Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:28][CH2:27][CH2:26][C:25]5=[O:29])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:30][CH:31]=1
Reactant: O=C1CCCN1Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Yield: 86.7 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-(2-pyrrolidon-1-yl) methylindoline (80 mg) obtained in Example 202, activated manganese dioxide (400 mg) and chloroform (10 ml) were treated as in Example 285 to give the title compound (69 mg) as an oil. This oil was then crystallized from ethyl acetate by using oxalic acid (13 mg) to give the oxalate (54 mg) of the title compound as a white powder (yield: 61%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]([NH:16][C:17]([NH:19][C:20]3[CH:38]=[CH:37][C:23]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([CH:34]5[CH2:36][CH2:35]5)=[O:33])[CH:26]=4)=[CH:22][CH:21]=3)=[O:18])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH2:2]1.C=O.O.[C:42]([O-])(O)=O.[Na+]>CO>[CH3:42][N:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:7]=[C:8]([NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]([CH:34]5[CH2:35][CH2:36]5)=[O:33])[CH:26]=4)=[CH:37][CH:38]=3)=[O:18])[CH:9]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:11]=2)[CH2:2]1
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1)Nc1cc(OC2CNC2)cc(C(F)(F)F)c1
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC(Oc2cc(NC(=O)Nc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3)cc(C(F)(F)F)c2)C1
Yield: 7 %

Procedure:
Dissolve N-[4-[4-[[3-(azetidin-3-yloxy)-5-(trifluoromethyl)phenyl]carbamoylamino]-phenoxy]-2-pyridyl]cyclopropanecarboxamide (210 mg, 0.4 mmol) in methanol (10 mL), add 35% aqueous formaldehyde solution (205 mg, 2.39 mmol), sitr for 1.5 hrs. Add Na(CN)BH3 (150 mg, 2.39 mmol) and stir at room temperature for 3 hrs. After reaction, pour the reaction mixture to water (50 mL), adjust pH=7 with saturated NaHCO3 solution, extract with EtOAc (15 mL×3), combine the organic layers, wash with brine (100 mL), dry over anhydrous Na2SO4. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, DCM:MeOH=20:1) affords the target compound (16 mg, 7%). MS: (M+1): 542.3.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([NH2:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([NH:14][S:24]([CH3:23])(=[O:26])=[O:25])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: NC(=O)c1ccc2c(c1)CCCC2=O
Reactant: CS(=O)(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(=O)c1ccc2c(c1)CCCC2=O
Temperature: 55 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
A sample of 5-Oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide (Example 81, Step 1) (29.4 mg, 0.16 mmol) in tetrahydrofuran (71 μL) is treated with K2CO3 (36.5 mg, 0.26 mmol), powdered KOH (32.9 mg, 0.82 mmol) and tetrabutylammonium hydrogen sulfate (2.6 mg, 0.008 mmol) in that order. The reaction is warmed to 55° C. and vigorously stirred for 20 minutes. Then a solution of methanesulfonyl chloride (23.2 mg, 0.20 mmol) in tetrahydrofuran (140 μL) is added over 20 minutes and the reaction was stirred at 55° C. overnight. The reaction is then cooled to room temperature, diluted with ethyl acetate and extracted with water twice. The organic phase is then dried over MgSO4, filtered and the solvent is removed. The crude sulfonamide (35.5 mg 86% yield) is taken on without purification; LC/MS calculated for [M+H]+ C12H13NO4S: 268.1, found: 268.1.
Reaction SMILES: C1(C[C@H](N[C:18](=[O:39])[C@H:19]([CH2:24][C:25]2[N:26]=[C:27]([NH:30][C:31]([O:33][CH2:34][C:35]([Cl:38])([Cl:37])[Cl:36])=[O:32])[S:28][CH:29]=2)[CH2:20][C:21]([OH:23])=[O:22])[C@@H](O)[C@@H](O)CC(C)C)CCCCC1.[OH2:40].OO.O.[OH-].[Li+]>C1COCC1>[Cl:38][C:35]([Cl:36])([Cl:37])[CH2:34][O:33][C:31]([NH:30][C:27]1[S:28][CH:29]=[C:25]([CH2:24][C@H:19]([CH2:20][C:21]([OH:23])=[O:22])[C:18]([OH:39])=[O:40])[N:26]=1)=[O:32]
Reactant: O
Reactant: CC(C)C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](CC(=O)O)Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](Cc1csc(NC(=O)OCC(Cl)(Cl)Cl)n1)C(=O)O
Reaction time: 0.08 h

Procedure:
The amido acid, 4-{[1(S)-(cyclohexylmethyl)-2(R),3(S)-dihydroxy-5-methylhexyl]amino}-4-oxo-3(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butanoic Acid: A solution of the product of section (f) of this example (57.5 mg, 0.10 mmol) in THF (1.5 mL ) and H2O (0.5 mL ) was cooled to 0°. A 30% aqueous solution of H2O2 (91.3 μL, 0.80 mmol of H2O2) and lithium hydroxide monohydrate (8.5 mg, 0.20 mmol) were added serially to the cooled solution. The mixture was stirred at 0° for 5 min and then at room temperature for 2.5 h. Excess H2O2 was quenched by the addition of a 1.5M aqueous solution of Na2SO3. The resulting mixture was diluted with H2O and washed with CH2Cl2 (3×). The aqueous layer was rendered acidic with 1N aqueous HCl and extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried (MgSO4) and concentrated to dryness to yield the desired monoprotected dicarboxylic acid, i.e. the 4-tert-butyl ester of 2(R)-{{2-[(2,2,2-trichloroethoxy)carbonylamino]-4-thiazolyl}methyl}butanedioic acid. The monoprotected dicarboxylic acid was used for the following coupling step without purification.
Reaction SMILES: [F:1]C1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28](F)[CH:27]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[F:34])=[S:45])=[CH:28][C:27]=1[F:1]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(N=C=S)c1ccccc1F
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4F)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
2-Fluoro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-fluoro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-fluoro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 86%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[F:14][C:15]([F:21])([F:20])[C:16](=[O:19])[CH2:17][CH3:18]>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]([OH:19])([CH2:17][CH3:18])[C:15]([F:21])([F:20])[F:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,4-dibromobenzene (2.5 g, 10.6 mmol) in THF (50 mL) at −78° C. was added n-BuLi (6.5 mL, 10 mmol; 1.6 M in hexanes) and the mixture was stirred at −78° C. for 15 min. 1,1,1-Trifluoro-2-butanone (1.3 g, 10 mmol) was then added. After further stirring for 15 min., the mixture was quenched with aqueous NH4Cl and extracted with Ethyl acetate. Purification by combi-flash chromatography (40 g column; eluted with hexanes—Ethyl acetate (10% -20%) in 20 min.; flow rate: 35 mL/min and collected 18 mL/fraction) to yield the title compound as a colorless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[Li+].CC([N-]C(C)C)C.Cl[Si:29]([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([Si:29]([CH3:32])([CH3:31])[CH3:30])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:12])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Br)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cc2cc(Br)cnc2n1S(=O)(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a well stirred solution of 5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (6.0 g, 17.8 mmol) in dry THF (60 mL) was added LDA (2M in THF; 16.0 mL, 32 mmol) at −78° C. slowly over 15 min. The reaction mixture was stirred at −70° C. for 1 h and then cooled back to −78° C. Chlorotrimethylsilane (4.1 mL, 32 mmol) was added slowly, and the reaction mixture was allowed to warm to ambient temperature over 4 h (TLC monitoring: 20% ethyl acetate in hexanes). Solvent was removed under reduced pressure keeping temperature below 40° C. to give a residue. It was extracted with ethyl acetate (2×50 mL) and washed with water (40 mL), followed by brine (10 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield a brown solid which was purified by column chromatography using 10% ethyl acetate in hexanes to yield the title compound as a white solid (4.8 g, 66%). 1H NMR (CDCl3, 300 MHz): δ=0.51 (s, 9H), 6.72 (s, 1H), 7.47-4.59 (m, 3H), 7.91 (d, J=2.1 Hz, 1H), 8.09-8.12 (m, 2H), 8.37 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=O)[CH3:5].C([O-])([O-])=O.[K+].[K+].[Br:14][C:15]1[CH:20]=C[CH:18]=[C:17](CCl)[CH:16]=1>CCO>[Br:14][C:15]1[CH:20]=[C:5]([CH2:4][CH2:3][C:2](=[O:7])[CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)CC(C)=O
Reactant: ClCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1cccc(Br)c1
Yield: 67 %

Procedure:
To a stirred mixture of pentane-2,4-dione (2.7 g, 26.7 mmol) and K2CO3 (3.4 g, 24.3 mmol) in EtOH (50 mL), 1-bromo-3-(chloromethyl)benzene (5.0 g, 24.3 mmol) was added at RT and the reaction mixture was refluxed overnight. After removal of volatiles under reduced pressure, the residue was taken up in EtOAc (100 mL) and washed with H2O (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated to afford the crude product, which was purified by silica gel column chromatography (EtOAc:Petroleum ether=1:10) to afford 4-(3-bromophenyl)butan-2-one as a colorless oil (3.7 g, 67%). MS (ES+) C10H11BrO requires: 226, 228 found: 227[M+H]+, 229 [M+2+H]+(1:1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)c1ccc(N)cc1O
Temperature: 25 °C
Yield: 87.2 %

Procedure:
To a refluxing solution of 2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL) was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10% Pd—C. The reaction mixture was refluxed for additional 30 min, cooled to room temperature and filtered through a plug of Celite. The filtrate was concentrated to dryness and purified by column chromatography (20-30% EtOAc-Hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.04 (d, J=2.3 Hz, 1H), 5.93 (dd, J=8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H); HPLC ret. time 2.26 min, 10-99% CH3CN, 5 min run; ESI-MS 166.1 m/z (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=[N:8][CH:9]=1)([O-:3])=[O:2].[N+:22](C1C=CC(CCCCC(C)(C)C(O)=O)=NC=1)([O-])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.N.[Cl-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([NH2:22])=[O:16])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)(C)CCCCc1ccc([N+](=O)[O-])cn1
Reactant: CC(C)(CCCCc1ccc([N+](=O)[O-])cn1)C(=O)O
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)(CCCCc1ccc([N+](=O)[O-])cn1)C(N)=O
Temperature: 25 °C

Procedure:
Ethyl 6-(5-nitropyridin-2-yl)-2,2-dimethylhexanoate was treated in the same manner as the one of Example 18 and 661 mg of 6-(5-nitropyridin-2-yl)-2,2-dimethylhexanoic acid thus obtained was dissolved in 15 ml of tetrahydrofuran. After adding 695 mg of carbonyldiimidazole, the resulting mixture was heated under reflux for 2 hours. Then the reaction mixture was cooled to room temperature and 25 ml of saturated aqueous ammonia was added thereto followed by stirring over day and night. After the completion of the reaction, the reaction mixture was poured into a saturated aqueous solution of sodium chloride and repeatedly extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and the residue was purified by silica gel column chromatography (eluted with toluene/acetone) to thereby give 453 mg of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([F:23])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([F:23])[CH:12]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
A solution of nickel (II) chloride hexahydrate (115 mg, 0.24 mmol) and (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (400 mg, 1.21 mmol) in methanol (10 mL) was cooled to 0° C. and then treated with sodium borohydride (275 mg, 3.63 mmol) in two portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with a 3N aqueous hydrochloric acid solution (30 mL) and ethyl acetate (50 mL). The two layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid methyl ester (400 mg, 99%) as a viscous oil: EI-HRMS m/e calcd for C17H21FN4O2 (M+) 332.1648, found 332.1645.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]([Sn:11](Cl)([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10]>C(OCC)C>[CH2:16]([Sn:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccsc1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
5 g of 3-bromothiophene was dissolved in 35 ml of anhydrous ethyl ether, and with stirring under cooling at -70° to -65° C., 19 ml of a 15% n-butyllithium-hexane solution and 10.5 g of tributyltin chloride were added. The mixture was stirred at the above temperature for 1 hour and then at room temperature for 1 hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, and then the solvent was evaporated. The residue was purified by distillation under reduced pressure to give 8.5 g (yield 74%) of tributyl(3-thienyl)tin, b.p. 150°-158° C./2 mmHg.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH3:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=1[C:10](Cl)=[O:11].O>O1CCCC1>[CH3:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][C:9]=1[C:10]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(C(F)(F)F)cc1C(=O)Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(C(F)(F)F)cc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Potassium tert-butoxide (5.40 g, 48.1 mmol) was added to an ice-cooled solution of 2-methyl-5-trifluoromethylbenzoyl chloride (10.5 g, 47.2 mmol) (manufactured by Apollo Scientific Inc.) in tetrahydrofuran (180 ml) in a small portion and the mixture was stirred for 1 hour. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with a 5% aqueous sodium hydrogencarbonate solution, water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=60/1-20/1) to give tert-butyl 2-methyl-5-(trifluoromethyl)benzoate as a colorless oil (9.90 g, yield: 81%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:10](=[O:11])[N:9]([CH:12]3[C:18](=[O:19])[NH:17][C:15](=O)[CH2:14][CH2:13]3)[C:7](=[O:8])[C:5]=2[CH:6]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[O:19]=[C:18]1[CH:12]([N:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH2:13][CH2:14][C:15](=[S:29])[NH:17]1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C1NC(=S)CCC1N1C(=O)c2ccccc2C1=O
Yield: 132.6 %

Procedure:
Compound 203 (1.14 g, 5 mmol) was suspended in CH2Cl2 (100 mL). To the mixture was added CF3COOH (10 mL) and this then was stirred at room for 4 h. The solvent was evaporated to give crude 204 (1.25 g): 1H NMR (DMSO-d6) δ 11.42 (s, 1H), 8.70 (br, 2H), 4.31 (dd, J=5.4 Hz, J=13 Hz), 2.88-2.72 (m, 2H), 2.25-2.09 (m, 2H). A mixture of crude 204 (1.25 g) and phthalic anhydride (0.89 g, 6 mmol) and Et3N (1.39 ml, 10 mmol) in THF (150 mL) was refluxed for two days. The reaction mixture was concentrated and the residue was crystallized from ethyl acetate to give thalidomide (201) (0.89 g, 69%) as white crystals; mp 276° C. (lit.276-279° C.). A mixture of thalidomide 201 (258 mg, 1 mmol) and Lawesson's reagent (222 mg, 0.55 mmol) in toluene (50 ml) was stirred at reflux for 12 h; thereafter, solvent was removed under vacuum. The resulting residue was purified by column chromatography using CH2Cl2 as the eluent to afford compound 205 (200 mg, 73%) as a yellow solid: mp 225-226° C.; 1H NMR (DMSO-d6) δ 12.83 (s, 1H, NH), 8.00-7.92 (m, 4H, Ph), 5.32 (dd, J=5.6 Hz, J=12.9 Hz, 1H, H-3′), 3.28-3.25 (m, 2H, H-5′), 2.60-2.54 (m, 1H, H-4′), 2.17-2.10 (m, 1H, H-4′); 13C NMR (DMSO-d6) δ 208.7 (C-6′), 165.3 (C-2′), 165.2 (C-1 & C-3), 133.1 (C-5 & C-6), 129.3 (C-3a, C-7a), 121.7 (C-4 & C-7), 46.9 (C-3′), 38.9 (C-5′), 21.79 (C-4′); MS (CI/CH4) m/z 274 (M+); Anal. (C13H10N2O3S) C, H, N.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])#[N:8].F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].Cl>C(OCC)(=O)C.CN(C)C=O>[F:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([CH:9]([C:7]#[N:8])[C:10]([O:12][CH3:13])=[O:11])[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: COC(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C#N)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel and having an inner volume of 100 ml were charged 3.03 g (21.9 mmol) of potassium carbonate, 5.0 ml of N,N-dimethylformamide, 2.17 g (21.7 mmol) of methyl cyanoacetate with a purity of 99% and 1.45 g (8.94 mmol) of 2,4-difluoronitrobenzene with a purity of 98% under argon atmosphere, and under stirring, the mixture was reacted at 60° C. for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, 50ml of ethyl acetate was added to the mixture, and 2.9 ml (34.8 mmol) of 12 mol/l hydrochloric acid was gradually added dropwise to the mixture while stirring. Then, the organic layer was separated, and washed successively with 20 ml of water and 30 ml a saturated saline solution in this order, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (filler: Daisogel 1002W, eluent: toluene) to obtain 1.81 g (isolation yield: 84%) of methyl 2-(5-fluoro-2-nitrophenyl)-2-cyanoacetate as a yellowish oily product with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: N.C1O[CH:5]([C:6]2[C:7]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[N:8][N:9](C(OC)=O)[CH:10]=2)[O:4]C1.Cl>CN(C)C=O.O>[N+:20]([C:17]1[O:16][C:15]([C:7]2[C:6]([CH:5]=[O:4])=[CH:10][NH:9][N:8]=2)=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: COC(=O)n1cc(C2OCCO2)c(-c2ccc([N+](=O)[O-])o2)n1
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c[nH]nc1-c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Add dropwise 292 ml of a 25% ammonia solution to a suspension of 513 g of 1-methoxycarbonyl-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde-ethyleneacetal in 2000 ml of dimethylformamide and 250 ml water at 20° to 25° C within a period of approximately 20 minutes, whereupon the precipitate is dissolved. Then stir for a further 30 minutes. While cooling to a moderate extent, add approximately 1000 ml of 2N hydrochloric acid; a strongly acidic reaction is obtained. Stir for 2 hours at 30° C and add 1.7 kg of ice. Draw off the thrown-down precipitate under cold conditions and wash with water until neutral to obtain 3-(5-nitro-2-furyl)-1H-pyrazole-4-carboxaldehyde [m.p. 187° to 187.5° C]with a yield of 96%.