Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:4]=O.[S:12]1[CH2:18][C:16](=[O:17])[NH:15][C:13]1=[S:14].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:1]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:18]1[S:12][C:13](=[S:14])[NH:15][C:16]1=[O:17])([OH:11])=[O:10]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=S)SC1=Cc1ccccc1C(=O)O

Procedure:
To a hot stirred solution of 20.5 g. (134 mM) of phthalaldehydic acid and 17.95 g. (135 mM) of rhodanine in 90 ml. of glacial acetic acid is added 36.0 g. (438 mM) of sodium acetate. While heating the resulting solution to reflux, a precipitate forms and an additional 30 ml. of acetic acid is added. After refluxing the mixture for 0.5 hour, it is cooled, poured into water, and filtered to separate a yellow solid. The solid is washed with water and boiled with 500 ml. of isopropanol. The resulting mixture is cooled and filtered to separate 31.14 g. (87.5%) of the 5-o-carboxybenzylidenerhodanine as yellow needles, m.p. 276°-278°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][N:28]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: -5 °C
Yield: 60.7 %

Procedure:
Sodium hydride (60%, 0.16 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.20 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C. with stirring. To the reaction solution is added dropwise a solution of 2,3-dichloro-5-trifluoromethyl pyridine (0.80 g) in 1,2-dimethoxyethane (20 ml) at -5° C. for 10 minutes, which is further stirred for 15 minutes. On completion of the reaction, the reaction solution is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 1.10 g of desired compound (melting point: 47.0°-49.0° C.).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([O:16]C)=[O:15])=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1conc1-c1ccc(CCl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1conc1-c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
Methyl 3-(4-chloromethylphenyl)isoxazole-4-carboxylate (7.59 g, 30.16 mmol) was dissolved in THF-water (2:1, 225 ml), lithium hydroxide monohydrate (5.06 g, 120.6 mmol) was added, and the mixture was stirred at room temperature for 6 hours. THF was evaporated under reduced pressure, 2N hydrochloric acid was added to weakly acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (7.14 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]=[O:18])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[I-].[CH3:20][S+](C)C.CC([O-])(C)C.[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]([CH:17]3[CH2:20][O:18]3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[S+](C)C
Reactant: COC(=O)c1cc(C=O)nn1-c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc(C2CO2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.9 %

Procedure:
5.00 g (18.8 mmol) of methyl 1-(3-chloropyridin-2-yl)-3-formyl-1H-pyrazole-5-carboxylate (known from WO 2006/000336) and 5.76 g (28.2 mmol) of trimethylsulphonium iodide were initially charged in 12.5 ml of dimethyl sulphoxide, and 2.64 g (23.5 mmol) of t-BuOK in 12.5 ml of dimethyl sulphoxide were added dropwise at room temperature. After 1.5 hours of stirring at room temperature, 60 ml of water were carefully added dropwise with ice cooling, whereupon the reaction mixture was extracted repeatedly with ethyl acetate. The combined organic phases were washed three times with water and then dried over magnesium sulphate. The solvent was distilled off under reduced pressure and the residue was chromatographed on silica gel, which gave 1.10 g (21% of theory) of methyl 1-(3-chloropyridin-2-yl)-3-(oxiran-2-yl)-1H-pyrazole-5-carboxylate. (logP: 1.67; MH+: 280.0; 1H-NMR (400 MHz, CD3CN, δ, ppm): 3.10 (m, 2H), 3.71 (s, 3H), 3.98 (s, 1H), 6.92 (s, 1H), 7.56 (m, 1H), 8.07 (m, 1H), 8.51 (m, 1H).)
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.C(C1C=CN=CC=1)#N.[CH2:27]([N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)C1C=CC=CC=1.B(O)(O)C1C=CC=C(F)C=1>ClCCl.CO>[C:39]1([C:35]2[N:34]=[CH:27][C:38]([C:12]3[NH:8][C:9]([C:13]4[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=4)=[N:10][CH:11]=3)=[CH:37][N:36]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: c1ccc(Cn2ccnc2-c2ccccc2)cc1
Reactant: c1ccc(Cn2ccnc2-c2ccncc2)cc1
Agent: N#Cc1ccncc1
Agent: OB(O)c1cccc(F)c1
Solvent: CO
Solvent: ClCCl
Product: c1ccc(-c2ncc(-c3cnc(-c4ccncc4)[nH]3)cn2)cc1

Procedure:
The title compound was prepared by the method described in Example 1, except that 4-(1-benzyl-1H-imidazol-2-yl)pyridine (prepared according to Example 8, Step A, except that commercially available 4-cyanopyridine was used instead of 3-fluorobenzonitrile) was used in place of the 1-benzyl-2-phenyl-1H-imidazole in Step C; Rf 0.26 with 95:5 v/v dichloromethane-methanol; melting point 300° C.; 1H-NMR (400 MHz; DMSO-d6) δ 9.40 (s, 2H), 8.73 (d, 2H), 8.50-8.45 (m, 2H), 8.25 (bs, 1H), 8.00 (d, 2H), 7.62-7.55 (m, 4H); MS (ESI+) m/z 300.0 (M+1); H-PGDS FPBA IC50: 0.125 μM; H-PGDS inhibitor EIA IC50: 0.075 μM.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)[C:15]=1[C:16]#[N:17]
Reactant: OCc1cc(F)cc(F)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,5-Difluorobenzyl alcohol (595.2 mg; 4 mmol) was added to a cooled (0° C.) slurry of sodium hydride (172.5 mg; 4.3 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. The reaction mixture was then added to a cooled (0° C.) solution of 2,6-difluorobenzonitrile in dimethylformamide, stirred for 4 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 547.3 milligrams of 2-fluoro-6-(3,5-diflurophenylmethoxy)benzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[C:13](O)(=O)[CH3:14]>>[Br:1][C:2]1[C:3]2[N:12]=[C:13]([CH3:14])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: CC(=O)O
Product: Cc1nc2c(Br)cc([N+](=O)[O-])cc2[nH]1
Yield: 56.6 %

Procedure:
A mixture of 3-bromo-5-nitrobenzene-1,2-diamine (90 g, 389 mmol) in acetic acid (800 mL) was stirred under reflux for 18 h. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1) to give the product (56 g, 56.6%) as a brown solid; LC/MS: MS (ES+) m/e 256 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.60 (s, 3H), 8.20 (d, J=1.8 Hz, 3H), 8.34 (d, J=1.8 Hz, 2H), 13.25 (s, br, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:5]2[O:14][CH2:13][C:12]3[C:11]([C:15](=[O:19])[CH2:16][C:17]#[N:18])=[N:10][N:9]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:8]=3[C:6]=2[CH:7]=1.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:17]([CH:16]([C:15]([C:11]1[C:12]2[CH2:13][O:14][C:5]3[C:4]([CH2:26][N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:8]=2[N:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1)=[O:19])[C:40]([NH:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:41])#[N:18]
Reactant: O=C=Nc1ccccc1
Reactant: N#CCC(=O)c1nn(-c2ccccc2)c2c1COc1c(CN3CCOCC3)cc(F)cc1-2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1COc1c(CN3CCOCC3)cc(F)cc1-2
Temperature: 0 °C
Yield: 53.2 %

Procedure:
3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanenitrile (2.8 g) is reacted with phenylisocyanate (0.8 g) in dimethylformamide (20 ml) in the presence of triethylamine (0.7 g) at 25°-30° C. for 30 min. The reaction mixture is diluted with ice water and acidified with citric acid to pH 3. The precipitate is filtered and dissolved in chloroform. The organic solution is washed with 2% citric acid solution and then with water until neutral. Evaporation to dryness in vacuo gives a residue which is crystallized from chloroform/ethanol to yield 1.9 g of 2-cyano-3-(8-fluoro-1,4-dihydro-6-morpholinomethyl-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 249°-253° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([O:25]C)=[O:24])[CH:13]=2)[CH2:3][CH2:2]1.CO.[OH-].[Li+]>O1CCCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=[O:24])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(OC2CCOc3ccccc32)c2nc(C)n(C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a stirred solution of methyl 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylate (1.0 g, 2.8 mmol, STEP 1) in methanol (20 mol) and tetrahydrofuran (30 mL) was added 4M lithium hydroxide aqueous solution (4 mL, 16 mmol) at room temperature. After stirring for 5 hours at 60° C., the reaction mixture was concentrated in vacuum. The residue was dissolved with water and acidified (pH=3) with 2M hydrochloric acid. The resulting precipitate was filtrated, and dried in vacuum to afford the title compound as a white solid (0.85 g, 89%):
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[O:24])[CH2:21][CH2:22]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C(O)C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)C2CCN(c3ccc(Cl)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1

Procedure:
Synthesized as described in Method X-Step c starting from 1-[3-(1H-Benzoimidazol-2-yl)-4-chloro-phenyl]-piperidine-4-carboxylic acid (0.1 g, 0.28 mmol) and 1-methyl-piperazine (37 μL, 0.34 mmol). Obtained 30 mg (24%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([CH3:30])[CH:23]=1)(=[O:20])[C:18]#[CH:19]>C1COCC1.[Cu]I>[N+:8]([C:4]1[CH:3]=[C:2]([C:19]#[C:18][C:17]([O:21][C:22]2[CH:23]=[C:24]([CH3:30])[C:25]([Br:29])=[C:26]([CH3:28])[CH:27]=2)=[O:20])[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C#CC(=O)Oc1cc(C)c(Br)c(C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OC(=O)C#Cc2cccc([N+](=O)[O-])c2)cc(C)c1Br
Temperature: 65 °C
Yield: 28.6 %

Procedure:
1-Iodo-3-nitrobenzene (41.05 g, 164.3 mmol) in THF (100 mL) was degassed under reduced pressure at −78° C., and then nitrogen gas was introduced. To the solution was added K2CO3 (41.27 g, 298.6 mmol), CuI (2.27 g, 11.9 mmol) and PdCl2(Ph3P)2 (1.11 g, 1.57 mmol), and the mixture was stirred at 65° C. 4-bromo-3,5-dimethylphenyl propiolate (6-1) (37.79 g, 149.3 mmol) in THF (68 mL) was added by syringe pump over a period of 5.4 hr, and the mixture was stirred an additional 1 h after addition was complete. After being cooled to room temperature, the mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography. The fractions containing the desired compound were concentrated. To the concentrate added hexane and the precipitated solid was collected by filtration. The solid was washed with hexane and dried to give the title compound 6-2 (15.96 g, 29% yield) as a brown solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([N:22]2[CH2:27][CH2:26][N:25]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CNS(=O)(=O)c1ccc(F)cc1
Product: O=C(O)CNS(=O)(=O)c1ccc(N2CCN(c3ccccc3)CC2)cc1

Procedure:
In a manner similar to Example 3(b), (4-fluoro-benzenesulfonylamino)-acetic acid was condensed with 4-phenyl-piperazine to give the title compound, mp=120-124° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]2[N:11]([CH:15]=[N:16][CH:17]=2)[CH:12]=[CH:13][CH:14]=1)=[O:4]>C(O)C.[OH-].[Na+].O>[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]2[N:11]([CH:15]=[N:16][CH:17]=2)[CH:12]=[CH:13][CH:14]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCCc1cccn2cncc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCc1cccn2cncc12

Procedure:
A solution of 8-(4-methoxycarbonylbutyl)-imidazo[1,5-a]pyridine (30 mg) in 0.3 ml of ethanol and 0.3 ml of 1 N sodium hydroxide is refluxed for 2 hours, cooled, diluted with 2 ml of water and extracted with ethyl acetate (1×5 ml). The aqueous phase is brought to pH=6 and is extracted with methylene chloride (4×10 ml). The extracts are dried and evaporated to yield 8-(4-carboxybutyl)imidazo[1,5-a]pyridine, melting at 195°-197°.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[CH:12]=[C:13]([Cl:28])[C:14]=1[CH2:15][C@@H:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:17]1=[O:27].[CH3:40][N:41]=[C:42]=[O:43]>C(Cl)Cl>[CH3:40][NH:41][C:42]([N:24]1[CH2:23][CH2:22][CH:21]([N:18]2[CH2:19][CH2:20][C@@H:16]([CH2:15][C:14]3[C:13]([Cl:28])=[CH:12][C:11]([C:29]4[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:31][CH:30]=4)=[CH:10][C:9]=3[Cl:8])[C:17]2=[O:27])[CH2:26][CH2:25]1)=[O:43]
Reactant: CN=C=O
Reactant: O=C1[C@H](Cc2c(Cl)cc(-c3ccc(OC(F)(F)F)cc3)cc2Cl)CCN1C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)N1CCC(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(OC(F)(F)F)cc4)cc3Cl)C2=O)CC1
Yield: 37.8 %

Procedure:
Treat a solution of (R)-3-(3,5-Dichloro-4′-trifluoromethoxy-biphenyl-4-ylmethyl)-1-piperidin-4-yl-pyrrolidin-2-one trifluoroacetic acid (Preparation 33) (85 mg, 0.17 mmol) in CH2Cl2 (4 mL) with methyl isocyanate (11 mg, 0.19 mmol). Stir the reaction overnight at room temperature. Quench the reaction with 1N HCl and extract with Et2O. Wash the organic with brine, dry over MgSO4, and filter. Purify the crude by silica gel column chromatography using Hexanes:EtOAc to elute pure product. Remove the solvent to afford 0.035 g (37%) of product. MS (m/e): 544 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:12]O)[C:8]2=[O:11])=[CH:4][C:3]=1[O:14][CH3:15].[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=[O:25])=CC=1>>[C:7]([CH2:6][C:5]1[CH:4]=[C:3]([O:14][CH3:15])[C:2]([F:1])=[CH:10][C:9]=1[C:8]([OH:11])=[O:25])#[N:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1F)C(=O)C(=NO)C2
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(CC#N)c(C(=O)O)cc1F
Temperature: 50 °C
Yield: 89.7 %

Procedure:
6-Fluoro-5-methoxy-indan-1,2-dione 2-oxime (3.9 g) was added to a solution of 36.4 ml 8% NaOH, and the mixture was heated to 50° C. Then p-Toluenesulfonyl chloride (4.62 g) was added in portions to the mixture, and the mixture was heated at 80° C. for 15 min. After cooled to room temperature, the precipitate was removed from the mixture. The filtrate was acidified with concentrated HCl to PH=3-4 and the precipitate was collected and dried to give product as colorless solid (3.5 g, 90% yield). LC-MS: m/e 208 (M−1)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.[H-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH:16]3[CH2:17][O:18]3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(OCC3CO3)cc2)cc1
Yield: 83.3 %

Procedure:
A procedure similar to that described in preparation 46 was repeated, except that 4.00 g of 4-phenylphenol, 3.97 g of epibromohydrin, 1.27 g of sodium hydride (as a 55% by weight dispersion in mineral oil) and 80 ml of anhydrous dimethylformamide were used, to give 4.43 g of the title compound, melting at 80.2° to 82.9° C.
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(Br)cc3)cc2)C1
Yield: 51.2 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (1 g, 5.25 mmol) in CH2Cl2/pyridine 9:1 (50 ml) was treated with 4-bromobenzenesulfonyl chloride (1.34 g, 5.25 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (1.1 g, 51%) as a colourless gum.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[H-].[Na+].[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:20]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(OCCO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCOc1ccc([N+](=O)[O-])cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 40.5 %

Procedure:
2-(2-Hydroxyethoxy)-5-nitropyridine (obtained as described in Annalen der Chemie., 1936, 521, 286) (114 g) was added portionwise to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in mineral oil; 24.8 g) in N,N-dimethylformamide (DMF) (600 ml), at such a rate that the temperature did not exceed 10° C. The solution was stirred at 0° C. for 10 minutes, and then tert-butylchlorodiphenylsilane (171 g) was added dropwise at such a rate that the temperature did not exceed 10° C. The solution was stirred for 72 hours and then added to water (2 l). The mixture was extracted with ethyl acetate (2 ×1 l), and the extracts were washed with water (1 l) and saturated sodium chloride solution (500 ml), and then dried (MgSO4). Volatile material was removed by evaporation, and the residue was purified by flash chromatography, eluting with hexane to give 2-[2-(t-butyldiphenylsilyl)oxyethoxy]-5-nitropyridine (B) (106 g), as an oil which solidified on standing, m.p. 63°-64° C. (from hexane); NMR (d6 -DMSO): 1.0(s,9H), 4.0(t,2H), 4.55(t,2H), 7.0(d,1H), 7.3-7.5(m,6H), 7.55-7.75(m,4H), 8.45(dd,1H), 9.0(d,1H).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][NH:16][CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.Br[CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C(#N)C>[CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:15][C:14]=2[C:13]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([F:27])=[CH:22][C:21]=2[F:28])=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCNC2)C(C)(C)C
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NC)C(C)(C)C)C1
Temperature: 60 °C
Yield: 57 %

Procedure:
A mixture of intermediate 84 (0.39 g), DIEA (0.35 mL) and ethyl bromoacetate (0.22 mL) in acetonitrile was heated at 60° C. for 1.5 h. After evaporation of MeCN, the residue was extracted between EtOAc and saturated sodium bicarbonate. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography with 70% to 90% EtOAc/Hex to give compound 83 (0.27 g, 57%). LCMS (+ESI) m/z=510.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26]>>[OH:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)(=[O:27])=[O:26])=[CH:3][CH:4]=1
Reactant: Nc1ccc(CO)cc1
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Nc1ccc(CO)cc1)c1ccccn1
Yield: 47 %

Procedure:
Reaction of (4-Amino-phenyl)-methanol (249 mg, 2.03 mmol), N,N-diisopropylethylamine (294 μL, 1.69 mmol), and pyridine-2-sulfonyl chloride (300 mg, 1.69 mmol) for 1 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH 194:3) gave the title compound (210 mg, 47%) as a red solid. 1H NMR (300 MHz, CDCl3) δ 4.60 (d, 2H, J=6.0 Hz), 7.07 (br s, 1H), 7.15 (d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.7 Hz), 7.44-7.48 (m, 1H), 7.83 (ddd, 1H, J=7.5, 7.5, 1.8 Hz), 7.89 (d, 1H, J=7.8 Hz), 8.72 (d, 1H, J=4.5 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[C:15]1([NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH2:22])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: Nc1ccccc1NS(=O)(=O)c1cccc2cccnc12

Procedure:
The sulfonamide was synthesized from 8-quinolinyl sulfonyl chloride (0.01 mol) and o-phenylene diamine (0.01 mol) by general Method C. It was purified by recrystallization from EtOH (0.82 g, 27%). EI-MS m/z 300 (M+H)+