Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]1([CH2:22][CH2:23][C:24](OC)=[O:25])[CH2:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.Cl>O1CCCC1>[C:1]([O:5][C:6]([C@@:8]12[CH2:22][CH2:23][C:24](=[O:25])[C@@H:12]1[C:11](=[O:13])[N:10]([C@@H:14]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC[C@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CCC(=O)[C@@H]2C1=O
Reaction time: 1 h
Yield: 69.4 %

Procedure:
(3S)-3-(2-Methoxycarbonyl-1-ethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (35.0 g, 93.2 mmol) was dissolved in tetrahydrofuran (1 L). A 2 M lithium diisopropylamide/heptane/tetrahydrofuran/ethylbenzene solution (100 mL, 200 mmol) was added dropwise in a nitrogen atmosphere at an internal temperature of −69° C. over 30 minutes. After stirring at the same temperature for one hour, the reaction solution was poured into a 1N hydrochloric acid solution (2 L) in an ice bath, followed by extraction with ethyl acetate (2 L, 1 L). The organic layers were combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the precipitated solid was collected by filtration to give 22.2 g of the title compound as pale red crystals. The filtrate was further concentrated to give 2.88 g of the title compound as pale red crystals. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:1) to give 2.09 g of the title compound as colorless crystals.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:26])=[CH:14][CH:15]=2)[N:10]=1.[C:27](Cl)(Cl)=[O:28].[CH2:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>C1COCC1>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:27](=[O:28])[NH:35][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:26])=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)CN
Reactant: COc1ccccc1-c1nc(N2CCC(O)CC2)c2ccc(C)cc2n1
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CCC(OC(=O)NCC(C)C)CC3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
To a stirring solution of 1-[2-(2-Methoxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-ol (100 mg, 0.30 mmol) and THF (500 μL) under N2, was added phosgene (317 μL, 0.60 mmol, 20% in toluene). The mixture was stirred at room temperature for 15 minutes. Isobutylamine (300 μL, 3.0 mmol) was added dropwise over a 2 minute period followed by stirring at room temperature for 1 hour. The mixture was evaporated to dryness and the obtained residue was purified via silica gel chromatography using 97% CH2Cl2/3% MeOH to obtain the desired carbamate intermediate as a clear oil (90 mg, 0.20 mmol). To a stirring solution of the carbamate intermediate (90 mg, 0.20 mmol) and CH2Cl2 (15 mL), under N2, at −78° C., was added BBr3 (0.60 mL, 0.60 mmol, 1.0 M in CH2Cl2) dropwise over a period of 2 minutes. The mixture was then allowed to warm to room temperature and was then heated at 50° C. for 15 minutes. The mixture was poured into a saturated aqueous NaHCO3 solution (80 mL) and the organic portion was evaporated to dryness. The residue was purified via HPLC to obtain the desired carbamate as a TFA salt (66 mg, 0.12 mmol, 39% yield). LC/MS (10-99%) M/Z 435.3 retention time 3.08 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=3.[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:35](O)[CH3:36]>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.C(Cl)Cl.O>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]3[NH:6][C:7]4[C:12]([C:13]=3[CH:14]=2)=[CH:11][C:10]([C:3]2[C:35]3[C:36](=[CH:12][CH:7]=[CH:8][CH:9]=3)[CH:13]=[CH:14][CH:2]=2)=[CH:9][CH:8]=4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCO
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Reactant: OB(O)c1cccc2ccccc12
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: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(-c3ccc4[nH]c5ccc(-c6cccc7ccccc67)cc5c4c3)cccc2c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Firstly, 8.12 g (25.0 mmol) of 3,6-dibromo-carbazole and 9.46 g (55.0 mmol) of 1-Naphthylboronic acid are dissolved in 100 ml of toluene, and then an aqueous solution of 30 ml of 2M sodium carbonate (Na2CO3) and 30.0 ml of ethanol is added to the above-mentioned solution. After the mixed solution is degassed with nitrogen for 30 minutes, 577 mg (0.5 mmol) of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) is added to the solution under nitrogen and then the solution is heated to 90° C. After reacting for 8 hours, the solution is cooled to room temperature, added and stirred with methylene chloride and deionized water. Then, the extracted organic layer is dried with anhydrous magnesium sulfate (MgSO4), and the solvent is removed by reducing the pressure. The remains are passed through the silica gel column with petroleum ether:methylene chloride (V:V)=2:1 to obtain a white solid of 9.3 g (22.2 mmol, 89% yield) of 3,6-bis(1-naphthyl) carbazole. The specific reaction is shown in the reaction formula (1-A):
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Li]C(C)(C)C.C(OC([N:26]1[CH2:31][CH2:30][C:29]2([CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[CH2:28][CH2:27]1)=O)(C)(C)C>C1COCC1>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:34]1[CH2:35][CH2:36][C:29]3([CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)[CH2:32][CH:33]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc2cc(C3=CCC4(CCNCC4)CC3)ccc2c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Was prepared according to method A with the following variation: To a solution of 2-bromo-6-methoxynaphthalen in dry THF (30 mL) cooled to −40° C., tert-BuLi (1.5 M in pentane (5.55 mL)) was added drop-wise. The mixture was stirred for 1 h at −40° C. and then allowed to warm up to −10° C. 9-Oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (495 mg, 1.85 mmol) in dry THF (10 mL) was added drop-wise and stirred for 3 h at 0° C. Beige solid. Mp. 146.9-149.5° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH:13]1([CH:16]([OH:53])[CH2:17][O:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][CH:52]=[C:26]34)[CH2:21][CH2:20]2)[CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([CH:16]([OH:53])[CH2:17][O:18][C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:37][CH:38]=4)=[C:28]([CH2:47][CH2:48][CH3:49])[N:27]4[N:50]=[CH:51][CH:52]=[C:26]34)[CH2:23][CH2:24]2)[CH2:14][CH2:15]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C3CC3)CC2)c2ccnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C3CC3)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogen carbonate (1.0 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C. for 30 min, 4′-({4-[trans-4-(2-cyclopropyl-2-hydroxyethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.45 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, then with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.40 g, 81%).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.C(C1C=CC(N)=CC=1)=C>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[C:3]([CH:24]=[CH2:25])[CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: C=Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: C=Cc1cccc(-n2cnc3c(-c4ccccc4)csc3c2=O)c1
Yield: 11.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (50 mg, 0.21 mmol), triethyl orthoformate (0.47 ml), 4-vinylaniline (47.5 mg, 0.39 mmol), and acetic acid (0.06 ml) were used to give 8 mg (0.024 mmol, 11.5% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:19]1[N:20]=[C:21]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:22]2[CH:27]=[C:26]([CH2:28][N:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:31][CH2:30]3)[S:25][C:23]=2[N:24]=1>>[CH3:8][C:7]1[CH:6]=[C:5]([C:19]2[N:20]=[C:21]([N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)[C:22]3[CH:27]=[C:26]([CH2:28][N:29]4[CH2:30][CH2:31][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:33][CH2:34]4)[S:25][C:23]=3[N:24]=2)[CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1C
Product: Cc1cc(-c2nc(N3CCOCC3)c3cc(CN4CCN(S(C)(=O)=O)CC4)sc3n2)cnc1C

Procedure:
2,3-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine was reacted with 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine in General Procedure A. Purification on silica yielded 371. NMR: (CDCl3): (400 MHz, CDCl3): 2.40 (3H, s, Me), 2.59 (3H, s, Me), 2.63-2.68 (4H, m), 2.82 (3H, s, Me), 3.29-3.31 (4H, m), 3.84 (2H, s, CH2), 3.90-3.92 (4H, m), 3.98-4.00 (4H, m), 7.17 (1H, s, Ar), 8.41 (1H, s, Ar) and 9.35 (1H, s, Ar). MS: (ESI+): MH+503.15
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([Cl:18])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][C@@H:10]([CH3:12])[C:9]=2[C:13]=1[Cl:18]
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(Cl)c21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1CNCCc2ccc(Cl)c(Cl)c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
A solution of (S)—N-trifluoroacetyl-8,9-dichloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.270 g, 1.2 mmol) in methanol (10 mL) was treated with 15% aqueous NaOH (10 mL), and stirred for 3.5 hours at 25° C. The product mixture was concentrated, extracted 3 times with CH2Cl2 (25 mL), dried with Na2SO4 and concentrated to give 0.270 g of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8 Hz, 1H), 7.16 (d, J=8 Hz, 1H), 4.17 (m, 1H), 3.55 (m, 2H), 3.5-3.3 (m, 2H), 3.2-3.0 (m, 2H), 1.43 (d, J=7 Hz, 3H). MS calculated for C11H13Cl2N+H: 230, observed: 230.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:10])[C:7]=1[CH2:8][N:34]1[C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]2[C:30]1=[O:40]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1c(Br)cncc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1c(Br)cncc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of benzylic alcohol 18 (300 mg, 1.13 mmol), triphenylphosphine (357 mg, 1.36 mmol) and phthalimide (200 mg, 1.36 mmol) in dry THF (10 mL) was added DIAD (0.26 mL, 1.36 mmol) under an N2 atmosphere. The resulting mixture was stirred at 25° C. for 24 hours after which solvents were evaporated under reduced pressure. The crude product mixture was purified by chromatography on silica gel to give the title compound 19 as a white (300 mg, 0.762 mmol, 67%). 1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 2H), 7.88-7.83 (m, 2H), 7.78-7.75 (m, 2H), 5.13 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 168.1, 151.8, 142.7, 135.1, 132.4, 124.4, 43.3; MS (ESI) Calculated for C14H9N2O2Br2 [M+H]+: 397.04. Found: 396.90.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])O.[Na+].O.[Br:15][CH:16]([CH:20]([CH3:22])[CH3:21])[C:17](Cl)=[O:18]>C(OCC)(=O)C>[Br:15][CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:18]
Reactant: CC(C)C(Br)C(=O)Cl
Reactant: Nc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(Br)C(=O)Nc1ccccc1O

Procedure:
To a mixture of 2-aminophenol (27 25 g), sodium hydrogencarbonate (31.5 g), ethyl acetate (250 ml), and water (200 ml), a solution of 2-bromo-3-methylbutyryl chloride (49.8 g) in ethyl acetate (100 ml) was added dropwise with ice-cooling and with stirring. After stirring with ice-cooling for further 1 hour, the ethyl acetate layer was separated, washed with water, and dried (MgSO4), and the solvent was evaporated off. The residue was crystallized from hexane, to give 2-(2-bromo-3-methylbutyryl)aminophenol. Yield was 59.7 g (87.9%). Recrystallization from isopropyl ether gave colorless prisms, mp 110°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=O)[NH:15][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:21])=O>[Cl-].C[N+](C)(C)C>[Cl:21][C:14]1[NH:15][C:11]2[CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=[CH:17][C:12]=2[N:13]=1
Reactant: COc1cccc(-c2ccc3[nH]c(=O)[nH]c3c2)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: C[N+](C)(C)C
Agent: [Cl-]
Product: COc1cccc(-c2ccc3nc(Cl)[nH]c3c2)c1

Procedure:
Heat a mixture of 5-(3-methoxyphenyl)benzimidazolidin-2-one (1.4 g) and tetramethylammonium chloride (ca. 2 g) in phosphorous oxychloride at 100° C. for 8 hours. After cooling, concentrate the mixture in vacuo, triturate with water, and neutralize with ammonium hydroxide. Collect the precipitate and air-dry to obtain 2-chloro-5-(3-methoxyphenyl)benzimidazole.
Reaction SMILES: [NH2:1][C@@H:2]([C@@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1>C(Cl)Cl>[Cl:20][C:21]1[S:25][C:24]([S:26]([NH:1][C@@H:2]([CH2:3][OH:4])[C@@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:28])=[O:27])=[CH:23][CH:22]=1.[Cl:20][C:21]1[S:25][C:24]([S:26]([NH:1][C@H:2]([CH2:3][OH:4])[C@@H:5]([CH2:11][CH3:12])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: CC[C@@H](CC(F)(F)F)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Product: CC[C@@H](CC(F)(F)F)[C@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a stirred solution of (2S, 3S)-2-amino-3-ethyl-5,5,5-trifluoropentan-1-ol (145 mg, 0.78 mmol), triethylamine (0.22 mL, 1.56 mmol) and methylene chloride (5 mL) cooled to 0° C., was added 5-chlorothiophene-2- sulfonyl chloride (225 mg, 0.861 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction mixture was allowed to attain 25° C. overnight. Additional methylene chloride (15 mL) was added and the reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (0.250 g) that was purified via flash chromatography, eluent: 1:6 ethyl acetate-hexane. This produced the title compound 5-chloro-N-[(1S, 2S)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as an oil (140 mg, 53.8%). The crude oil was further purified by recrystallization from 1:4 EtOAc-heptane. The mixed solvent system was added to 5-chloro-N-[(1S,2S)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, heated to obtain a solution, allowed to cool to 25° C. for 3 h and then stored at 0° C. for 19 h. A crystalline white solid precipitated which was filtered and washed with ice-cold heptane to afford 5-chloro-N-[(1R,2S)-2-ethyl-4,4,4-trifluoro-1-(hydroxymethyl)butyl]thiophene-2-sulfonamide as a white crystalline solid (50 mg, 19.2%, chiral purity 91%, analytical purity 100%). Mass Spectrum (−ESI): 364 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]=1[CH3:8])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fuming sulfuric acid (180 mL) is added dropwise to 4-fluoro-2-nitrotoluene (50.21 g) under an argon atmosphere. The internal temperature of the mixture is maintained at 0°-5° C. using an ice/sodium chloride bath. A preformed (ice bath) mixture of fuming nitric acid (30 mL) and fuming sulfuric acid (90 mL) is added dropwise to the previous solution over three hours. The reaction is then allowed to warm to room temperature. After stirring at room temperature for two hours, the mixture is poured slowly into ice and the products are extracted with methylene chloride (4×500 mL). The combined extracts are dried over magnesium sulfate, filtered and rotary evaporated. The crude mixture is filtered through a short pad of silica gel, using 10% ethyl acetate/hexane as solvent, then recrystallized from ethyl acetate/exane to afford 2,6-dinitro-4-fluorotoluene as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]#[N:13])=[CH:10][C:4]=2[O:3]1.Br[CH2:16][CH2:17]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:12]#[N:13])[CH2:17][CH2:16]3)=[CH:10][C:4]=2[O:3]1
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Reactant: ClCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A stock solution of 50% w/w NaOH was degassed via nitrogen sparge for no less than 16 h. An appropriate amount of MTBE was similarly degassed for several hours. To a reactor purged with nitrogen was charged degassed MTBE (143 mL) followed by (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was noted and the mixture was degassed via nitrogen sparge for 30 min. Enough degassed MTBE is charged to return the mixture to the original volume prior to degassing. To the stirring mixture at 23.0° C. was charged degassed 50% w/w NaOH (143 mL) over 10 min followed by 1-bromo-2-chloroethane (44.7 g, 311.6 mmol) over 30 min. The reaction was analyzed by HPLC in 1 h intervals for % conversion. Before sampling, stirring was stopped and the phases allowed to separate. The top organic phase was sampled for analysis. When a % conversion>99% was observed (typically after 2.5-3 h), the reaction mixture was cooled to 10° C. and was charged with water (461 mL) at such a rate as to maintain a temperature<25° C. The temperature was adjusted to 20-25° C. and the phases separated. Note: sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1 N HCl (163 mL) and 5% NaCl (163 mL). The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40-50° C. The solution was charged with ethanol (256 mL) and again concentrated to 164 mL under vacuum at 50-60° C. Ethanol (256 mL) was charged and the mixture concentrated to 164 mL under vacuum at 50-60° C. The resulting mixture was cooled to 20-25° C. and diluted with ethanol to 266 mL in preparation for the next step. 1H NMR (500 MHz, DMSO) δ 7.43 (d, J=8.4 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H), 7.30 (dd, J=8.4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[OH-].[K+]>CN1CCCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:13]1[CH:12]=[CH:17][CH:16]=[CH:15][C:14]=1[S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2o1
Reactant: Brc1ccccc1-c1ccccn1
Agent: CN1CCCC1
Agent: [K+]
Agent: [OH-]
Product: c1ccc(-c2ccccc2Sc2nc3ccccc3o2)nc1
Yield: 4.3 %

Procedure:
2-Mercapto benzoxazole (604 mg; 4 mmole) was reacted with 2-(2-bromophenyl)pyridine (936 mg; 4 mmole) in the presence of KOH (224 mg; 4 mmole) in N-methyl pyrrolidine (16 ml). The mixture was heated under reflux for 6 hours, worked up and flash chromatographed (silica), using ethyl acetate/petroleum ether (2/3) eluant to give the sub-title compound as a pale brown oil (52 mg; 4.3%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[NH:15][C:14]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH3:12])[O:10][C:6]=2[C:5]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[N:15]([CH3:26])[C:14]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)c2o1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
0.50 g (1.3 mmol) of 3-(4-chloro-2-ethyl-6-fluorobenzofuran-7-yl)-6-trifluoromethyluracil and 0.30 g (2.3 mmol) of potassium carbonate, were suspended in 20 ml of N,N-dimethylformamide, and 0.23 g (1.6 mmol) of methyl iodide was dropwise added thereto under cooling with ice. After stirring at room temperature for 3 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.48 g (yield: 92%) of the desired product as white crystals. Melting point: 142-143° C.