Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)=[O:12])[C:4]=1[CH3:22].[CH2:23]=[O:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:13]2[N:14]([CH2:23][OH:24])[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:12])[C:4]=1[CH3:22]
Reactant: C=O
Reactant: COc1c(C)cnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3ccccc3n2CO)c1C
Reaction time: 0.03 h

Procedure:
2-[[(4-Methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (3.15 g, 10 mmoles) and N,N-dimethylaminopyridine (120 mg, 1 mmol) was dissolved in methylene chloride (50 ml). A solution of formaldehyde (5M, 10 ml, 50 mmol) was added and the mixture was stirred violently for 2 minutes. The phases were separated and the methylene chloride solution was dried (sodium sulphate), filtered and evaporated to dryness. The slightly red residue was the title compound as an essentially pure oil.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1.CCOC(C)=O>O1CCOCC1>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=[S:46])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 60 °C
Yield: 127.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-carboxylate (7.58 g, 13.8 mmol) in 1,4-dioxane (130 mL) was added Lawesson's reagent (3.37 g, 8.32 mmol) and the reaction mixture was heated to about 60° C. for about 2 h then cooled to ambient temperature and concd under reduced pressure. The crude residue was dissolved with EtOAc (40 mL) and washed with saturated aqueous NaHCO3, (3×40 mL), brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford (R)-tert-butyl 3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (5.6 g, 74%, UV purity 97%): LC/MS (Table 1, Method b) Rt=2.60 min; MS m/z: 530 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([N:9]2[C:13](Cl)=[C:12]([CH:15]=[O:16])[N:11]([CH3:17])[C:10]2=[O:18])[CH:6]=[CH:7][CH:8]=1.[CH3:21][NH:22][CH3:23]>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([N:22]([CH3:23])[CH3:21])=[C:12]([CH:15]=[O:16])[N:11]([CH3:17])[C:10]2=[O:18])[CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(C=O)c(Cl)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CNC
Product: CN(C)c1c(C=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 750 mg. of 1-(3-(trifluoromethyl)phenyl)-5-chloro-2,3-dihydro-3-methyl-2-oxo-1H-imidazole-4-carboxaldehyde from Example 14 and 15 ml. of 25% aqueous dimethylamine was warmed on a steam bath for 5 minutes. The solution was cooled and the solid was collected by filtration and recrystallized from ethanol-water. After drying the product at 50° C. for 30 minutes, 320 mg. of 1-(3-(trifluoromethyl)phenyl)-5-chloro-2,3-dihydro-3-methyl-2-oxo-1H-imidazole-4-carboxaldehyde was recovered. M.P. 87°-90° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Na].Cl[C:9](=[CH2:14])[C:10](OC)=[O:11]>CO>[OH:11][C:10]1[CH:9]=[CH:14][S:3][C:2]=1[C:1]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CS
Reactant: C=C(Cl)C(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sccc1O
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A solution of methyl thioglycolate (19.2 g, 181 mmoles) in methanol (100 mL) is added to a solution of sodium (8.0 g, 348 mmoles) in methanol (100 mL) with stirring, and cooling with an ice bath. A solution of methyl α-chloroacrylate (22.1 g, 183 mmoles) in methanol (25 mL) is then added at such a rate that the temperature does not exceed 30° C. After 1 hour at ambient temperature, the methanol is removed under reduced pressure. The residue is dissolved in water, acidified with HCl and steam distilled until the distillate is clear. The distillate is cooled and shaken, and the resulting precipitate filtered off, rinsed with water and dried to afford the product (21.3 g); mp 43°-45° C.
Reaction SMILES: [C:1]1(=[CH:7][C:8]2[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[Pt]=O.C(O)(=O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:9]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:8]([CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1C=C1CCCCC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CS(=O)(=O)Nc1ccc(N)cc1CC1CCCCC1
Yield: 93.4 %

Procedure:
Fifty ml of an acetic acid solution containing 2.0 g of N-(2-cyclohexylidenemethyl-4-nitrophenyl)methanesulfonamide obtained in Example 14 and 0.1 g of platinum oxide was subjected to catalystic reduction under a hydrogen atmosphere at room temperature with stirring. The catalyst was removed by filtration, and the filtrate was concentrated, neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 1.7 g of N-(4-amino-2-cyclohexylmethylphenyl)methanesulfonamide.
Reaction SMILES: CC(=CC)C.P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:24][C@H:23]2[CH:25]=[O:26])=[CH:15][N:14]=1.Cl([O-])=[O:35].[Na+]>O.CC(C)=O.O>[Cl:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:24][C@H:23]2[C:25]([OH:35])=[O:26])=[CH:15][N:14]=1
Reactant: [O-][Cl+][O-]
Reactant: Cc1nc(Cl)ncc1OC[C@@]1(c2cccc(F)c2)C[C@H]1C=O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(Cl)ncc1OC[C@@]1(c2cccc(F)c2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
2-methyl-2-butene (11.7 ml) and sodium dihydrogen phosphate (3.98 g) were added to an acetone-water (80 ml-20 ml) solution of the compound 323-2 (7.1 g). The reaction solution was cooled on ice. Sodium chlorite (4 g) was added to the reaction solution, and the obtained mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1 to 3:7), so as to obtain the title compound (5.77 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:27]1([C:33]2[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+]>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:36]2[CH:37]=[N:38][C:33]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)=[CH:34][CH:35]=2)[CH:3]=1)=[O:15]
Reactant: OB(O)c1ccc(N2CCOCC2)nc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCOCC4)nc3)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 110 °C
Yield: 94.5 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (110 mg, 0.26 mmol) and [6-(4-morpholinyl)-3-pyridinyl]boronic acid (82 mg, 0.39 mmol) in DME/water (3 mL: 1 mL). PdCl2(dppf)-CH2Cl2 (10.76 mg, 0.013 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (66.4 mg, 0.79 mmol) was added and the insoluble mixture was heated in a microwave at 110° C. for 20 min. It was evaporated, DCM/MeOH (1:1) was added, it was pre-absorbed on silica gel and purified by SiO2 chromatography (eluent: gradient 100% DCM to 80:20:2 DCM/MeOH/NH4OH). Fractions were evaporated. EtOH was added, it was sonicated and the solids that precipitated were filtered, washed with hexanes and dried to afford the title compound (123 mg, 89%) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H) 8.69 (d, J=2.27 Hz, 1H) 8.61 (t, J=4.93 Hz, 1H) 8.36 (s, 1H) 8.08-8.12 (m, 2H) 7.85 (d, J=1.01 Hz, 1H) 6.98 (d, J=8.84 Hz, 1H) 5.89 (s, 1H) 5.14 (quin, J=6.57 Hz, 1H) 4.39 (d, J=5.05 Hz, 2H) 3.71-3.75 (m, 4H) 3.50-3.55 (m, 4H) 2.22 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.49 (s, 3H). MS(ES) [M+H]+ 501.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:26]([F:29])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[OH:21])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O)(=[O:32])[CH3:31].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]([C:20]([C:22]([F:23])([F:25])[F:24])([C:26]([F:29])([F:27])[F:28])[OH:21])[CH2:9]2)[CH:3]=1)(=[O:32])[CH3:31]
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2cccc(Br)c2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CC(=O)c1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccccc1-c1cccc(C2CC(C(O)(C(F)(F)F)C(F)(F)F)=NN2c2ccccc2Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 23.1 %

Procedure:
5-(3-Bromo-phenyl)-1-(2-chloro-phenyl)-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole (20.0 mg, 0.04 mmol) prepared in Step 4 of Preparation 16, 2-acetylphenylboronic acid (8.0 mg, 0.05 mmol), Pd(dppf)Cl2 (2.0 mg, cat.), and a 2N sodium carbonate solution (0.5 mL) were added to N,N-dimethylformamide (0.5 mL). The reaction mixture was stirred at 80° C. for 16 hours and then ethyl acetate was added thereto. The reaction mixture was washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.Cl[CH2:22][C:23]([NH:25][C:26]([NH2:28])=[O:27])=[O:24]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:22][C:23]([NH:25][C:26]([NH2:28])=[O:27])=[O:24])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: NC(=O)NC(=O)CCl
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Product: CC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CN(CC(=O)NC(N)=O)CC1

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-8-isopropyl-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with chloroacetylurea according to the method of Example 2; m.p. 164°-166°.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[Cl:33][CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl.O>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3N)C2=O)cnc1OCC(F)(F)F
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(C(C)N2Cc3c(ccnc3NC(=O)CCl)C2=O)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 4-amino-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (230 mg, 0.63 mmol, Example-17, single enantiomer) and pyridine (250 mg, 3.1 mmol) in DCM (5 mL) is added 2-chloroacetyl chloride (89 mg, 0.79 mmol) at rt. The mixture is stirred for 1 hour at rt, and the mixture is diluted with water. The mixture is extracted with DCM. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The filtrate is concentrated. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (3:1 to 1:1) to give 270 mg (96% yield) of the title compound as pale brown solid.
Reaction SMILES: CS(Cl)(=O)=O.[F:6][C:7]([F:33])([F:32])[S:8]([O:11][C:12]1[C:13]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:14][C:15]([C:18]2(O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1)(=[O:10])=[O:9].C(N(CC)CC)C.ClCCl>C(OCC)(=O)C.O>[F:33][C:7]([F:6])([F:32])[S:8]([O:11][C:12]1[C:13]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:14][C:15]([C:18]2[CH2:23][CH2:22][O:21][CH2:20][CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Oc1ccc(C2(O)CCOCC2)nc1Cc1ccccc1)C(F)(F)F
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(C2=CCOCC2)nc1Cc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
57.9 μl of methanesulfonyl chloride was added dropwise to a mixture of 104 mg of 2-benzyl-6-(4-hydroxytetrahydro-4H-pyran-4-yl)-3-pyridyl trifluoromethane sulfonate, 139 μl of triethylamine and 2 ml of dichloromethane under ice-cooling. After stirring at room temperature for 3 hours, water and ethyl acetate were added thereto. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 15% ethyl acetate/hexane, to give 60.7 mg of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)c4ccccc4)cc3CO1)CC2
Yield: 25.8 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (155 mg, 0.50 mmol, HPLC 0.776 min) and benzenesulfonyl chloride (70 ul, 0.55 mmol) according to the procedure described for Example 27. Obtained the title compound as an off-white solid (58 mg, 26%, HPLC 1.576 min), MS (ISP) m/e=450.2 [(M+H)+].
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH:4]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[CH2:27][CH2:28]Cl)=[CH:21][CH:20]=2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1.CN(C=O)C.C(Cl)Cl>[NH:4]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:30])[CH2:27][CH2:28][N:2]([CH3:3])[CH3:1])=[CH:21][CH:20]=2)[N:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CCCl)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)CCC(=O)Nc1ccc(Nc2ncc(Br)c(Nc3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 9 %

Procedure:
A solution of dimethylamine in tetrahydrofuran (2.0M; 4 ml) was added to a solution of 4-anilino-5-bromo-2-[4-(3-chloropropionamido)anilino]pyrimidine (Method 37; 60 mg, 0.135 mmol) in DMF (0.2 ml). The solution was heated at 80° C. for 1 hour, diluted with DCM (4 ml) and loaded onto a Varian Mega Bond Elut column. Elution with 0-10% 2.0M methanolic ammonia solution in DCM gave the product (5.4 mg, 9%). MS (MH+): 455, 457; HPLC (RT): 2.70.
Reaction SMILES: [CH:1]1([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C.C(Cl)Cl.CCCCCC>[CH:1]1([C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([OH:10])[C:7]([O:9][CH3:17])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(O)(c1ccccc1)C1CCCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)C(O)(c1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (−)-cyclopentylmandelic acid, R(−)1, (1.83 g, 8.3 mmol) and potassium carbonate (2.87 g, 21 mmol) in DMF (21 ml), methyl iodide (3.53 g, 25 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 h, and then poured into water and extracted with hexane three times. Evaporation of dried hexane extract gave a crude product. Flash chromatography of the crude product on silica gel with 1.5:1 hexane:methylene chloride gave pure product R(−)2 (1.90 g, 95%). 1H NMR (CDCl3, 300 MHz): 1.32-1.36, 1.43-1.61 [8H, m, (CH2)4], 2.90 [1H, p, CHC(OH)], 3.71 (1H, s, OH), 3.79 (3H, s, CH3), 7.25-7.28, 7.31-7.35, 7.63-7.65 (5H, m, Ph) ppm.
Reaction SMILES: [C:1]1([OH:14])[C:2]([C:7]2[C:8]([OH:13])=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1.[OH-].[K+].CS(C)=O.[CH2:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH2:21]([O:14][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCCCCCBr
Reactant: Oc1ccccc1-c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCOc1ccccc1-c1ccccc1OCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A 100 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser with nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with 3.74 grams (0.02 moles) of 2,2′-biphenol, 2.8 grams (0.04 moles, 85 wt. %) of potassium hydroxide, and with 25 mL of dimethylsulfoxide. The mixture was stirred under nitrogen while heating to 100° C. After about 2½ hours, the potassium hydroxide had dissolved, and the mixture was cooled to about 70° C. Dodecyl bromide (9.60 mL; d 1.038; 9.97 grams; 0.04 moles) was added in one portion. An exotherm to about 86° C. was observed. After the exotherm subsided, the reaction mixture was stirred at 70° C. After about 5 hours, the reaction mixture was poured into about 400 mL of water. The white solids that separated were collected by filtration, and were washed on the filter with several portions of water. The solids were first air-dried, and then were dried in a vacuum oven at 50° C. for about 2 hours. The yield of product was 9.49 grams (91%), having a melting point of 33-35° C. The structure was confirmed by IR, 1H- and 13C-NMR, and GC/MS analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]3[CH3:22])=[C:12]([F:23])[CH:11]=2)[OH:9])=[CH:4][C:3]=1[S:24]([NH2:27])(=[O:26])=[O:25].C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:9])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]3[CH3:22])=[C:12]([F:23])[CH:11]=2)=[CH:4][C:3]=1[S:24]([NH2:27])(=[O:26])=[O:25]
Reactant: Cc1ccc(C)n1-c1ccc(C(O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1ccc(C)n1-c1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Following method B, 2-chloro-5-((4-(2,5-dimethyl-pyrrol-1-yl)-3-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamide is synthesized from the corresponding aryl bromide. In the next step, a solution of 100 mg of 2-chloro-5-((4-(2,5-dimethyl-pyrrol-1-yl)-3-fluoro-phenyl)-hydroxy-methyl)-benzenesulfonamide (0.24 mmol, 1 equivalent), 43 mg of 4-methylmorpholine N-oxide, and 122 mg of 4 Å molecular sieves in 5 mL of dichloromethane is stirred at room temperature as 5 mg of tetrapropylammonium perruthenate is added. The reaction is stirred at room temperature for 1 h, then filtered through a pad of silica gel, eluted with ethyl acetate and concentrated in vacuo. After purification by flash chromatography, 45 mg of product is obtained. 1H NMR (400 MHz, CDCl3): δ 2.05 (s, 6H), 5.20 (s, 2H), 6.0 (s, 2H), 7.40 (t, 1H, J=8 Hz), 7.65-7.75 (m, 3H), 8.05 (dd, 1H, J=8 Hz), 8.55 (d, 1H, J=2 Hz). MS (m/z): 407 (M+1).
Reaction SMILES: [CH2:1]([C:4]([CH:13]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7]C)=O)[CH:2]=[CH2:3].C[O-].[Na+].Cl>CO>[CH3:12][O:11][C:9]([C:4]1([CH2:1][CH:2]=[CH2:3])[CH:13]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:5]1=[O:7])=[O:10]
Reactant: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1ccccc1N)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=CCC1(C(=O)OC)C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
A suspension of α-(2-propenyl)-[2-(2-aminophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (6.87 g, 17.28 mmol) in 44 ml of methanol with sodium methoxide solution (29.63 ml of a 25 weight percent solution, 129.6 mmol) was refluxed under argon overnight. Although the reaction mixture was nearly homogeneous under reflux, the reaction had not gone to completion (by TLC). After cooling to room temperature, 1M hydrochloric acid was added in several increments (total reaction volume was 200 ml). The crude product was collected by filtration, washed with 90/10 water/methanol, and recrystallized from methanol/water (2 crops) to yield 3.65 g of a white crystalline solid, melting point 175°-176.5° C.