Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[Na+].C(O)(=O)C.IC1C=CC(C2N=[C:19]([C@H:23]([N:25](C)[C:26](=[O:35])[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)C)N(C)C=2)=CC=1.[C:37]([O-:40])([OH:39])=O.[Na+]>O1CCOCC1>[NH:25]([C:26]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:35])[C@@H:23]([C:37]([OH:40])=[O:39])[CH3:19]
Reactant: C[C@H](c1nc(-c2ccc(I)cc2)cn1C)N(C)C(=O)OCc1ccccc1
Reactant: O=C([O-])O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 65 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C. until TLC show no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution, and extracted with ethyl acetate. The organic solution was dried over Na2SO4 and concentrated. Purification with flash column chromatography (EtOAc:Hexs 1:1) gave product 3 (9.11 g, 79%) as white solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:29]=[CH:28][N:13]([C@@H:14]2[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12](=[O:30])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[C:34]([O:53][CH3:54])=[C:35]([CH:50]=[CH:51][CH:52]=1)[C:36](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:1]([NH:9][C:10]1[CH:29]=[CH:28][N:13]([C@@H:14]2[O:27][C@H:24]([CH2:25][O:26][C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:35]3[CH:50]=[CH:51][CH:52]=[C:33]([O:32][CH3:31])[C:34]=3[O:53][CH3:54])[C@@H:22]([OH:23])[C@H:15]2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:12](=[O:30])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C(Cl)(c2ccccc2)c2ccccc2)c1OC
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2cccc(OC)c2OC)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Yield: 69.5 %

Procedure:
N4-Benzoyl-2'-O-pentylcytidine (3.0 g, 0.007 mol) was treated with dimethoxytrityl chloride (2.7 g, 1.1 eq) as per the procedure of Example 72 to give 3.5 g of pure product. Anal. Calcd. for C42H53N3O8. 1/2H2O: C, 69.21; H, 6.36; N, 5.76. Found: C, 69.51; H, 6.30; N, 5.71.
Reaction SMILES: [CH3:1][C:2]([C:15]1[C:16]([CH3:24])=[N:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)(C(OCC)=O)[C:3]([O:5][C:6](C)(C)[CH3:7])=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:24][C:16]1[C:15]([CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:20][CH:19]=[C:18]([N+:21]([O-:23])=[O:22])[N:17]=1
Reactant: CCOC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)c1ccc([N+](=O)[O-])nc1C
Temperature: 25 °C

Procedure:
A mixture of tert-butyl ethyl methyl(2-methyl-6-nitropyridin-3-yl)propanedioate (2.8 g, 8 mmol) in a mixed solution of TFA/DCM (30 mL/30 mL) was stirred over night at room temperature. The mixture was concentrated under reduce pressure to give ethyl 2-(2-methyl-6-nitropyridin-3-yl)propanoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[N:10].C(OC(=O)C)(=O)C>>[OH:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([C:9]#[N:10])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(O)cn1
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1ccc(CCc2ccc(O)cn2)cc1
Yield: 20.8 %

Procedure:
A mixed solution of 3-hydroxy-6-methylpyridine (3.3 g, 0.03 mol), 4-cyanobenzaldehyde (3.9 g, 0.03 mol) and acetic anhydride (6.1 g, 0.06 mol) was heated under reflux for 25 hours, followed by cooling the reaction mixture, thereafter adding toluene (30 cc), separating the resulting solids by filtration, washing the solids with toluene till the toluene filtrate became colorless, adding methanol (20 cc) and conc. hydrochloric acid (20 cc) to the solids, heating the mixture for 3 hours, cooling, neutralizing with aqueous ammonia, filtering, dissolving the resulting precipitate in ethanol (50 cc), adding Pd-C catalyst (0.3 g), and subjecting the mixture to catalytic reduction at room temperature and the atmospheric pressure. After completion of the reaction, the catalyst was filtered off, followed by distilling off the solvent under reduced pressure and recrystallizing the remaining solids from a mixed solvent of methanol/water (2:1) to obtain 3-hydroxy-6-[β-(4-cyanophenyl)ethyl]pyridine (1.4 g). To this compound were then added toluene (50 cc) and pyridine (3 cc), followed by adding 4-pentoxybenzoyl chloride (1.4 g) to the resulting solution, allowing the mixture to stand overnight, washing with water, then with 2N-hydrochloric acid, further with 2N-NaOH aqueous solution and finally with water till the washing water became neutral, distilling off toluene under reduced pressure and recrystallizing the remaining solids from ethanol to obtain the objective 6-[β-4-(cyanopheny)ethyl]-3-(4-pentyloxybenzoyl)pyridine (0.7 g) having as its phase transition points, a crystalline-nematic point (C-N point) of 107.8°-108.7° C. and a nematic-clearing point (N-I point) of 156.5°-156.8° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)=[C:17]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[N:16]=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:20]=3)=[C:17]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Nc3ccccc3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2ncn(C3CCNCC3)c2-c2ccnc(Nc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(1-t-butoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-anilino-4-pyridinyl)imidazole (175 mg, 0.34 mmol) was added a cooled solution of TFA (12 mL) at -10° C. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 0.5 h. The solvent was evaporated under reduced pressure and the residue was dissoved in H2O (10 mL) to which 3N HCl (0.5 mL) was added. The acidic solution was extracted twice with EtOAc and made basic with 50% NaOH and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a white solid; 0.70 g (50%): ESMS m/z=414 (M+ +H)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:14]([NH:15][NH2:16])=[CH:13][C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:4][CH:3]=1.[CH3:22][N:23]=[C:24]=S.CO>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:14]3[NH:15][N:16]=[C:22]([NH:23][CH3:24])[C:13]=3[C:11](=[O:12])[N:10]([CH2:17][CH2:18][CH3:19])[C:8]2=[O:9])=[CH:20][CH:21]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccc(F)cc2)c1=O
Reactant: CN=C=S
Solvent: CN(C)C=O
Solvent: CO
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccc(F)cc2)c1=O
Yield: 36 %

Procedure:
A solution of 1-(4-fluorobenzyl)-6-hydrazino-3-propyluracil (1.5 g, 5.1 mM) and methyl isothiocyanate (1.2 ml, 17 mM) in DMF (20 ml) was heated at 120° C. for 24 hours. To the solution was added 50% methanol (10 ml) and the mixture was cooled to give crystals. Recrystallization from DMF/methanol/water gave pale yellow crystals (0.62 g, 36%), m.p. 262°-265° C.
Reaction SMILES: C(S[C:4](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])C.[C:15]([NH:23][NH2:24])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[C:16]1([C:15]2[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]([CH2:5][CH2:6][CH3:7])=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCC(=Nc1ccccc1)SCC
Reactant: NNC(=O)c1ccccc1
Solvent: CCCCO
Product: CCCc1nnc(-c2ccccc2)n1-c1ccccc1
Temperature: 130 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
Next, 5.40 g of N-[1-(ethylsulfanyl)butylidene]aniline, 3.19 g of benzoylhydrazine, and 30 mL of 1-butanol were put in a 100 mL three-neck flask and heated and stirred at 130° C. for 12 hours. After the stirring, butanol was distilled off under a reduced pressure to give a brown solid. This solid was washed with ethyl acetate, and subjected to suction filtration to give a solid. The given solid was purified by silica gel column chromatography. As developing solvents, first, hexane:ethyl acetate=1:9 was used, and then ethyl acetate was used. The resulting fraction was concentrated to give a solid. This solid was recrystallized from a mixed solvent of hexane and ethyl acetate, so that 3,4-diphenyl-5-propyl-4H-1,2,4-triazole (abbreviation: HPrptz) was prepared (a white solid, yield: 28%). The synthetic scheme of Step 4 is shown by (d-7).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:18][C:19](=[O:22])[O:20][CH3:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: COC(=O)Nc1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1

Procedure:
Methyl {3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}carbamate (2.53 g, 8.18 mmol) was dissolved in 50 mL of EtOAc containing a catalytic amount of 10% Pd/C. The solution was shaken under H2 atmosphere (40 psi) using a Parr hydrogenation apparatus overnight at rt. The solution was filtered through Celite and the solvent was evaporated. Yield: 2.29 g (99%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.40 (m, 2 H), 1.70-1.74 (m, 1 H), 1.74-1.77 (m, 1 H), 1.81-1.92 (m, 1 H), 2.99 (d, J=6.64 Hz, 2 H), 3.34 (br.s, 2 H), 3.41 (m, 2 H), 3.74 (s, 3 H), 3.99 (d, J=3.51 Hz, 1 H), 4.02 (d, J=3.51 Hz, 1 H), 6.38 (br.s, 1 H), 6.55-6.60 (m, 1 H), 6.62-6.68 (m, 1 H), 6.95 (br.s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[C:10](=[O:23])[C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([N:24]2[CH:28]=[N:27][CH:26]=[N:25]2)[CH:10]([OH:23])[C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1Cl)C(=O)C(Cc1ccc(Cl)cc1)n1cncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(Oc1ccc(Cl)cc1Cl)C(O)C(Cc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 143.4 %

Procedure:
10 g (0.0228 mol) of 5(4-chlorophenyl)-2-(2,4-dichlorophenoxy)-2-methyl-4-(1,2,4-triazol-1-yl)-pentan-3-one, compound 2 of Example 2 hereinabove, were dissolved in 100 ml of methanol, 1 g of sodium borohydride was added in portions at 0° to 5° C., the mixture was subsequently stirred at room temperature for 15 hours, and 50 ml of 2N hydrochloric acid were added. After 4 hours, the mixture was concentrated by the solvent being distilled off in vacuo. The residue was taken up in 200 ml of methylene chloride and the organic phase was stirred with 100 ml of saturated sodium bicarbonate solution, separated off, washed twice with 100 ml of water each time, dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in 100 ml of ether, and ethereal hydrochloric acid was added. 7.8 g (81% of theory) of 5-(4-chlorophenyl)-2-(2,4-dichlorophenoxy)- 2-methyl-4-(1,2,4-triazol-1-yl)-pentan-3-ol hydrochloride of melting point 46° to 50° C. were obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([CH3:18])(O)[CH:13]([CH2:19][CH3:20])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[O-]S([O-])(=O)=O.[Mg+2]>C1C=CC=CC=1>[CH2:19]([C:13]1[CH2:12][CH:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][C:14]=1[CH3:18])[CH3:20]
Reactant: CCC1CC(CCOCc2ccccc2)CCC1(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: c1ccccc1
Product: CCC1=C(C)CCC(CCOCc2ccccc2)C1

Procedure:
A mixture of 5-(2-benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution (16.6 mL, 8.28 mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol) was added via syringe and the mixture was stored at rt for 48 h. Another portion of NaOMe (8.3 mmol) and EtI (35 mmol) was added and the mixture was allowed to react until the starting material was not present (by TLC). The solution was quenched with an aqueous work-up and the resultant residue was purified by chromatography to yield 5-(2-benzyloxy-ethyl)-1-ethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (Intermediate K2, 1.87 g (86%). The keto-ester (Intermediate K2) was heated at 90° C. in 10% KOH (100 mL) for 10 h, then 6 h at rt. The mixture was cooled to 0° C. and acidified with HCl. The solution was warmed to 40° C. for 15 min. and then stored at rt for 2 h. The mixture was neutralized to pH 7 with NaOH and the organic material was recovered by extraction with chloroform. The resulting 4-(2-benzyloxy-ethyl)-2-ethyl-cyclohexanone (Intermediate K3) was isolated by standard work-up and used without further purification (88%). Intermediate K3 (1.36 g, 5.24 mmol) was dissolved in THF (75 mL) and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0° C. and reacted at rt for 1 h. The organic material was isolated from an aqueous, acidic work-up and purified by chromatography to give 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol 1.36 g (94%). 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol (1.39 g, 5.04 mmol) and TsOH—H2O (0.48 g, 2.52 mmol) were heated to reflux in benzene (˜100 mL) for 18 h in the presence of MgSO4 (˜250 mg). After an aqueous work-up and chromatographic purification, the product [2-(3-ethyl-4-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate K4) was isolated as a pale yellow oil 0.912 g (71%).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][C@@H:30]([C:32]4[CH:43]=[CH:42][C:35]5[O:36][C:37]([CH3:41])([CH3:40])[O:38][CH2:39][C:34]=5[CH:33]=4)[O:29][C:28]3=[O:44])[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CCOC(C)=O.CCO.[Pt]=O>[CH:1]1([S:6]([C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][C@@H:30]([C:32]4[CH:43]=[CH:42][C:35]5[O:36][C:37]([CH3:40])([CH3:41])[O:38][CH2:39][C:34]=5[CH:33]=4)[O:29][C:28]3=[O:44])[CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCC#Cc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCCCCc4cccc(S(=O)(=O)C5CCCC5)c4)C(=O)O3)ccc2O1
Yield: 92.4 %

Procedure:
A solution of (5R)-3-[6-({5-[3-(cyclopentylsulfonyl)phenyl]-4-pentyn-1-yl}oxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (215 mg) in EtOAc (10 ml) and EtOH (10 ml) was hydrogenated over platinum oxide (30 mg). When hydrogen uptake had ceased the mixture was filtered through celite and the solvent was evaporated in vacuo to give the title compound (200 mg). LCMS RT=3.83 min.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:32]=[N:33][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:35][CH:36]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.1 %

Procedure:
To a cooled and stirred solution of 3′-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.56 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.39 g, 74%). MS (ISP) 525.2 [(M+H)+]; mp 211° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH2:13][CH3:14])=[N:7][C:6]=1Cl)[CH3:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([S:12][CH2:13][CH3:14])=[N:7][C:6]=1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1cc(F)c(SCC)nc1Cl
Solvent: CCO
Product: CCOC(=O)c1cc(F)c(SCC)nc1NCc1ccc(OC)cc1
Yield: 64.2 %

Procedure:
A solution of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester (66) (53 g, 201 mmol) in anhydrous ethanol was purged with argon and added p-methoxybenzylamine (52.5 mL, 402 mmol) at room temperature. The solution was refluxed overnight under argon. The solution was cooled and the solvent was evaporated under reduced pressure. The residue was taken in dichloromethane, sonicated briefly and undissolved solids were filtered off. The filtrate washed by water, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography eluting with hexane:CH2Cl2 (1:1) to yield 47 g (64%) of 6-ethylsulfanyl-5-fluoro-2-(4-methoxy-benzylamino)-nicotinic acid ethyl ester (67) as a viscous oil which solidified to a white solids after keeping several days under vacuum at room temperature. Mp 59° C. 1H-NMR (DMSO-d6): δ 1.18 (t, J=7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 3.08 (q, J=7.2 Hz, 2H), 3.71 (s, 3H), 4.26 (q, J=7.2 Hz, 2H), 4.62 (d, J=5.6 Hz, 2H), 6.87 (m, 2H), 7.24 (m, 2H), 7.71 (d, J=10 Hz, 1H), 8.32 (m, 1H); EIMS m/z 365 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2([C:33]([O:35]C)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:23][CH:22]=1.Cl>[OH-].[K+].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][C:28]2([C:33]([OH:35])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1
Reactant: COC(=O)C1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CCCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CCCC1

Procedure:
A solution of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-(1-methoxycarbonyl-cyclopent-1-yloxy)-benzyl]-benzene (0.20 g) in aqueous potassium hydroxide solution (4 mol/l, 5 mL) and methanol (5 mL) is stirred at ambient temperature for 4 h. After neutralizing with aqueous hydrochloric acid (1 mol/l), the mixture is concentrated under reduced pressure, diluted with aqueous NaHCO3 solution and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4), the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→4:1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.[CH3:27][N:28]([CH3:33])[S:29](Cl)(=[O:31])=[O:30]>>[CH3:27][N:28]([CH3:33])[S:29](=[O:31])(=[O:30])[O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:8]2[CH:9]=[N:10][C:11]3[C:2]([NH2:1])=[N:3][C:4]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:5]=4[C:6]=3[CH:7]=2)=[C:15]([CH3:21])[CH:16]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OS(=O)(=O)N(C)C)cc3C)cc12

Procedure:
4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl dimethylsulfamate was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) following the procedure described for Example 138, but using dimethylsulfamoyl chloride. 1H NMR (Acetone-d6): δ 8.79 (s, 1H), 8.72 (s, 1H), 8.28 (d, 1H), 7.42 (s, 1H), 7.27 (d, 1H), 7.17 (s, 1H), 7.14 (t, 1H), 7.05-7.10 (d, 1H), 3.19-3.25 (m, 2H), 3.11-3.17 (m, 2H), 2.92 (s, 6H), 2.46 (s, 3H), 2.37 (s, 3H). LRMS [M+H]=451.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[CH2:23][C:24]#[N:25].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:23]([C:24]#[N:25])([C:17]2[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=2[F:15])[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
To bis(2-chloroethyl)-carbamic acid tert-butyl ester (1.0 g, 3.8 mmol) and 2,4-difluorophenyl acetonitrile (0.581 g, 3.8 mmol) in DMF (35 ml), NaH (95%) (0.258 g, 9.68 mmol) was added in one batch at 0° C. The solution was stirred for 10 minutes at room temperature. When foaming subsided, the solution was heated at 60° C. for 24 hours. It was then quenched with water at 0° C. and concentrated. The residue was extracted with ethyl acetate (25 mL) and washed three times with water (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (hexane:ethyl acetate 4:1) yielded 0.720 g (62%) of the product as a syrup.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>COCCOC>[F:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1cccc(F)c1
Yield: 72.3 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 3-fluoro-phenylboronic acid (27 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (38 mg, 73%). LC-MS m/e 405.28 (M+H+)