Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[NH:31][CH2:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35][CH2:34]3)[C@H:14]2[CH3:45])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl[C:49]([O:51][CH3:52])=[O:50].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([O:26][C:27]([F:29])([F:30])[F:28])[CH:23]=[CH:22][C:21]=3[N:31]([CH2:32][C@H:33]3[CH2:38][CH2:37][C@H:36]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:35][CH2:34]3)[C:49]([O:51][CH3:52])=[O:50])[C@H:14]2[CH3:45])[CH:4]=[C:3]([C:2]([F:1])([F:46])[F:47])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](CNc2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1CC[C@H](CN(C(=O)OC)c2ccc(OC(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a stirred solution of ethyl [trans-4-({[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl]amino}methyl)cyclohexyl]acetate (Step A; 50 mg; 0.73 mmol) in CH2Cl2 (3 mL) was added methyl chloroformate (50 μL) followed by diisopropylethylamine (102 μL; 0.585 mmol). The reaction stirred at 40° C. for 24 h. The reaction was diluted with EtOAc (25 mL) and washed successively with sat. NaHCO3, brine, 1N HCl and brine (15 mL each), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) and chiral HPLC (4% IPA/heptane; AD column) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethoxy)phenyl](methoxycarbonyl)amino]methyl}cyclohexyl)acetate as a clear glass. LCMS=743.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.90-7.85 (m, 1 H), 7.78 (s, 1 H), 7.75 (s, 1 H), 7.27-7.17 (m, 3 H), 5.71 (d, J=8.0 Hz, 1 H), 5.00-4.54 (m, 1 H), 4.12 (q, J=7.1 Hz, 2 H), 4.10-4.02 (m, 1 H), 3.98-3.82 (m, 2 H), 3.80-3.58 (m, 3 H), 3.14-3.00 (m, 1 H), 2.17 (d, J=6.9 Hz, 2 H), 1.87-1.66 (m, 4 H), 1.52-1.41 (m, 2 H), 1.25 (t, J=7.1 Hz, 3 H), 1.13-0.94 (m, 4 H), 0.69 (d, J=6.4 Hz, 3 H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]1([S:21]([CH2:24][C:25]2[C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29](O)[C:28]([C:36]3[CH:40]=[CH:39][O:38][C:37]=3[CH:41]([OH:43])[CH3:42])=[CH:27][CH:26]=2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]1([S:21]([CH2:24][C:25]2[C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29]3[C:28]([C:36]4[CH:40]=[CH:39][O:38][C:37]=4[CH:41]([CH3:42])[O:43]3)=[CH:27][CH:26]=2)(=[O:22])=[O:23])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2C(C)O)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc2c1OC(C)c1occc1-2
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Diisopropyl azodicarboxylate (0.02 g) was added to a solution of methyl 6-(benzenesulfonylmethyl)-2-hydroxy-3-[2-(1-hydroxyethyl)-furan-3-yl]-benzoate (Intermediate 20, 0.042 g) and triphenylphosphine (0.026 g) in THF (2 mL) and the mixture was stirred for 1 hour. The mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-10% to give methyl 7-(benzenesulfonylmethyl)-4-methyl-4H-furo[2,3-c]chromene-6-carboxylate (0.038 g) as a white solid.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C.O>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([N:1]([N:16]=[O:17])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:13]=1
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)nc(N(N=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a solution of 2.0 g of 2-anilino-4,6-dimethylpyrimidine in 15 ml of acetic acid was added dropwise a solution of 1.4 g of sodium nitrite in 10 ml of water. After 30 minute's stirring, 50 ml of water was added to the mixture. The resulting crystals were collected by filtration and dried. Recrystallization from ethanol afforded 1.7 g (yield: 74%) of 4,6-dimethyl-2-(N-nitrosoanilino)pyrimidine having a melting point of 117°-121° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:10]2[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[C:12]([Cl:32])[CH:11]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>CO.C1COCC1.O>[Cl:32][C:12]1[CH:11]=[C:10]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9]2)[CH:15]=[C:14]([O:16][CH2:17][C:18]([F:20])([F:21])[F:19])[C:13]=1[C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=1
Reactant: CCOC(=O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(c2cc(Cl)c(-c3ccc(C(F)(F)F)cc3)c(OCC(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.3 %

Procedure:
Ethyl-1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylate (0.2 g, 0.41 mmol) was dissolved in 25 mL of MeOH/THF/H2O (10:10:5, vvl), LiOH (0.10 g, 4.1 mmol) was added. The reaction mixture was stirred for 5 h at room temperature and concentrated under reduced pressure. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by column chromatography over silica gel (DCM/MeOH, 95:5) gave the compound 1-(2-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-4-yl)cyclobutanecarboxylic acid (0.06 g) as a white solid. 1H NMR (500 MHz, CDCl3/TMS): δ 7.72 (d, 2H), 7.41 (d, 2H), 7.19 (s, 1H), 6.79 (s, 1H), 4.23 (q, 2H), 3.92 (m, 2H), 2.58 (m, 2H), 2.19 (m, 1H), 1.97 (m, 1H);
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=2)=[CH:19][CH:18]=1
Reactant: OCc1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1cncc(-c2ccc(F)cc2)c1
Temperature: 85 °C
Yield: 84.4 %

Procedure:
To a solution of 3-bromo-5-hydroxymethyl-pyridine (3.3 g, 17.5 mmol) in toluene (35 ml) was added Pd(PPh3)4 (0.6 g, 0.52 mmol), an aqueous solution of Na2CO3 (17.5 ml of a 2M solution) and p-fluorphenylboronic acid (2.65 g, 19 mmol, dissolved in 8.5 ml EtOH). The mixture was heated at 80-90° C. for 1 hr and vigorously stirred. After the reaction was completed, the biphasic reaction mixture was cooled, the organic layer was collected and washed with saturated NaCl. The aqueous layer was washed with EtOAc and the combined organic layers were dried on Na2SO4. The drying agent was removed by filtration and the solvent was evaporated in vacuo to give a dark oil which was purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH/NH4OH, 95/4.5/0.5) and yielded 3-(p-fluorophenyl)-5-hydroxymethyl-pyridine (3.0 g, 84%). The product was converted into its monohydrochloride salt; the residue was dissolved in Et2O and treated with 16.5 eq of ethanolic HCl. The product 3-(p-fluorophenyl)-5-hydroxymethyl-pyridinium hydrochloride Q4-OH.HCl precipitated as a white solid which was collected by filtration and subsequent drying.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:12])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:13](OC(=O)C)(=[O:15])[CH3:14]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C(F)(F)F)c(F)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 80.6 %

Procedure:
To a mixture of 3-fluoro-4-trifluoromethyl-phenylamine (16.9 g, 92.6 mmol), N,N-dimethyl-4-aminopyridine (1.13 g, 9.26 mmol), and toluene (230 mL) was added acetic anhydride (13.1 mL, 0.139 mol). The reaction mixture was heated at reflux for 3 h, and stirred at 23° C. for 16 h. The reaction mixture was concentrated and the crude product was dissolved in EtOAc (100 mL). The organic layer was washed with water (40 mL) and brine (40 mL), dried, filtered, and concentrated under reduced pressure. The crude solid was triturated from DCM/hexanes to yield the titled compound (16.5 g, 81% yield). MS (ESI/CI): mass calcd. for C9H7F4NO, 221.1; m/z found, 222.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.68 (d, J=12.5 Hz, 1H), 7.52 (t, J=8.3 Hz, 1H), 7.45 (br s, 1H), 7.19 (d, J=8.5 Hz, 1H), 2.22 (s, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:5][CH:4]=1.[I:25]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[I:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: N#Cc1cccc([C@@H](OC2CCCCO2)c2ccc(CO)cc2)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: N#Cc1cccc([C@@H](OC2CCCCO2)c2ccc(CI)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
Add sequentially a solution of (S)-3-[(4-hydroxymethyl-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]-benzonitrile (2.0 g, 6.18 mmol) dichloromethane (20 ml) and a solution of iodine (1.72 g, 6.80 mmol) in dichloromethane (30 ml) to a cooled (0° C.) solution of triphenylphosphine (1.78 g, 6.80 mmol) and imidazole (635 mg, 9.33 mmol) in dichloromethane (20 ml). Allow to warm to room temperature, then stir for 1.5 hours. Pour the mixture into a cold (0° C.) solution of sodium thiosulfate (3.63 g, 23 mmol) in an ice/water mixture (250 g) and stir for 30 minutes. Extract the aqueous layer with dichloromethane (30 ml). Combine the organic extracts and wash with water, dry with sodium sulfate, filter and concentrate. Purify the crude product via silica chromatography eluting with 15:85 ethyl acetate:hexanes to give the title compound (2.19 g, 82%). MS (m/z). Parent ion not observed.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][CH:22]([CH3:26])[CH2:23]2)[C@H:19]1[CH2:27][OH:28])=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:11]([O:15][C:16]([N:18]1[CH2:25][C@H:24]2[C@H:20]([CH2:21][CH:22]([CH3:26])[CH2:23]2)[C@H:19]1[CH:27]=[O:28])=[O:17])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](CO)[C@H]2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1C[C@H]2CN(C(=O)OC(C)(C)C)[C@H](C=O)[C@H]2C1
Reaction time: 0.17 h

Procedure:
To a cold (−60° C.) solution of oxalyl chloride (0.081 mL, 1.2 eq) in dry DCM (2.2 mL) was added dropwise a solution of DMSO (0.13 mL, 2.2 eq) in dry DCM (1.7 mL) within 4 min. After 10 min, was added dropwise (1S,2S,5R)-2-hydroxymethyl-7-methyl-3-aza-bicyclo[3.3.0]-octane-3-carboxylic acid tert.-butyl ester (206 mg) in dry DCM (1.2 mL) during 5 min. After 2 min a white suspension was formed. Stirring was continued 30 min at −55° C., then DIPEA (0.690 mL, 5 eq) (which was dried over 3A M.S.) was added during 3-4 min. The reaction mixture was allowed to come to RT, diluted with water and extracted with DCM. The combined org. extracts were washed with citric acid (5%), brine, dried over anh. MgSO4, filtered and evaporated to yield the title compound as an oil, which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][NH2:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:16]([O-])([O-])(OCC)[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:16]([CH3:17])=[N:15][N:14]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CCOC(C)([O-])[O-]
Product: Cc1nnc2ccc(-c3ccc(Cl)cc3)cn12

Procedure:
A mixture of 8.5 g. of 5-(4-chlorophenyl)-2-hydrazinopyridine and 80 ml. of ethyl orthoacetate is refluxed for 5 hours, the mixture is filtered and the solid is washed with hexane to afford 5.0 g. of the product of the Example as a tan solid, m.p. 192°-193.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7](S(C1C=CC=CC=1)(=O)=O)[CH:6]=[C:5]2[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:25]([CH3:36])[CH2:24]1.[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@@H:25]([CH3:36])[CH2:24]1
Reactant: C[C@H]1CN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)CCN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2c[nH]c(=O)c3ccc(Br)cc23)CCN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
A solution of tert-butyl (2S)-4-{[6-bromo-1-oxo-2-(phenylsulfonyl)-1,2-dihydroisoquinolin-4-yl]methyl}-2-methylpiperazine-1-carboxylate (Example 34a, 3.2 g) dissolved in DMF (20 mL) was treated with sodium hydroxide (0.444 g) in water (20 mL) under nitrogen. The resulting mixture was stirred at 20° C. for 2 h. The reaction mixture was diluted with water (20 mL), and extracted with ethyl acetate (25 mL). The organics were dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution 100% diethyl ether). Pure fractions were evaporated to dryness to afford the subtitle compound (0.780 g) as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CS(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1

Procedure:
(S)-1-benzyl-3-hydroxypyrrolidine in an amount of 44.18 g was dissolved in 38.34 g of toluene, and thereto was added 66.88 g of a 30% by weight aqueous sodium hydroxide solution. Next, methanesulfonyl chloride was added dropwise at a rate to allow the internal temperature to be kept at 5 to 10° C. After sodium chloride which was precipitated in the aqueous layer was dissolved by adding 90 ml of water, and liquid separation was performed, thus obtained organic layer was concentrated under reduced pressure to give the title compound as 60.14 g of a pale brown oily material.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([N+:23]([O-])=O)[CH:17]=2)=[N:8][N:9]([CH3:15])[C:10]=1[O:11][CH:12]([F:14])[F:13].C(OCC)(=O)C>C(O)C.[Fe]>[NH2:23][C:18]1[CH:17]=[C:16]([C:7]2[C:6]([Cl:5])=[C:10]([O:11][CH:12]([F:13])[F:14])[N:9]([CH3:15])[N:8]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: Cn1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)c(Cl)c1OC(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(-c2ccc(Cl)c(N)c2)c(Cl)c1OC(F)F
Reaction time: 1 h

Procedure:
155 ml of acetic acid were added to a suspension of 32.1 g (0.576 mol) of iron powder in 305 ml of ethanol. 64.9 (0.192 mol) of 4-chloro-3-(4-chloro-3-nitrophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole were added a little at a time to this mixture at 70-75° C. After 1 hour, 0.5 l of ethyl acetate was added and the solution was then filtered over a silica gel bed and subsequently concentrated. The residue was taken up in ethyl acetate. The ethyl acetate phase was washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, then dried over magnesium sulfate and finally concentrated. Yield: 56.4 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:5]([C:25]([F:28])([F:27])[F:26])=[N:6][N:7]([CH2:9][C:10]([NH:12][C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22]([NH2:24])=[O:23])=[O:11])[CH:8]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[CH3:36][S:37]([O:1][CH2:2][CH2:3][C:4]1[C:5]([C:25]([F:26])([F:28])[F:27])=[N:6][N:7]([CH2:9][C:10]([NH:12][C:13]2[S:17][C:16]3[CH2:18][CH2:19][CH2:20][CH2:21][C:15]=3[C:14]=2[C:22](=[O:23])[NH2:24])=[O:11])[CH:8]=1)(=[O:39])=[O:38]
Reactant: NC(=O)c1c(NC(=O)Cn2cc(CCO)c(C(F)(F)F)n2)sc2c1CCCC2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cn(CC(=O)Nc2sc3c(c2C(N)=O)CCCC3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.9 %

Procedure:
2-(2-(4-(2-Hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (Example 64, 480 mg, 1.153 mmol) was dissolved in DCM (10 mL). Triethylamine (117 mg, 1.153 mmol) was added, followed by methanesulfonyl chloride (132 mg, 1.153 mmol). The reaction mixture was stirred at RT for 3 h. Water was added and the reaction mixture extracted with DCM (×3). The combined DCM layers were then washed with brine, dried over MgSO4, filtered and the solvent removed in vacuo to yield the desired product (450 mg, 0.91 mmol, 79%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[C@H:12]([CH3:31])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[N:15]1.O.NN>C(O)C>[NH2:3][C@H:12]([CH3:31])[CH2:13][N:14]1[CH:18]=[CH:17][C:16]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)=[N:15]1
Reactant: C[C@H](Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Yield: 58 %

Procedure:
(R)-4-(1-(2-(1,3-dioxoisoindolin-2-yl)propyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (0.199 g, 0.469 mmol) was mixed with ethanol (15 ml). Hydrazine hydrate (0.227 ml, 4.69 mmol) was added and the mixture was refluxed for 3 h. After cooling to RT the precipitate was filtered and washed with ethanol. The filtrate was purified with CombiFlash using DCM and methanol as eluents. Drying in the vacuum afforded 0.080 g of the title product. 1H-NMR (400 MHz; d6-DMSO): δ 0.96 (d, 3H), 3.21-3.29 (m, 2H), 4.01-4.03 (m, 2H), 7.05 (d, 1H), 7.88 (d, 2H), 8.18 (d, 1H), 8.26-8.28 (m, 1H), 8.31 (s, 1H).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH:15]=[C:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:30][CH:31]1[O:33][CH2:32]1)(=O)=O>O>[O:33]1[CH2:32][CH:31]1[CH2:30][O:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH:15]=[C:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18]
Reactant: O=C1OCCC1=Cc1ccccc1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OCC2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1OCCC1=Cc1ccccc1OCC1CO1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
Dimethylformamide (30 ml) and potassium carbonate (4.4 g) were added to α-(2′-hydroxybenzylidene)-γ-butyrolactone (3 g), and a racemic compound of glycidyl nosylate (3.4 g) was added. The mixture was stirred at 50° C. for 3 hr. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give oily α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (3.2 g). This compound (0.4 g) was reacted in methanol with 4-(naphthalen-2-yl)piperidine (0.5 g) in the same manner as in Example 307 to give the title compound, melting point 127-128° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)#[N:13].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([C:17]3[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccc3c(c2)CCC3=O)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a stirred solution of 5-bromo-1-indanone (0.40 g, 1.90 mmol) and 4-cyanophenyl boronic acid (0.36 g, 2.47 mmol) in glyme (17 mL) was added a solution of sodium carbonate (0.60 g, 5.70 mmol) in water (3 mL) and tetrakis(triphenylphosphine)palladium (0) (0.11 g, 0.10 mmol). The resulting solution was heated to reflux for 2.5 hours. The solution was cooled to room temperature and partitioned between a saturated aqueous ammonium chloride solution (50 mL) and ethyl acetate (80 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified on a silica gel column (20% ethyl acetate in hexane) and triturated with ether to give 4-(1-oxo-2,3-dihydro-1H-inden-5-yl)benzonitrile as a white solid (0.35 g, 79%). MS (ESI) m/z 234.0936; HRMS: calcd for C16H11NO+H+, 234.09134; found (ESI, [M+H]+), 234.0936.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12>>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])[CH2:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1C=CCC1
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1

Procedure:
In Scheme II, Step A, cyclopentenone (8) is reacted with phthalimide in a Michael addition to give (±)-2-(3-oxo-cyclopentyl)-isoindole-1,3-dione (9). The reaction is performed in methanol/2N Na2CO3 in a ratio of 10/1 by volume preferably at ambient temperature using conditions similar to those described by O. Nowitzki, et. al. in Tetrahedron 1996, 52, 11799-11810. The product is isolated by addition of water and (9) obtained as a white solid.