Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9](/[CH:11]=[N:12]/[OH:13])=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.C1C(=O)N(Cl)C(=O)C1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([CH2:33][F:34])=[CH2:32])[CH:28]=[C:27]([Cl:35])[C:26]=1[Cl:36].Cl>CN(C=O)C.CC(=O)OCC.O>[F:34][CH2:33][C:31]1([C:29]2[CH:28]=[C:27]([Cl:35])[C:26]([Cl:36])=[C:25]([Cl:24])[CH:30]=2)[O:13][N:12]=[C:11]([C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][C:4]([CH3:15])([CH3:14])[C:5]=3[CH:10]=2)[CH2:32]1
Reactant: CC1(C)OB(O)c2ccc(/C=N/O)cc21
Reactant: C=C(CF)c1cc(Cl)c(Cl)c(Cl)c1
Agent: Cl
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(CF)(c4cc(Cl)c(Cl)c(Cl)c4)C3)cc21
Temperature: 45 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
To a solution of (E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime (225.5 mg, 1.1 mmol) in DMF (10 mL) at rt was added NCS (177 mg, 1.32 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 h and cooled to rt. To a solution of 1,2,3-trichloro-5-(3-fluoroprop-1-en-2-yl)benzene (260 mg, 1.1 mmol) and TEA (122.2 mg, 1.21 mmol) in DMF (20 mL) was added the above mixture dropwise at 0° C. The mixture was stirred at this temperature for 1 h and then at rt overnight. The mixture was acidified with HCl (3 N) to pH of 2 and then poured into water followed by extraction with EA (100 ml×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE:EA (2:1) to give the final title compound (200 mg, yield 41%) as a white solid: 1H NMR (300 MHz, DMSO-d6): δ 9.14 (s, 1H), 7.77 (s, 2H), 7.69-7.68 (m, 3H), 4.91 (s, 1H), 4.75 (s, 1H), 3.80 (s, 2H), 1.45 (s, 6H). MS: m/z=443 [M+H]+.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][NH:21][C:22]([CH:24]1[NH:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([NH:33][C:34]2[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=2[CH3:42])=[O:32])[CH2:25]1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]([CH2:30][C:31]([NH:33][C:34]3[C:39]([CH3:40])=[CH:38][C:37]([CH3:41])=[CH:36][C:35]=3[CH3:42])=[O:32])[CH2:25][CH:24]2[C:22]([NH:21][CH3:20])=[O:23])=[CH:7][CH:8]=1
Reactant: CNC(=O)C1CN(CC(=O)Nc2c(C)cc(C)cc2C)CCN1
Reactant: Fc1ccc(C(CCCI)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)C1CN(CC(=O)Nc2c(C)cc(C)cc2C)CCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
A mixture of 6.7 g of 1,1′-(4-iodobutylidene)bis[4-fluorobenzene], 5.2 g of 3-[(methylamino)carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide, 2.3 g sodium carbonate and 38 ml DMF is stirred for 18 hours at 70° C. The reaction mixture is cooled and poured onto ice-water. The product is extracted with DCM. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is dried, yielding 4.23 g of 4-[4,4-bis(4-fluorophenyl)butyl]-3-[(methylamino)-carbonyl]-N-(2,4,6-trimethylphenyl)-1-piperazineacetamide (compound 1, mp. 82.3° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Mg+].[Br-].[CH3:26]COC(C)=O.[CH3:32]CCCCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@@H:21]([OH:22])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([OH:22])[CH3:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: CCCCCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Product: C[C@H](O)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of intermediate (2S,3S)-N-tert-Butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-formylpyrrolidine (4.7 g, 14.26 mmol) in THF (70 mL) at −78° C. was added dropwise MeMgBr (3.0 M in THF, 23.8 mmol). The reaction was stirred at −78° C. for 3 h and TLC (20% EtOAc/hexane) showed complete reaction. The reaction was quenched by the addition of HOAc (5.0 mL) at −78° C., warmed to rt and diluted with EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated to give the crude product. Purification by flash chromatography (120 g ISCO silica gel column, 0-30% EtOAc/hexane) provided 80A-a (760 mg) and 80A-b(1.54 g) as colorless oil. 80A-a: For (20% EtOAc/hexane) 0.29. 80A-b: For (20% EtOAc/hexane) 0.25.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCOC(C)=O>CN(C=O)C>[N:13]1([CH2:19][CH2:20][NH:21][C:2]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cccc(F)c1F
Reactant: NCCN1CCCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(F)c1NCCN1CCCCC1
Temperature: 100 °C
Yield: 63 %

Procedure:
Methyl 2,3-difluorobenzoate (0.816 g, 4.741 mmol) and 2-(piperidin-1-yl)ethanamine (2.7 mL, 18.93 mmol) were dissolved in DMF (15 mL) and heated in a microwave for 30 mins at 100° C. The reaction mixture was transferred to a separatory funnel with EtOAc (75 mL) the organics washed with 10 ml pure water. The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The crude material was purified by silica gel column chromatography eluting with EtOAc/Hexanes to give methyl 2-(2-(piperidin-1-yl)ethylamino)-3-fluorobenzoate (837 mg, 63%). LC/MS: 281.17 (M+1) Rt=1.63 min (10-90% 3/5 min (grad/run) with formic acid).
Reaction SMILES: [CH3:1][C:2]1[C:20]([N:21]([C:23](=[O:40])[CH2:24][NH:25][C:26](=[O:39])[CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([C:35](=[O:38])[NH:36][CH3:37])=[CH:31][CH:30]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([CH3:41])[C:3]=1[CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([SH:15])[N:11]([CH3:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1.[C:42](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:1][C:2]1[C:20]([N:21]([C:23](=[O:40])[CH2:24][NH:25][C:26](=[O:39])[CH:27]=[CH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35](=[O:38])[NH:36][CH3:37])=[CH:33][CH:34]=2)[CH3:22])=[CH:19][CH:18]=[C:17]([CH3:41])[C:3]=1[CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([S:15][CH3:42])[N:11]([CH3:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(COc3cccc4c3nc(S)n4C)c2C)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(C)c(COc3cccc4c3nc(SC)n4C)c2C)cc1
Reaction time: 16 h
Yield: 59.3 %

Procedure:
To a mixture of 4-[2,6-dimethyl-3-[N-(4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-mercapto-1-methyl-1H-benzimidazole (34.9 mg), potassium carbonate (10.1 mg) and N,N-dimethylformamide (0.4 ml) was added methyl iodide (4 μl) at ambient temperature, and the mixture was stirred for 16 hours. The reaction mixture was poured into water, and extracted with chloroform. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate:methanol=10:1, v/v) to give 4-[2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-1-methyl-2-methylthio-1H-benzimidazole (21.2 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=1)[O:23][CH2:24][CH2:25][OH:26].[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[NH:13]1[C:14]2[C:10](=[C:9]([C:20]3[CH:21]=[C:22]([CH:27]=[CH:28][CH:29]=3)[O:23][CH2:24][CH2:25][OH:26])[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: OCCOc1cccc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCOc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)1H-indole (5.49 g, 22.5 mmol) and 2-(3-bromo-phenoxy)-ethanol (4.9 g, 22.5 mmol) in THF (68 mL) was added Palladium catalyst Pd(PPh3)4 (473 mg, 0.03 eq.) and the freshly prepared sodium hydroxide solution (2.7 g in 31.5 mL of water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for overnight. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed with brine (4×), and dried over Na2SO4 and concentrated. The residue was purified on a silica gel column to give 5.4 g (95%) of 2-[3-(1H-indol-4-yl)-phenoxy]-ethanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:34]([O:35][CH3:36])=[CH:33][C:24]2[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[CH:22]=1.Cl.COCCO.C(=O)([O-])[O-]>O1CCOCC1.CCOC(C)=O>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:34]([O:35][CH3:36])=[CH:33][C:24]3[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCO
Solvent: C1COCCO1
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)c(OC)cc21
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.4 mmol), and 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (104 mg, 0.444 mmol), 4 M of Hydrogen chloride in 1,4-Dioxane (100 uL), 2-Methoxyethanol (4.5 mL, 57 mmol) were charged into Radley tube. Heat 110° C. for about 3 hours, cooled to room temperature. The mixture was treated with excess MP-carbonate and stirred 30 min. Filtration followed by concentration gave a yellow film. Treatment with EtOAc and sonication provided an off-white solid. This material was stripped onto Celite and purified on ISCO column (40 g SiO2, gradient 50% EtOAc hexane to 100% EtOAc to 5% MeOH/EtOAc) gave 2-[5-Chloro-2-(1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a white solid (42.06 mg, 20%). MP: 232-233° C. 1H-NMR (dmso, 400 MHz) δ 11.56 (s, 1H), 8.74 (d, J=4.5 Hz, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 7.73 (d J=7.8 Hz, 1H), 7.67 (s, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.05 (s, 1H) 3.85-3.80 (broad m, 2H), 3.83 (s, 3H), 2.80 (d, J=4.2 Hz, 3H), 2.50-2.49 (m, 2H), 2.12-2.10 (m, 2H), 2.10-1.99 (m, 2H), 1.01 (t, J=7.0 Hz, 3H); LC/MS: 495.37 (M+H).
Reaction SMILES: [OH-:1].[Na+].[NH2:3][C@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N[C@@H](C(O)=O)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([NH:3][C@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [OH-]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1ccccc1

Procedure:
If a NaOH solution is used in place of the Na2CO3 in Example 1 and substantially following the procedure set forth in Carter, H. E. et al., J. Biol. Chem. 138, 627 (1941), optical activity is maintained. That is if L-Phe or D-Phe is the starting material, Nα -benzoyl-L-Phe or Nα -benzoyl-D-Phe respectively is produced.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[NH:10][C@@H:9]2[C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.BrCC1C=CC([C:34]#[N:35])=CC=1>>[O:13]=[C:11]1[NH:10][C@H:9]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=2)[C@@H:8]([C:4]2[CH:5]=[CH:6][C:7]([C:34]#[N:35])=[CH:2][CH:3]=2)[O:12]1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C1N[C@H](c2cncc(C#Cc3ccccc3)c2)[C@@H](c2cccc(F)c2)O1
Product: N#Cc1ccc([C@H]2OC(=O)N[C@@H]2c2cncc(C#Cc3ccccc3)c2)cc1

Procedure:
Prepared according to the same procedure as (4R,5R)-5-(3-fluorophenyl)-4-(5-(phenylethynyl)pyridin-3-yl)oxazolidin-2-one, starting with 4-(bromomethyl)benzonitrile. 1H NMR (CDCl3, 500 MHz) δ: 8.80 (d, J=1.8 Hz, 1H), 8.44 (d, J=2.1 Hz, 1H), 7.90 (t, J=2.0 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.53-7.63 (m, 2H), 7.35-7.48 (m, 5H), 5.39 (d, J=7.3 Hz, 1H), 4.77 (d, J=7.3 Hz, 1H). 13C-NMR (CDCl3, 126 MHz) δ: 158.1, 153.2, 146.8, 141.7, 136.4, 133.3, 133.2, 131.9, 129.4, 128.7, 126.4, 122.0, 121.6, 118.1, 113.6, 94.5, 85.0, 84.5, 62.4, 43.8, 15.0. Mass spec.: 365.9 (MH)+. The sample was further purified by SFC Prep HPLC (Chiralpak AS-H, 20% MeOH in CO2).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([NH:22][CH2:23][C:24]2([N:30]([CH3:32])[CH3:31])[CH2:29][CH2:28][S:27][CH2:26][CH2:25]2)=[O:21])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:8]([CH3:19])=[C:7]([C:20]([NH:22][CH2:23][C:24]2([N:30]([CH3:32])[CH3:31])[CH2:25][CH2:26][S:27](=[O:41])[CH2:28][CH2:29]2)=[O:21])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)NCC2(N(C)C)CCSCC2)cc(C(C)(C)C)n1CCc1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1c(C(=O)NCC2(N(C)C)CCS(=O)CC2)cc(C(C)(C)C)n1CCc1ccc(F)cc1

Procedure:
A 400 mg portion of 5-tert-butyl-N-{[4-(dimethylamino)tetrahydro-2H-thiopyran-4-yl]methyl}-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide was dissolved in 4 ml of chloroform and, under ice-cooling, 210 mg of 3-chloroperbenzoic acid was added, followed by stirring under ice-cooling for 1 hour. Then, 100 mg of 3-chloroperbenzoic acid was added, followed by stirring for 30 minutes. A 10% sodium hydrogen sulfite aqueous solution and a saturated sodium bicarbonate aqueous solution to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol:hexane=1:0:0-100:1:0-50:1:0-30:1:0) to obtain 213 mg of 5-tert-butyl-N-{[4-(dimethylamino)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide as a colorless oil. This product was dissolved in 2.5 ml of acetonitrile at 80° C., 44 mg of oxalic acid was added, followed by stirring at the same temperature for 10 minutes and then stirring at room temperature for 2 hours. The resulting solid was collected by filtration and then washed with acetonitrile to obtain 199 mg of 5-tert-butyl-N-{[4-(dimethylamino)-1-oxidotetrahydro-2H-thiopyran-4-yl]methyl}-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxamide oxalate as a colorless solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]([Li])(C)([CH3:9])[CH3:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH:20]=[C:19]([CH:26]=[O:27])[CH:18]=[CH:17]2.[Cl-].[NH4+]>C1COCC1.CCCCC>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[CH:20]=[C:19]([C:26]([C:2]1[N:3]=[CH:4][NH:5][CH:6]=1)([OH:27])[CH:7]([CH3:9])[CH3:8])[CH:18]=[CH:17]2
Reactant: Brc1c[nH]cn1
Reactant: [Li]C(C)(C)C
Reactant: COc1cc2ccc(C=O)cc2cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1cc2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2cc1OC
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
4-Bromo-1H-imidazol (1.95 g) was dissolved in THF (30 ml) and the mixture was cooled to −78° C. A solution (1.7 M; 20 ml) of t-butyllithium in pentane was added. The mixture was stirred at 0° C. for 1.5 h and again cooled to −78° C. A solution (20 ml) of 6,7-dimethoxy-2-formyl naphthalene (3.32 g) in THF was added and the mixture was warmed from −78° C. to room temperature. The mixture was stirred at room temperature for 16 h and aqueous solution of ammonium chloride was added. The mixture was extracted with ethyl acetate and the organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (eluate, dichloromethane:methanol=10:1) and crystallized from dichloromethane-methanol to give the title compound (1.31 g) as a colorless solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.C([Li])CCC.[CH:40]([OH:43])([CH3:42])[CH3:41]>>[CH:40]([O:43][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)([CH3:42])[CH3:41]
Reactant: CC(C)O
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CC(C)Oc1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 20 (30 mg, 0.06 mmol) with 2 equivalents each of n-butyl lithium and isopropyl alcohol by the procedure described in Reference Example 6 and 7 to afford the title compound: HPLC/MS: m/e=521 (M++1); Rt=4.93 min. 1H-NMR 400 MHz (CDCl3): δ 1.33 (d, J=6 Hz, 6H), 5.02-5.09 (m, 1H), 6.90-6.94 (m, 1H), 7.04-7.10 (m, 1H), 7.12-7.28 (m, 7H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([O-:3])=[O:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H-].[Na+]>>[CH2:10]([C:4]1([N+:1]([O-:3])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])C1CCCCC1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])C1(Cc2ccccc2)CCCCC1

Procedure:
Nitrocyclohexane and benzylbromide are subjected to condensation reaction in the presence of sodium hydride to obtain 1-benzyl-1-nitrocyclohexane. The product is reduced with lithium aluminum hydride to obtain 1-benzyl-1-aminocyclohexane. The product is reacted with methyl chloroformate to obtain 1-benzyl-1-methoxycarbonylaminocyclohexane, and the product is subjected to intramolecular cyclization in the presence of phosphorous oxychloride to obtain spiro[1,2,3,4-tetrahydroisoquinoline-2,1'-cyclohexan]-1-one.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(Cl)Cl.[O:8](S(C(F)(F)F)(=O)=O)[S:9]([C:12]([F:15])([F:14])[F:13])(=O)=[O:10]>O>[S:9]([N:1]=[N+:2]=[N-:3])([C:12]([F:15])([F:14])[F:13])(=[O:10])=[O:8]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: [N-]=[N+]=NS(=O)(=O)C(F)(F)F

Procedure:
To a solution of NaN3 (3445 mg, 53 mmol) in H2O (12 mL) was added CH2Cl2 (18 mL). The resulting biphasic mixture was cooled in an ice bath and stirred vigorously and treated with Tf2O (3000 mg, 106 mmol) over a period of 60 min. The reaction mixture was stirred in an ice bath for 4 h. The organic phase was separated and the aqueous phase was extracted once with CH2Cl2 (20 mL). The organic extracts were washed with saturated Na2CO3 solution and used without further purification.
Reaction SMILES: [ClH:1].[F:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH3:6])[C:4]1=[O:27])[C@:17]1([CH3:18])[C:12]2(O[CH:13]2[C:14](=[O:23])[CH:15]=[C:16]1[CH3:22])[C:11](=[CH2:25])[C@H:10]3[CH3:26].O>C(O)(=O)C>[F:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:5]2([CH3:6])[C:4]1=[O:27])[C@:17]1([CH3:18])[C:12](=[C:13]([Cl:1])[C:14](=[O:23])[CH:15]=[C:16]1[CH3:22])[C:11](=[CH2:25])[C@H:10]3[CH3:26]
Reactant: C=C1[C@@H](C)[C@H]2[C@@H]3C[C@@H](F)C(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)C(C)=CC(=O)C3OC132
Reactant: Cl
Solvent: CC(=O)O
Solvent: O
Product: C=C1C2=C(Cl)C(=O)C=C(C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@@H]2[C@@H]1C

Procedure:
Gaseous hydrogen chloride is introduced for about 30 min into a solution of 16α-fluoro-4,5-epoxy-1,7α-dimethyl-6-methylenandrost-1-ene-3,17-dione (359 mg) in glacial acetic acid (5 ml). Thereupon water is added, the precipitate filtered off, washed with diethylether and chromatographed on silica gel to yield pure 16α-fluoro-4-chloro-1,7α-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione (264 mg). Found: C 70.05, H 6.89, Cl 9.32, F 4.99. C22H26ClFO2 requires: C 70.11, H 6.95, Cl 9.41, F 5.04.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:31])([CH3:30])[CH2:18][O:19][C:20]1[C:21]([CH3:29])=[CH:22][C:23]([CH:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:22]=[C:21]([CH3:29])[C:20]([O:19][CH2:18][C:17]([F:31])([F:16])[CH3:30])=[CH:25][N:24]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)ncc1OCC(C)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(C)(F)F
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (585 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (522 mg, 1.88 mmol, Step-1 of Intermediate-1) and 1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (500 mg, 1.88 mmol, Amine-76, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]1[C:4](/[CH:9]=[N:17]/[S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1C=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1cccnc1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-methoxy-pyridine-2-carbaldehyde (2.95 g, 21.51 mmol) in DCM (26 mL) was added (S)-2-methylpropane-2-sulfinamide (5.3 g, 43.7 mmol) and copper(II) sulfate (6.95 g, 43.5 mmol). The suspension was stirred at rt under argon for 18 hours, filtered, and the solid washed with DCM (2×20 mL). The filtrates were concentrated, and the product thus obtained was purified by silica gel flash column chromatography (using a 80G ISCO cartridge) and eluted using hexanes/EtOAc gradient followed by DCM/MeOH to yield the desired product (S,E)-N-((3-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide as a light-yellow solid after drying under high vacuum.