Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)C.[CH3:9][C:10]1[C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:11]=1.[N:25]1([NH2:34])[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[CH:27]=[CH:26]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:25]1([NH:34][C:16]([C:15]2[C:10]([CH3:9])=[N:11][C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[N:13][CH:14]=2)=[O:18])[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[CH:27]=[CH:26]1
Reactant: Nn1ccc2cccnc21
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2cccnc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
Diethyl-iso-propylamine (1.13 mmol) is added a solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (0.75 mmol), pyrrolo[2,3-b]pyridine-1-ylamine (0.75 mmol) and TBTU (0.9 mmol) in anhydrous DMF (7 mL) at rt, and the reaction mixture is stirred at 80° C. overnight. The reaction mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with saturated aqueous Na2CO3 and water, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 10% CH3CN in DCM to give a crude product. The crude product is crystallized from EtOAc to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid pyrrol[2,3-b]pyridine-1-ylamide (95 mg, 38%) as a solid. MS: 331 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.89 (s, 3H), 6.65 (d, H), 7.23 (m, H), 7.48-7.66 (m, 2H), 8.01-8.15 (m, 2H), 8.29 (m, H), 8.64 (d, H), 8.77 (d, H), 9.33 (s, 2H).
Reaction SMILES: C(O[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][S:13](=[O:16])[CH2:12][CH2:11]2)[C:7]([N+:17]([O-:19])=[O:18])=[C:6]([O:20][CH2:21][CH3:22])[N:5]=1)C.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH2:21]([O:20][C:6]1[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][S:13](=[O:16])[CH2:14][CH2:15]2)[C:7]=1[N+:17]([O-:19])=[O:18])[CH3:22]
Reactant: CCOc1nc(OCC)c([N+](=O)[O-])c(N2CCS(=O)CC2)n1
Reactant: C1CNCCN1
Product: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
2 gm (6 millimols) of 2,6-di-ethoxy-5-nitro-4-(1-oxido-thiomorpholino)-pyrimidine (m.p. 130°-132°C) were heated together with 8.6 gm (100 millimols) of piperazine at 125°C for 4 hours. The reaction mixture was then poured over ice, and the crystals formed thereby were suction-filtered off and recrystallized from ethanol. Yield: 0.53 gm (23.6% of theory); m.p. 221°-222°C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH2:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[NH:37][C:38]([NH2:40])=[S:39])[CH3:29]>>[CH2:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[NH:37][C:38]([NH:40][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:39])[CH3:29]
Reactant: CCc1cccc(C)c1NC(N)=S
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: CCc1cccc(C)c1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-ethyl-6-methylphenyl)thiourea (CA39) isolated as a white solid (0.137 g, 45%): 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 10.13 (s, 1H), 9.42 (s, 1H), 8.16-8.05 (m, 2H), 8.05-7.96 (m, 2H), 7.62 (ddd, J=7.9, 2.0, 1.0 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt, J=7.7, 1.4 Hz, 1H), 7.21-7.12 (m, 1H), 7.13-7.05 (m, 2H), 7.00 (t, J=5.7 Hz, 1H), 3.47 (q, J=6.7 Hz, 2H), 2.90 (t, J=6.9 Hz, 2H), 2.47 (dd, J=7.6, 2.9 Hz, 2H), 2.14 (s, 3H), 1.14-1.08 (m, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 569 ([M+H]+), 567 ([M−H]−).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25](Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CO>[CH3:25][N:13]([C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1
Reactant: Oc1ccc(CCCCN[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCCc1ccc(O)cc1)[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of trans-4-[4-(4-phenylcyclohexylamino)-butyl]phenol (370 mg, 1.1 mmol) in a mixture of MeOH (5 mL) H2O (0.5 mL), and CH2Cl2 (5 mL) was added ρformaldehyde (170 mg, 5.7 mmol). After stirring for 10 minutes, NaBH(OAc)3 (300 mg, 1.4 mmol) was added, and the reaction mixture was stirred for 12 hours. Solid NaOH was added to give a clear solution, which was then concentrated under reduced pressure. Purification by flash chromatography (silica, 89:10:1 CH2Cl2:MeOH:NH4OH) and formation of the HCl salt gave (b) trans-4-{4-[methyl-(4-phenylcyclohexyl)amino]butyl}-phenol (230 mg, 56%), as a white solid: mp 234-236° C.; IR (KBr): 2942, 1613, 1515 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 9.96 (br s, 1H), 9.13 (s, 1H), 7.31-7.18 (m, 5H), 7.00 (d, J=8.5 Hz, 2H), 6.68(d, J=8.5 Hz, 2H), 3.33-3.23 (m, 1H), 3.17-3.09 (m, 1H), 3.02-2.95 (m, 1H), 2.67(d, J=5 Hz, 3H), 2.55-2.49 (m, 3H), 2.16-2.06 (m, 2H), 1.95-1.89 (m, 2H), 1.72-1.50 (m, 8H); CI—MS (methane) (m/z): 338 [M+H]+; HPLC: method A, 6.38 minutes (>99%); method B, 11.28 minutes (>99%); Anal. Calcd for C23H31NO.HCl: C, 73.87; H, 8.62; N, 3.75. Found: C, 73.61; H, 8.55; N, 3.66.
Reaction SMILES: N[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[I:17]I.N(OCCCCC)=O>C(Cl)(Cl)Cl>[I:17][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1snc(-c2ccccc2)c1N
Reactant: II
Agent: CCCCCON=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1snc(-c2ccccc2)c1I
Temperature: 25 °C
Yield: 40.7 %

Procedure:
To a solution of methyl 4-amino-3-phenylisothiazole-5-carboxylate (500 mg, 2.134 mmol) in chloroform (15 mL) was added iodine (287 mg, 11.31 mmol) and amyl nitrite (0.430 mL, 3.20 mmol). The resulting mixture was heated at reflux for 30 min., cooled to room temperature, washed with aqueous sodium thiosulfate and water. The organic layer was dried over Na2SO4. Removal of the solvent in vacuo and crystallization from ethanol yielded methyl 4-iodo-3-phenylisothiazole-5-carboxylate (300 mg, 0.869 mmol, 40.7% yield) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:13]#[C:14][C:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH:16]=2)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C:40]([N:42]=[C:43]=[O:44])=[O:41])=[CH:35][CH:34]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C(Cl)Cl>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:43]([NH:42][C:40](=[O:41])[CH2:39][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[O:44])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:13]#[C:14][C:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:17][CH:16]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc(N)cc2F)CC1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC=C(C#Cc2cnccc2Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of tert-butyl 4-(2-(4-(4-amino-2-fluorophenoxy)pyridin-3-yl)ethynyl)cyclohex-3-enylcarbamate (50 mg, 0.12 mmol) in dry CH2Cl2 (2 mL) was treated with a 0.3 M solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.8 mL, 0.24 mmol) and the mixture stirred at rt for 1 h. The solvents were evaporated under vacuum and the residue purified by flash chromatography on silica gel eluting with 10-60% EtOAc/hexanes to give the title compound (50 mg, 69%) as a white solid. 1H NMR (DMSO-d6) δ 11.03 (s, 1H), 10.57 (s, 1H), 8.57 (s, 1H), 8.36 (d, 1H, J=5.7 Hz), 7.78 (dd, 1H, J=1.8, 13.1 Hz), 7.41-7.29 (m, 3H), 7.16 (dd, 3H, J=8.6, 8.6 Hz), 6.85 (d, 1H, J=8.3 Hz), 6.70 (d, 1H, J=5.7 Hz), 6.13-6.08 (m, 1H), 3.73 (s, 2H), 3.51-3.41 (m, 1H), 2.38-2.27 (m, 1H), 2.27-2.20 (m, 2H), 1.82-1.72 (m, 1H), 1.54-1.28 (m, 2H), 1.37 (s, 9H); ESI MS): m/z 603.24 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:17]([N:24]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[C:29](Cl)[N:28]=[CH:27][N:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCN(CC)CC>O1CCOCC1>[CH2:35]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:25]1[N:26]=[CH:27][N:28]=[C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:6][CH:7]=2)[C:30]=1[N+:31]([O-:33])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1N(Cc1ccccc1)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)c1ccc(Nc2ncnc(N(Cc3ccccc3)Cc3ccccc3)c2[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a solution of tert-butyl 4-aminophenyl(methyl)carbamate (36) (7 g, 31.5 mmol) and N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (11.2 g, 31.5 mmol) in dioxane (100 mL) was added Et3N (8 mL) and the reaction mixture was stirred at 60° C. overnight. The mixture was cooled to room temperature, the solvent was evaporated before water (200 mL) and EA (100 mL) was introduced. The organic layer was separated and extracted with EA (60 mL×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by column chromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether) to give tert-butyl 4-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl(methyl)carbamate (37) 9 g as yellow solid (yield 53%). LC-MS (ESI): m/z (M+1) 541.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:36]([N:8]1[C:9](=[O:26])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]1[CH3:27])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, (bromomethyl)benzene (0.67 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.64 g, 51%).
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[OH:4].[C:22]1(=O)[CH2:26][CH2:25][CH2:24][CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:21][C:17]1[CH:16]=[C:15]([CH:2]([NH:1][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[OH:4])[CH:20]=[CH:19][N:18]=1
Reactant: NC(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: OC(c1cccc(C(F)(F)F)c1)C(NC1CCCC1)c1ccnc(F)c1
Yield: 90.5 %

Procedure:
The 2 -amino-2-(2-fluoro-pyridin-4-yl)- 1 -(3-trifluoromethyl-phenyl)-ethanol (5) (1.0 g, 3.3 mmol), cyclopentanone (0.42 g, 5.0 mmol), and Na(OAc)3BH (1.4 g, 6.7 mmol) in 1,2 dichloroethane (20 mL) were stirred under argon at RT for 15 hrs. The resulting mixture was treated with sat. aqueous NaHCO3 (50 mL), extracted with ethyl acetate (3×75 mL), dried (sodium sulfate), and concentrated. The resulting residue was purified by silica gel chromatography using 50% ethyl acetate in methylene chloride to give the title product (1.1 g, 92%). 1H NMR (300 MHz, CDCl3) d 8.05 (d, J=4.9 Hz, 1 H, Pyr), 7.51 (d, J=7.9 Hz, 1 H, Ar), 7.36 (t, J=7.8 Hz, 1 H, Ar), 7.32 (s, 1 H, Ar), 7.22 (d, J=7.9 Hz, 1 H, Ar), 6.81 (d, J=4.9 Hz, 1 H, Pyr), 6.64 (s, 1 H, Pyr), 5.00 (d, J=4.6 Hz, 1 H, PhCHOH), 4.01 (d, J=4.9 Hz, 1 H, CHCHNH), 2.99 (quin, J=3.0 Hz, 1 H, CH2CHCH2), 1.85-1.25 (m, 8 H, CH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[H-].[Na+].[Cl:15][C:16]1[N:17]=[N:18][CH:19]=[C:20](Cl)[CH:21]=1>CN(C)C=O>[Cl:15][C:16]1[N:17]=[N:18][CH:19]=[C:20]([O:12][C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)[CH:21]=1
Reactant: Clc1cnnc(Cl)c1
Reactant: Oc1cc(F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(Oc2cnnc(Cl)c2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-fluoro-5-(trifluoromethyl)phenol (1.6 mmol) in 4 mL of N,N-Dimethyl formamide at 0 degree, is added Sodium hydride (100 mg) and the reaction mixture is allowed to stirred at 0 degree for 20 minutes. 3,5-dichloropyridazine (1.6 mmol) is added and the reaction mixture is warmed to room temperature. The reaction mixture is stirred at room temperature until formation of the desired compound. The reaction mixture is quenched with water and extracted with Ethyl acetate. The combined Ethyl acetate layers are dried over Sodium Sulfate and solvent is removed under reduced pressure. The residue can be purified by Prep-HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]([F:31])([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:30])[F:31])=[CH:25][CH:24]=1)(=[O:28])=[O:27])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)-phenyl-methanone and 4-Trifluoromethoxy-benzenesulfonyl chloride. 1H NMR (CDCl3): δ 7.06 (d, J=8.0 Hz, 2H), 7.36 (m, 3H), 7.40-7.44 (m, 2H), 7.49 & 7.62 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H), 9.81 (s, 1H). MS: m/z 456.0 (M++1).
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)Cl.C1(C)C=CC=CC=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH2:1]([O:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:3]1[O:5][CH2:4]1
Reactant: Oc1ccccc1
Reactant: ClC[C@@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(OC[C@H]2CO2)cc1
Reaction time: 50 h
Yield: 68.7 %

Procedure:
To a reaction vessel were added (S)-epichlorohydrin (99% ee, 2.64 g, 29 mmol), toluene (6 ml) and water (6 ml), and the mixture was cooled with ice. After adding phenol (1.78 g, 19 mmol), thereto 24% aqueous NaOH solution (4.75 g, 29 mmol) was dropped under stirring over a ten minute period. The mixture was stirred for 30 minutes under ice-cooling and then for 50 hours at room temperature. The aqueous layer was removed and the organic layer was neutralized with 5% HCl and washed with water twice. The solvent was removed to give objective crude (R)-glycidylphenyl ether (1.96 g, yield 69%, optical purity 98% ee) as an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:23][CH2:24][C:25](=O)[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)(=[O:22])[CH3:21].C[Si]([N:44]=[N+:45]=[N-:46])(C)C>C1COCC1.CCOC(C)=O>[C:20]([O:23][CH2:24][C:25]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([F:38])([F:37])([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:46]=[N:45][N:44]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)OCC(=O)Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nnnn1-c1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Triphenylphosphine (16.2 g, 61.9 mmol) and diisopropylazodicorboxylate (12.5 g, 61.8 mmol) were added to a solution of 2-oxo-2-{[4-(pentafluoro-λ6-sulfanyl)phenyl]amino}ethyl acetate (Intermediate 42, 8.50 g, 26.2 mmol) in THF (100 mL) at 0° C. and the mixture was stirred for 30 min. Trimethylsilyl azide (7.11 g, 61.7 mmol) was added dropwise at room temperature and the mixture was heated to reflux for 4 hr. The reaction mixture was diluted with EtOAc and washed with ice-water and brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product (5.32 g). This was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:25])[N:14]([CH3:24])[N:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]=1[S:18][CH3:19])[CH3:2].C(=O)([O-])[OH:27].[Na+].ClC1C=C(C=CC=1)C(O)=O.S([O-])([O-])=O.[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:25])[N:14]([CH3:24])[N:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:17]=1[S:18]([CH3:19])=[O:27])[CH3:2]
Reactant: O=C([O-])O
Reactant: CCc1cc(C)cc(CC)c1-c1c(SC)c(C(F)(F)F)nn(C)c1=O
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(S(C)=O)c(C(F)(F)F)nn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a 50 ml volume three-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfanyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-46)-(1)-39) (0.51 g) and chloroform (12.5 ml) were added at room temperature. Sodium hydrogen carbonate (0.46 g) and meta-chlorobenzoic acid (0.48 g) was added and the resulting mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was poured into water (20 ml), added sodium sulfite (0.3 g), and extracted with t-butyl methyl ether (40 ml) 2 times. Then, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (hexane: ethyl acetate=3:1 to hexane: ethyl acetate=1:1) to give 0.461 g of 4-(2,6-diethyl-4-methylphenyl)-2-methyl-5-methylsulfinyl-6-trifluoromethyl-2,3-dihydro-3-pyridazinone ((2-49)-(1)-39).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.C1([NH3+])CCCCC1.[C:44]1([S-:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[P:51](=[S:54])([O-])[O-:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1([NH3+])CCCCC1.C1([NH3+])CCCCC1.O>N1C=CC=CC=1>[C:44]1([SH:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[P:51]([O:13][CH2:12][C@H:11]2[O:14][C@@H:7]([N:6]3[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]3=[O:16])[CH2:8][C@@H:9]2[OH:10])(=[S:54])[OH:52])[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: [O-]P([O-])(=S)[S-](c1ccccc1)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: [NH3+]C1CCCCC1
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COP(O)(=S)[SH](c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A solution of 500 mg (2.03 mmol) of 2'-deoxy-5-fluorouridine in 5 ml of pyridine was cooled to -10° C. to 0° C. in an ice-water bath. To this solution was added dropwise a mixture of 1.00 g (3.30 mmol) of 2,4,6-triisopropylbenzenesulfonylchloride, 1.36 g (3.56 mmol) of S,S-diphenylphosphorodithioate monocyclohexylammonium and 5 ml of pyridine over the period of 10 minutes. After the completion of the dropwise addition, the mixture was stirred at room temperature overnight. To this reaction mixture was added 100 ml of water. The mixture was extracted with 10 ml of chloroform repeatedly three times. The extract was washed with an aqueous solution of dilute hydrochloric acid and water in order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure The obtained residue was subjected to silica gel column chromatography with the use of a mixture of chloroform and methanol (9:1 v/v) as the eluent to give 599 mg of 2'-deoxy-5-fluorouridine 5'-(S,S-diphenylphosphorodithioate) in a glassy form (Yield 55%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[F:31][C:32]([F:85])([F:84])[C:33]1[CH:34]=[C:35]([CH:77]=[C:78]([C:80]([F:83])([F:82])[F:81])[CH:79]=1)[C:36]([N:38]1[CH2:42][C@@:41]([CH2:50][CH2:51][N:52]2[CH2:57][CH2:56][C:55]3([C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[CH2:59][C@@H:58]3[O:66][CH2:67][C:68]([N:70]([CH3:76])[CH2:71][CH2:72][CH2:73][NH:74][CH3:75])=[O:69])[CH2:54][CH2:53]2)([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[O:40][CH2:39]1)=[O:37]>C(Cl)Cl>[F:83][C:80]([F:81])([F:82])[C:78]1[CH:77]=[C:35]([CH:34]=[C:33]([C:32]([F:31])([F:85])[F:84])[CH:79]=1)[C:36]([N:38]1[CH2:42][C@@:41]([CH2:50][CH2:51][N:52]2[CH2:53][CH2:54][C:55]3([C:65]4[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=4)[CH2:59][C@@H:58]3[O:66][CH2:67][C:68]([N:70]([CH3:76])[CH2:71][CH2:72][CH2:73][N:74]([CH3:75])[C:14]([C:12]3[S:13][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:11]=3)=[O:16])=[O:69])[CH2:56][CH2:57]2)([C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)[O:40][CH2:39]1)=[O:37]
Reactant: CNCCCN(C)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)s1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCN(C)C(=O)c1ccc(NC(=O)OC(C)(C)C)s1)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
The compound (94 mg, 0.385 mmol) obtained in Example 4c was dissolved in methylene chloride (4 mL), triethylamine (80 μL, 0.578 mmol) and pivaloyl chloride (52 μL, 0.424 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 15 minutes. The compound (300 mg, 0.385 mmol) obtained in Example 1k was added to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:2→0:100, v/v) to give the title compound (366 mg; yield, 94%) as a white solid.