (2.03 g, 90.22 mmol) in acetonitrile(20 ml), and the mixture was heated under reflux for 2 hours. The insoluble substances were removed by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography(methylene chloride/methanol=100/1) to afford benzyl 4-(2-oxopropyl)piperazine-1-carboxylate (2.24 g, yield 88%) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28][N:27]([C:34]3[CH:39]=[C:38]([N+:40]([O-])=O)[CH:37]=[CH:36][C:35]=3[C:43]([F:46])([F:45])[F:44])[C:26]2=[O:47])=[C:20]([F:48])[CH:19]=1)(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>[Pt]=O.C(O)C>[NH2:40][C:38]1[CH:37]=[CH:36][C:35]([C:43]([F:44])([F:45])[F:46])=[C:34]([N:27]2[C:26](=[O:47])[N:25]([CH2:24][C:21]3[CH:22]=[CH:23][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:9](=[O:10])(=[O:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:19][C:20]=3[F:48])[C:29]([CH2:30][CH2:31][CH2:32][CH3:33])=[N:28]2)[CH:39]=1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)OC(C)(C)C)cc1F
Yield: 66.6 %

Procedure:
A mixture of 185 mg (0.267 mmol) of 4-[[2'-[N-(t-butoxycarbonyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step C), 25 mg of platinum oxide, 2 mL of ethyl acetate, and 10 mL of ethanol was shaken with hydrogen at approximately 3 atm for 2 hours. The mixture was centrifuged, and the supernatant was concentrated. Flash chromatography of the residue on silica gel (gradient elution with 1-5% MeOH in CH2Cl2) yielded 118 mg (67%) of the title compound as a white foam, homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 664 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[CH:19]1([CH:22]([NH2:25])[CH2:23][CH3:24])[CH2:21][CH2:20]1>>[CH:19]1([CH:22]([NH:25][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[CH:5]=[CH:4][N:3]=2)[CH2:23][CH3:24])[CH2:21][CH2:20]1
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1Cl
Reactant: CCC(N)C1CC1
Product: CCC(Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 736.6 %

Procedure:
2-Chloro-4-(2,4-dichloro-phenyl)-3-nitro-pyridine (0.26 g, 0.86 mmol) and 1-cyclopropyl-propylamine (0.23 g, 1.71 mmol) were substantially as described in Part D of Example 9 to produce 2.32 g (100%) of crude (1-cyclopropyl-propyl)-[4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-amine: MS (AP) m/z 366.2 [(M+H)+, 96].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11]2([CH2:15][C:16]([OH:18])=O)[CH2:14][CH2:13][CH2:12]2)=[CH:5][C:4]=1[CH3:19].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:19])=[C:5]2[C:6](=[CH:7][C:8]=1[CH3:9])[NH:10][C:11]1([CH2:12][CH2:13][CH2:14]1)[CH2:15][C:16]2=[O:18]
Reactant: COc1c(C)cc(NC2(CC(=O)O)CCC2)cc1C
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(C)cc2c(c1C)C(=O)CC1(CCC1)N2
Yield: 165.1 %

Procedure:
To a solution of 2-(1-(4-methoxy-3,5-dimethylphenylamino)cyclobutyl)acetic acid (650 mg) in 10 mL toluene was added a large excess of polyphosphoric acid. The mixture was refluxed for 30 minutes, water was added, and the solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation, giving 6′-methoxy-5′,7′-dimethyl-1′H-spiro[cyclobutane-1,2′-quinolin]-4′(3′H)-one as a yellow solid (1 g). 1H-NMR (300 MHz, CDCl3) δ=6.25 (s, 1H), 2.78 (s, 2H), 2.55 (s, 3H), 2.125-2.38 (m, 5H), 1.95-2.06 (m, 2H), 1.73-1.83 (m, 2H) ppm. MS: m/z 246 (100, M+H)+
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:28])[CH2:14][CH2:15][CH2:16]/[C:17](=[CH:18]\[CH:19]=[C:20]3\[CH2:21][C@@H:22](O)[CH2:23][CH2:24][C:25]\3=[CH2:26])/[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:29]1(=[O:39])[N:33]([CH:22]2[CH2:23][CH2:24][C@@:25]3([CH3:26])[CH:20]([CH2:19][CH2:18][C@@H:17]4[C@@H:16]3[CH2:15][CH2:14][C@@:13]3([CH3:28])[C@H:12]4[CH2:11][CH2:10][C@@H:9]3[C@H:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:21]2)[C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=C1CC[C@H](O)C/C1=C/C=C1\CCC[C@]2(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(N5C(=O)c6ccccc6C5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of dihydrocholesterol (5.0 g, 12.9 mmol, Aldrich), phthalimide (2.0 g, 13.6 mmol, Aldrich), and triphenylphosphine (3.8 g, 13.6 mmol, Aldrich) in THF (20 ml, Aldrich) stirred at 0° C. under a nitrogen atmosphere was added dropwise diethylazodicarboxylate (2.3 ml, 14.5 mmol, Aldrich). Upon the completion of addition the reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was concentrated in vacuo to a residue. This residue was dissolved in 50 ml hexane/ethyl acetate 95/5 and a precipitate formed. The mixture was filtered. The filtrate was concentrated to dryness in vacuo, dissolved in 25 ml of hexane/ethyl acetate 95/5 and chromatographed on 200 g silica gel (eluent 2 L hexane/ethyl acetate 95/5 then 1 L hexane/ethyl acetate 90/10). A 7.6% yield of the desired 3-phthalimidocholestane (5.43 g) was obtained.
Reaction SMILES: [OH-:1].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:15][C@@:14]3([F:29])[CH3:28])=[C:10]([C:30]#[N:31])[CH:9]=[N:8][N:7]2[CH:32]=1.OO>CS(C)=O.CO>[Br:3][C:4]1[CH:5]=[C:6]2[C:11]([NH:12][C@@H:13]3[CH2:17][N:16]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[CH2:15][C@@:14]3([F:29])[CH3:28])=[C:10]([C:30](=[O:1])[NH2:31])[CH:9]=[N:8][N:7]2[CH:32]=1
Reactant: [OH-]
Reactant: C[C@]1(F)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C#N)cnn2cc(Br)cc12
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: C[C@]1(F)CN(C(=O)OCc2ccccc2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A 2.0 M aqueous NaOH (0.6 mL, 1.200 mmol) was added dropwise to a solution of (3S,4R)-benzyl 4-((6-bromo-3-cyanopyrrolo[1,2-b]pyridazin-4-yl)amino)-3-fluoro-3-methylpyrrolidine-1-carboxylate (120 mg, 0.254 mmol) in methyl sulfoxide (2 mL), methanol (2 mL) and hydrogen peroxide (0.3 mL, 2.94 mmol) at 0° C. After 1 h at 0° C., the mixture was quenched with saturated NaHCO3 (5 mL), diluted with ethyl acetate (80 mL), washed with water, brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography, eluting with 20 to 80% ethyl acetate in hexanes, to give (3S,4R)-benzyl 4-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-3-fluoro-3-methylpyrrolidine-1-carboxylate (115 mg, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 10.71 (d, J=8.4 Hz, 1H), 7.98-7.85 (m, 1H), 7.73-7.59 (m, 1H), 7.51-7.30 (m, 5H), 6.79 (d, J=7.5 Hz, 1H), 5.79-5.54 (m, 2H), 4.69-4.33 (m, 1H), 4.32-4.08 (m, 1H), 4.00-3.74 (m, 1H), 3.59-3.42 (m, 2H), 1.61-1.43 (m, 3H); MS (ES+) m/z: 490.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]([NH2:14])=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.S.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12](=[S:17])[NH2:14])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cnc2c(c1)CCCC2C(N)=O
Agent: S
Solvent: c1ccncc1
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 0 °C
Yield: 180.7 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (27.9 g. 0.14 m) in dry pyridine (300 ml.), saturated with H2S gas, was treated with P2S5 (26 g., 0.14 m) and heated at reflux for 45 min. whilst maintaining a slow stream of H2S gas. The reaction mixture was evaporated to dryness in vacuo and cooled to 0° C., made alkaline with 10% sodium hydroxide and the solution extracted with chloroform (3× 100 ml.). The combined extracts were washed with brine, dried and evaporated in vacuo. The residual oil was triturated with benzene and the solid filtered and recrystallised from benzene to give the title compound as pale yellow needles m.p. 149° (21.8 g., 87%). The hydrochloride was prepared as already described in Example 18 and isolated as colourless needles m.p. 219° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:20](Cl)=[O:21]>C(Cl)CCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])=[CH:7][C:3]=1[C:4]([N:6]=[C:20]=[O:21])=[O:5]
Reactant: NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Yield: 91.3 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzamide (0.700 g, 2.5 mmol), oxalyl chloride (0.3 mL, 3.0 mmol) and EDC (30 mL) to afford 0.700 g of the desired product.
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]([N:11]([CH3:18])[C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[C:8]([OH:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH:21]C(C)CC(C)C)[CH3:20].BrCC#N.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][CH2:6][C@H:7]([N:11]([CH3:18])[C:12](=[O:17])[CH2:13][CH2:14][CH:15]=[CH2:16])[C:8]([O:10][CH2:20][C:19]#[N:21])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC(C)CC(C)C
Reactant: C=CCCC(=O)N(C)[C@@H](COC(C)(C)C)C(=O)O
Agent: N#CCBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCC(=O)N(C)[C@@H](COC(C)(C)C)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.1 %

Procedure:
(S)-3-(tert-butoxy)-2-(N-methylpent-4-enamido)propanoic acid (Compound SP746) (1.01 g, 3.92 mmol) and N-ethylisopropylpropan-2-amine (EtN(iPr)2, 1.37 mL, 7.85 mmol) were dissolved in N,N-dimethylformamide (3.92 ml) under a nitrogen atmosphere, 2-bromoacetonitrile (0.82 ml, 11.8 mmol) was added and the mixture was stirred at room temperature for 45 minutes. 50 ml of ethyl acetate was added to the reaction solution, and the organic layer was separated by 50 ml of a saturated aqueous ammonium chloride solution and 50 ml of brine. The organic layer was collected and concentrated under reduced pressure, and the residue was purified by reverse-phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol solution) to afford (S)-cyanomethyl 3-(tert-butoxy)-2-(N-methylpent-4-enamido)propanoate (Compound SP747) (1.00 g, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[CH2:12]([N:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1)[CH3:13].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:12][CH3:13])[CH2:15][CH2:16]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CCN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a mixture of 4-amino-3-chloro-benzoic acid (Fluorochem; 2.575 g, 15 mmol) and 1-ethylpiperidin-4-amine (Fluorochem; 2.12 g, 16.5 mmol) in DMF (50 mL), was added DIPEA (5.2 mL, 30 mmol). The mixture was cooled with an ice-bath. HATU (6.27 g), added and the reaction mixture stirred at ambient temperature for 18 hours. The solvent was evaporated and the residue partitioned between saturated aqueous sodium bicarbonate solution (100 mL), and Ethyl Acetate (4×50 mL). The organic extracts were washed with brine (2×75 ml), dried over anhydrous Magnesium sulphate, filtered, and the solvent evaporated to give the crude product as a gum, which was triturated with ether to yield the title compound as a tan solid (3.54 g, 84%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.C([O-])([O-])=O.[K+].[K+].CC(C)=O>CCOC(C)=O>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1
Reactant: N#Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.9 %

Procedure:
A flask charged with imidazole-4-carbonitrile (0.5 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.80 g (70%) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. for C10H17N3OSi, 224.1 (M+H). found 224.1.
Reaction SMILES: [C:1]([Cl:4])(Cl)=O.C1(C)C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:15]=1[CH2:16][N:17]1[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=[CH:22][C:21]=2[NH:20]C(=O)[C:18]1=[O:32]>CN(C)C=O>[Cl:4][C:1]1[C:18](=[O:32])[N:17]([CH2:16][C:15]2[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:14]=2[O:13][CH3:12])[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(Cn2c(=O)c(=O)[nH]c3ccc4ccccc4c32)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c(Cl)nc3ccc4ccccc4c32)c(OC)c1
Temperature: 0 °C
Yield: 90 %

Procedure:
A solution of 20% phosgene in toluene (10 ml, 19 mmol) was added to a solution of 1-(2,4-dimethoxybenzyl)benzo[f]quinoxaline-2,3(1H, 4H)-dione (950 mg; 2.6 mmol) in dry N,N-dimethylformamide (100 ml) with stirring at 0° C. The mixture was stirred at room temperature overnight, and evaporated to dryness. The residue was triturated with ice/water, filtered and dried in vacuo to give 900 mg (90%) of the title compound, m.p. 186° C. 1H-NMR (DMSO-d6): δ 3.80 (s, 3H), 3.82 (s, 3H), 5.65 (s, 2H), 6.45 (dd, 1H), 6.55 (d, 1H), 7.00 (d, 1H), 7.35 (m, 1H), 7.55 (m, 1H), 7.75 (m, 2H), 7.90 (m, 1H), 8.22 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.S(Cl)(Cl)=O.[CH3:18]O>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)c(N)cc1OC

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.0 g, 99.2 mmol) in methanol (250 mL) was added thionyl chloride (7.2 mL, 99.2 mmol). The reaction was refluxed for 16 h then concentrated in vacuo. Purification by silica gel chromatography (0-90% ethyl acetate/hexanes) provided methyl 4-amino-5-chloro-2-methoxybenzoate (21.3 g, quantitative yield). LC/MS m/z 216.3 [M+H]+.
Reaction SMILES: [F:1][C:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[S:14][C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)([F:4])[F:3].[OH:19]O>C(O)(=O)C>[F:3][C:2]([F:1])([F:4])[C:5]1[NH:6][C:7]2[C:12]([C:13]=1[S:14]([C:15]([F:16])([F:17])[F:18])=[O:19])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: OO
Reactant: FC(F)(F)Sc1c(C(F)(F)F)[nH]c2ccccc12
Solvent: CC(=O)O
Product: O=S(c1c(C(F)(F)F)[nH]c2ccccc12)C(F)(F)F
Temperature: 50 °C
Yield: 50 %

Procedure:
A mixture of 2-(trifluoromethyl -3-[(trifluoromethyl)thio]indole (0.96 g, 3.36 mmole) and 30% hydrogen peroxide (1.15 mL, 10.1 mmole) in acetic acid is heated at 50° C. for 16 hours, cooled to room temperature, poured onto water and filtered. The filter cake is air-dried to give the title product as a colorless solid, 0.535 g (50% yield), mp 183°-185° C., identified by IR, 1HNMR, 13CNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([O:23]C)=[C:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[C:17]=1[CH3:35])[C:9](=[O:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.CCCCCC>[CH2:1]([N:8]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[C:18]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:17]=1[CH3:35])[C:9](=[O:15])[CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C)c(N(Cc2ccccc2)C(=O)CC(C)(C)C)c(C)c1Cc1ccc(C(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(O)c(Cc2ccc(C(C)C)cc2)c(C)c1N(Cc1ccccc1)C(=O)CC(C)(C)C
Yield: 83 %

Procedure:
Using N-benzyl-N-(3-(4-isopropylbenzyl)-4-methoxy-2,6-dimethylphenyl)-3,3-dimethylbutanamide obtained in Reference Example 332, the title compound was synthesized in the same manner as in Reference Example 335. Yield 83%. Melting point: 167-168° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:22][NH:23][O:24][CH3:25].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:9][C:10]([N:23]([O:24][CH3:25])[CH3:22])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)Cc1ccc(F)cc1
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)CN(Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 66 h

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-N-(4-fluorobenzyl)glycine (10.5 g, 37.2 mmol) in CH2Cl2 (37 mL) was added N,O-dimethylhydroxylamine hydrochloride (3.62 g, 37.2 mmol). The resulting suspension was treated with N-methylmorpholine (4.08 mL, 37.2 mmol) and cooled to 0° C. The mixture was then treated with a 1 M solution of N,N′-dicyclohexylcarbodiimide in CH2Cl2 (37.2 mL, 37.2 mmol) and was then allowed to warm to ambient temperature under inert atmosphere. After stirring for 66 h, the mixture was filtered, washing the solid residue with excess CH2Cl2. The filtrate was concentrated in vacuo and resuspended in EtOAc. After stirring for 1 h, the mixture was filtered, washing the solids with excess EtOAc. The filtrate was again concentrated in vacuo to give an orange oil. Purification by silica gel chromatography (20% to 60% EtOAc/hexanes) afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.27-7.20 (m, 2H), 7.03-7.01 (m, 2H), 4.52 (d, J=13.6 Hz, 2H), 4.09 (s, 1H), 3.95 (s, 1H), 3.63 (d, J=20.4 Hz, 3H), 3.18 (s, 3H), 1.47 (s, 9H). ES MS (M+1)=327.17.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11]C([O-])=O.N1CCCCC1>N1C=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][C:10]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CC(=O)[O-]
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(O)cc1
Yield: 80.1 %

Procedure:
To 20 g of p-hydroxybenzaldehyde and 32.5 g of monoethyl malonate were added 6 ml of pyridine and 0.2 ml of piperidine, then the mixture thus obtained was heated at 100° to 110° C. for 10 hours under stirring. The reaction mixture was then cooled, extracted with chloroform, and the chloroform layer was washed with a saturated aqueous solution of potassium hydrogen sulfite and water in this order, the chloroform extract was dried with magnesium sulfate. The solvent was removed by evaporation and the residue thus obtained was crystallized from isopropyl ether-n-hexane to yield 25.2 g of ethyl 4-hydroxycinnamate. Light yellow indefinite form crystals. Melting point: 70°-71° C.