Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25].O>CN(C)C=O>[C:16]1([CH3:28])[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([N:8]1[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:25])=[O:26]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)n2cc(C=O)nc2-c2ccccc2)c(C)c1
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 523 mg) at room temperature, and the mixture was stirred for 1 hr. Mesitylsulfonyl chloride (2.42 g) was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, 3% aqueous potassium hydrogensulfate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=7:3→3:2) to give the title compound as a pale-yellow oil (yield 1.76 g, 49%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([F:12])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N(Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH2:1][Br:17])[C:11]=1[F:12])(=[O:14])=[O:15]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1CBr

Procedure:
30.75 g (0.12 mol) of methyl 2-methyl-3-fluoro-4-methylsulfonylbenzoate were introduced in 600 ml of CCl4. 35.5 g (0.2 mol) of N-bromosuccinimide and 0.86 g (0.002 mol) of benzoyl peroxide were mixed. A third of the amount is added at RT. Then the batch is heated to reflux and “irradiated”. Over the course of an hour the remaining NBS/benzoyl peroxide mixture is added in portions, followed by stirring under reflux for 2 h more. The batch is allowed to cool and is washed with a 10% strength sodium hydrogen sulfite solution, and dried over MgSO4, and the organic phase is concentrated to completion.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)[CH2:11][CH2:10]1)(OC(C)(C)C)=O>CCOC(C)=O>[ClH:1].[ClH:1].[NH:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[NH:16][CH2:15][CH:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccccc3[nH]2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
HCl gas was passed through a solution of 5-2 (1.3 g, 3.9 mmol) in EtOAc (25 mL) at 0° C. for 3 min. After stirring at 0° C. for an additional 2 hrs, the reaction mixture was concentrated to give 5-3 as a solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([OH:14])[C:4]1=[O:15])[CH3:2].[N:16]1([CH2:22][CH2:23]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:7][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:14][CH2:23][CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:4]1=[O:15])[CH3:2]
Reactant: CCN1CC(c2ccccc2)=C(O)C1=O
Reactant: ClCCN1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CC(c2ccccc2)=C(OCCN2CCCCC2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 30.5 g. 1-ethyl-3-hydroxy-4-phenyl-3-pyrrolin-2-one is reacted with 21.5 g. β-piperidinoethyl chloride. The base obtained is converted into the crystalline hydrochloride in ethyl acetate by means of gaseous hydrogen chloride. There is obtained 22.5 g. (42% of theory) 1-ethyl-3-(β-piperidinoethoxy)-4-phenyl-3-pyrrolidin-2-one hydrochloride; m.p. 120° C., (decomp.), after recrystallization from methyl ethyl ketone.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:47]=[CH:46][C:45](C4C(C#N)=CSC=4)=[CH:44][CH:43]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19].[CH3:55][N:56]1[CH2:61][CH2:60][N:59]([CH2:62]C2C=CC(O)=CC=2)[CH2:58][CH2:57]1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C:18]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[CH2:28][N:27]([C:30]1[S:31][C:32]([CH2:38][CH2:39][CH2:40][O:41][C:42]3[CH:43]=[CH:44][C:45]([CH2:55][N:56]4[CH2:61][CH2:60][N:59]([CH3:62])[CH2:58][CH2:57]4)=[CH:46][CH:47]=3)=[C:33]([C:35]([OH:37])=[O:36])[N:34]=1)[CH2:26][CH2:25]2)=[O:19]
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Reactant: CN1CCN(Cc2ccc(O)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(Cc2ccc(OCCCc3sc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)cc2)CC1

Procedure:
The title compound 89 was prepared as a TFA salt in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 89A: 1H NMR (DMSO-d6): δ 8.03 (d, J=7.67 Hz, 1H), 7.79 (d, J=7.98 Hz, 1H), 7.67 (d, J=7.06 Hz, 1H), 7.34-7.50 (m, 4H), 7.28 (d, J=8.59 Hz, 2H), 6.93 (d, J=8.59 Hz, 2H), 4.83 (s, 2H), 3.98 (d, J=6.29 Hz, 2H), 3.16-3.19 (m, 4H), 3.03 (t, J=5.83 Hz, 2H), 2.76 (s, 3H), 1.97-2.03 (m, 2H). ESI (+)/MS: 683 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:20])([CH2:18]O)[CH2:16][OH:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:9][CH2:10][CH2:11][Cl:12])[O:17][CH2:16][C:15]([CH3:20])([CH3:18])[CH2:14][O:13]2)=[CH:6][CH:7]=1
Reactant: O=C(CCCCl)c1ccc(Br)cc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)COC(CCCCl)(c2ccc(Br)cc2)OC1

Procedure:
10 g (38.2 mmol) of 4′-bromo-4-chlorobutyrophenone, 4 g (38.2 mmol) of 2,2-dimethyl-1,3-propanediol and 200 mg (1 mmol) of p-toluenesulfonic acid monohydrate were heated under reflex in benzene for 3 days to conduct the azeotropic dehydration. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. After the extraction with ethyl acetate, the extract was washed with water and saturated aqueous common salt solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]#[N:20].[OH-].[NH4+:22]>>[NH2:22][C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[C:3]=1[C:19]#[N:20]
Reactant: CSc1nc(Cl)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Reactant: [NH4+]
Agent: [OH-]
Product: CSc1nc(N)c(C#N)c(-c2cccc([N+](=O)[O-])c2)n1
Reaction time: 8 h

Procedure:
A solution of 6-chloro-5-cyano-4-(3-nitrophenyl)-2-methylthio-pyrimidine (example 9b, 10.0 g) was treated with ammonium hydroxide (28% NH3 in water, 15 ml) and the mixture was stirred overnight. The formed crystals were collected by filtration and washed with water. The product was dried at 50° C. under vacuum yielding the title compound.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[C:7]#[N:8].[C:20]([NH:23][C:24]1[CH:34]=[CH:33][CH:32]=[C:26]2[C:27]([O:29][C:30](=O)[C:25]=12)=[O:28])(=[O:22])[CH3:21]>C(O)(=O)C.CCOC(C)=O>[C:7]([CH:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH3:19])[CH:10]=1)[N:5]1[C:30](=[O:29])[C:25]2[C:26](=[CH:32][CH:33]=[CH:34][C:24]=2[NH:23][C:20](=[O:22])[CH3:21])[C:27]1=[O:28])#[N:8]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)C#N)ccc1OC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOc1cc(C(C#N)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Yield: 85.3 %

Procedure:
To a mixture of 2-amino-2-(3-ethoxy-4-methoxyphenyl)ethanenitrile acetate (4.1 g, 14.6 mmol) and 3-acetamidophthalic anhydride (3.0 g, 14.6 mmol) in glacial acetic acid (60 mL), was heated to reflux for 17 hours. The mixture was concentrated in vacuo to provide an oil. The oil was dissolved in EtOAc and washed with water, brine and dried over MgSO4. Solvent was removed, and the residue was purified by chromatography (SiO2, Hexane:EtOAc 6:4) to give 4.9 g (83%) of N-{2-[cyano(3-ethoxy-4-methoxyphenyl)methyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid; mp 118-120° C.; 1H NMR(CDCl3) δ 9.43 (s, 1H), 8.76 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.7 Hz, 1H), 7.51 (d, J=7.2 Hz, 1H), 7.05-6.82 (m, 3H), 5.60-5.54 (dd, J=6.63 and 10.0 Hz, 1H), 4.10 (q, J=6.8 Hz, 2H), 3.81 (s, 3H), 3.81-3.74 (m, 1H), 3.29-3.20 (dd, J=6.2 and 16.8 Hz, 1H), 2.27 (s, 3H), 1.46 (t, J=7 Hz, 3H); 13C NMR (CDCl3) δ 169:56, 169.12, 167.19, 149.92, 148.64, 137.73, 136.30, 130.87, 128.70, 125.11, 119.92, 118.29, 116.76, 114.94, 112.14, 111.98, 64.56, 55.94, 51.08, 24.92, 21.04, 14.68. Aanly. Calculated for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 65.01; H, 5.10; N, 10.19.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Mn]([O-])(=O)(=O)=[O:28].[K+].S(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]([OH:28])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
2.0 g (5.6 mmol) of 4-(4-octyloxyphenylcarbonyloxy)benzaldehyde was dissolved in 100 ml of acetone and then 900 mg (5.6 mmol) of potassium permanganate was added dropwise thereto over about 5 minutes. After the mixture was stirred at room temperature for a night, 1.0 g (9.6 mmol) of sodium bisulfite dissolved in 20 ml of water was added thereto to adjust pH to not more than 1. After the acetone was distilled off, the white precipitate was taken out by filtration and recrystallized from 60 ml of ethanol to obtain 1.8 g (yield: 85%) of a white crystal.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[N:13][C:12]=1Cl)[CH3:8].[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>CN(C=O)C>[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)=[N:13][C:12]=1[O:37][C:34]1[CH:35]=[CH:36][C:31]([O:30][C:29]([F:28])([F:38])[F:39])=[CH:32][CH:33]=1)[CH3:8]
Reactant: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Cl
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(C#N)cc2)nc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
Potassium carbonate (60 mg, 0.43 mmol) was added to a stirred and cooled (0° C.) solution of 2-chloro-6-(4-cyano phenoxy)nicotinic acid ethyl ester 0.13 g (0.43 mmol) in 10 ml DMF and stirred for 10 min at the same temperature. This was followed by the addition of 76.5 mg (0.43 mmol) of 4-trifluoromethoxy phenol, dissolved in 2 ml of DMF, over a period of 10 min. After the addition was completed, the contents were allowed to stir at RT. This was followed by heating for 3 h at 80° C. The reaction mixture was concentrated under reduced pressure, poured into ice-cold water and dissolved in 50 ml of ethyl acetate. Organic layer was then washed with brine solution followed by water and the crude product was purified by column chromatography using hexane:ethyl acetate (8:2) to afford 0.18 g of the required product. Percentage purity: LCMS−ve mode): 20.12%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])=[CH:5][CH:4]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CSc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 49.6 %

Procedure:
Using 0.22 g of 4-(methylthio)benzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.15 g of 2-(4-(methylthio)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (34)).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[CH:4][C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OC(=O)C)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:18](=[C:8]1/[CH2:9][CH2:10][CH2:11][CH2:12][C:5]2[C:6]/1=[N:7][C:2]([CH3:1])=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:4]=2)/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)c1cc2c(nc1C)CCCCC2
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)/C(=C/c1ccccc1)CCCC2
Yield: 33.3 %

Procedure:
Ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.07 g, 4.40 mmol) and benzaldehyde (583.6 mg, 5.50 mmol) were dissolved in acetic anhydride (2.0 ml), and the solution was mixed with zinc chloride (40.0 mg, 0.30 mmol) at room temperature and then heated under reflux for 36 hours. After cooling, acetic anhydride was evaporated under reduced pressure, and the thus obtained residue was mixed with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:6-1:5) to obtain the title compound (471.4 mg, 33.4%) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH:29]=[CH2:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-:43].[Na+].OO>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=4)[CH2:16][C@H:15]([CH2:28][CH2:29][CH2:30][OH:43])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:32][CH:33]=1
Reactant: C=CC[C@H]1C[C@H](c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1[C@@H](CCCO)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-3-allyl-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (61.5 mg, 0.13 mmol) in dry THF (1 mL) at 0° C. and argon is added dropwise a 9-BBN solution (0.57 mL, 0.5 M in hexane). After the addition is complete, the reaction mixture is stirred at 0° C. for 2 h and at room temperature for 3 h. The mixture is then cooled to 0° C. and treated with a 3M NaOH (0.3 mL). The oxidation is carried out by slow addition of 35% H2O2 (0.3 mL) at 0° C. The reaction mixture is stirred at 0° C. for 1 h and then at room temperature overnight. The resulting solution is poured into ethyl acetate (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered and evaporated. The residue is purified on silica gel (0-50% ethyl acetate in hexane) to give (3S,5R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]-3-(3-hydroxypropyl)pyrrolidin-2-one (64 mg, 100%) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.60-7.51 (m, 1H), 7.50-7.43 (m, 2H), 7.43-7.35 (m, 3H), 7.28-7.22 (m, 2H), 6.93-6.83 (m, 4H), 5.24 (dd, J=10.5, 3.0 Hz, 1H), 3.70 (t, J=7.2 Hz, 2H), 2.87-2.75 (m, 1H), 2.45-2.33 (m, 1H), 2.26-2.16 (m, 1H), 2.11-1.98 (m, 1H), 1.87 (s, br, 1H), 1.75-1.58 (m, 3H). HPLC-MS calculated for C26H23ClF3NO3 (M+H+) 490.13, found 490.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([NH:13][C:20](=[O:22])[CH3:21])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(N)ccc1OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(C)=O)ccc1OC
Reaction time: 20 h

Procedure:
Combine methyl 2-methoxy-5-aminobenzoate (2.0 g, 11 mmol), pyridine, 2.8 mL, 35 mmol), and acetic anhydride (3.2 mL, 34 mmol) in tetrahydrofuran (50 mL). After 20 hours, concentrate the reaction mixture in vacuo to remove most of the tetrahydrofuran, partition between ethyl aqueous layer water. Separate the layers and extract the aqueous layer twice with ethyl acetate. Combine the organic layers, extract with brine, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Crystallize the residue from ethyl acetate/cyclohexane to give methyl 2-methoxy-5-acetamidobenzoate.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]N1C(=O)CCC1=O.Cl>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=2)[C:10]([Cl:21])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2c(Cl)cn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of the compound [4] obtained in Example 4 (82 mg) in tetrahydrofuran (1 mL) was added N-chlorosuccinimide (26 mg) at room temperature, and then the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 4N-hydrochloric acid for acidification, and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (19 mg) as a red solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:22][CH:23]([F:35])[CH2:24][O:25][C:26]1[N:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:32]([C:29]3[CH:28]=[N:27][C:26]([O:25][CH2:24][CH:23]([F:35])[F:22])=[CH:31][N:30]=3)=[O:33])[CH:3]=[CH:4][C:5]=2[F:21])([CH2:19][F:20])[N:9]=1
Reactant: O=C(O)c1cnc(OCC(F)F)cn1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Product: NC1=N[C@](CF)(c2cc(NC(=O)c3cnc(OCC(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)O1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-2) and 5-(2,2-difluoroethoxyl)pyrazine-2-carboxylic acid [Y. Suzuki et al. WO2009091016 (2009)] following General Procedure G yielded the title compound as a colorless solid. MS: m/z=496.6 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[F:23][C:18]1[C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: O=C(OCc1ccccc1)N1CCC(c2cccnc2F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: Fc1ncccc1C1CCNCC1
Yield: 310.1 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(2-fluoropyrid-3-yl)piperidine (0.36 g) in 5 mL of trifluoroacetic acid was heated to reflux for 30 minutes and evaporated. The residue thus obtained was dissolved in chloroform and evaporated. After repeating this process three times, the named product was obtained as an oil (0.64 g); MS: 181; NMR: 1.6-2.1 (m, 4), 3.0-3.4 (m, 5), 7.2-7.5 (m, 2), 7.8-7.9 (m, 4), 8.1 (m, 1), 8.2-8.8 (br, 2).
Reaction SMILES: [CH2:1]=[C:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4][O:3]1.CC1(C)O[O:14]1>C(Cl)Cl>[C:6]1([CH:5]2[C:2]3([CH2:1][O:14]3)[O:3][CH2:4]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C1OCC1c1ccccc1
Reactant: CC1(C)OO1
Solvent: ClCCl
Product: c1ccc(C2COC23CO3)cc1
Yield: 99 %

Procedure:
A solution of 2-methylene-3-phenyloxetane (0.10 g, 0.69 mmol) in dry CH2Cl2 (˜0.5 M) was cooled to −78° C. A solution of DMDO (˜0.35 M in CH2Cl2, 1.0-1.2 equiv) was added dropwise with stirring. The reaction mixture was stirred at −78° C. for 1 hour after which the solvent was removed in vacuo to give 3-phenyl-1,5-dioxaspiro[3.2]hexane as a colorless oil (0.11 g, 99%) and as a mixture of diastereomers (93:7). Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 4.85 (m, 1H), 4.49 (m, 2H), 2.93 (d, J=3.4 Hz, 1H), 2.54 (d, J=3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 136.6, 128.9, 127.8, 127.5, 95.0, 70.1, 50.5, 47.9. Minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.33 (m, 5H), 4.85 (m, 1H), 4.65 (app t, J=6.6 Hz, 1H), 4.58 (dd, J=6.3, 5.0 Hz, 1H), 3.06 (d, J=3.4 Hz, 1H), 2.76 (d, J=3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 135.5, 129.3, 128.6, 128.2, 92.7, 72.0, 51.4, 46.7; HRMS (FAB) calculated for C10H11O2 (M++1) m/z: 163.0759. Found: 163.0762.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2S[CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([OH:25])=[O:24].Cl[C:27]1[C:36](=O)[C:35]2[C:30](=CC=CC=2)/[C:29](=N/S(C2C=CC3C(=CC=CC=3)C=2)(=O)=O)/[CH:28]=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][C:18]3[C:36](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:35]=2)(=[O:14])=[O:15])=[CH:4][C:3]=1[S:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C1C(Cl)=C/C(=N\S(=O)(=O)c2ccc3ccccc3c2)c2ccccc21
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Product: O=C(O)CSc1cc(NS(=O)(=O)c2ccc3ccccc3c2)c2ccccc2c1O

Procedure:
5.2.59 2-(1-hydroxy-4-(naphthalene-2-sulfonamido)naphthalen-2-ylthio)acetic acid (14q) was prepared according to the procedure of procedure B for 10a except using (E)-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)naphthalene-2-sulfonamide (12f), which afforded the title compound 64.3 mg (73.5%) as a white solid, m.p.: 185-187° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@@H:31]2[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]2[C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@@H]3CCCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 100 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1R,2R)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (55.0 mg, 0.0893 mmol) prepared in Example 168d, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (41.6 mg, 99%) as a colorless solid.