Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([C:26]([O:28]CC)=[O:27])[C:21]([O:23]CC)=[O:22])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>Cl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([C:21]([OH:23])=[O:22])[C:26]([OH:28])=[O:27])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(=O)OCC
Agent: Cl
Product: CC(C)(C)c1csc(-c2cc3cc(CC(C(=O)O)C(=O)O)ccc3o2)n1
Yield: 27.7 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2,2-diethoxycarbonylethyl)benzofuran-2-yl]thiazole (3.99 g) and conc. hydrochloric acid (20 ml) was stirred under reflux for 6 hours. After being cooled, the resulting mixture was extracted with ethyl acetate. The extract was allowed to stand until there were no further precipitates separated out. The precipitates were collected by filtration and washed with ethyl acetate to give 4-tert-butyl-2-[5-(2,2-dicarboxyethyl)benzofuran-2-yl]thiazole (0.96 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH2:16]([O:23][CH2:24][CH2:25][NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>>[CH2:16]([O:23][CH2:24][CH2:25][NH:26][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: NCCOCc1ccccc1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCOCc2ccccc2)c1Cl
Yield: 82.9 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), 2-benzyloxyethyl amine(1.04 g, 6.88 mmol) and triethylamine(1.92mL, 13.76 mmol) were reacted to form the desired product (2.31 g, 83%). 1H NMR (MeOD-d4): δ 7.69 (d, 1H), 7.53 (d, 1H), 7.25 (m, 3H), 7.14 (d, 2H), 4.26 (s, 2H), 3.45 (t, 2H), 3.36 (t, 2H).
Reaction SMILES: [CH3:1][C:2]([S:5]([N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])([CH3:4])[CH3:3].F[C:20](F)(F)[C:21]1C=CC(C=O)=C[CH:22]=1.C([Mg]Br)C=C>C(Cl)Cl>[CH3:4][C:2]([S:5]([NH:7][CH:8]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:22][CH:21]=[CH2:20])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)S(=O)N=Cc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: C=CC[Mg]Br
Solvent: ClCCl
Product: C=CCC(NS(=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-N-{[4-(trifluoromethyl)phenyl]methylene}propane-2-sulfinamide (prepared according to the procedure described in Example 99 step 1, using 4-(trifluoromethyl)benzaldehyde) (5 g, 0.18 mol) was dissolved in CH2Cl2 and the solution cooled to −50° C. Allylmagnesium bromide (10.8 mL, 2M in THF, 0.22 mol) was added dropwise and the resulting solution was stirred at 0° C. for 30 min. The mixture was quenched with NH4Cl and diluted with water and was extracted with CH2Cl2. The organic layer was separated and was washed with brine, then dried (MgSO4) and concentrated in vacuo to give the product as a 3:2 mixture of diastereoisomers.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(Cl)(Cl)[C:31]([N:33]=C=O)=[O:32]>ClCCl.O1CCCC1>[C:31](=[O:32])([O:27][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:4]2[C:5]([CH3:18])=[CH:6][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])=[C:2]([Br:1])[C:3]2=[O:28])=[CH:21][CH:22]=1)[NH2:33]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(CO)cc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccc(COC(N)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
Compound of Example 206 (0.868 g, 1.93 mmol) was suspended in dichloromethane (7.0 mL). Trichloroacetyl isocyanate (4.00 mL, 0.53 M in toluene, 2.12 mmol) was added. The resulting mixture was stirred at room temperature for 3 hours then diluted with tetrahydrofuran (50 mL) and Al2O3 (5.0 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a pad of Celite® washing with methanol. The filtrate was then concentrated and the residue was redissolved in tetrahydrofuran (30 mL). Al2O3 (5.0 g) was added and the mixture was heated to 40° C. for 3 hours. After cooling to room temperature, the reaction was filtered through a pad of Celite® washing with methanol. The filtrate was concentrated and the resulting solid was washed with diethyl ether to give an off-white solid (0.831 g, 87%). 1H NMR (400 MHz, CDCl3) δ 7.54 (app q, J=7.7 Hz, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 6.25 (app dt, J=2.0, 8.3 Hz, 1H), 6.86-6.30 (m, 1H), 5.97 (s, 1H), 5.32 (s, 2H), 5.18 (s, 2H), 5.02 (s, 2H), 4.81 (br s, 2H), 2.25 (s, 3H). ES-HRMS m/z 493.0580 (M+H calcd for C22H20BrF2N2O4 requires 493.0569).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=[O:2].[CH:12]([O-])([O-])[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[C:1]([CH2:4][N:5]1[C:9](=[O:10])[C:8](=[CH:12][O:13][CH2:14][CH3:15])[S:7][C:6]1=[S:11])([OH:3])=[O:2]
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C1SC(=S)N(CC(=O)O)C1=O
Yield: 62.5 %

Procedure:
A mixture of 36 g (0.189 mole) of 3-carboxymethylrhodanine, 33.6 g (0.225 mole) of ethyl orthoformate and 225 ml of acetic anhydride was subjected to reactiqn under reflux for about 1 to 2 hours and then the reaction mixture was concentrated. A precipitate was formed by the addition of a small amount of chloroform to the residue. The precipitate was separated and recrystallized from ethyl acetate to give 29.2 g of 3-carboxymethyl-5-ethoxymethylidenerhodanine in the form of brownish white crystal (yield: 62.5 %).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH3:23][N:24]([CH3:39])[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][CH:29]=[C:30]2[S:35](Cl)(=[O:37])=[O:36]>C(Cl)(Cl)Cl>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:35]([C:30]3[C:31]4[C:26](=[C:25]([N:24]([CH3:39])[CH3:23])[CH:34]=[CH:33][CH:32]=4)[CH:27]=[CH:28][CH:29]=3)(=[O:37])=[O:36])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Yield: 53.3 %

Procedure:
Using the general method of Example 245 except that chloroform was used as the solvent, 1-(3-aminopropyl)-2-(methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with 5-dimethylamino-1-naphthalenesulfonyl chloride (5.87 mmol) to provide 1.45 g of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-5-(dimethylamino)naphthalene-1-sulfonamide as a yellow solid, m.p. 210-215° C. Analysis: Calculated for C28H32N6O3S 1.50H2O: % C, 60.09; % H, 6.30; % N, 15.02; Found: % C, 59.89; % H, 6.22; % N, 14.86.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[C:3]=1[C:10](=[O:12])[CH3:11].[BH4-].[Na+].[NH4+].[Cl-]>CO>[Cl:9][C:4]1[C:5]([F:8])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH:10]([OH:12])[CH3:11]
Reactant: CC(=O)c1c(Cl)ccc(F)c1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(O)c1c(Cl)ccc(F)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 105.2 %

Procedure:
To a solution of 2′,6′-dichloro-5′-fluoroacetophenone (10.4 g, 50 mmol) in MeOH (anhydrous, 80 mL) was added NaBH4 (3.78 g, 100 mmol) in portions at 0° C. After the addition of NaBH4, the solution was stirred at 0° C. for 10 min, then allowed to warm to room temperature and stirred at room temperature for 30 min. The reaction solution was concentrated to remove the solvent to give the residue. A saturated solution of NH4Cl (60 mL) was added slowly. The aqueous phase was then extracted with EtOAc (3×65 mL). The combined organic phase was washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to afford (±)1-(2,6-dichloro-3-fluorophenyl)ethanol (11 g, 100%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14](Cl)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>CN(C=O)C>[Cl:1][C:2]1[C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:14]([NH:26][CH:23]2[CH2:25][CH2:24]2)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1
Reactant: NC1CC1
Reactant: Fc1ccc2nn3c(Cl)c(-c4ccccc4)c(Cl)nc3c2c1
Solvent: CN(C)C=O
Product: Fc1ccc2nn3c(NC4CC4)c(-c4ccccc4)c(Cl)nc3c2c1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
1 g (7.5 mmol) 2,4-Dichloro-9-fluoro-3-phenylpyrimido[1,2-b]indazole (intermediate example Int-1-0, step 2) and 430 mg (8.4 mmol) cyclopropylamine were dissolved in 8.4 mL DMF and heated in the microwave for 20′ at 100° C. The solvent was evaporated and the residue was purified by chromatography on silicagel (eluents: dichloromethane/methanol) to yield 560 mg (52.7%) of the desired compound.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([N:12]([C:20]1[S:21][CH2:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][C@:24]2([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([N:36]=[N+]=[N-])[CH:30]=2)[N:25]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:11])([CH3:8])([CH3:7])[CH3:6]>CO.[Zn]>[C:16]([O:15][C:13]([N:12]([C:20]1[S:21][CH2:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][C@:24]2([C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([NH2:36])[CH:30]=2)[N:25]=1)[C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Cl)cc(N=[N+]=[N-])c3)CCC[C@H]2CS1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(N)cc(Cl)c3)CCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Ammonium formate (12.4 mg) and zinc (3.86 mg) were added to a solution of (±)-N,N-bis(t-butoxycarbonyl) [(4aR*,7aS*)-7a-(3-azido-5-chlorophenyl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl]amine (20.0 mg) in methanol (2 mL). The mixture was stirred at room temperature overnight, and then the excess of methanol was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with an ammonium chloride solution. The solvent was evaporated under reduced pressure and the residue was purified by pTLC to obtain the title compound (13.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(O)(=O)C>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:30])[CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:23][CH:24]=2)=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(=Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)OC
Yield: 101.2 %

Procedure:
2-{4-[2-(4-Methanesulfonyloxyphenyl)ethoxy]benzylidene}malonic acid dimethyl ester (described in Example 10) (2.31 g; 5.32 mmole) was hydrogenated for 2.5 hours at atmospheric pressure in ethyl acetate (140 ml) and acetic acid (5 ml) using Pd/C (0.8 g) as catalyst and then filtered through hyflo. The solvent was evaporated in vacuo, dichloromethane and diluted sodium bicarbonate solution were added and the phases were separated. The organic phase was washed with brine, dried (sodium sulfate), filtered and evaporated in vacuo to give 2.35 g (yield 100%) of 2-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]benzyl}malonic acid dimethyl ester.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([O:16]CC)=[O:15])[N:13]=1.[Li+].[OH-].Cl>C1COCC1.O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=[O:15])[N:13]=1
Reactant: CCOC(=O)c1csc(-c2ccccc2CO)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(-c2ccccc2CO)n1
Yield: 79.7 %

Procedure:
To a solution of 2-(2-hydroxymethyl-phenyl)-thiazole-4-carboxylic acid, ethyl ester (1.3 g) in THF (5 mL) was added an aqueous solution of LiOH:H2O (472 mg in 5 mL water) and the resulting biphasic mixture was stirred vigorously at room temperature for 3 h. The reaction mixture was then acidified with 1N HCl, diluted with water and extracted three times with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated. The crude product was dissolved in a small amount of ethyl acetate and precipitated by addition of hexanes to give 2-(2-hydroxymethyl-phenyl)-thiazole-4-carboxylic acid (926 mg) as a light yellow solid. HRMS calcd for Cl1H9NO3S (M+) 235.0303, observed 235.0302.
Reaction SMILES: Cl.[CH2:2]([C:9]1([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:18][CH2:17][C:12]2(OCC[O:13]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([C:9]1([NH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(CNC2(Cc3ccccc3)CCC3(CC2)OCCO3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(CNC2(Cc3ccccc3)CCC(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
6 M hydrochloric acid (7 ml) was added to a solution of (8-benzyl-1,4-dioxaspiro[4,5]dec-8-yl)(4-methoxybenzyl)amine (1.2 g, 3.3 mmol) in acetone (17 ml). The reaction solution was stirred for 20 h at room temperature, then made alkaline (pH˜9) with 25% potassium carbonate solution and extracted with diethyl ether (3×20 ml). The combined organic phases were dried with sodium sulfate and concentrated to approx. 10 ml under vacuum. The precipitated deposit was filtered off and dried under vacuum. Yield: 790 mg (74%), white solid. Melting point: 122-124° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([NH2:9])[CH:3]=1.[CH2:10](Cl)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C1C=CC=CC=1.C(Cl)Cl>[CH2:11]([C:10]1[S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=C(CCl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: Clc1ccc2sc(Cc3ccccc3)nc2c1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
A round bottom flask fitted with a Dean-Stark trap was charged with 4-Chloro-2-aminobenzenethiol (3.47 g, 21.7 mmol) and phenacyl chloride (3.0 mL, 22.7 mmol) in benzene (40 mL), and the mixture heated 18 h in an 80° C. oil bath. The reaction mixture was diluted with CH2Cl2, and the organics washed sequentially with aqueous Na2CO3, brine, then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel chromatography eluting with 35-100% CH2Cl2/hexanes to provide the title compound as a white solid (1.94 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[Mg]Br.FC1C=CC(F)=CC=1Br.[Mg].[Cl:21][CH2:22][C:23](=[O:33])[C@H:24]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:25].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(#N)C.O>[Cl:21][CH2:22][C:23]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])([OH:33])[CH:24]([O:26][C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])[CH3:25]
Reactant: C[C@@H](OC(=O)C(C)(C)C)C(=O)CCl
Reactant: Fc1ccc(F)c([Mg]Br)c1
Agent: Fc1ccc(F)c(Br)c1
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of 2,5-difluorophenylmagnesium bromide prepared from 5.79 g (30.0 mmol) of 2,5-difluorobromobenzene and 0.759 g (31.2 mmol) of magnesium by the same method as that in Example 3 was cooled to 0° C., and a solution of 3.10 g (15.0 mmol) of (R)-1-chloro-3-pivaloyloxybutan-2-one in 15 mL of toluene was added dropwise thereto. After the completion of the dropwise addition, stirring was continued for another 1 hour, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. A quantitative analysis was performed by HPLC. Thereby, the title compound was obtained in a yield of 63% ((2S,3R)/(2R,3R)=94/6) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=6/4, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 17.0 minutes (2S,3R), 13 minutes (2R,3R)). 1H-NMR (400 MHz, CDCl3) (2S,3R) δ: 1.07 (d, 3H, J=6.3 Hz), 1.24 (s, 9H), 3.86 (d, 1H, J=11.5 Hz), 4.20 (d, 1H, 11.5 Hz), 5.42 (q, 1H, J=6.3 Hz), 7.00-7.03 (m, 2H), 7.40-7.44 (m, 1H); (2R,3R) δ: 1.03 (s, 9H), 1.58 (d, 3H, J=6.3 Hz), 3.91 (d, 1H, J=11.5 Hz), 4.28 (d, 1H, 11.5 Hz), 5.31 (q, 1H, J=6.3 Hz), 6.99-7.02 (m, 2H), 7.26-7.37 (m, 1H).
Reaction SMILES: C(Cl)Cl.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(OCC)(=O)C>CCOCC>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:15]2[CH:16]=[CH:17][N+:18]([O-:37])=[CH:19][CH:20]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)c1cc(F)ccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc[n+]([O-])cc1)c1cc(F)ccc1F
Reaction time: 20 h
Yield: 79.7 %

Procedure:
To methylene chloride (20 ml) of the 4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridine (221 mg, 0.58 mmol) obtained in Example 20 was added 3-chloroperbenzoic acid (100 mg, 0.58 mmol). The resulting mixture was stirred for 20 hours. The reaction mixture was diluted with ether (60 ml). The diluted mixture was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried and then filtered. The filtrate was concentrated under reduced pressure to afford a residue. The resulting residue was subjected to silica gel chromatography (ethyl acetate) to give the title compound (183 mg, 80%). The compound was crystallized from ethanol to afford colorless needle crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:20]([F:23])([F:22])[F:21])([O:15][Si](C)(C)C)[CH2:10][CH2:9][CH2:8][C:7]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([F:24])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:20]([F:23])([F:21])[F:22])([OH:15])[CH2:10][CH2:9][CH2:8][C:7]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(F)cc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCCc2c1[nH]c1c(Cl)cc(F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
8-Chloro-6-fluoro-1-(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.1 g, 0.26 mmol) was dissolved in THF (10 mL) and KOH (0.073 g, 1.3 mmol), in water (2 mL), was added. The reaction mixture was stirred at room temperature for 2 h, diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:4) as eluant] to provide the title compound (0.02 g, 24%) (HPLC 96%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.27 (bs, 1H), 7.12-7.11 (d, J=9.0 Hz, 1H), 7.08-7.0 (d, J=8.5 Hz, 1H), 2.82-2.77 (m, 1H), 2.71-2.65 (m, 1H), 2.49 (s, 1H), 2.29-2.23 (m, 1H), 2.12-2.09 (m, 1H), 2.05-2.02 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](B(O)O)[C:5]([O:11][CH3:12])=[CH:4][N:3]=1.[N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CO.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:28][C:25]([O:24][C:22]([N:13]([C:6]1[C:5]([O:11][CH3:12])=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:23])([CH3:26])[CH3:27]
Reactant: COc1cnc(Br)cc1B(O)O
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Product: COc1cnc(Br)cc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 20 h
Yield: 11.8 %

Procedure:
A mixture of 2-bromo-5-methoxypyridine-4-boronic acid (10 g, 43.1 mmol), di-tert-butyl azodicarboxylate (9.93 g, 43.1 mmol), and copper(II) acetate (7.48 mg, 0.041 mmol) in MeOH (150 mL) was stirred 20 h at 50° C., filtered, concentrated, diluted with brine (100 mL), and extracted with EtOAc. The organic layers were combined, washed with brine, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5→3:1) to provide 2.13 g of the title compound. tR: 1.21 min (LC-MS 4); ESI-MS: 418.2 [M+H]+ (LC-MS 4); Rf=0.67 (hexane/EtOAc, 1:1).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[N:11]=[C:10]([NH:12][C:13]2[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=2)[CH:9]=[CH:8][CH:7]=1.[C:22](O)(=[O:26])[C:23]#[C:24][CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C:10]2[N:11]=[C:6]([O:5][CH2:4][CH2:3][NH:2][C:22](=[O:26])[C:23]#[C:24][CH3:25])[CH:7]=[CH:8][CH:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Nc2cccc(OCCN)n2)c1=O
Reactant: CC#CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CC(=O)NCCOc1cccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.2 %

Procedure:
A mixture of 3-(6-(2-aminoethoxyl)pyridin-2-ylamino)-5-bromo-1-methylpyridin-2(1H)-one hydrochloride 103a (1.0 g, 2.66 mmol), but-2-ynoic acid (268 mg, 3.19 mmol), HATU (1.21 g, 3.19 mmol) and DIPEA (1.14 mL, 6.65 mmol) in DMF (10 mL) was stirred at rt overnight. The reaction mixture was diluted with EA and washed with water. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was washed with PE/EA (2 mL/20 mL) and dried to give N-(2-(6-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)pyridin-2-yloxy)ethyl)but-2-ynamide 116a (800 mg, 74%) as light yellow solid. ESI-LCMS: m/z=404.9