Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:24](I)([CH3:26])[CH3:25]>C(#N)C.O>[CH:24]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH2:5][CH2:6]1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: O=c1[nH]cc(C2=CCNCC2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)N1CC=C(c2c[nH]c(=O)c3ccccc23)CC1
Temperature: 40 °C

Procedure:
4-(1,2,3,6-Tetrahydropyridin-4-yl)-2H-isoquinolin-1-one (0.4 g) obtained in Example 205 and potassium carbonate (1 g) were suspended in acetonitrile (10 mL) and water (1 mL), and isopropyl iodide (0.35 mL) was added at room temperature. The mixture was stirred under heating overnight at 40° C. After the completion of the reaction, the solvent was evaporated. Aqueous potassium carbonate solution was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography (NH silica gel, Fuji Silysia Chemical Ltd.). The fraction eluted with chloroform:methanol=25:1 was concentrated, and the precipitated crystals were collected by filtration to give 4-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[N:14][C:15]=2[NH2:17])[NH:10][N:9]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:38](Cl)[CH3:39])[C:22]2[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][C:23]=2[C:36]=1[CH3:37]>CN(C)C=O.C(OCC)(=O)C>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:38]([C:21]3[C:22]4[O:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24][C:23]=4[C:36]([CH3:37])=[C:19]([Cl:18])[CH:20]=3)[CH3:39])[N:9]=[C:8]([CH3:7])[C:16]=12
Reactant: Cc1c(Cl)cc(C(C)Cl)c2c1CN(C(=O)OC(C)(C)C)CCO2
Reactant: Cc1n[nH]c2ncnc(N)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc(C(C)n2nc(C)c3c(N)ncnc32)c2c1CN(C(=O)OC(C)(C)C)CCO2
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
Cesium carbonate (500 mg, 2 mmol) was added to a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.98 mmol) in N,N-dimethylformamide (30 mL) and stirred for 10 minutes. To this was added tert-butyl 7-chloro-9-(1-chloroethyl)-6-methyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (290 mg, 0.82 mmol) in N,N-dimethylformamide (1 mL) and the reaction was stirred at 80° C. for 1 hour. The mixture was diluted with ethyl acetate and washed with water and brine. The extracts were dried over sodium sulfate, filtered and evaporated. The crude was dissolved in methylene chloride and filtered to remove insoluble material (unwanted regioisomer). Purification on silica gel using ethyl acetate in hexanes (0-100%) followed by methanol in ethyl acetate (0-15%) gave the desired compound (240 mg, 62%). LCMS calculated for C23H30ClN6O3(M+H)+: m/z=473.2; found: 473.2. 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.29 (m, 1 H), 6.32 (m, 1 H), 4.70 (m, 1 H), 4.40 (m, 1 H), 3.83 (m, 2 H), 3.57 (m, 2 H), 2.58 (s, 3 H), 2.48 (m, 3 H), 1.78 (m, 3 H), 1.39 (, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][CH2:13]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:13][CH2:12][CH2:11][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(CCCO)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCCBr)c(OC)c1
Yield: 76.6 %

Procedure:
Compound 19-1 (2.68 g) was dissolved in methylene chloride (30 ml), triphenylphosphine (3.99 g) and N-bromosuccinimide (2.69 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to give the object product (2.71 g) as a pale-brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 0 °C
Yield: 22.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (58.6 g) in conc. sulfuric acid (100 ml), there was dropwise added a mixture of conc. nitric acid (25.3 g) and conc. sulfuric acid (15 ml) at a temperature of 0° to -10° C. The resultant mixture was stirred at 0°-5° C. for 1 hour, poured into ice-water and extracted with toluene. The toluene layer was washed with water and an aqueous sodium hydrogen carbonate solution and concentrated. The residue was purified by silica gel chromatography to give 16.4 g of 4-bromo-2-fluoro-5-nitroaniline. M.P., 90°-92° C.
Reaction SMILES: C(O)C.[CH3:4][C:5]1[N:10]=[C:9]([CH:11]=O)[CH:8]=[CH:7][CH:6]=1.Cl.[OH:14][NH2:15].C([O-])([O-])=O.[K+].[K+]>>[CH3:4][C:5]1[N:10]=[C:9](/[CH:11]=[N:15]/[OH:14])[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(C=O)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cccc(/C=N/O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To 6-methylpicolinaldehyde ethanol solution (642 mg, 5.3 mmol/2.1 mL) was added hydroxyamine hydrochloride (368 mg, 5.3 mmol) and K2CO3 aqueous solution (0.88 g/4.2 mL). The resulting solution was then heated to reflux via external oil bath for 30 min. The reaction mixture was cooled down to 0° C., and stirred for 30 min. The white solid suspension was collected via filtration, and the filter cake was washed with some ice-cold water. The filter cake was air dried, and further dried under high vacuum as the first crop product (0.565 g). The filtrates were combined, and concentrated to dryness. The residue was redissolved in water (2 mL), cooled to 0° C. and stirred for 20 min. The solid product was collected via filtration as the second crop of product (70 mg) as light yellow solid. The two crops of product were combined to provide (E)-6-methylpicolinaldehyde oxime (88%). LCMS (m/z) 136.9 (MH+) 0.21 min.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=1)[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of [2-amino-5-(trifluoromethyl)benzyl][3,5-bis(trifluoromethyl)benzyl]amine (Example 3) (270 mg, 0.65 mmol) in methylene chloride at 0° C., acetic anhydride (0.061 mL, 0.65 mmol) in methylene chloride and then triethylamine were added (0.018 mL, 0.13 mmol). The solution was stirred for 0.5 hours at 0° C. This solution was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was purified by column chromatography using 40% EtOAC/hexane. 1H NMR (CDCl3, 500 MHz) δ 7.80 (s, 1H), 7.56 (s, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.04 (s, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.67 (s, 2H), 4.65 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[N:24]([C:27]1[C:28]([Cl:47])=[CH:29][C:30]([F:46])=[C:31]([N:33]2[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]2=[O:45])[CH:32]=1)=[N+]=[N-].O.[C:49](O)(=[O:51])[CH3:50]>>[CH3:50][C:49]1[O:51][C:32]2[C:31]([N:33]3[C:38](=[O:39])[CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]([CH3:44])[C:34]3=[O:45])=[C:30]([F:46])[CH:29]=[C:28]([Cl:47])[C:27]=2[N:24]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N=[N+]=[N-])c(Cl)cc2F)c1=O
Reactant: CC(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: Cc1nc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere a stirred solution of 4.0 grams (28 mmole) of phosphorus pentoxide and 10 mL (47 mmole) of hexamethyldisiloxane was heated at 90° C. for 30 minutes. To this was added dropwise during a 5.0 minute period a solution of 0.80 gram (2.2 mmole) of 3-(5-azido-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione in 5.0 mL of acetic acid. Upon completion of the addition the reaction mixture was heated at reflux for 5.0 hours, cooled to ambient temperature, and poured into 50 mL of water. The reaction mixture was extracted with three 25 mL portions of ethyl acetate. The combined extracts were washed with 50 mL of aqueous saturated sodium bicarbonate solution and 50 mL of aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.7 gram of a residual oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 3:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.40 gram of an oily white solid, 3-(2-methyl-4-chloro-6-fluorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 64°-66° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=1.[CH:17]1([CH:20]=O)[CH2:19][CH2:18]1.OOS([O-])=O.[K+]>CN(C=O)C.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:20]([CH:17]3[CH2:19][CH2:18]3)[N:9]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[C:3]=2[CH:4]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: O=CC1CC1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1nccc(-n2c(C3CC3)nc3ccc(Br)cc32)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (400 mg, 1.43 mmol) in DMF (4 mL) were added cyclopropanecarbaldehyde (130 mg, 1.86 mmol) and oxone (527 mg, 0.86 mmol). The reaction was stirred at RT for 3 days. The mixture was diluted with EtOAc (20 mL) and washed with water. The aqueous layer was extracted with more EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (Isolute column, 100% DCM to 2% MeOH/DCM) afforded the title compound as an orange solid: 1H NMR (500 MHz, MeOD) δ 1.16-1.24 (2H, m), 1.24-1.29 (2H, m), 2.32-2.48 (1H, m), 6.98 (1H, d, J=5.36 Hz), 7.41-7.45 (1H, m), 7.47-7.52 (1H, m), 7.90 (1H, d, J=1.89 Hz), 8.51 (1H, d, J=5.20 Hz); LC-MS (Method B): m/z=+330.0, 331.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[N:8][S:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[NH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Br)c[nH]2)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 57.6 %

Procedure:
To a solution of 5-bromopyridin-2-amine (10.4 g, 60 mmol, Aldrich, St. Louis, Mo.) in pyridine (50 mL) was added p-toluenesulfonyl chloride (13 g, 66 mmol). The mixture was heated to 85° C. for 12 h. The solvent was removed under reduced pressure and the residue was taken up in 1 L of water and stirred for 1.5 h. The solid was collected by filtration and recrystallized from EtOAc to afford N-(5-bromopyridin-2(1H)-ylidene)-4-methylbenzenesulfonamide (11.3 g, 57% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.23 (s, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.89 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.79 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.03 (d, J=8.8 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]([O:11]C)=O)[CH2:3][CH2:2]1.[NH3:13]>CO>[CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]([NH2:13])=[O:11])[CH2:3][CH2:2]1
Reactant: N
Reactant: COC(=O)c1snnc1C1CC1
Solvent: CO
Product: NC(=O)c1snnc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Methyl 4-cyclopropyl-1,2,3-thiadiazole-5-carboxylate (2 g; 11 mmols) was dissolved in methanol (5 ml), and aqueous ammonia (5 ml) was added thereto, followed by stirring at room temperature for 1 hour. Subsequently, the reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane to obtain 1 g of 4-cyclopropyl-1,2,3-thiadiazole-5-carboxamide.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C([Sn](=O)CCCC)CCC.[N:45]([Si](C)(C)C)=[N+:46]=[N-:47].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([C:6]1[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]([CH:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:2](=[O:1])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:47][N:46]=[N:45][N:22]=2)=[CH:11][CH:10]=1)[CH2:24][CH3:25]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 41.5 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.33 g), dibutyltin oxide (0.083 g), azidotrimethylsilane (2.3 g) and toluene (20 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 46%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:14])=O.[OH-].[Na+]>CCCCCC>[F:1][C:2]1[C:3]([C:9]([Cl:14])=[O:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ncc(Cl)cc1F
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(Cl)c1ncc(Cl)cc1F
Temperature: 90 °C
Reaction time: 5 h

Procedure:
71.38 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid is initially introduced into a round-bottomed flask and heated up to 90° C. 59 ml of thionyl chloride are added dropwise from a dropping funnel in the course of 30 minutes, and the gas formed is passed into sodium hydroxide solution. The mixture is subsequently stirred at 100° C. for a further 5 hours. The thionyl chloride is then distilled off under normal pressure. After addition of 50 ml of dry toluene, 20 ml thereof are distilled off. The solution thus obtained is poured onto 200 ml of n-hexane and the mixture is stirred overnight. After cooling in an ice-bath, the mixture is filtered and the material on the filter is washed twice with n-hexane. 68.7 9 of the desired compound are obtained as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To the stirred solution of dimethyl 2,6-dichlorobenzene-1,4-dicarboxylate (2 g, 7.6 mmol, Step b) in tetrahydrofuran and water (1:1, 20 mL), sodium hydroxide (304 mg, 7.6 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and the residue was neutralized using cold hydrochloric acid (1N). The precipitated solid was filtered under suction, washed with hexane and dried to afford 3,5-dichloro-4-(methoxycarbonyl)benzoic acid as an white solid (1.5 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.I[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH3:24]
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3Cl)c(=O)c12
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccc(F)cc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 86.3 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 21; 290 mg, 0.90 mmol) and iodomethane (0.15 mL, 2.3 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. Water was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (magnesium sulfate), filtered, and evaporated to give (4S,7R)-2-(2-chloro-4-fluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (260 mg, 86%) as a yellow solid. ES(+)-MS (M+H) 335.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CC(O)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:34])[N:12]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)c1nccc(-n2c(-c3ccc(F)cc3)nc3nc(Cl)ccc32)n1
Yield: 103.1 %

Procedure:
5-Chloro-2-(4-fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)imidazo[4,5-b]pyridine (372 mg 1 mmol) is dissolved in CH2Cl2/HOAc (7 ml 5/2) and treated with MCPBA (270 mg 70% 1.1 mmol) at 0° C. for 30 min. The reaction mixture is poured on 2N Na2CO3 and extracted with ethyl acetate three times. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (ethyl acetate) to yield the title compound (400 mg 100%) as yellow foam.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:24]([F:27])([F:26])[F:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>C(N(CC)CC)C>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:36]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[C:15]3[C:10](=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:12]=[CH:13][CH:14]=3)[N:9]=[CH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:18]=1)=[O:37]
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2c(-c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1F

Procedure:
The title compound was prepared from {3-[3-phenyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 2-fluorophenyl isocyanate in substantially the same manner as described in Example 61 with one change: no triethylamine was used; off-white solid:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[C:26]1([C@@H:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@H]2c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=S(=O)(c1ccc(O)cc1)N1c2ccccc2-c2ccccc2[C@H]1c1ccccc1

Procedure:
The title compound was prepared from (R)-5-[(4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine* (1.35 g, 3.16 mmol), cyclohexene (6.16 g, 75 mmol), and 1.0 M boron tribromide in dichloromethane (20 mL, 20 mmol) according to the procedure and in the same manner as described in Example 1, step b; and yielded, after chromatographic purification and crystallization from diethyl ether-hexane, 4-{[(R)-6-phenylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.691 g, 1.67 mmol, 53%) as a homogeneous, colorless, crystalline, single enantiomer*, m.p. 208-210° C.;
Reaction SMILES: [H-].[Na+].O1CCCC1.[Br:8][C:9]1[S:10][C:11]([C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)=[C:12]([Br:14])[N:13]=1.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>>[Br:8][C:9]1[S:10][C:11]([C:15]2[N:19]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:18]=[CH:17][N:16]=2)=[C:12]([Br:14])[N:13]=1
Reactant: Brc1nc(Br)c(-c2ncc[nH]2)s1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1-c1sc(Br)nc1Br
Yield: 50.9 %

Procedure:
To a mixture of sodium hydride (2.89 g, 72.2 mmol) in tetrahydrofuran (431 mL, 5310 mmol) was added 2,4-dibromo-5-(1H-imidazol-2-yl)thiazole (18.81 g, 60.88 mmol) in tetrahydrofuran (60 mL, 700 mmol) at 0° C. The mixture was stirred for 30 min before [β-(Trimethylsilyl)ethoxy]methyl chloride (11.85 mL, 66.96 mmol) in tetrahydrofuran (24 mL, 3.0E2 mmol) was added slowly at 0° C. The reaction was quenched with MeOH. The solvent was evaporated and the residue was purified by column chromatography on silica gel to afford 2,4-dibromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazole (13.6 g, 81.7%). LCMS (AA) ES+ 440, 442.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=O)[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[OH:19].[O:20]=[C:21]([CH2:42][CH2:43][CH3:44])[CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:11][C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:5](=[O:19])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:7]2[CH2:22][C:21](=[O:20])[CH2:42][CH2:43][CH3:44]
Reactant: Cc1cc2c(cc1C)C(O)N(c1cccnc1)C2=O
Reactant: CCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Yield: 36.2 %

Procedure:
5,6-dimethyl-3-hydroxy-2-(3-pyridyl)isoindolin-1-one (0.30 g, 1.2 mmol) and 2-oxo-1-triphenylphosphoranylidene-pentane (0.61 g, 1.8 mmol) was heated under reflux in toluene (20 ml) under an argon atmosphere for 20 hrs. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:acetone=10:1) to give 0.14 g of the title compound.