Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]([C:18]1[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[C:20]([OH:21])[C:19]=1O)([CH3:17])([CH3:16])[CH3:15].[C:30](=[O:33])([O-])[O-].[K+].[K+]>CS(C)=O>[C:12]([C:6]1[CH:5]=[C:4]([CH:11]=[CH:10][C:7]=1[C:8]#[N:9])[O:21][C:20]1[CH:19]=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]=1[O:33][C:30]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]#[N:13])[CH:5]=1)#[N:13]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: CC(C)(C)c1cc(O)c(O)c(C(C)(C)C)c1
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Oc2ccc(C#N)c(C#N)c2)c(Oc2ccc(C#N)c(C#N)c2)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.4 %

Procedure:
3.60 g (0.02 moles plus 0.14 g excess) of 4-nitrophthalonitrile was dissolved in 50 ml anhydrous DMSO in a 100 ml three-necked flask fitted with a magnetic stirrer bar, nitrogen-gas inlet and thermometer. 2.22 g (0.01 moles) of 3,5-ditertiarybutylcatechol (supplied by Fluka) was added to the mixture followed by 5 g of anhydrous potassium carbonate. The mixture was stirred at room temperature for 24 hours and the mixture was precipitated into 400 ml water. The white solid product was washed three times with water and a further three times with methanol to yield 4.70 g (99.1% of theoretical yield) of a snow-white product which was further recrystallized from acetonitrile to yield 4.1 g of product with the formula: ##STR10## The melting point of this product was 247°-248° C. The elemental analysis for C30H26N4O2 was calc.: C, 75.94%; H, 5.48%; N, 11.81%; found: C, 76.07%; H, 5.51%; N, 1.86%.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17](=[O:25])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]([O:25][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccccc2)=NN1c1ncccc1Cl
Reaction time: 2 h
Yield: 94 %

Procedure:
Triethylamine (1.85 g, 18.5 mmol) was added dropwise over 1 h to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 1, Step A) (5.0 g, 18.5 mmol) and benzenesulfonyl chloride (3.27 g, 18.5 mmol) in dichloromethane (20 mL) at 0° C. The temperature was not allowed to exceed 1° C. After stirring the reaction mixture for an additional 2 h, a further portion of benzenesulfonyl chloride (0.5 g, 1.85 mmol) was added. Then a further portion of triethylamine (0.187 g, 1.85 mmol) was added dropwise to the mixture. After stirring for 0.5 h more, the mixture was partitioned between water (100 mL) and dichloromethane (100 mL). The organic layer was dried (MgSO4) and evaporated to provide the title product as an orange solid (7.18 g, 94% yield). Product recrystallized from ethyl acetate/hexanes melted at 84-85° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4]Cl.[CH3:7][N:8]=[C:9]=[O:10].[OH-].[K+]>C(Cl)Cl.C(N(CC)CC)C.C(O)C>[Cl:1][CH2:2][CH:3]1[O:6][C:9](=[O:10])[N:8]([CH3:7])[CH2:4]1
Reactant: OC(CCl)CCl
Reactant: CN=C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: CN1CC(CCl)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
A solution of 64.5 g (0.5 mole) of 1,3-dichloro-2-propanol in 200 ml of methylene chloride was treated with 28.5 g (0.5 mole) of methyl isocyanate and a few drops of triethylamine and allowed to stir at ambient temperature overnight. The solution was concentrated and the residue was dissolved in 200 ml of 95% ethanol and treated with a solution of 33.6 g (0.6 mole) of potassium hydroxide in 300 ml of 95% ethanol. The mixture was stirred at ambient temperature for 3.5 hr and then concentrated. The residue was partitioned between 250 ml of benzene and 100 ml of water. The organic layer was washed successively with 50 ml of a 2N hydrochloric acid solution and 100 ml of brine, dried over anhydrous sodium sulfate and concentrated to give 50.5 g of oil as residue. The oil was subjected to vacuum distillation to yield 36.9 g (49%) of clear oil, b.p. 131°-133° C. at 0.3 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=[CH:9][N:8]=1.O=[C:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[C:31]([O:30][C:28]([N:25]1[CH2:26][CH2:27][CH:22]([NH:14][CH2:13][C:12]2[C:7]([NH:6][CH2:5][C:4]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=3[O:2][CH3:1])=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:23][CH2:24]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1ccc(CNc2ncccc2CN)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2ncccc2CNC2CCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a stirred solution of N-(2,4-Dimethoxybenzyl)-3-(aminomethyl)pyridin-2-amine (2.04 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.41 g, 2.04 mmol) in DCE (8 ml) and AcOH (115 μL, 2.04 mmol) was added NaBH(OAc)3 (0.43 g, 2.04 mmol) and the reaction stirred at RT until judged complete by LCMS. The reaction mixture was diluted with DCM and sat. aq. Na2CO3, the layers were separated and the organic layer was dried (Na2SO3) and evaporated to dryness. Purification by column chromatography (MeOH/DCM) gave the desired product (0.64 g, 69%). LC/MS (10% to 99%): M/Z (M+H)+ (obs)=457; tR=2.19.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.CCN(CC)CC.[CH2:27]([O:34][C:35](Cl)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([O:34][C:35]([NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[CH:9][CH:8]=2)[CH2:3]1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N)C2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](NC(=O)OCc3ccccc3)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
A solution of compound 17 (4.37 g, 16.72 mmol) in THF (30 mL) was cooled to 0° C. and treated successively with Et3N (4.6 mL, 3.38 g, 33 mmol) and benzylchloroformate (2.8 mL, 3.42 g, 20 mmol). The reaction mixture was allowed to stir for 2 hrs at 0° C., quenched by adding an aqueous saturated NH4Cl solution (30 mL) and extracted with EtOAc. The extract was dried over Na2SO4, filtered and concentrated. Crude product was purified by flash chromatography using 30% EtOAc in hexanes as an eluent to provide title compound 115 (3 g, 45% yield). LRMS (ESI): (calc) 396.20 (found) 397.2 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15].[OH-].[Na+].C(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([F:1])=[CH:11]2
Reactant: O=c1cc[nH]c2cc(F)cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Fc1cnc2c(Cl)ccnc2c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione. A 150 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione (6.0 g, 41.6 mmol) and trimethyl orthoformate (41.6 mL, 41.6 mmol). This was heated to 100° C., and stirred at this temperature for 2 hours. Reaction then cooled to 30° C. and 5-fluoropyridin-3-amine (4.7 g, 41.6 mmol) added portion-wise. Reaction vessel resealed and mixture stirred at 100° C. for 3 hours. LC/MS shows completion. Reaction mixture was cooled to room temperature, diluted with hexane, filtered, and air dried to yield 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.1 g, 82% yield) as a bright yellow solid. MS [M+H]=267.2. Calc'd for Cl2H11FN2O4=266.2. 2) 7-fluoro-1,5-naphthyridin-4(1H)-one. A 500 mL round bottom flask equipped with a reflux condenser was charged with 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.0 g, 30.0 mmol) and diphenyl ether (83.5 mL). This was heated to 250° C. in heating mantle and allowed to stay at this temperature for five minutes. Cooled to room temperature, diluted with hot hexanes, and filtered to afford 7-fluoro-1,5-naphthyridin-4(1H)-one (2.2 g, 45% yield) as a crude brown solid. The title compound was used without further purification. MS [M+H]=165.2, Calc'd for C8H5FN2O=164.14. 3) 8-chloro-3-fluoro-1,5-naphthyridine. A pressure resistant vial was charged with 7-fluoro-1,5-naphthyridin-4(1H)-one (600 mg, 3.66 mmol) and POCl3 (6.8 mL, 73.1 mmol). Vessel sealed and stirred at 110° C. for 16 hrs. Reaction mixture was cooled to room temperature and poured onto ice while stirring vigorously. While keeping reaction mixture at 0° C., it was basified to pH˜8 with 6N NaOH. Product extracted with dichloromethane. Organic layer collected, dried over sodium sulfate and concentrated to afford desired material. This was passed through a silica plug in 1-5% (90:10:1 DCM/MeOH/NH4OH)/DCM to afford 8-chloro-3-fluoro-1,5-naphthyridine (430 mg, 64% yield) as a tan solid. MS [M+H]=182.9. Calc'd for C8H4ClFN2=182.58
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:15]=2)[CH2:10][CH2:9][C:8](=[CH2:11])[CH2:7][CH2:6]1)=[O:4].[CH2:33]([Zn]CC)C.ICI>C1(C)C=CC=CC=1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:5]2([C:3]([OH:2])=[O:4])[CH2:6][CH2:7][C:8]3([CH2:33][CH2:11]3)[CH2:9][CH2:10]2)=[O:32])=[CH:15][C:16]=1[O:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1
Reactant: C=C1CCC(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)(C(=O)OC)CC1
Reactant: CC[Zn]CC
Solvent: Cc1ccccc1
Solvent: ICI
Product: COc1ccc(C(=O)NC2(C(=O)O)CCC3(CC3)CC2)cc1OCCc1cccc(C)c1
Temperature: 60 °C
Yield: 3.8 %

Procedure:
The compound of step 1 of example 56 (400 mg, 0.91 mmol) was dissolved in toluene (8 ml) and diethylzinc (2.7 ml, 2.7 mmol, solution in hexane) was added. The mixture was heated to 60° C. and diiodomethane (1.10 g, 4.11 mmol) was added with stirring. This mixture was reacted at 60° C. overnight, the addition of diethyl zinc and diiodomethane was repeated and stirring continued for another night. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase was extracted with EA, the combined organic phases were washed with aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and evaporated to dryness. The obtained methyl ester was hydrolyzed in analogy to step 4 of example 1 to yield the title compound (15 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=C=O.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35][NH2:36]>>[CH3:15][O:14][N:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:19][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=2)=[O:7])[C@H:9]([C:16]([NH:36][CH2:35][C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[O:18])[CH2:10]1
Reactant: COc1cccc(N=C=O)c1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCc1cccs1
Product: CON=C1C[C@@H](C(=O)NCc2cccs2)N(C(=O)Nc2cccc(OC)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methoxybenzene, and 2-thienylmethylamine the title compound was obtained in 79% purity by LC/MS. MS(ESI+): m/z=403.2.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH2:9][C:10]1[C:14](=[CH2:15])[CH:13]=[CH:12][CH:11]=1.B(F)(F)F.CCOCC.O>C(Cl)Cl>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([CH2:15][C:14]2[C:10](=[CH2:9])[CH:11]=[CH:12][CH:13]=2)=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C=C1C=CC=C1CO
Agent: FB(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C=C1C=CC=C1Cc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 174.5 %

Procedure:
Phenol (40 mg, 0.4 mmol) was added to a solution of hydroxymethyl-fulvene (70 mg, 0.28 mmol) in dry CH2Cl2 (25 mL). The mixture was cooled to -78° C. and boron triflouride etherate (0.3 mL, 2.7 mmol) was added dropwise.. The reaction was stirred at that temperature for 1 hour and water was added to quench the reaction. The organic layer was washed with H2O, NaHCO3 and brine, and dried over MgSO4. Chromatography on silica gel with hexane-ethyl acetate yielded 90 mg (98%) of red crystals (m.p. 143°-144° C). 1H NMR δ0.59-1.43 (m, 4 H), 1.36 (s, 3 H), 1.76 (s, 3 H), 2.07 (s, 3 H), 3.95 (s, 1 H), 3.97 (d, J=7.2 Hz, 2 H), 4.83 (s, 1 H), 6.74 (d, J=8.4 Hz, 2 H), 6.91 (d, J=8.4 Hz, 2 H), 7.22 (s, 1 H). MS m/Z 322 (M+), 294 (M+-2 CH2), 279 (M+-2 CH2 -CH3), 251 (M+-2 CH2 -CH3CO), 215, 107 UV 228 nm (12×104, with inflections at 243 and 262 nm), 325 (7.1×103), 410 nm (2.6×103). The compound has the structure: ##STR16##
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:22][C:23](=O)[CH2:24][C:25]([O:27]CC)=O)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1.C(O)C.O.[NH2:35][NH2:36]>C1COCC1>[Br:1][C:2]1[C:3]([CH2:22][C:23]2[CH2:24][C:25](=[O:27])[NH:36][N:35]=2)=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)Cc1cc(Nc2nc(CCc3ccccc3)cs2)ncc1Br
Reactant: NN
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C1CC(Cc2cc(Nc3nc(CCc4ccccc4)cs3)ncc2Br)=NN1
Temperature: 45 °C
Reaction time: 4 h
Yield: 55.6 %

Procedure:
A flask was charged with ethyl 4-(5-bromo-2-(4-phenethylthiazol-2-ylamino)pyridin-4-yl)-3-oxobutanoate (0.0500 g, 0.1024 mmol) and ethanol (2 mL), and hydrazine hydrate (0.007471 mL, 0.1536 mmol) was added. The mixture was stirred at 45° C. for 4 hours. THF (2 mL) was added, and the mixture was stirred for 18 hours at 60° C. The mixture was concentrated and the residue was triturated with 50% ethyl acetate/hexane to afford the desired product (26 mg, 55.65% yield) as a white solid. 1H NMR (d6-DMSO) δ 2.83-2.96 (m, 4H), 3.87 (s, 2H), 5.27 (s, 1H), 6.59 (s, 1H), 6.94 (s, 1H), 7.17-7.29 (m, 5H), 8.38 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:25]=[CH:24][C:7]2[NH:8][C:9]([S:11]([CH2:13][C:14]3[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=3)=[O:12])=[N:10][C:6]=2[CH:5]=1.[Na].C(=O)([O-])[O-].[Na+].[Na+].[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>ClCCl>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:8]2[C:7]3[CH:24]=[CH:25][C:4]([O:3][CH:2]([F:1])[F:26])=[CH:5][C:6]=3[N:10]=[C:9]2[S:11]([CH2:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=2)=[O:12])(=[O:43])=[O:42])=[CH:37][CH:36]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH:2]([F:1])[F:26])[CH:25]=[CH:24][C:7]=3[N:8]=[C:9]2[S:11]([CH2:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][N:15]=2)=[O:12])(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3[nH]2)c1OC
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3cc(OC(F)F)ccc3n2S(=O)(=O)c2ccc(Cl)cc2)c1OC
Product: COc1ccnc(CS(=O)c2nc3ccc(OC(F)F)cc3n2S(=O)(=O)c2ccc(Cl)cc2)c1OC
Temperature: 4 °C
Reaction time: 8 h

Procedure:
5-Difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole, sodium salt sesquihydrate (432 mg, 1 mmole) was suspended in 30 ml of dichloromethane in the presence of anhydrous sodium carbonate (100 mg). 4-Chlorobenzenesulfonyl chloride (211 mg, 1 mmole) was added to the suspension and stirred at 4° C. overnight. The organic layer was separated by filtration and concentrated under reduced pressure. The residual solid was crystallized from dichloromethane-ethyl ether-heptane. 417 mg of isomer, 1-(4-chlorobenzenesulfonyl)-5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole and 1-(4-chlorobenzenesulfonyl)-6-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (5:4 ratio by NMR), was obtained. Yield 74.5% M.P. 82-83° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O[C@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc(O[C@@H]2CCOC2)cc1
Temperature: 85 °C
Yield: 35.8 %

Procedure:
A mixture of 4-bromophenol (2.1 g, 12.4 mmole), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (2.5 g, 10.3 mmole) and K2CO3 (4.3 g, 30.9 mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by ISCO (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (896 mg). MS (ESI) m/z: Found: 244.3 (M++1). Calc. 243.1 (M+).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[OH-].[K+].I[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>[Cu].O>[CH2:2]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=C(O)c1ccccc1I
Reactant: CCOc1cccc(N)c1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1cccc(Nc2ccccc2C(=O)O)c1
Reaction time: 16 h

Procedure:
m-Phenetidine (5 ml, 38.7 mmol) is added to a solution of KOH (7.385 g, 131.6 mmol), water (77 ml) and 2-iodobenzoic acid (9.6 g, 38.7 mmol). Powdered copper (77 mg, 1.22 μmol) is added and the mixture is refluxed under stirring over night (16 h).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[CH3:12]O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1F
Yield: 64 %

Procedure:
4-bromo-2-fluorobenzoic acid (30 g, 0.14 mol) was dissolved in methanol with a few drops of sulfuric acid. The reaction medium was refluxed for 20 hours. The cooled reaction mixture was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered and evaporated to give methyl 4-bromo-2-fluorobenzoate (20.7 g, yield 64%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm); 3.85 (s, 3H), 7.55-7.58 (m, 1H), 7.70-7.73 (m, 1H), 7.79-7.83 (m, 1H); LC-MS (ESI) m/z: 233 (M+1)+, 235 (M+3)+
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[NH2:22].C(N(CC)CC)C.O>CN(C=O)C>[CH3:29][O:28][C:24]1[CH:23]=[C:21]([NH:22][S:7]([C:3]2[CH:2]=[C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])[CH:20]=[C:19]([O:18][CH3:17])[C:25]=1[O:26][CH3:27]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=S(=O)(Cl)c1cccc(-c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(NS(=O)(=O)c2cccc(-c3ccccc3)c2)cc(OC)c1OC
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 65 mg of biphenyl-3-sulfonyl chloride (0.25 mmol), 44 mg of 3,4,5-trimethoxyaniline (0.24 mmol), and 0.3 mmol of triethylamine in 5 mL DMF was stirred overnight. The reaction mixture was treated with water and extracted with ethyl acetate. After a conventional workup, column chromatography (silica gel, petroleum ether/ethyl acetate) gave 88 mg compounds (4d) (91.7%). 1H NMR (500 MHz, CDCl3) δ 7.96 (t, 1H, J=1.8 Hz), 7.81-7.74 (m, 2H), 7.57-7.40 (m, 6H), 6.33 (s, 2H), 3.86 (s, 3H), 3.80 (s, 6H). MS (ESI) m/z 422.1 (M+Na)+.
Reaction SMILES: [CH2:1]([S:17]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[CH:29]=[C:28]([OH:31])[CH:27]=[CH:26]2)(=[O:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1.[N:43]([O-])=O.[Na+]>O.O1CCCC1.CO>[CH2:1]([S:17]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[C:29]([N:43]=[N:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=1)=[C:28]([OH:31])[CH:27]=[CH:26]2)(=[O:18])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: COc1ccc(N)cc1
Reactant: O=N[O-]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc2ccc(O)c(N=Nc3ccc(OC)cc3)c12
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a stirred mixture of 89.5 g (0.20 mole) 8-hexadecanesulfonamido-2-naphthol, 37 g sodium hydroxide, 1800 ml methanol, and 1200 ml tetrahydrofuran at 0° was added a diazonium salt solution prepared from 24.6 g (0.20 mole) p-anisidine dissolved in 360 ml water containing 60 ml concentrated hydrochloric acid and a solution of 13.8 g (0.20 mole) sodium nitrite in 240 ml water. The addition required 15 min., and the mixture was stirred at 0° for 0.5 hr. and at room temperature for 0.5 hr. longer before being poured into 6 liters of water containing 250 ml acetic acid. There was obtained 107.7 g of product.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1=[O:16].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][C:21]=1[S:31]([NH2:34])(=[O:33])=[O:32]>O1CCOCC1>[OH:10][C:9]1[CH:8]=[CH:7][N:6]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:5](=[O:16])[C:4]=1[C:3]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:22][C:21]=2[S:31](=[O:33])(=[O:32])[N:34]=1
Reactant: CSC(SC)=C1C(=O)C=CN(CCC(C)C)C1=O
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: C1COCCO1
Product: CC(C)CCn1ccc(O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c1=O
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A solution of the product of Example 457C (0.195 g, 0.68 mmol) in dioxane (10 mL) was reacted with the product of Example 425D (0.17 g, 0.64 mmol) at 115° C. for 1 hour. After cooling to about 25° C., the solid precipitate was collected by filtration and dried to provide the title compound (0.258 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=6.25 Hz, 6 H) 1.58 (m, 3 H) 3.08 (s, 3 H) 3.99 (m, 2 H) 6.33 (d, J=6.62 Hz, 1 H) 7.57 (m, 2 H) 7.67 (d, J=8.82 Hz, 1 H) 8.07 (d, J=6.62 Hz, 1 H) 10.25 (s, 1 H) 13.84 (s, 1 H) 14.28 (s, 1 H). MS (ESI−) m/z 453 (M−H)−.