Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[C:10]([NH:19][C:20]3[CH:21]=[N:22][C:23]([O:27][CH3:28])=[C:24]([F:26])[CH:25]=3)=[N:11][CH:12]=[C:13]([CH:18]=2)[C:14](OC)=[O:15])[N:3]=1.[CH2:29]([Mg]Br)[CH3:30].C([O-])(O)=O.[Na+].CC(O)C.C(Cl)Cl>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:18]=[C:13]([C:14]3([OH:15])[CH2:30][CH2:29]3)[CH:12]=[N:11][C:10]=2[NH:19][C:20]2[CH:21]=[N:22][C:23]([O:27][CH3:28])=[C:24]([F:26])[CH:25]=2)[N:3]=1
Reactant: COC(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N)n2)c1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C3(O)CC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 7 %

Procedure:
To a slurry of methyl 5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.400 g, 1.038 mmol) and titanium(iv) isopropoxide (0.365 mL, 1.246 mmol) in 8 mL THF at ambient temperature was added ethylmagnesium bromide 1.0 M solution in THF (5.61 mL, 5.61 mmol) over 2-3 min. The reaction became dark brown and warm, with bubbling. The reaction was cooled briefly with an ice bath and then allowed to stir at ambient temperature. After 1 h, an additional 2.4 equiv 1.0 M ethylmagnesium bromide in THF was added at ambient temperature. After 30 min, the reaction was cooled to 0° C. and quenched with ice and sat'd aq. NH4Cl. The reaction was partitioned between sat'd aqueous NH4Cl and DCM. The aqueous layer was extracted with DCM 3 times, and ethyl acetate once, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by RPHPLC (Gradient, Acetonitrile+0.1% TFA/water+0.1% TFA) provided 0.070 g of a sticky orange film. The material was treated with sat'd aq. NaHCO3 and 10% iPrOH/DCM. The aq. layer was extracted 3×10% iPrOH/DCM and combined organics dried over sodium sulfate, filtered, and concentrated in vacuo to give 1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)cyclopropanol (0.027 g, 0.070 mmol, 7% yield) as a yellow solid. m/z (ESI, +ve ion) 384 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.90 (s, 1H), 8.82 (d, J=2.5Hz, 1H), 8.29-8.48 (m, 2H), 8.20 (d, J=2.5 Hz, 1H), 7.91 (br. s., 1H), 7.75 (br. s., 1H), 6.03 (s, 1H), 3.93 (s, 3H), 2.44 (s, 3H), 1.04-1.13 (m, 2H), 0.86-0.98 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][S:12]([CH2:15][C:16](OC)=O)(=[O:14])=[O:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(N(CC)C(C)C)(C)C.FC(F)COS([C:36]([F:39])([F:38])F)(=O)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:3]([O:2][CH3:1])=[O:4])[S:12]([CH2:15][CH2:16][CH:36]([F:38])[F:39])(=[O:13])=[O:14])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: COC(=O)CS(=O)(=O)Nc1nccnc1C(=O)OC
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nccnc1N(C(=O)OC)S(=O)(=O)CCC(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 110.7 %

Procedure:
To a solution of 3-methoxycarbonylmethanesulfonylamino-pyrazine-2-carboxylic acid methyl ester (Example 9.1) (1.212 g) in acetonitrile (12 ml) was added N,N-diisopropylethylamine (“Hunig's base”) (0.8 ml) at ambient temperature. The mixture was stirred at ambient temperature for 5 minutes before dropwise addition of a solution of 2,2-difluoroethyltrifluoromethanesulfonate (0.978 g) in acetonitrile (5 ml) at ambient temperature. The reaction mixture was stirred at ambient temperature for 20 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate (30 ml) and aqueous sulfuric acid (2M) (30 ml). The phases were separated and the organic layer was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:2) to give 3-[(2,2-difluoro-ethyl)-methoxycarbonyl-methanesulfonyl-amino]-pyrazine-2-carboxylic acid methyl ester (0.819 g). 1H-NMR (400 MHz, CDCl3): 8.70 (d, 1H), 8.65 (d, 1H), 6.06-6.29 (m, 1H), 4.32-4.38 (m, 2H), 4.18 (s, 2H), 4.02 (s, 3H), 3.78 (s, 3H) ppm.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][C@H:6]([OH:8])[C@@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C[C@@H](O)CCCCCC.C[C@H](O)CCCCCC>>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1O
Agent: CCCCCC[C@@H](C)O
Agent: CCCCCC[C@H](C)O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
d-menthol, Example 23: (R)-2-octanol, Example 24: (S)-2-octanol.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([C:8](Cl)=[O:9])[CH:4]=[CH:3]1.[NH2:11][C:12]1[CH:13]=[C:14]([O:18][C:19]2[N:24]=[CH:23][C:22]3[N:25]=[C:26]([C:30]4[C:31]([NH2:35])=[N:32][O:33][N:34]=4)[N:27]([CH2:28][CH3:29])[C:21]=3[CH:20]=2)[CH:15]=[CH:16][CH:17]=1.O>N1C=CC=CC=1>[NH2:35][C:31]1[C:30]([C:26]2[N:27]([CH2:28][CH3:29])[C:21]3[CH:20]=[C:19]([O:18][C:14]4[CH:13]=[C:12]([NH:11][C:8]([C:5]5[CH:4]=[CH:3][C:2](=[O:1])[NH:7][CH:6]=5)=[O:9])[CH:17]=[CH:16][CH:15]=4)[N:24]=[CH:23][C:22]=3[N:25]=2)=[N:34][O:33][N:32]=1
Reactant: O=C(Cl)c1ccc(=O)[nH]c1
Reactant: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(N)c3)cc21
Solvent: c1ccncc1
Solvent: O
Product: CCn1c(-c2nonc2N)nc2cnc(Oc3cccc(NC(=O)c4ccc(=O)[nH]c4)c3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
The product of Step 1 (93 mg, 0.6 mmol) was added to a solution of the product of Example 3 (200 mg, 0.6 mmol) in pyridine (1 mL) and the resulting mixture was allowed to stir at rt for 30 min. The solution was poured into H2O and the precipitate which formed as filtered, washed with H2O and Et2O and dried to give the title compound as a tan solid (150 mg, 55%). MS (ES+) m/e 459 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([CH3:20])[CH2:5][C@@H:6]1[CH2:10][N:9]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:8](=[O:19])[CH2:7]1.[H-].[Na+].[CH3:23]I>CS(C)=O.O>[CH3:23][O:1][CH2:2][CH2:3][CH:4]([CH3:20])[CH2:5][C@@H:6]1[CH2:10][N:9]([C@H:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[C:8](=[O:19])[CH2:7]1
Reactant: CI
Reactant: CC(CCO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCCC(C)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To alcohol 89 (2 g, 7.66 mmol) in DMSO (60 mL) at room temperature was added NaH (368 mg, 60% in oil). After 30 minutes the methyl iodide (1.08 g, 7.66 mmol) was added and the solution stirred at room temperature overnight, upon which the reaction was diluted with water (500 mL). The solution was extracted with ether, and the combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (90% to 50% hexane/acetone) of the residue gave the product 90 as an oil (1.1 g, 52%). MS m/z 290 (M+H, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.COC(C)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:14][C@H:15]([O:17][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)CN(C(=O)OCc2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](OC(=O)c2ccccc2)CN(C(=O)OCc2ccccc2)C1
Yield: 76.4 %

Procedure:
To a solution of 2.8 g (7.8 mmol) (3R,5R)-3-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-piperidine-1-carboxylic acid benzyl ester in 70 ml dry THF were consecutively added 1.0 g (8.5 mmol) benzoic acid, 1.7 g (8.5 mmol) diethyl azodicarboxylate and 2.2 g (8.5 mmol) triphenylphosphine at 0° C. After 6 h the reaction mixture was diluted with tert-butyl methyl ether washed with a 2N aqueous solution of sodium carbonate. The aqueous layer was extracted with 3 portions of tert-butyl methyl ether. The combined organic extracts were washed with a 2N aqueous solution of sodium carbonate and brine and dried over sodium sulfate. Flash chromatography gave 2.8 g (78%) of the title compound as a yellow oil. MS m/e (%): 470 (M+H+, 100)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=1[Cl:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:23]([O:22][C:20]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[Cl:19])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1Cl)C(=O)OC(C)(C)C
Agent: [Ni]
Product: CC(C)(C)OC(=O)N(Cc1cc(N)ccc1Cl)C(=O)OC(C)(C)C
Yield: 98 %

Procedure:
Using the compound obtained in Example 554 as a starting material and also using Raney nickel as a catalyst, the same procedure of Example 2 gave 3.17 g of the titled compound (yield, 98%).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:31])[CH:14]([CH3:30])[CH2:15][CH2:16][CH:17](O)[C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:19]1)(C)(C)C>ClCCl.O>[CH3:30][CH:14]1[CH2:15][CH2:16][CH:17]([C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:22][CH2:23]2)[O:31][C:13]1=[O:12]
Reactant: CCCCC[C@H]1CC[C@H](C(O)CCC(C)C(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C2CCC(C)C(=O)O2)CC1

Procedure:
A solution of 14.2 mL (185 mmol) of trifluoroacetic acid dissolved in 60 mL of dichloromethane was added dropwise under cooling with ice to a solution of 12.6 g (37.0 mmol) of tert-butyl 2-methyl-5-hydroxy-5-(trans-4-pentylcyclohexyl)pentanoate (36) obtained in the first step dissolved in 60 mL of dichloromethane, and reacted at room temperature for 5 hours. The reaction mixture was put in 200 mL of water, and then extracted with 100 mL of dichloromethane. The resulting organic layer was washed with water (150 mL×2) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (developing solvent: heptane/ethyl acetate=9/1, column packing: silica gel) and then recrystallized from heptane to obtain 3.7 g (13.7 mmol) of 3-methyl-6-(trans-4-pentylcyclohexyl)tetrahydro-2-pyranone (Compound No. 6). The resulting compound was in the form of colorless crystals, and the yield based on the compound (36) was 37%.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:33])[CH2:31]Br)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:30]([CH2:31][O:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[O:8][C:9]3[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][CH2:19][CH3:20])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[C:10]=3[C:11]=2[CH3:12])=[CH:4][CH:3]=1)([O:29][CH2:27][CH3:28])=[O:33]
Reactant: CCOC(=O)CBr
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(O)cc3)c(C)c2c1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(Cl)c2oc(Cc3ccc(OCC(=O)OCC)cc3)c(C)c2c1OC(C)=O

Procedure:
A mixture of 2-(p-hydroxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran (107 mg; 0.28 mmole), ethylbromoacetate (100 mg, 0.60 mmole), potassium carbonate (100 mg, 0.73 mmole) in acetone (10 mL) was refluxed for 30 minutes. The solids were filtered off, the filtrate was concentrated in vacuo to yield a residue that was purified by chromatography on silica gel. Elution with 20% ethylacetate in hexane yielded 133 (100%) of 2-(p-carboethoxymethoxybenzyl)-3-methyl-4-acetoxy-5-propyl-7-chlorobenzofuran.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH2:12]([N:18]=[C:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>>[CH2:12]([NH:18][C:19]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example I, compound 6x (91% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and n-hexyl isocyanate as a white solid. IR(CHCl3) 3298, 1713, 1539 cm−1; 1H-NMR (CDCl3) δ0.89 (t, J=6.8 Hz, 3H), 1.28-1.43 (m, 6H), 1.60-1.68 (m, 2H), 3.40-3.46 (m, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.58 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 8.77 (s, 1H); ESIMS m/e 313 and 315 (M++1, 35Cl and 37Cl).
Reaction SMILES: O=[S:2]1(=[O:29])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([O:18]CC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:13]=[CH:14][C:3]1=2.O=S1C2C=CC=CC=2C2C=C(NC(OCC3C=CC([N+]([O-])=O)=CC=3)=O)C=CC1=2.[CH3:58][NH:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=1>CCOC(C)=O>[O:29]=[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:59]([CH2:60][CH2:61][C:62]3[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=3)[CH3:58])=[O:18])[CH:13]=[CH:14][C:3]1=2
Reactant: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CNCCc1ccncc1
Agent: O=C(Nc1ccc2c(c1)-c1ccccc1S2=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: CN(CCc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5,5-Dioxo-2-(4-nitrobenzoxycarbonylamino)dibenzothiophene contaminated with 5-oxo-2-(4-nitrobenzoxycarbonylamino)dibenzothiophene (Examples 24 and 25; 396 mg, 1.0 mmol) was suspended in EtOAc (10 ml) and 4-[2-(methylamino)ethyl]pyridine (272 mg, 2.0 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 16 hours then further EtOAc (100 ml) was added and the solution was washed with 1 M sodium hydroxide (2×25 ml), water (2×25 ml) and brine (25 ml), dried and evaporated in vacuo. The resulting mixture was separated by preparative HPLC (Dynamax C-18 60A column eluted with 20-90% acetonitrile in water plus 0.1% trifluoroacetic acid). Two products were obtained:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([OH:24])([CH3:23])[CH3:22])=[CH:17][C:16]=4[Cl:25])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:26]([OH:29])[CH2:27][CH3:28])=[CH:4][CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>N1C=CC=CC=1>[C:30]([O:29][CH:26]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([OH:24])([CH3:23])[CH3:22])=[CH:17][C:16]=4[Cl:25])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:27][CH3:28])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)(C)O)cc1Cl
Solvent: c1ccncc1
Product: CCC(OC(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)(C)O)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of 1-{9-chloro-1-[2-chloro-4-(1-hydroxy-1-methylethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}propan-1-ol (78.3 mg, 0.180 mmol) in pyridine (0.5 mL) was added acetic anhydride (0.2 mL) at 0° C. The reaction mixture was stirred at room temperature for 4 hrs. The mixture was concentrated. The residue was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The residue was recrystallized from ethanol/n-hexane to give the title compound as a colorless powder (47.4 mg, 0.0995 mmol, 55%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([O:11][CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[C:4]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:10]2[C:9]([O:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[C:4]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:3]1
Reactant: Cn1cc(-c2ccc(S(C)(=O)=O)cc2)c2ncnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2ccc(S(C)(=O)=O)cc2)c2ncnc(OC3CCNCC3)c21
Reaction time: 1 h

Procedure:
To tert-butyl 4-(5-methyl-7-(4-methanesulfonyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate obtained in Example 25, dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were added, and stirred for 1 hour. After completion of the reaction, the reaction was terminated with saturated sodium bicarbonate, and dichloromethane layer was extracted and washed with a saline solution. Subsequently, the washed layer was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29](F)[CH:28]=2)[N:3]=1.CCO.CCN(C(C)C)C(C)C.[NH2:48][NH2:49]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:27]2[CH:28]=[C:29]3[C:30]([C:33]([NH2:34])=[N:48][NH:49]3)=[CH:31][CH:32]=2)[N:3]=1
Reactant: NN
Reactant: COc1cccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1cccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Into a sealable tube, (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-N-{[3-(methyloxy)phenyl]methyl}-3-piperidinecarboxamide (186 mg, 0.392 mmol), EtOH (5 mL), Hunig's base (0.068 ml, 0.392 mmol), and hydrazine anhydrous (0.074 mL, 2.35 mmol) were added, and the yellow suspension mixture was heated overnight at 110° C. in an oil bath. When the temperature of the reaction reached to 100° C., the solid in the mixture was all dissolved. After overnight, there was a yellow solution as well as a little amount of black colored solid formed. LCMS showed mainly product. CH3OH (5 mL) was added to the solution. The black solid was filtered from the yellow solution. Water (20 mL) was added to the yellow solution, and a solid was formed. The solid was filtered, washed by water, and dried in vacuum. The solid was recrystallized from CH3CN, and the solid was filtered, washed by CH3CN, and dried in vacuum to afford the title compound (31 mg) as a light yellow solid. LC-MS (ES) m/z=487 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.16 (d, J=6.8 Hz, 3H), 1.58-1.71 (m, 2H), 1.76 (m, 1H), 1.86 (m, 1H), 2.36 (m, 1H), 3.75 (s, 3H), 4.19 (m, 1H), 4.23 (m, 1H), 4.33 (m, 1H), 4.37 (m, 1H), 5.38 (s, 2H), 6.08 (s, 2H), 6.59 (s, 1H), 6.81-6.91 (m, 3H), 7.26 (m, 1H), 7.52-7.63 (m, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.94 (s, 1H), 8.48 (m, 1H), 11.50 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14]>>[C:12]([N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)(=[O:15])[CH:13]=[CH2:14]
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N(C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-methylamino-nitrobenzene and acrylic acid chloride
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].I[CH:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][CH:12]([O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1)[CH3:14]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A mixture of 3-nitrophenol (20 g; 144 mmol), 2-iodopropane (21.45 m 36.6 g; 216 mmol) and potassium carbonate (23.8 g; 172 mmol) in dimethylformamide (100 ml) was stirred at 50° for 2 h and then the temperature was increased to 70° for a further 2 h. More 2-iodopropane (7.15 ml; 72 mmol) was added and stirring at 70° continued for a further 1.5 h whereupon the mixture was poured into water (400 ml) and extracted with ethyl acetate (2×400 ml). The combined organic extracts were washed with sodium hydroxide (300 ml), then saturated brine (300 ml), dried and evaporated. The residue was chromatographed on silica (675 g) using petroleum ether (40°-60°)-ethyl acetate (10:1) as eluant to give the title compound (Intermediate 43; 22.37 g; 86%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.[CH2:9]([S:11][C:12]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=1)=[O:15])[CH3:10].C(=O)(O)[O-].[Na+].[CH3:40][C:41](C)=O>CN(C=O)C>[CH2:40]([N:16]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=1)[C:14](=[O:15])[C:13]1[CH:27]=[CH:28][C:29]([C:31]([F:34])([F:32])[F:33])=[CH:30][C:12]=1[S:11][CH2:9][CH3:10])[CH3:41]
Reactant: CC(C)=O
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCSc1cc(C(F)(F)F)ccc1C(=O)N(CC)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.21 g of potassium carbonate and 0.78 g of methyl iodide were added to a mixture of 0.39 g of 2-ethylsulfanyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide and 3 mL of acetone, and the mixture was stirred at room temperature for 1 hour. 3 mL of DMF was added to the reaction mixture, and the mixture was stirred at 60° C. for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.31 g of N-ethyl-2-ethylsulfanyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 4).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N-:21]=[N+]=[N-].[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[NH:21][CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1CN(Cc2ccccc2)CCC(=O)N1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
1-Benzyl-3-methyl-piperidin-4-one (5.00 g, 24.6 mmol) was dissolved in CHCl3 (50 mL), the reaction mixture was cooled to 0° C. and conc H2SO4 (12 mL) was added dropwise. NaN3 (3.20 g, 49.2 mmol) was added portionwise over 10 min and the reaction mixture was stirred at room temperature for 18 h and at 50° C. for 2 h. Iced water (120 mL) was added and the reaction mixture was neutralized with NaOH, extracted with DCM (2×50 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (4.86 g, 91%) as an off-white solid. LCMS (ES+): 219.3 [MH]+.