Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.CN1CCOCC1>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6])[C:11]([OH:13])=[O:12]
Reactant: C1CCNC1
Reactant: O=C(O)c1ccc(C(=O)O)c(Br)c1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1

Procedure:
100 g (0.388 mol) of 2-bromoterephthalic acid is dissolved in 700 mL of N,N-dimethylformamide and slowly combined with 69.2 g (0.427 mol) of N,N′-carbonyldiimidazole with stirring. After total dissolution, the mixture is stirred for 15 minutes at ambient temperature and then 48.5 mL (0.582 mol) of pyrrolidine and 93.9 mL (0.854 mol) of N-methylmorpholine are slowly added dropwise one after the other. The mixture is stirred for 2.5 days at ambient temperature and then concentrated in vacuo. The residue is combined with distilled water and acidified with 2 molar hydrochloric acid solution. The aqueous phase is extracted with ethyl acetate. The precipitate formed is suction filtered and dried at 40° C. Yield: 29.4 g (25%); Rf value: 0.30 (silica gel; dichloromethane/ethanol=9:1); C12H12BrNO3 (298.14); mass spectrum: (M+H)+=298/300 (bromine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]([O:23]C)=[O:22])=[N:6][CH:7]=1.[Li+].[OH-].Cl>CO.C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:21]([OH:23])=[O:22])=[N:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of methyl 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carboxylate (0.20 g, 0.55 mmol) in 6 ml of 1:1 MeOH/THF was added 1N LiOH (2.19 ml, 2.19 mmol). After 1 h at room temperature, the reaction was acidified by 3N HCl. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to yield 5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazole-4-carboxylic acid as a white solid (0.19 g). The acid was used without further purification. LCMS [M+H]=351.3. 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J=3 Hz, 1H), 8.09 (dd, J=8.6, 5.5 Hz, 2H), 7.61 (dd, J=8.5, 3 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H), 7.15 (dd, J=8.6, 8.6 Hz, 2H), 3.94 (s, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>OS(O)(=O)=O>[C:5]([N:9]1[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)n1cccn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)(C)n1cc([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
HNO3 (11.7 g, 185 mmol)was added dropwise to a mixture of 1-tert-butyl-1H-pyrazole (23 g, 185 mmol) in conc. H2SO4 (30 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 min and was poured onto crashed ice. The aqueous mixture was extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-4-nitro-1H-pyrazole (20 g, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ8.85 (s, 1H), 8.23 (s, 1 H), 1.52 (s, 9 H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](F)[C:10]=1[C:11]#[N:12]>>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([O:7][CH2:6][C@@H:2]2[CH2:3][CH2:4][CH2:5][NH:1]2)[C:10]=1[C:11]#[N:12]
Reactant: OC[C@@H]1CCCN1
Reactant: N#Cc1c(N)cccc1F
Product: N#Cc1c(N)cccc1OC[C@@H]1CCCN1

Procedure:
Prepared as in Example 24d from (S)-pyrrolidin-2-ylmethanol and 2-amino-6-fluorobenzonitrile as brown solid (51%). MS 218 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([NH2:12])=[S:11])=[N:6][CH:7]=1.[O-]CC.[Na+].[C:17]([CH2:19][C:20](OCC)=[O:21])#[N:18].Cl>>[NH2:18][C:17]1[N:9]([CH2:8][C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)[C:10](=[S:11])[NH:12][C:20](=[O:21])[CH:19]=1
Reactant: Cc1cnc(CNC(N)=S)cn1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cnc(Cn2c(N)cc(=O)[nH]c2=S)cn1
Yield: 84.7 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(b) by using 1-[(5-methylpyrazin-2-yl)methyl)thiourea (1.30 g, 7.10 mmol, obtained from Example 14(a)), sodium ethoxide (21% w/w, 28.4 ml, 28.4 mmol) and ethyl cyanoacetate (3.00 ml, 28.4 mmol) with the exception that the pH was adjusted by using 2N HCl until the mixture became cloudy. The mixture was then concentrated in vacuo until precipitation occurred. The solid was collected by filtration, washed with water and dried in vacuo to give the title compound (1.50 g, 81% yield) as a yellow solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:16][C:17](=[O:25])[NH:18][C@H:19]([CH2:23]O)[CH2:20][CH2:21][CH3:22])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[C:12]([O:16][C:17](=[O:25])[NH:18][C@H:19]([CH2:23][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:20][CH2:21][CH3:22])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC[C@@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of phthalimide (1.43 g, 9.72 mmol), ((S)-1-hydroxymethyl-butyl)-carbamic acid tert-butyl ester (prepared according to the procedure described in US 2007/0032433 page 232) (1.97 g, 9.69 mmol) and triphenylphosphine (2.55 g, 9.72 mmol) in DCM (25 mL) at 0° C. is added DEAD (1.6 mL, 10.2 mmol) dropwise. The reaction mixture is stirred at RT overnight. The reaction mixture is adsorbed onto SiO2 and purification by chromatography (SiO2, EtOAc/iso-hexane, gradient of 0-15% EtOAc) affords the title compound as white solid. [M+H]+ 233.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=O)=O.[CH3:19][S-:20].[Na+]>CN(C)C=O>[CH3:19][S:20][CH2:6][CH2:7][O:8][CH2:9][CH2:10][NH:11][C:12](=[O:13])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCOCCOS(C)(=O)=O
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCOCCNC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 96.6 %

Procedure:
A suspension of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl methanesulfonate (28 g, 99 mmol) and sodium thiomethoxide (8.3 g, 119 mmol) in N,N-dimethylformamide (DMF, 200 mL) was heated to 80° C. and maintained at that temperature until analysis by thin layer chromatography (TLC) indicated that the starting material had been consumed. The reaction mixture was allowed to cool to ambient temperature and was then quenched with water (200 mL). The reaction mixture was extracted with diethyl ether (2×200 mL). The combined extracts were washed sequentially with saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to provide 22.5 g of tert-butyl 2-[2-(methylthio)ethoxy]ethylcarbamate as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([CH3:10])[O:8][C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])=[N:6]1)=[O:4].C1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:11]([NH:14][C:15]([C:17]2[C:18]3[CH:25]=[N:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[C:19]=3[CH:20]=[N:21][CH:22]=2)=[O:16])[CH2:12][CH3:13])[O:8][C:9]=1[CH3:10])=[O:4]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1=N[C@H](C(=O)OC)[C@H](C)O1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1nc(C(=O)OC)c(C)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a chilled (0° C.) solution of (4S,5S)-2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (0.529 g, 1.20 mmol) and DBU (360 μL, 2.40 mmol) in CH2Cl2 (10.0 mL) was added BrCCl3 (125 μL, 1.26 mmol). The mixture was then warmed to room temperature. After 18 hours, the mixture was diluted with CH2Cl2 (50 mL) and extracted with saturated aqueous ammonium chloride (2×50 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in heptane to afford the title compound as white solid. MS m/z 438.74 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]([OH:14])=[O:13])[NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>O>[CH3:21][O:20][C:18]([NH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[C:12]([OH:14])=[O:13])=[O:19]
Reactant: NC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)NC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86.3 %

Procedure:
To a stirred mixture of (±)-2-(4-nitrophenyl)glycine (20) (Heyns et al., Justus Lieberg's Annalen der Chimie 611:55-56 (1958)) (3.2400 g, 16.5 mmol) and NaOH (0.6611 g, 16.5 mmol) in water (150 mL) were added methyl chloroformate (1.404 mL, 18.2 mmol), 2N NaOH (9.1 mL), and water (6 mL) at 0° C. After adjusting pH to 9 with 2N NaOH (1 mL) and stirring at 25° C. for 17 h, the mixture was basified to pH 10 with 2N NaOH and washed with diethyl ether before it was acidified with 5N HCl in the presence of EtOAc. The organic fractions (1 L) were dried (MgSO4) and evaporated to yield 19 (3.62 g, 86%): mp 152° C.; 1H NMR (DMSO-d6) δ 3.53 (s, 3H, OCH3), 5.35 (d, J=8.7 Hz, 1H, CH), 7.66 (d, J=8.4 Hz, 2H, aromatic), 8.20 (d, J=8.4 Hz, 3H, aromatic and NH). MS (FAB) m/z 255.0.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:7]([O:9]CC)=O)=[CH:5][C:4]2([CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[O:3]1.[NH2:17][C:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][C:20](=[O:26])[CH:19]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(OC(=O)C)C>[OH:9][C:7]1[C:6]2[C:2](=[O:1])[O:3][C:4]3([CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:5]=2[C:19]2[C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH2:23][C:18]=2[N:17]=1
Reactant: CCOC(=O)C1=CC2(CCOCC2)OC1=O
Reactant: CC1(C)CC(=O)C=C(N)C1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)c2c(nc(O)c3c2C2(CCOCC2)OC3=O)C1
Temperature: 200 °C
Reaction time: 18 h

Procedure:
10 g Ethyl 2-oxo-1,8-dioxaspiro[4.5]dec-3-ene-3-carboxylate and 6.15 g 3-amino-5,5-dimethylcyclohex-2-enone are mixed and heated to 200° C. for 20 minutes under a vacuo of 20 mbar. The mixture is cooled to room temperature and dissolved in 100 ml ethylacetate. 10 g 2,3-dichloro-5,6-dicyano-p-benzoquinone are added and the mixture is stirred for 4 hours at 50° C. and for 18 hours at room temperature. The product is isolated by filtration and washed with ethylacetate.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6]([SH:12])=[N:5][N:4]=1.I[CH2:14][CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([S:12][C:6]1[N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:3]([CH2:2][OH:1])=[N:4][N:5]=1)[CH3:15]
Reactant: CCI
Reactant: CC(C)Cn1c(S)nnc1CO
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCSc1nnc(CO)n1CC(C)C
Yield: 87 %

Procedure:
A solution of 3-hydroxymethyl-4-isobutyl-5-mercapto-4H-1,2,4-triazole (1.0 g), iodoethane (1.0 g) and triethylamine (1.1 ml) in ethanol (10 ml) was stirred for 2 days at 70° C. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:9→1:5), to give 5-ethylthio-3-hydroxymethyl-4-isobutyl-4H-1,2,4-triazole (1.0 g) as pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23]Br)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Reactant: C1CCNC1
Solvent: CC#N
Product: c1ccc(Cn2c3ccccc3c3c(OCCN4CCCC4)cccc32)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A mixture of 9-benzyl-4-(2-bromoethoxy)-9H-carbazole (0.020 g, 0.0526 mmol), pyrrolidine (0.040 g, 0.562 mmol), and acetonitrile (1.0 mL) is stirred over the weekend at room temperature; much starting material remained so the mixture is heated at 75° C. in a capped vial for 24 h. After cooling and removal of the solvent, the residue is partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate; chromatography on silica gel eluting with CH3OH—CH2Cl2 (4/96) gave 0.0165 g (85%) of the title compound as a waxy solid; 1H NMR (CDCl3) δ1.97, 3.04, 3.36, 4.59, 5.30, 6.71, 7.02, 7.12, 7.2-7.4, 8.32. Anal. Calcd for C25H26N2O: C, 81.05; H, 7.07; N, 7.56. Found: C, 79.84; H, 7.02; N, 7.44.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][C:2]1=S.[CH:13]([NH:15][NH2:16])=O>>[CH:13]1[N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][CH2:4][CH2:3][C:2]2=[N:16][N:15]=1
Reactant: NNC=O
Reactant: S=C1CCNc2ccccc2N1
Product: c1ccc2c(c1)NCCc1nncn1-2
Yield: 37.3 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-thione (0.8 g) and 0.80 g of N-formylhydrazine in 8 ml of p-butanol is stirred and refluxed for 18 hours and the solvent removed under vacuum. Ice water is added to the residual solid and the mixture filtered to give 0.312 g of a gray solid, m.p. 162°-165° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.Cl>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[CH:14][C:10]=1[C:11]([N:21]([CH3:22])[CH3:20])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Br)cc(F)c1OCc1ccccc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN(C)C(=O)c1cc(Br)cc(F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzyloxy-5-bromo-3-fluoro-benzoic acid (product from step 2) (0.2 g, 0.615 mmol) is dissolved in THF (10 ml) and treated with 2M dimethylamine in THF (0.308 ml), N-methylmorpholine (0.270 ml, 2.46 mmol) and HATU (0.234 g, 0.615 mmol) and stirred at room temperature overnight. The reaction mixture is diluted with 2M HCl and extracted with EtOAc (2×), the organic portions are combined washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting crude residue is dry loaded onto silica and purification by flash chromatography eluting with EtOAc affords the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]>C(O)C.[Ni]>[Cl:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][CH:5]=[C:6]([Cl:11])[C:7]=1[NH2:8]
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1Cl
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(Cl)c(N)c1Cl
Reaction time: 8 h

Procedure:
A solution of 62.4 g of 2,4-dichloro-3-nitroanisole in 750 ml of ethanol is treated with 19 g of Raney-nickel and hydrogenated for 8 hours. The obtained solution is filtered and evaporated in vacuo. The residue is taken up in methylene chloride and the solution is washed with a dilute sodium carbonate solution. After drying the organic phase over sodium sulfate and evaporating in vacuo, there is obtained 2,6-dichloro-3-methoxyaniline of boiling point 84° (0.1 Torr).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCNC1
Product: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (S)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate. LC-MS (Condition 6) tR=2.7 min, m/z=559.0/561.0 [M+H]+, m/z=581.0 [M+Na]+.
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.I[CH3:25]>>[CH3:25][O:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1
Reactant: CSc1ccc(C2(O)CCC(C#N)(c3ccccc3)CC2)cc1
Reactant: CI
Product: COC1(c2ccc(SC)cc2)CCC(C#N)(c2ccccc2)CC1

Procedure:
1.50 g of 4-hydroxy-4-(4-methylsulfanylphenyl)-1-phenylcyclohexanecarbonitrile were reacted with iodomethane according to the process described in Example 40. 1.19 g of the title compound were obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:13](=[O:14])[CH2:12][C:10](=[O:11])[N:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]1=2.[OH-].[K+]>CO>[CH3:1][N:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10](=[O:11])[CH2:12][C:13]1=[O:14]
Reactant: CN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21
Reaction time: 24 h
Yield: 84.1 %

Procedure:
A suspension of 103 g of clobazam, 1 liter of methanol, 23 g of potassium hydroxide in solution in 400 ml of methanol and 50 g of Raney's nickel washed beforehand with water and with methanol, was hydrogenated for 24 hours under a pressure of 800 mbars. 1 liter of methylene chloride was added and the catalyst was filtered off. The solvents were concentrated under reduced pressure and the residue was taken up in methylene chloride. The mixture was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The product obtained was crystallized from methanol, washed with ether and dried to obtain 76.69 g of the sought product melting at 173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12](=[O:14])[CH3:13])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COc1cc(C(C)=O)cc(OC)c1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)cc(OC)c1OCCN1CCOCC1
Temperature: 80 °C
Yield: 69.8 %

Procedure:
In a vial, 500 mg (2.5 mmol) of 3′,5′-dimethoxy-4′-hydroxyacetophenone was combined with 4-(2-chloroethyl)morpholine hydrochloride (600 mg, 3.2 mmol), and powdered potassium carbonate (1.5 g, excess). Dimethylformamide (2 mL) was added, the vial was sealed, and the rxn was heated to 80° C. overnight. The reaction was diluted with water and extracted with diethyl ether. The organic extract was washed with brine, dried (Na2SO4), and evaporated in vacuo to afford 540 mg (67%) of 14 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:21])[CH3:22])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C(=O)O)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
120 mg (333 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoic acid (racemate) and 70.7 mg (366 μmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 134 mg (75% of theory)
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=[O:7])[CH2:2]1.[CH3:9]C1C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH2:5][CH2:4][CH:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:2]1
Reactant: O=C(O)C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C1CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5122.6 %

Procedure:
A solution of tetrahydrofuran-3-carboxylic acid (540 mg, 4.65 mmol, 1.00 equiv) and TsOH (10 mg, 0.06 mmol, 0.01 equiv) in methanol (40 mL) was stiffed at 66° C. in an oil bath. After 16 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 10 mL of ether, washed with 1×20 mL of NaHCO3 (aq., sat.) followed by 3×20 mL of brine, and concentrated under reduced pressure to yield 0.40 g (66%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[C:11]3[C:16]([C:17](=O)[C:3]1=2)=[CH:15][C:14]([CH3:19])=[CH:13][CH:12]=3.O.NN.[OH-].[K+]>C(O)COCCO.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2[C:11]3[C:16]([CH2:17][C:3]1=2)=[CH:15][C:14]([CH3:19])=[CH:13][CH:12]=3
Reactant: Cc1ccc2c(c1)C(=O)c1c-2c2ccccc2n1C
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: Cc1ccc2c(c1)Cc1c-2c2ccccc2n1C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 1.04 g (0.0042 mol) of 5,8-dimethylindeno[2,1-b]indol-6(5H)-one and 1.12 mL (0.0224 mol) of hydrazine monohydrate in 20 mL of diethylene glycol was stirred at 80° C. for 1 h and then refluxed for 1 h. The resulting mixture was cooled to r.t., treated with a solution of 1.2 g (0.0214 mol) of KOH in 5 mL of water and then it was refluxed for 2 h. The resulting mixture was poured into 100 mL of water, the precipitate was filtered, washed 5 times with 50 mL of water and dried. Yield 0.84 g (86%) of greenish solid.
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:18].C(O)C>O>[NH2:18]/[C:8](/[C:10]([F:13])([F:12])[F:11])=[C:2](/[CH3:1])\[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)/C(C)=C(\N)C(F)(F)F
Temperature: 25 °C
Yield: 88 %

Procedure:
Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (10.2g, 51 mmoles), ammonium acetate (11.9, 150 mmoles), ethanol (20 g), and water (1 g) were combined in a 100 mL round-bottom flask. The mixture was heated for 6 hr. at 70° C. The mixture was then cooled to room temperature and poured into water (50 mL). The aqueous mixture was extracted with ethyl acetate (approximately 40 mL) and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated to give an 88% yield of ethyl 3-amino-2-methyl-4,4,4-trifluorocrotonate.