Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21](Br)=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:5][C:6]([C:21]1[CH:20]=[C:19]2[C:24]([C:16]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:15])=[C:17]([O:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[N:18]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:23][CH:22]=1)=[O:7]
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Br)cc2n1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c2c1
Temperature: 120 °C
Yield: 63.8 %

Procedure:
A mixture of the compound of example 26, step 2, (100 mg, 0.16 mmol), triethylamine (166 mg, 1.6 mmol), 1,3-bis(diphenylphosphino)propane (7.4 mg, 18 μmol) and palladium(II) acetate (3.7 mg, 16 μmol) in DMF (8 ml) and MOH (2 ml) was heated to 120° C. for 2 h under an atmosphere of carbon monoxide. After cooling to room temperature, the mixture was partitioned between water and EA. The aqueous phase was extracted with EA. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (EA/HEP). 30 mg of the title compound were obtained.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:20]1([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>>[CH:20]1([C:23]2[CH:30]=[CH:29][C:26](/[CH:27]=[C:14]3\[N:13]=[C:11]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:19][CH:18]=4)[O:17][C:15]\3=[O:16])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1
Reactant: O=Cc1ccc(C2CC2)cc1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccc(OCCC3CC3)cc2)=N/C1=C\c1ccc(C2CC2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
A mixture of N-[4-(2-cyclopropylethoxy)benzoyl]glycine (184 mg, 0.699 mmol) prepared in Example 1 (1b), 4-cyclopropylbenzaldehyde (compound described in Tetrahedron Lett., (2002), 43, 6987-6990, 113 mg, 0.773 mmol), sodium acetate (75 mg, 0.914 mmol), and acetic anhydride (660 μL, 6.99 mmol) was stirred at 120° C. for 30 minutes and then allowed to cool to room temperature. The solidified product was ultrasonically washed with n-hexane (2 mL) and water (4 mL). Then, the precipitate was collected by filtration, washed with water and n-hexane, and dried by heating under reduced pressure to give 196 mg of the title compound (yellow powder, yield 74%). Hereinafter, the compound obtained by this cyclizing reaction is called oxazolone.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][C:16]=2[F:25])=[C:9]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:8]=1.[C:32]([O-])(O)=O.[Na+]>CO.O>[NH2:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH3:32])=[O:23])=[CH:17][C:16]=2[F:25])=[C:9]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[N:8]=1
Reactant: O=C([O-])O
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OC)cc1F
Temperature: 70 °C

Procedure:
Sulfuric acid (3 ml) was added to a solution of the product from step (viii) (0.54 g) in MeOH (6 mL). The mixture was heated to 70° C. for 2 h and allowed to cool. The mixture was diluted with cold water (10 mL) and the pH adjusted to ˜7 using NaHCO3. The aqueous phase was extracted with EtOAc and the combined organic phase was dried, filtered and evaporated. The crude product was purified by RPHPLC to afford the title compound as a colourless solid 0.08 g.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH:11]=[CH2:12].[H][H]>C(O)C.[Rh]>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12]
Reactant: [H][H]
Reactant: C=CCc1cc(CO)ccc1O
Agent: [Rh]
Solvent: CCO
Product: CCCc1cc(CO)ccc1O
Reaction time: 0.5 h

Procedure:
To a solution of 0.370 g (2.25 mmol) of the product of Step E dissolved in 25 mL of absolute ethanol was added 53 mg of a 5% rhodium on carbon catalyst and the mixture was shaken under a 40 psig pressure of hydrogen on a Parr apparatus. After 30 minutes, the reaction mixture was removed, filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 35% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]3[CH:19]=C(CO)[N:21]=[C:17]3[CH2:16][N:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:13]=2[CH:31]=1>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[N:21]=[C:17]2[CH2:16][N:15]=[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[C:13]3[CH:31]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=3[N:18]2[CH:19]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Solvent: c1ccncc1
Product: CC(=O)OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 70 h

Procedure:
0.96 ml of acetic anhydride was added dropwise to a solution of 1.36 g of 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol in 30 ml of pyridine. The reaction mixture was stirred at room temperature for 70 h. and then evaporated in a vacuum. The residue was treated with saturated aqueous sodium hydrogen carbonate solution and this was extracted twice with dichloromethane. The dichloromethane extracts were dried over sodium sulphate and the solution was chromatographed over 50 g of silica gel. 1.4 g of an oil were eluted with dichloromethane/ethanol 197:3 and this was crystallized from diethyl ether/diisopropyl ether. There were obtained 2.1 g of 2-acetoxymethyl-8-chloro-6-(2-fluorophenyl)-4H-imidazo [1,2-a][1,4]benzodiazepine of m.p. 134-136° C. which was converted into the hydrochloride.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li][C:28](C)(C)C.CI>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([CH3:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Reactant: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (166 mg, 0.444 mmol) was dissolved in anhydrous THF (4 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., cooled to −78° C. and methyl iodide (3 equiv) was added dropwise and stirred for 1 h. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude product, which was purified by flash chromatography (0-2% EtOAc/hexanes) to afford the title compound as a clear oil (76 mg, 44%): 1H NMR (CDCl3, 600 MHz) δ 7.28-7.25 (m, 2H), 7.17-7.16 (m, 3H), 6.64 (s, 1H), 4.72 (t, 1H, J=7.2 Hz), 2.59 (t, 2H, J=7.8 Hz), 2.29 (s, 3H), 1.90-1.82 (m, 2H), 1.62-1.59 (m, 2H), 1.43-1.34 (m, 6H), 0.88 (s, 9H), 0.08 (s, 3H), −0.04 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 164.9, 143.7, 139.3, 129.2, 129.1, 126.4, 123.2, 69.5, 37.2, 36.8, 32.3, 30.0, 26.6, 26.6, 26.0, 19.1, 11.7, −4.2, −4.3.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([O:21]C)=[O:20])[C:13]=2[CH:12]=[CH:11]1>>[OH:9][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:1][N:10]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([OH:21])=[O:20])[C:13]=2[CH:12]=[CH:11]1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: c1ccc(C2CO2)cc1
Product: O=C(O)c1cccc2c1ccn2CC(O)c1ccccc1
Yield: 56.9 %

Procedure:
The same procedures used in Example 1 were repeated except for using 4.53 g of styrene oxide and 6.00 g of methyl indole-4-carboxylate as a starting material to give 5.48 g of 1-(2-hydroxy-2-phenylethyl) indole-4-carboxylic acid as a yellow amorphous substance. The yield thereof was found to be 57%.
Reaction SMILES: C1(S([CH2:9][CH2:10][CH:11]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)/[C:12](/[F:29])=[C:13](\[F:28])/[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=O)C=CC=CC=1>ClC1C=CC=CC=1Cl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH:11]([CH:10]=[CH2:9])/[C:12](/[F:29])=[C:13](\[F:28])/[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=2)=[CH:35][CH:34]=1
Reactant: O=S(CCC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1)c1ccccc1
Solvent: Clc1ccccc1Cl
Product: C=CC(/C(F)=C(\F)Cc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 59.6 %

Procedure:
A solution of (4E)-3-(4-chlorophenyl)-4,5-difluoro-6-(3-phenoxyphenyl)-4-hexenyl phenyl sulfoxide (0.318 g, 0.60 mmol) in o-dichlorobenzene (2.4 ml) under nitrogen was heated at 165° C. for 4.5 hours. The solution was cooled to 100° C. and the solvent removed in vacuo. The residue was chromatographed on a preparative thin layer silica gel plate eluting with ethyl acetate:hexane (5:95) to yield the title compound as a pale yellow oil (0.142 g) which was characterized by IR, 1HNMR and mass spectral analysis.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[OH-].[K+]>O1CCOCC1.O>[F:1][C:2]([F:16])([F:17])[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
A mixture of methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (6.0 g, 24.2 mmol) and KOH (2.72 g, 48.4 mmol) in 1,4-dioxane (100 mL) and H2O (50 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature, evaporation of the solvent 1,4-dioxane in vacuo. The aqueous residue was acidified with 2N HCl and extracted with CH2Cl2. The extracts were washed with brine and dried. Flash chromatography of the residue, using 3:7 EtOAc-hexane, gave 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid: 1H NMR (CDCl3) δ 11.0 (br, 1H), 7.95 (d, J=6.8 Hz, 2H), 7.71 (d, J=6.8 Hz, 2H), 6.73 (s, 1H), 1.71 (s, 3H); ms 235.0 (M+H+).
Reaction SMILES: [C:1]([O:4][CH:5]([CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:18]([O:29]CC2C=CC=CC=2)[CH:17]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:6])(=[O:3])[CH3:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:18]([OH:29])[CH:17]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)C(CCc1ccccc1)c1ccc(Oc2ccccc2)c(OCc2ccccc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC(C)C(CCc1ccccc1)c1ccc(Oc2ccccc2)c(O)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
200 mg of (2RS,3SR)-2-acetoxy-3-(3-benzyloxy-4-phenoxyphenyl)-5-phenylpentane was dissolved in 5 ml of methylene chloride, and 0.2 ml of boron tribromide was added under cooling to -78° C., followed by stirring at the same temperature for 3 hours. Then, the temperature was gradually brought to 0° C. The reaction solution was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate and then washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→5/1), to obtain 161 mg (yield: 85%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:11]([O-])([OH:13])=[O:12].C(=O)(O)[O-].[Na+]>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenyl methyl sulphone (4.0 g) was added, portionwise, to fuming nitric acid stirred at 0° C. The reaction mixture was allowed to warm to room temperature, stirred for 1 hour, and then poured carefully onto ice. The solution was carefully neutralised with sodium bicarbonate and the mixture filtered at the pump. The solid collected was washed with water and dried under reduced pressure over potassium hydroxide to give the title compound as a white solid (5.63 g) in a sufficient state of purity for the next reaction.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][C:18]([CH3:23])([CH:21]=[O:22])[CH2:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH2:20][CH2:19][C:18]([CH2:21][OH:22])([CH3:23])[CH2:17][CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C=O)CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled solution of 4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-ene carbaldehyde (0.41 g, 1.33 mmol) in THF (10.0 mL) was added to LAH (0.100 g, 2.70 mmol) and the reaction mixture stirred at 0° C. for 3 h. The reaction mixture was then quenched by methanol followed by aqueous HCl (1N, 2 mL) until all of the black/brown precipitate was dissolved. The resulting mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried over MgSO4 and purified by SiO2 (50% ethyl acetate/hexane) to yield [4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-enyl]-methanol as a liquid.
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:31][C:32]([F:42])([F:41])[O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[SH:40]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32]([F:31])([F:42])[F:41])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:26][CH2:27]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: FC(F)(F)Oc1ccccc1S
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2ccccc2OC(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 2-trifluoromethoxy-benzenethiol yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2-trifluoromethoxy-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a colorless foam. MS: 470.3 [M−H]−.
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:8][CH2:9][C:10](=O)[CH2:11]Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:2]([C:1]1[O:6][CH:11]=[C:10]([CH2:9][Cl:8])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(N)=O
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(CCl)co1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 38.1 %

Procedure:
A mixture of pivalamide (30 g) and 1,3-dichloro-2-propanone (37.66 g) was stirred at 160° C. for 1.5 hrs. Saturated aqueous sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture, and insoluble materials were removed by filtration. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5-1:2, v/v). The obtained oily substance (a mixture (41 g) of 2-tert-butyl-4-chloromethyl-1,3-oxazole and 1,3-dichloro-2-propanone) was dissolved in tetrahydrofuran (500 mL) ethanol (50 mL), sodium borohydride (5 g) was added, and the mixture was stirred at room temperature for 16 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:20, v/v) to give 2-tert-butyl-4-(chloromethyl)-1,3-oxazole as a colorless oil (19.61 g, yield 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([O:29]CC)=[O:28])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([C:18]3[CH:23]=[CH:22][C:21]4[O:24][CH2:25][O:26][C:20]=4[CH:19]=3)[CH:10]2[C:27]([OH:29])=[O:28])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1C(c2cccc(OC)c2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(C2c3ccccc3C(c3ccc4c(c3)OCO4)C2C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl(1RS,2RS,3SR)-1-(3-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (43 mg, 0.10 mmol) in EtOH (1 ml) was added 6M KOH (0.10 mL, 0.60 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted several times with EtOAc. The combined EtOAc extracts were washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford an oil, which was crystallized from Et2O/hexanes. The title compound was obtained as a solid; m.p. 131°-133° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]([F:46])([F:45])[C:37]1C=C(C=[CH:43][CH:44]=1)C=O>>[CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:43][CH:44]=[C:37]([C:36]([F:46])([F:45])[F:35])[CH:9]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2cccc(C(F)(F)F)c2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 3-(trifluoromethyl)benzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s, 1H), 7.68-7.63 (m, 1H), 7.55-7.51 (m, 3H), 4.84-4.76 (m, 1H), 4.14-4.08 (m, 2H), 3.87-3.84 (m, 1H), 3.71-3.69 (m, 1H), 3.62-3.54 (m, 2H), 3.36 (t, J=8.3 Hz, 1H), 3.01 (m, 1H), 2.86 (m, 1H), 2.63-2.60 (m, 1H), 2.50-2.27 (m, 3H), 1.98-1.83 (m, 3H), 1.21 (d, J=6.6 Hz, 3H). MS: (M+H m/z 462.1).
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].[Cl:7][C:8]1[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>ClC1C=CC=CC=1Cl>[Cl:7][C:8]1[CH:9]=[C:10]([S:14]([N:17]=[C:2]=[O:3])(=[O:15])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Solvent: Clc1ccccc1Cl
Product: O=C=NS(=O)(=O)c1cccc(Cl)c1
Yield: 40 %

Procedure:
5,7-Dichloro-4-[3-chlorobenzenesulfonimide]-1,4-dihydroquinoline-2-carboxylic acid, methyl ester ##STR30## Combine oxalyl chloride (25mL) and 3-chlorobenzenesulfonamide (4.3g, 23mmol) and reflux overnight. Remove oxalyl chloride in vacuo and combine the resulting residue with o-dichlorobenzene (25mL) and reflux. Evaporate the solvent in vacuo to distill to give [3-chlorobenzenesulfonyl]isocyanate (2g, 40%); bp 92°-5° C.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:12])[C@@H:6]([OH:11])[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].ClC(Cl)(Cl)C(=N)O[CH:17]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCCl>[Br:30][C:27]1[CH:26]=[CH:25][C:24]([CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:11][C@@H:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:12])=[CH:29][CH:28]=1
Reactant: N=C(OC(c1ccccc1)c1ccc(Br)cc1)C(Cl)(Cl)Cl
Reactant: CC(C)C[C@H](O)C(=O)NCC#N
Solvent: ClCCCl
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(Br)cc1)C(=O)NCC#N
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 626.4 %

Procedure:
(2S)-N-(cyanomethyl)-2-hydroxy-4-methylpentanamide from example 67 step 1 (22.5 g, 0.132 mol) and (1R)-(-1-10-camphorsulfonic acid (2.85 g, 0.012 mol, 0.1 eg) were added to 1,2-dichloroethane (135 mL) and the suspension was heated to 50° C. (4-bromophenyl)(phenyl)methyl 2,2,2-trichloroethanimidoate (50 g, 0.123 mol, 0.93 eg) was added portionwise over 15 min. then reaction mixture was stirred at 50° C. for 10 min. The reaction was repeated with 2×50 g and 1×69 g of (4-bromophenyl)(phenyl)methyl 2,2,2 trichloroethanimidoate, using same proportions of other reagents. All the batches were combined and evaporated to give a dark red oil (320 g). The latter was dissolved in toluene (600 mL); insoluble material was filtered off and the filtrate was charged on a chromatography column, eluted with 5% EtOAc/toluene to give the title compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[OH-].[K+].[C:11](O)(=O)[CH3:12]>>[CH3:11][C:12]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Product: Cc1nc2ccccc2[nH]1
Yield: 77 %

Procedure:
Phenylene diamine (32 grams) and glacial acetic acid (60 ml) were refluxed for 2 hours. Ice and KOH were added to bring the pH to 8.0, and the resulting light violet solid was filtered and collected. Recrystallization from benzene yielded 30 grams of 2-methyl benzimidazole as a light yellow solid having a melting point of 170° C. and total yield of 77%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23]>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2cccc(C(=O)O)c2)C1
Yield: 69 %

Procedure:
Following the general methods as outlined under Intermediate 13, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 3-aminobenzoic acid, the title compound was isolated in 69% yield (98% purity by HPLC). MS(ESI+): 332.4; MS(ESI−): 330.6.