Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[S:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH:13]=2)[NH:8][C:7]=1[CH3:26])C.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CO>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH2:16][C:17]4[S:18][C:19]5[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=5[N:21]=4)=[CH:11][CH:10]=3)[C:6]([CH2:5][C:4]([OH:3])=[O:27])=[C:7]2[CH3:26])=[CH:31][CH:30]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OCc3nc4ccccc4s3)cc12
Solvent: CO
Product: Cc1c(CC(=O)O)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
The title compound is prepared according to the method of Example 16 using 2-methyl-5-(2-benzothiazolylmethoxy)-1H-indole-3-acetic acid ethyl ester and 4chlorobenzyl chloride; however, the hydrolysis is carried out in aqueous methanol. Recrystallization from acetonitrile affords white crystals, m.p. 175°-176° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH:29]=O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C[C@H]1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@H](NCCc2ccccc2)C[C@H]1Cc1ccccc1
Yield: 59.3 %

Procedure:
1 g (3.44 mmol) of (2R*,4S*)-2-benzyl-1-t-butyloxycarbonyl-4-piperidinamine is reacted in analogy to Example 11a with 1 ml (4.48 mmol) of phenylacetaldehyde, 0.433 g (6.89 mmol) of sodium cyanoborohydride, 0.791 g (9.64 mmol) of sodium acetate and 434 μl of acetic acid to give the title compound (805 mg, 60%). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.35, FD-MS: M+ =394.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([C:20](=O)[NH2:21])[CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)(=[O:8])=[O:9])=[C:4]([C:20]#[N:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C(N)=O)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2C#N)cc1
Yield: 94.9 %

Procedure:
To a solution of 4′-chloro-2′-carbamoyl-N-methyl-p-toluenesulfonanilide (0.70 g (2.07 mmol)) in pyridine (3.0 ml), under cooling with ice and with stirring, trifluoroacetic anhydride (0.40 ml (2.83 mmol)) was added dropwise. The temperature of the reaction mixture was brought to room temperature and the mixture was stirred at the same temperature for 2 hours. Then, the mixture was poured into water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diisopropyl ether was added to the residue and crystals separated was filtered and washed to give 0.63 g (95%) of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1.ClC1C=CC=C(C(OO)=[O:36])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)=[O:36])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(N)=O)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1cc(F)ccc1F)S(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl) [(4-fluorophenyl)thio]methyl]-4-meth ylpyridine-2-carboxamide (152 mg, 0.39 mmol) in methylene chloride (5 ml), 3-chloroperbenzoic acid (104 mg, 0.39 mmol) was added at 0° C. After stirring for 2 hours at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=7:3 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and hexane, and was collected by filtration to obtain the title compound (91 mg, 0.23 mmol, 58%) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[C:11]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)(=[O:13])[CH3:12].C(O)C>O1CCCC1>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:11]([CH2:12][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[O:13]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccco1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccco1
Temperature: 0 °C
Yield: 60.6 %

Procedure:
Sodium hydride (4.4 grams) and 10.7 grams of diethyl carbonate are suspended in 60 ml of tetrahydrofuran and 10 grams of 2-acetylfuran is gradually added thereto by keeping the inner temperature at 40°to 50° C. A small amount of ethanol is added thereto, heated to reflux for three hours, and the reaction is made stopped by addition of 20 ml of ethanol. The mixture is poured into ice water, extracted with ether, the ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate, and ether is evaporated therefrom. The resulting oil is purified by distilling in vacuo to give 10 grams of pale yellow oily product, b.p. 90° C./3 mmHg.
Reaction SMILES: [CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]([OH:30])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29].ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CCCCCC>[CH:1](=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:1]([O:30][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:15])[CH3:2]
Reactant: CCCCC=CCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: CCCCC=CCCCCCCCC=O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCC=CCCCCCCCCOC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
A 2/1 trans to cis ratio of 9-tetradecenal was evaluated in the same manner as was used in the preceding example. The 9-tetradecenal was prepared from 9-tetradecenyl alcohol prepared in the same manner as described in the preceding example. About 21 grams of the alcohol in a 50/50 weight ratio selection of dichloromethane was added dropwise to a flask charged with 43 g (0.2 mol) pyridinium chlorochromate, 20 g celite and 200 mL dichloromethane. The mixture was stirred at room temperature for about 2 hours after addition of the alcohol solution was complete. Then 200 mL of hexane was added and the mixture was filtered. The solvent was evaporated and the product vacuum distilled through a 2 ft.×3/4 in. packed column (Penn State stainless steel packing). A 36% yield of pure 9-tetradecenyl acetate was obtained.
Reaction SMILES: CS[C:3]1[NH:4][CH:5]=[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)[C:7](=[O:9])[N:8]=1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:38])([F:37])[F:36]>N1C=CC=CC=1>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:3]3[NH:4][CH:5]=[C:6]([CH2:10][C:11]4[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=4)[C:7](=[O:9])[N:8]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:36])([F:37])[F:38]
Reactant: CSc1nc(=O)c(Cc2ccc(=O)[nH]c2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: c1ccncc1
Product: O=c1ccc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)c[nH]1
Yield: 13.1 %

Procedure:
2-methylsulfanyl-5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (20 mg, 0.08 mmol, 1 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (40 mg, 0.127 mmol, 1.58 eq) were heated in 300 μl of dry pyridine at 150° C. for 16 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/30% MEOH in DCM solvent system (gradient 5-100% of 30% MeOH in DCM in 25 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-(6-oxo-1,6-dihydro-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (5.4 mg, yield=11.7%, purity=90%). MS: [M+H]=517.34. 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.81 (t, J=7.032 Hz, 2H), 3.23 (s, 2H), 3.43-3.53 (m, 2H), 6.24 (d, J=9.45 Hz, 1H), 6.36 (br.s., 1H), 7.03-7.14 (m, 3H), 7.20-7.37 (m, 4H), 7.41 (d, J=2.55 Hz, 1H), 7.54 (s, 1H), 7.70 (d, J=8.82 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[Li]CCCC.O>O1CCCC1.CCCCCC>[N:18]1([C:4]2[CH:5]=[C:6]([S:8]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)(=[O:10])=[O:9])[CH:7]=[CH:2][N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(S(=O)(=O)c2ccnc(N3CCCC3)c2)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
10.0 g (0.026 Mol) 4-(2-Bromo-6-pyrrolidin-1-yl-pyridine-4-sulfonyl)-phenylamine were dissolved in tetrahydrofuran (200 ml), cooled at -40° C. and 33 ml (0.053 Mol) nBuLi in hexane were added. The reaction mixture was stirred at -15° C. for 1 h. Then water (10 ml) was added, the mixture was extracted with ethylacetate, the organic phase was washed with water and brine and dried over Na2SO4. After chromatography on SiO2 with ethyl acetate hexan 1:1 and drying in a high vacuum, it was obtained 3.6 g (45%) of 4-(2-pyrrolidin-1-yl-pyridine-4-sulfonyl) -phenylamine as light yellow cristals; mp.: 186-187° C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:29])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][CH3:27])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:28]>C1COCC1.O.C(Cl)Cl>[F:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:29])=[O:4])=[C:8]2[CH3:28])(=[O:17])=[O:18])=[CH:20][C:21]=1[O:26][CH3:27]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(F)c(OC)c2)c2ncccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COc1cc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)ccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1M Lithium hydroxide (119 μl) is added dropwise to a cooled (0° C.) solution of [1-(4-fluoro-3-methoxy-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.044 g, 0.119 mmol) in THF/water (4 ml of a 1:1 mixture). After stirring at room temperature for 4 hours, the reaction mixture is diluted with DCM. The resulting mixture is passed through a phase separation cartridge and the aqueous portion is acidified to pH 1-3 with 1M HCl. This portion is extracted with DCM and the organic extracts are combined and concentrated in vacuo to yield the titled compound as a pale yellow solid. (MH+ 379)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([N+:23]([O-])=O)C=[CH:20][CH:21]=2)[CH:16]=CN=1.[NH4+:26].[Cl-].[CH3:28][CH2:29]O.O>[Fe]>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[CH:21]=[CH:20][N:26]=[C:18]([NH2:23])[C:17]=2[CH:16]=[CH:28][CH:29]=1
Reactant: CCO
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1cccc2c(Nc3ccc(C(F)(F)F)cc3F)nccc12
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: Nc1nccc2c(Nc3ccc(C(F)(F)F)cc3F)cccc12

Procedure:
The title compound was prepared following the procedure described in Intermediate-1, step-2 using N-(2-fluoro-4-(trifluoromethyl)phenyl)-5-nitroisoquinolin-1-amine (190 mg, 0.54 mmol), iron powder (303 mg, 5.41 mmol), and NH4Cl (232 mg, 4.32 mmol) in EtOH:H2O (3:1, 4 mL) to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.93 (s, 1H), 7.89 (t, J=8.4 Hz, 1H), 7.82 (d, J=6.0 Hz, 1H), 7.64 (d, J=10.8 Hz, 1H), 7.51 (t, 8.4 Hz, 2H), 7.40 (d, J=6.0 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H0, 6.84 (d, J=7.2 Hz, 1H), 5.83 (s, 2H); MS (m/z): 322.33 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:12])[C:6]2=[O:11].[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([N+:13]([O-:15])=[O:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:12])[C:6]2=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CN1Cc2c(Br)cccc2C1=O
Agent: O=S(=O)(O)O
Product: CN1Cc2c(Br)ccc([N+](=O)[O-])c2C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
An 8M solution of methylamine in ethanol (10 mL, 80 mmol) was added to a solution of methyl 3-Bromo-2-(bromomethyl)benzoate in THF (30 mL) and allowed to stir for 2 h. The reaction mixture was concentrated to dryness and the residue was triturated with water. The solids produced were collected by filtration and dried to afford 4-bromo-2-methyl-2,3-dihydroisoindol-1-one which used immediately in the next step. To a cold suspension of 4-bromo-2-methyl-2,3-dihydroisoindol-1-one (60 g, 265 mmol) in concentrated sulfuric acid (60 mL) was added pre-cooled mixture of conc. nitric acid (12.5 mL, 265 mmol) and conc. sulfuric acid (60 mL) over 20 min. The reaction mixture was stirred for 30 min at 0° C. and 2 h at room temperature. The reaction mixture was poured into an ice-water mixture (300 mL) and the precipitate that formed was collected by filtration and washed with water (3×100 mL). The solids were suspended in isopropanol (200 mL) and heated on a steam bath for 10 minutes. The mixture was cooled and the solid was collected by filtration and air dried to afford 53 g of the title compound (74%). 1H NMR (CDCl3, 300 MHz) δ 3.22 (s, 3H), 4.36 (s, 2H), 7.67 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[NH2:2].Cl[CH2:15][C:16](=O)[CH2:17][C:18]([O:20]CC)=[O:19]>C(OCC)(=O)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[C:1]1[O:3][CH:15]=[C:16]([CH2:17][C:18]([OH:20])=[O:19])[N:2]=1
Reactant: NC(=O)c1ccc2ccccc2c1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCOC(C)=O
Product: O=C(O)Cc1coc(-c2ccc3ccccc3c2)n1
Temperature: 160 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
A mixture of 2-carbamoylnaphthalene (2.64 g, 15.4 mmol) and ethyl 4-chloroacetoacetate (2.06 g, 12.5 mmol) was stirred at 160° C. for 1 hr. and then diluted with ethyl acetate (200 ml) at room temperature. The solution was washed with saturated sodium bicarbonate aqueous solution and brine in turn, and then dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=8−4) to give ethyl ester of [2-(2-naphthyl)oxazol-4-yl]acetic acid(459 mg, 13%) as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([NH:40][NH2:41])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1N=CN([C:58](N2C=NC=C2)=[O:59])C=1>C1COCC1>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]6[O:39][C:58](=[O:59])[NH:41][N:40]=6)=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH2:48][CH:47]([F:49])[CH2:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:4]=[C:3]([C:2]([F:1])([F:51])[F:52])[CH:8]=1
Reactant: COc1ncc(-c2ccc(C(=O)NN)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ncc(-c2ccc(-c3n[nH]c(=O)o3)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(3-fluoroazetidin-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzohydrazide (Step A, 108 mg, 0.147 mmol) in THF (1.5 mL) was treated with N,N-carbonyldiimidazole (71.6 mg, 0.442 mmol). The reaction was stirred at room temperature overnight. The reaction was purified directly by silica gel chromatography, eluting with a gradient of 25-100% ethyl acetate/hexanes to give the titled compound. LCMS (M+H)+: 760.5. 1H NMR (CDCl3, 500 MHz): δ 9.08 (br, 1H), 8.22 (d, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.74 (s, s, 3H), 7.49 (d, 1H), 7.36 (d, 1H), 5.68 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.73 (d, 1H), 4.47 (m, 3H), 4.31 (m, 2H), 4.01 (m, s, 4H), 2.38 (s, 3H), 0.76 (d, 3H). RTA IC50: 12 nM.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][N:4]=[C:3]1[S:13][CH2:14][C:15](=[O:17])[CH3:16].F[C:19](F)(F)S(OC)(=O)=O.C(Cl)[Cl:28]>C(OCC)(=O)C>[Cl-:28].[CH3:19][NH+:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:2]([CH3:1])[CH:3]1[S:13][CH2:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)CSc1ncc(-c2ccccc2)n1C
Reactant: ClCCl
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(=O)CSC1N(C)C(c2ccccc2)=C[NH+]1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.25 gram (0.001 mol) of the 1-methyl-5-phenyl-2[(2-oxopropyl)thio]imidazole, prepared as above described, in 10 mL of methylene chloride was added 0.164 g (0.001 mol) of methyl trifluoromethanesulfonate, and the solution was stirred overnight at room temperature. The solvent was evaporated and the residue was converted to the chloride ion form by dissolving in 20% methanol/water and passing through Dowex-1 (Cl-)ion exchange column. The column was eluted with 20 percent methanol in water and the eluate subjected to reduced pressure to evaporate the solvent and to obtain a residue. The residue was stirred overnight in ethyl acetate, filtered and recrystallized from isopropanol/hexane to obtain purified 1,3-dimethyl 4-phenyl-2[(2-oxopropyl)thio]-1H-imidazolium chloride, m.p. 143°-146° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([NH:23][CH3:24])=[CH:21][CH:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(OC)(C)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[N:23]([C:22]2[CH:25]=[CH:26][C:19]([Br:18])=[CH:20][CH:21]=2)[CH3:24])[CH2:13][CH2:14]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: CNc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(c1ccc(Br)cc1)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
To a solution of trans-4-(Boc-amino)cyclohexanecarboxylic acid (148 mg, 0.608 mmol) in DMF were successively added 4-bromo-N-methylaniline (0.084 ml, 0.669 mmol), Et3N (0.170 ml, 1.217 mmol) and HATU (278 mg, 0.730 mmol) at RT. The reaction mixture was heated at 80° C. for 6 h then additional HATU (278 mg, 0.730 mmol) was added and the mixture was further stirred at 80° C. for 14 h. The reaction mixture was cooled to RT, diluted with TBME and washed successively with HCl 2M in water and Na2CO3 2M in water. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The resulting crude material was purified by reverse phase prep-HPLC (gradient elution, H2O containing 0.1% TFA/MeCN 8:8→2:8) to yield the title compound (97 mg, 0.236 mmol, 39%) as a brownish solid. HPLC: AtRet=2.38 min; LC-MS: m/z 411.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 0.73-0.99 (m, 2H), 1.35 (s, 9H), 1.32-1.45 (m, 3H), 1.55-1.76 (m, 4H), 1.86-2.15 (m, 1H), 3.11 (br. s., 3H), 6.56 (br. s., 1H), 7.27-7.35 (m, 2H), 7.61-7.69 (m, 2H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C@H:36]3[CH2:41][CH2:40][C@H:39]([CH2:42]O)[CH2:38][CH2:37]3)[N:30]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:58]1(=[O:68])[NH:62][C:61](=[O:63])[C:60]2=[CH:64][CH:65]=[CH:66][CH:67]=[C:59]12>C1(C)C=CC=CC=1.O>[N:20]1([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][C@H:36]3[CH2:37][CH2:38][C@H:39]([CH2:42][N:62]4[C:58](=[O:68])[C:59]5[C:60](=[CH:64][CH:65]=[CH:66][CH:67]=5)[C:61]4=[O:63])[CH2:40][CH2:41]3)[N:30]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (972 mg, 1.2 eq) was added to a solution of trans-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexyl]-methanol (1 g, 1 equivalent; prepared in a similar manner as described in Example 4) in toluene (100 mL), it was then followed by the dropwise addition of DIAD (0.73 mL, 1.2 eq). The reaction mixture was stirred at RT for 10 minutes and then phthalimide (545 mg, 1.2 eq) was added. The mixture was stirred overnight at RT, water was then added and the resulting mixture was extracted 3 times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude residue was triturated with MeOH to give 976 mg (70% yield) of trans-2-[4-(4-benzo-triazol-1-yl-pyrimidin-2-ylamino)-cyclohexylmethyl]-isoindole-1,3-dione; MS=454.40 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1C=C[C:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:16](=[O:17])[C:15]([CH2:18][O:19]S(C)(=O)=O)=[CH:14][C:13]([C:24]3[CH:25]=[CH:26][C:27]4[O:31][CH2:30][CH2:29][C:28]=4[CH:32]=3)=[N:12]2)=[CH:4][CH:3]=1.[O:33]1C2C=CC(C3C=C(C(OC)=O)C(=O)NN=3)=CC=2CC1.ClC1C=CC=CC=1CCl>>[C:18]([C:15]1[C:16](=[O:17])[N:11]([CH2:10][C:9]2[CH:8]=[CH:5][CH:4]=[CH:3][C:2]=2[Cl:1])[N:12]=[C:13]([C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[CH:14]=1)([OH:33])=[O:19]
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CCCc2ccc(Cl)cc2)c1=O
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Agent: ClCc1ccccc1Cl
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccccc2Cl)c1=O

Procedure:
The general procedure of Example 1 (3) was carried out by use of 6-(2,3-dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-chlorobenzyl chloride, to thereby yield the title compound as yellow needle-like crystal (yield: 75.0%).