Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=O>CC(C)=O>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COc1ccccc1C(=O)CBr
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccccc3OC)cs2)c(C)s1
Yield: 104.4 %

Procedure:
Methyl 4-[4-(2-Methoxyphenyl)(1,3-thiazol-2-yl)]-5-metmylthiothiophene-2-carboxylate: 105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2′-methoxy acetophenone (0.467 mmol; 110 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the solution concentrated. The crude product was dissolved in 100 mL of CH2Cl2 and washed one time with 50 mL of 1N NaOH. The organic layer was obtained, dried over sodium sulfate, concentrated and purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 160 mg (95% yield) of methyl 4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH3:10])=[CH:7][C:6]([NH2:11])=[C:5]([NH2:12])[CH:4]=1)[CH3:2].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[CH2:9][CH3:10])[NH:11][C:16](=[O:17])[C:15](=[O:19])[NH:12]2)[CH3:2]
Reactant: O=C(O)C(=O)O
Reactant: CCc1cc(N)c(N)cc1CC
Agent: Cl
Solvent: O
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2cc1CC
Yield: 88 %

Procedure:
4,5-Diethyl-1,2-diaminobenzene 24 (459 mg, 2.80 mmol) was dissolved in 4N hydrochloric acid (12 mL) at 90° C. Oxalic acid dihydrate (983 mg, 6.47 mmoL) was added to this solution in one portion with stirring under N2. The mixture was refluxed at 130°-5° C. (oil bath) for 3 h. A yellow solid precipitated, which was collected by suction filtration and dried in vacuo overnight, giving 538 mg (88%) of the title compound 25 as a brown solid; mp>360° C.; 1H NMR (DMSO-d6, 300 MHz) δ1.092 (t, 6H, J=7.5 Hz), 2.510 (q, 4H, J=7.5 Hz), 6.867 (s, 2H), 11.742 (s, 2H). EIMS m/e 218 (95, M+), 203 (100, M+ -CH3). (HPLC purity 100%)
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:19][O:18][C:12]1[CH:17]=[CH:16][C:15]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reaction time: 120 h
Yield: 80 %

Procedure:
A mixture of 57 g (0.4 mole) of phthalic anhydride and 43 mL (0.4 mole) of anisole in 400 mL of benzene was treated with 105 g (0.8 mole) of aluminum chloride at 5°. The reaction was kept for five days at 5°, poured into 600 mL of 2N aqueous HCl and ice and filtered. The residue was triturated in aqueous sodium carbonate and filtered repeatedly until the solid no longer contained product. The sodium carbonate extracts were combined, washed with ether, and acidified with 2N aqueous HCl. The product was extracted into ether, dried over sodium sulfate and stripped. It was recrystallized from toluene to provide 80% yield of product, mp 145-147.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1>>[CH:19]1([C:22]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH3:18])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20]1
Reactant: O=C(Cl)C1CC1
Reactant: CCN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CCC(c2c[nH]c3ccc(NC(=O)C4CC4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.061 mMol) 5-amino-3-(1-ethylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.080 mMol) cyclopropanecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2.C([OH:19])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][C:11](=[O:19])[NH:12]2
Reactant: CCO
Reactant: Clc1ccccc1-c1cccc2[nH]ccc12
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: O=C1Cc2c(cccc2-c2ccccc2Cl)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To the suspension of 4-(2-chloro-phenyl)-1H-indole (2.4 g, 10.6 mmol) in t-BuOH:ethanol:acetic acid (67 mL: 40 mL: 21 mL) was added pyridinium tribromide (10.5 g, 32 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (52 mL). Zinc dust (3.5 g, 53 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 1.96 g (76%) of 4-(2-chloro-phenyl)-1,3-dihydro-indol-2-one.
Reaction SMILES: C([O-])=O.[K+].C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1>[Ru].CO>[Cl:8][C:9]1[CH:10]=[C:11]([C@@H:15]([OH:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: [Ru]
Agent: O=C[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CO
Product: C[C@H](O)c1cccc(Cl)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A ruthenium complex RuCl[(S,S)-BnSO2dpen] (mesitylene) (1.2 mg, 0.002 mmol), potassium formate (1.0 g, 12 mmol), formic acid (138 mg, 3 mmol) and 3′-chloroacetophenone (1.55 g, 10 mmol, substrate/catalyst ratio=5000) were set in a 20 mL glass Schlenk-type reaction tube under an argon atmosphere. Methanol (6 mL) was added thereto and stirred at 50° C. for 24 hours to give (S)-1-(3′-chlorophenyl)ethanol at 85% yield and 96.5% ee optical purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([C:15](O)=[O:16])[NH:13][C:12](=[O:18])[C:11]3[S:19][C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:21][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8].B.C1COCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:14]([CH2:15][OH:16])[NH:13][C:12](=[O:18])[C:11]3[S:19][C:20]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:21][C:10]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1N[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)c2cc(N3CCOCC3)sc21
Agent: B
Solvent: C1CCOC1
Product: O=C1N[C@@H](CO)[C@H](c2ccc(Cl)c(Cl)c2)c2cc(N3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.6 %

Procedure:
A flask was charged with rel-(4R,5R)-4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylic acid (0.100 g, 0.234 mmol) and borane in THF (1M, 2.34 mmol, 2.34 mmol) was added. The mixture was stirred at rt for 2 hours. The reaction mixture was quenched by addition of methanol and then purified using preparative HPLC to afford the product as a white solid (25.7 mg, 26.3%). LCMS (AA) ES+: 413.4, 415.4, 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=8.3 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.08 (dd, J=8.2, 2.1 Hz, 1H), 5.82 (s, 1H), 5.47 (s, 1H), 3.99 (d, J=8.9 Hz, 2H), 3.83-3.76 (m, 4H), 3.18-3.11 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:14][C@H:13]([OH:15])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:15][C@H:13]2[CH2:12][C@H:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14]2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O[C@H]1C[C@@H](CCOCc2ccccc2)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1C[C@H](CCOCc2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
In a 100 mL flask with cis-3-(benzyloxyethyl)cyclobutanol (1.84 g, 8.9 mmol), 4-nitrobenzoic acid (2.97 g, 17.8 mmol) and Ph3P (4.9 g, 18.7 mmol) inside, dry THF 25 mL was added under argon to give a colorless solution. This was cooled to 0° C. and DIAD (3.7 mL, 18.7 mmol) was added drop by drop. After 15 hr, the volatile materials were evaporated and the crude mixture was purified by silica gel flash chromatography (Hexane: EtOAc=9:1) to give off-white oil contaminated with some DIAD (3.74 g). 1H NMR (CDCl3, 400 MHz): δ 1.81-1.86 (m, 2H), 2.22-2.28 (m, 2H), 2.34-2.41 (m, 2H), 2.48-2.60 (m, 1H), 3.36-3.39 (t, J=6.4, 2H), 4.49 (s, 2H), 5.31-5.38 (m, 1H), 7.25-7.36 (m, 5H), 8.19-8.21 (dd, J=8.8, 2.0, 2H), 8.26-8.29 (dd, J=9.2, 2.0, 2H). 13C NMR (CDCl3, 100 MHz): δ 26.35, 34.84, 35.96, 68.82, 70.74, 73.17, 123.70, 127.76, 128.59, 130.88, 135.97, 138.65, 150.68, 164.42. MS (FAB): expected for C20H21NO5 (M−H)+ 354.38. Found 354.13378. IR (neat) νmax 2979, 2936, 2857, 1720, 1607, 1527, 1349, 1319, 1276, 1119, 1015, 874, 843, 738, 720, 698.
Reaction SMILES: O.NN.C([NH:12][C:13](=[S:47])[N:14]([C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH2:23][CH2:24][S:25]([N:28]2[CH2:45][CH2:44][C:31]3([N:35]=[C:34]([CH:36]4[CH2:41][CH2:40][CH:39]([CH3:42])[CH2:38][CH2:37]4)[NH:33][C:32]3=[O:43])[CH2:30][CH2:29]2)(=[O:27])=[O:26])=[C:18]([CH3:46])[CH:17]=1)[CH3:15])(=O)C1C=CC=CC=1>C(O)C>[CH3:46][C:18]1[CH:17]=[C:16]([N:14]([CH3:15])[C:13]([NH2:12])=[S:47])[CH:21]=[C:20]([CH3:22])[C:19]=1[CH2:23][CH2:24][S:25]([N:28]1[CH2:45][CH2:44][C:31]2([N:35]=[C:34]([CH:36]3[CH2:37][CH2:38][CH:39]([CH3:42])[CH2:40][CH2:41]3)[NH:33][C:32]2=[O:43])[CH2:30][CH2:29]1)(=[O:26])=[O:27]
Reactant: Cc1cc(N(C)C(=S)NC(=O)c2ccccc2)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc(N(C)C(N)=S)cc(C)c1CCS(=O)(=O)N1CCC2(CC1)N=C(C1CCC(C)CC1)NC2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.3 %

Procedure:
Hydrazine monohydrate (55 mg, 1.1 mmol) was added to a solution of 3-benzoyl-1-(3,5-dimethyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-1-methyl-thiourea (140 mg, 0.22 mmol) in ethanol (7 ml). The mixture was stirred at room temperature for 15 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 1-(3,5-dimethyl-4-{2-[2-(4-methyl-cyclohexyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-phenyl)-1-methyl-thiourea (119 mg).
Reaction SMILES: [CH3:1][CH:2](OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)[N:11]=2)=[CH:6][CH:5]=1.[N-:38]=[N+:39]=[N-:40].[Na+]>CN(C=O)C>[N:38]([CH:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][C:21]([CH3:23])([CH3:24])[NH:20][C:19]([CH3:25])([CH3:26])[CH2:18]3)[N:11]=2)=[CH:6][CH:5]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC(C)Cc2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)cc1)N=[N+]=[N-]

Procedure:
The title compound was prepared from toluene-4-sulfonic acid 1-methyl-2-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-ethyl ester and sodium azide in DMF.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.N1CCCCC1>CN(C=O)C>[CH2:35]([O:34][C:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:30][CH:29]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and ethyl 4-aminophenylacetate in DMF and subsequent treatment with piperidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4]([C:5]([CH3:13])=[CH:6][C:7](=[O:12])[C:8]=2[CH3:11])=[N:3]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O>[CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[C:5]([CH3:13])[CH:6]=[C:7]([OH:12])[C:8]=2[CH3:11])[NH:3]1
Reactant: CC1=CC(=O)C(C)=C2CC(C)(C)N=C12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(O)c(C)c2c1NC(C)(C)C2
Yield: 82.9 %

Procedure:
To a solution of 2,3-dihydro-2,2,4,7-tetramethyl-5H-indol-5-one (7.36 g, 38.9 mmol) in ethyl acetate (100 ml) was added a solution of sodium hydrosulfite (14.9 g, 85.6 mmol) in water (50 ml) and shaken. The aqueous layer was separated, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from ethanol-hexane to obtain 6.17 g of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=1[CH3:36]>CN(C=O)C>[C:38]([NH:37][C:32]1[CH:33]=[CH:34][C:35]([CH3:36])=[C:30]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)[CH:31]=1)(=[O:42])[CH:39]([CH3:41])[CH3:40]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C(C)C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 62 %

Procedure:
To a 50-mL RB-flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (500 mg, 1.62 mmol), K2CO3 (670 mg, 4.86 mmol) and PdCl2dppf (0.190 mmol, 155 mg) was added a solution of N-(3-bromo-4-methylphenyl)-2-methylpropanamide (415 mg, 1.62 mmol) in DMF (10.0 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight. After cooling to room temperature, the mixture was filtered through Celite and the Celite was washed with EtOAc (3×20 mL). The filtrates were washed with H2O (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified flash chromatography (20% EtOAc/hexane) to give tert-butyl 4-[5-(isobutyrylamino)-2-methylphenyl]-3,6-dihydro-1(2H)-pyridinecarboxylate (360 mg, 62%): ESMS m/e: 303.0 (M-56+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH:14]([NH:18][C:19](=[O:21])[CH3:20])[CH2:15]2)=[CH:10][CH:9]=1>>[C:19]([NH:18][CH:14]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([S:2]([Cl:1])(=[O:5])=[O:3])[C:8]([O:7][CH3:6])=[CH:17][C:16]=2[CH2:15]1)(=[O:21])[CH3:20]
Reactant: COc1ccc2c(c1)CC(NC(C)=O)CC2
Reactant: O=S(=O)(O)Cl
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCC(NC(C)=O)C2
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To chlorosulfonic acid (15 mL), cooled to −10° C. was added N-(7-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (1.44 g; 6.6 mmol). The reaction mixture was stirred at −10° C. for 15 min and quenched carefully by pouring over ice-water. The aqueous phase was extracted with CH2Cl2 (3×), the organic extracts combined, dried over Na2SO4, filtered and evaporated under reduced pressure to yield 6-acetylamino-3-methoxy-5,6,7,8-tetrahydronaphthalene-2-sulfonyl chloride as a white solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C@H:31]([C:45]([OH:48])([CH3:47])[CH3:46])[C:32]([NH:34][NH:35][C:36](=[O:44])[C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)=O)=[C:26]([CH3:49])[C:25]=1[C:50]([F:53])([F:52])[F:51])#[N:23]>C(Cl)Cl.C1COCC1>[F:43][C:40]1[CH:39]=[CH:38][C:37]([C:36]2[O:44][C:32]([C@H:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[C:25]([C:50]([F:52])([F:51])[F:53])[C:26]=3[CH3:49])[C:45]([OH:48])([CH3:47])[CH3:46])=[N:34][N:35]=2)=[CH:42][CH:41]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(F)cc2)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(F)cc3)o2)C(C)(C)O)ccc(C#N)c1C(F)(F)F
Reaction time: 0.5 h
Yield: 123.1 %

Procedure:
Triphenylphosphine (766 mg, 2.92 mmol) was dissolved in DCM (100 mL) followed by addition of I2 (741 mg, 2.92 mmol) and TEA (0.81 mL, 5.84 mmol) at 0° C. (R)—N′-(2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (660 mg, 1.46 mmol) in DCM (20 mL) and THF (10 mL) was added to the pre-cooled solution mixture of PPh3/I2/TEA system and stirred for 30 min. The reaction mixture was then concentrated to furnish a yellow solid (781 mg). The crude material was chromatographed with EtOAc:Hexanes (2:1) to furnish the title compound as a white solid (361 mg, 57%). 1H NMR (500 MHz, Acetone d6, δ in ppm): 7.97-7.94 (m, 2H), 7.49 (d, J=9 Hz, 1H), 7.19-7.14 (m, 2H), 6.81 (d, J=9 Hz, 1H), 5.55 (d, J=9 Hz, 1H), 4.72 (d, J=9 Hz, 1H), 2.35 (s, 3H), 1.50 (s, 3H) and 1.35.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=Cc1cccnc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NCc2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
(4-Amino-2-phenylbenzoyl)methionine methyl ester (1.15 g, 3.21 mmol), prepared as in Example 192B, and 3-pyridine carboxaldehyde (361 mg, 3.37 mmol) were combined in 15 mL methanol and sodium cyanoborohydride (302 mg, 4.81 mmol) was added followed by crushed molecular sieves. The reaction was adjusted to pH=6 with acetic acid and stirred at 25° C. for 3 hours. The reaction was concentrated and transferred directly to a column of silica gel and purified by flash chromatography (5%methanol-ethyl acetate) to give [4(3-pyridylmethylamino)-2-phenylbenzoyl]methionine methyl ester (1.38 g, 95%) as an oil that solidified after standing. 1H NMR (300 mHz, CDCl3) δ 8.6 (d, 1H), 8.52 (dd, 1H), 7.72-7.65 (m, 2H), 7.45-7.30 (m, 6H), 6.62 (dd, 1H), 6.48 (d, 1H), 5.72 (bd, 1H), 4.64 (dq, 1H), 4.42 (bs, 2H), 3.64 (s, 3H), 2.25-2.05 (m, 3H), 2.00 (s, 3H), 1.95-1.80 (m, 1H), 1.72-1.60 (m, 1H); CIMS MH+ 450.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]1([CH3:37])[C:35](O)=[CH:34][CH:33]=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH3:37])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: Cc1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: Cc1ccccc1OC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Cl)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and o-cresol: ESMS m/e: 505.4 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (15.4 g, 97.1 mmol) in N,N-dimethylformamide (100 mL) were added 4-chloroaniline (12.4 g, 97.2 mmol) and potassium carbonate (20 g, 140 mmol). The reaction mixture was stirred at 100° C. for 18 hours, and then poured into ice-water (200 mL). The precipitate was collected via filtration and washed with water (3×30 mL) to provide the product as a black solid. Yield: 15 g, 60 mmol, 62%. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 1H), 8.47-8.57 (m, 2H), 7.69 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.01 (dd, J=8.2, 4.6 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:6]=1[OH:28])(=[O:3])[CH3:2].[CH3:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH2:31].CO>C1(C)C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:30]([CH3:31])([CH3:29])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:7][C:6]=1[OH:28])(=[O:3])[CH3:2]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(NC(C)=O)c(O)c1
Reactant: C=C(C)c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOc1cc(O)c(NC(C)=O)cc1C(C)(C)c1ccccc1
Reaction time: 7 h

Procedure:
In 150 ml of toluene was dissolved 20 g of 2-acetylamino-5-hexadecyloxyphenol obtained in Preparation Example 3, and it was then heated at 80°-90° C. together with 8 g of Amberlyst 15 (produced by Rohm & Haas Co.). To this mixture was added dropwise 30 ml of α-methylstyrene, and the resulting mixture was heated as it is for about 7 hours. After the reaction was completed, Amberlyst 15 was removed by filtration and the filtrate was condensed. After the addition of methanol, the condensed filtrate was cooled with ice whereupon the desired product precipitated. The product was collected by filtration and washed well with methanol. Yield: 6.6 g.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Mn]([O-])(=O)(=O)=[O:35].[K+].S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([C:32]([OH:35])=[O:33])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (100 mg) in acetone (5 mL) was added an aqueous solution (1 mL) of potassium permanganate (45.0 mg), and the mixture was stirred overnight at room temperature. To the reaction mixture was added sodium sulfite, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give the title compound (50.0 mg, yield 49%) as a pale-yellow amorphous solid. MS: 481 (MH+).