Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:14][C:15]([F:16])([F:18])[F:17])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(N(CC(F)(F)F)C2CCOCC2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cc(Br)cc1N(CC(F)(F)F)C1CCOCC1
Temperature: 50 °C
Reaction time: 5.5 h
Yield: 91.4 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)(2,2,2-trifluoroethyl)amino]benzoate (572 mg, 1.4 mmol) in a mixture of THF (14 ml) and MeOH (2.1 ml), was added 4M NaOH (aq) (13.9 ml). The reaction mixture was stirred at 50° C. for 5.5 hours and then stirred at room temperature for 17 hours. THF was removed by concentrating in-vacuo and the aqueous residue was acidified to pH 4 with 6M HCl (aq) (9.5 ml). The resulting suspension was allowed to stand at room temperature for 20 minutes before collecting the solid by filtration. The solid cake was washed with water (20 ml) and dried under high vacuum for 2 hours to give the title compound (507 mg, 90%) as a white solid. LC-MS 98%, 2.04 min (3.5 minute LC-MS method), m/z=395.9, 396.9, 397.9, 398.9; 1H NMR (500 MHz, Chloroform-d) δ ppm 7.97 (d, J=1.73 Hz, 1H) 7.48 (d, J=1.73 Hz, 1H) 4.02 (dd, J=11.35, 3.94 Hz, 2H) 3.65 (br. s, 2H) 3.33 (t, J=11.59 Hz, 2H) 3.00 (tt, J=11.49, 3.80 Hz, 1H) 2.55 (s, 3H) 1.82 (d, J=11.98 Hz, 2H) 1.55-1.69 (m, 2H). OH not visible.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-:35].[Na+]>CC(C)=O>[CH:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([OH:35])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:32])=[CH:25][CH:24]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2

Procedure:
2,2,2-Trichloro-1-[(10-cyclohexylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]bernzodiazepin-3-yl]-ethanone of Example 7 (5.83 g) was added to a mixture of acetone (100 mL) and 2.5 N sodium hydroxide (8.5 mL). The reaction mixture was refluxed for one hour and then evaporated to dryness. Water was added to the residue and the solution was extracted with dichloromethane. The aqueous layer was acidified with glacial acetic acid and evaporated to dryness. The residual oil crystallized to provide the title compound as a light tan solid (3.03 g), m.p. 193–194° C.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([O:21][CH2:22][C:23]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CC(C)=O>[CH2:37]([O:36][CH2:35][C:23]([CH2:22][O:21][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH2:26][O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:24]([OH:3])=[O:25])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)=O
Reactant: OCC(COCc1ccccc1)(COCc1ccccc1)COCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)C(COCc1ccccc1)(COCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A Jones reagent (0.984 mmol) was added to 5 mL of a solution of 3-benzyloxy-2,2-bis(benzyloxymethyl)propan-1-ol (200 mg, 0.492 mmol) obtained in the Step A in acetone under ice-cooling, and the mixture was stirred at room temperature for one hour. Water was added to the mixture, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-benzyloxy-2,2-bis(benzyloxymethyl)propionic acid (206 mg, 100%) as a colorless solid.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:14]([C:16]1[CH:24]=[C:23]([Cl:25])[C:19]([C:20](Cl)=[O:21])=[C:18]([Cl:26])[CH:17]=1)#[N:15]>>[Cl:25][C:23]1[CH:24]=[C:16]([C:14]#[N:15])[CH:17]=[C:18]([Cl:26])[C:19]=1[C:20]([C:3]1[C:4]2[C:5](=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)=[O:21]
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Reactant: N#Cc1cc(Cl)c(C(=O)Cl)c(Cl)c1
Product: CC(=O)Nc1nccc2c(C(=O)c3c(Cl)cc(C#N)cc3Cl)c[nH]c12

Procedure:
N-[3-(2,6-Dichloro-4-cyanobenzoyl)-1H-pyrrolo[2,3-c]pyridin-7-yl]acetamide (Compound No. 21) was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl)acetamide and 4-cyano-2,6-dichloro benzoyl chloride.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[NH:8][C:9](=[O:11])[CH3:10])=[O:4].[NH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1>CC(C)=O>[BrH:1].[NH:15]=[C:16]1[N:20]([CH2:2][C:3]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=2)[NH:8][C:9](=[O:11])[CH3:10])=[O:4])[CH:19]=[CH:18][S:17]1
Reactant: Nc1nccs1
Reactant: CC(=O)Nc1cccc(C(=O)CBr)c1
Solvent: CC(C)=O
Product: Br
Product: CC(=O)Nc1cccc(C(=O)Cn2ccsc2=N)c1

Procedure:
A solution of 64.8 g. (0.253 mole) of 3'-bromoacetyl acetanilide (Example 1) and 25.3 g. (0.253 mole) of 2-aminothiazole in 450 ml. of acetone is heated at 50°-60° C for 2 hours. The precipitated product is filtered, washed with acetone and dried to give 58.74 g. of crude product which on recrystallization from methanol-ether gives the product melting point 225° dec. Anal. Calcd, for C13H14BrH3O2S: C, 43.83; H, 3.96; Br, 22.43; N, 11.80; S, 9.00. Found: C, 43.90; H, 4.21; Br, 22.21; N, 11.73; S, 8.69.
Reaction SMILES: [NH2:1][CH:2]1[CH:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH:8]=2)[CH2:3]1.Br[CH2:32][CH2:33][CH2:34]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O.ClCCl>[N:1]1([CH:2]2[CH:10]([CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:18][CH2:19][CH2:20][NH:21][S:22]([C:25]4[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=4)(=[O:24])=[O:23])[CH:8]=3)[CH2:3]2)[CH2:34][CH2:33][CH2:32]1
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N)C3)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2)C(N2CCC2)C3)c1
Reaction time: 0.33 h

Procedure:
To N-(2-(2-amino-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide (35.4 mg, 0.083 mmol; see example 193), 1,3-dibromopropane and potassium carbonate (12.62 mg, 0.091 mmol) in water (1 mL)+1 drop acetonitrile were added. Microwave at 120° C. for 20 min. Evaporated acetonitrile, re-dissolved in dichloromethane and extracted with water and brine, dried over sodium bicarbonate, filtered and evaporated to obtain the crude product and was purified by flash silica gel chromatography on 4 g SiO2-cartridge using 10% methanol in dichloromethane to obtain N-(2-(2-(azetidin-1-yl)-3-benzyl-2,3-dihydro-1H-inden-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide as a clear glass. m=3.1 mg (8%)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[C:11]([C:35]([F:38])([F:37])[F:36])=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([N:22]([C:31]([O:33][CH3:34])=[O:32])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[CH:15][CH:14]=[CH:13]2>C(Cl)(Cl)Cl>[CH3:8][O:9][C:10]1[C:11]([C:35]([F:36])([F:38])[F:37])=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([C:20]([N:22]([C:31]([O:33][CH3:34])=[O:32])[CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[CH:15][CH:14]=[CH:13]2
Reactant: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COC(=O)N(CC(=O)O)C(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 20 °C
Yield: 106.6 %

Procedure:
Trifluoroacetic acid (20.0 mL, 260 mmol) was added to a solution of N-[[6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine, 1,1-dimethylethyl ester (1.5 g, 3.41 mmol) in chloroform (25 mL) at 20° C. and the mixture refluxed for 1.5 hours. The solution was cooled to 20° C. and the solvent evaporated under reduced pressure. The residual solid was recrystallized from acetone-water and dried at 70° C./0.1 m.m. Hg to yield the pure product as a white solid (1.4 g, 100%), m.p. 148°-150° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[O-:17][CH2:18][CH3:19].[Na+].[Na].ClCCO>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:19][CH2:18][OH:17])=[CH:10][CH:11]=1
Reactant: Oc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: CC[O-]
Agent: OCCCl
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1

Procedure:
4-(3,5-Difluorophenoxy)phenol (9.0 g, 40.5 mmol) was added to an ethanolic solution of sodium ethoxide prepared from ethanol (40 ml) and sodium (939 mg, 40.9 mmol). To the resultant solution, 2-chloroethanol (3.26 g, 40.5 mmol) was dropwise added with stirring under reflux. After completion of the addition, the resultant mixture was stirred under reflux for 4 hours. After allowed to cool, ethanol was removed, and the residual oil was dissolved in toluene. The toluene layer was washed with water once, a 20% aqueous potassium hydroxide solution two times and a saturated aqueous sodium chloride solution once in order and dried over anhydrous magnesium sulfate. Removal of the solvent gave 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (6.50 g).
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:20][NH2:21]>C(O)C>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:20][NH2:21])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cccc2c1CC(=O)c1ccccc1S2
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1cccc2c1CC(=NN)c1ccccc1S2
Yield: 63.1 %

Procedure:
0.9 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin and 1 g of 100% hydrazine hydrate were dissolved in 10 ml of ethanol and the resulting mixture was heated under reflux for 3.5 hours. The reaction mixture was concentrated to 5 ml to separate crystals on cooling, which were collected by filtration. Recrystallization from ethanol afforded 0.6 g of 9-cyano-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin hydrazone as palo brown prismatic crystals having a melting point of 175°-177° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C([N:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[CH:14]=[C:13]1[C:22](=[O:46])[CH:23]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:38][CH:37]=1)[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C1(C)C=CC=CC=1>[C:42]([C:39]1[CH:38]=[CH:37][C:36]([CH2:35][CH:23]([C:22]([C:13]2[NH:12][C:20]3[C:15]([CH:14]=2)=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)=[O:46])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)=[CH:41][CH:40]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: COC(=O)c1ccc(CC(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc3cc(Cl)ccc3n2Cc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cc3cc(Cl)ccc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) flask containing AlCl3 (622 mg, 4.66 mmol) was added a solution of the title compound of Example 12 Step C (674 mg, 1.17 mmol) and anisole (0.253 mL, 2.33 mmol) in toluene (3 mL). After 30 min, the mixture was removed from the 0° C. bath and allowed to stir at room temperature for 1.5 h, whereupon it was poured into H2O. The aqueous phase was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30%, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS E, tr=4.50 min, m/z 488.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.92 (s, 1H), 7.86 (d, J=8.5 Hz, 2H), 7.57 (s, 1H), 7.29-7.25 (m, 2H), 7.23 (d, J=7.0 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.86 (d, J=2.0 Hz, 1H), 3.86-3.81 (m, 1H), 3.85 (s, 3H), 3.20 (dd, J=14.0, 9.0 Hz, 1H), 3.13 (dd, J=14.0, 7.5 Hz, 1H), 2.92 (dd, J=13.5, 5.5 Hz, 1H), 2.83 (dd, J=13.5, 7.0 Hz, 1H), 1.23 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[N:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:16][C:17]1[N:18]=[N:19][C:20]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])=[CH:21][CH:22]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN
Reactant: Clc1ccc(Cl)nn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(Cl)nn1
Temperature: 160 °C
Yield: 31.1 %

Procedure:
A solution of C-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine (206 mg, 1.0 mmol) and 3,6-dichloropyridazine (149 mg, 1.0 mmol) in DMSO (2 mL) containing N,N-diisopropyl ethyl amine (259 mg, 342 μL, 2.0 mmol) was heated with microwave irradiation to 160° C. for 1 h. After cooling to room temperature the reaction mixture was extracted (ethyl acetate/water). The organic phase was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (99 mg, 31%) as an off white solid after recrystallization from heptane:ethyl acetate. MS: m/e=319.1 [M+H]−.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[CH2:17]([N:19]1[CH2:23][CH:22]2[O:24][CH:21]2[CH2:20]1)[CH3:18].[C:25]([O-:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([O-:30])=[O:29]>Cl>[C:25]([OH:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([OH:30])=[O:29].[CH2:17]([N:19]1[CH2:23][C@@H:22]([NH:1][CH:2]2[C:3]3[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=3[CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[C@H:21]([OH:24])[CH2:20]1)[CH3:18]
Reactant: NC1c2ccccc2CCc2ccccc21
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: CCN1CC2OC2C1
Agent: Cl
Product: CCN1C[C@@H](O)[C@H](NC2c3ccccc3CCc3ccccc32)C1
Product: O=C(O)/C=C\C(=O)O
Temperature: 140 °C

Procedure:
A mixture of 7.5 g (0.036 mole) of 5-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene, 4.1 g (0.036 mole) of n-ethyl-3,4-epoxypyrrolidine and 2 drops concentrated hydrochloric acid was heated at 140° C. under a nitrogen atmosphere overnight. The residue was converted to the maleate. The salt was recrystallized twice from isopropyl alcohol, converted to the base, reconverted to the maleate, and recrystallized from isopropyl alcohol to yield 1.4 g. (7%) of white solid, m.p. 132°-135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=2)C=O)=[CH:4][CH:3]=1.C1(P(=[CH:62][CH:63]=[O:64])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:65]1C=CC=CC=1>>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:9]([C:12]2[N:13]=[N:14][N:15]([C:17]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:16]=2)[CH:65]=[CH:62][CH:63]=[O:64])=[CH:37][CH:38]=1
Reactant: O=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: c1ccccc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=CC=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
To a solution of 1.75 g (3.15 mmol) 3,3-bis(4-fluorophenyl)-2-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-2-propenal in 50 mL of dry benzene was added 0.96 g (3.15 mmol) triphenylphosphoranylidene acetaldehyde and the solution heated at reflux for 96 hours. The solution was concentrated in vacuo and the residue purified by chromatography on alumina (Alcoa Chemicals, grade F-20) eluting with 10% ethyl acetate in hexane to give upon concentration of the appropriate fractions 0.95 g of the title compound; m.p.=122°-124° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=2)[CH:2]([CH3:4])[CH3:3].[C:18](Cl)(=[O:22])[CH:19]([CH3:21])[CH3:20]>>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:8]=2)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2cc(CC(C)C)[nH]c2c1
Reactant: CC(C)C(=O)Cl
Product: COC(=O)c1ccc2c(C(=O)C(C)C)c(CC(C)C)[nH]c2c1

Procedure:
Methyl 2-isobutyl-3-isobutyrylindole-6-carboxylate (246 mg) was prepared from methyl 2-isobutylindole-6-carboxylate (300 mg) and isobutyryl chloride (0.41 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12](=[S:14])[NH2:13])=[C:5]2[N:4]=[N:3]1.[CH3:15][I:16]>C(#N)C>[IH:16].[CH3:1][N:2]1[C:7](=[O:8])[N:6]2[CH:9]=[N:10][C:11]([C:12]([S:14][CH3:15])=[NH:13])=[C:5]2[N:4]=[N:3]1
Reactant: CI
Reactant: Cn1nnc2c(C(N)=S)ncn2c1=O
Solvent: CC#N
Product: CSC(=N)c1ncn2c(=O)n(C)nnc12
Product: I
Yield: 87.4 %

Procedure:
A solution of 3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (2.75 g, 13.1 mmol) and methyl iodide (8.2 mL, 131 mmol) in acetonitrile (900 mL) was stirred at room temperature for 3 days. The mixture was concentrated under vacuum and the solid was suspended in diethyl ether. The precipitate was filtered and washed with diethyl ether to give the pure title compound as an orange solid (4.03 g, 88% yield). δH (DMSO-d6): 11.6 (1H, bs), 9.18 (1H, s) 3.94 (3H, s), 2.82 (3H, s).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:13]C([O-])(C)C.[K+].IC>C1COCC1>[I:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[N:4]([CH3:13])[N:3]=1
Reactant: N#Cc1ccc2c(I)n[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-iodo-1H-indazole-6-carbonitrile (2.0 g, 7.43 mmol), t-BuOK (1.2 g, 10.4 mmol) in THF (50 mL), iodomethane (1.2 g, 10.4 mmol) in THF (5 mL) was added dropwise at 0° C. under ice-water bath. The resulting mixture was stirred overnight at room temperature. Two isomers, which are methylated at N-1 and N-2 position respectively, were formed. The excess solvent was removed under reduced pressure, the residue was dissolved in EtOAc (100 mL), washed with brine (2×10 mL), the combined organics were dried over Na2SO4. After removal of drying agent and concentration, the crude mixture (1.6 g) was used in the next step without further purification. MS: (M+H)+=411;
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]([CH3:11])[CH3:10])[N:3]=1.[OH-:12].[K+].[CH3:14]O>>[CH3:14][O:12][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][CH:9]([CH3:11])[CH3:10])[N:3]=1
Reactant: [OH-]
Reactant: CO
Reactant: CC(C)Nc1cccc(Br)n1
Agent: [K+]
Product: COc1cccc(NC(C)C)n1

Procedure:
In the same reacting apparatus as in Example 1, 20 g of 2-bromo-6-isopropylaminopyridine, 70 ml of methanol and 14 g of potassium hydroxide were charged and they were subjected to reacting each other at 160° C. for 4 hours. After completion of the reaction, the similar experimental procedure as in Example 3 was carried out to give 7.3 g of 2-methoxy-6-isopropylaminopyridine of b.p. 127°-128° C./20 mmHg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](Cl)=[O:35].N1C=CC=CC=1C(O)=O.O=S(Cl)Cl>CN(C=O)C.C(N(CC)CC)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)=[O:35])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(Cl)c1ccccn1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Agent: O=C(O)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(C(=O)c4ccccn4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A26 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (16 mg, 0.037 mmol), triethylamine (50 μl), pyridine-2-carbonyl chloride (10 mg, 0.046 mmol) [Pyridine-2-carbonyl chloride was prepared by refluxing picolinic acid with SOCl2 for 3 hours and worked up in general method], DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 1.95 (m, 2H), 2.13 (m, 2H), 3.07 (s, 3H), 3.65 (m, 2H), 3.79 (m, 2H), 4.13 (m, 1H), 5.72 (m, 1H), 7.37 (m, 1H), 7.67 (m, 1H), 7.81 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41 (s, 1H), 8.60 (m, 2H), 10.19 (s, 1H). Exact mass calculated for C22H22N6O6S 498.13, found 499.3 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH2:7][CH:6]=[C:5]([Si:8]([CH3:11])([CH3:10])[CH3:9])[CH:4]=1.C([Li:18])CCC>CCCCCC>[CH3:9][Si:8]([CH3:11])([CH3:10])[C-:5]1[CH:6]=[CH:7][C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])=[CH:4]1.[Li+:18]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)C1=CCC([Si](C)(C)C)=C1
Solvent: CCCCCC
Product: C[Si](C)(C)c1cc[c-]([Si](C)(C)C)c1
Product: [Li+]
Yield: 58.2 %

Procedure:
1,3-Bis(trimethylsilyl)cyclopentadiene (10.5 g, 0.05 mole) is reacted with 32 ml of a 1.6M solution of butyllithium (0.05 mole) in hexane to give 6.3 g of lithium 1,3-bis(trimethylsilyl)cyclopentadienide.
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10](=[O:37])[C@@H:11]([NH:24][C@@H:25]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:26]([F:29])([F:28])[F:27])[CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]S[CH2:5][CH2:4]1)#[N:2].OO[S:40]([O-:42])=[O:41].[K+]>CO>[C:1]([C:3]1([NH:9][C:10](=[O:37])[C@@H:11]([NH:24][C@@H:25]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:26]([F:29])([F:27])[F:28])[CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:15])=[O:14])[CH2:4][CH2:5][S:40](=[O:42])(=[O:41])[CH2:7][CH2:8]1)#[N:2]
Reactant: O=S([O-])OO
Reactant: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccc(F)cc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CCSCC1
Agent: [K+]
Solvent: CO
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccc(F)cc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CCS(=O)(=O)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-(4-cyanotetrahydrothiopyran-4-yl)-3-(4-fluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide (24 mg) was weighed into a 25 mL pear flask fitted with a stir bar and vented cap. Methanol (4.75 mL) was added and the reaction mixture was stirred at 50° C. to obtain a clear colorless solution. OXONE® (0.43 mL of a 0.30M aqueous solution) was added. A white precipitate formed. After 2 h, methanol was removed on a rotary evaporator and the residue was partitioned between 10 mL water and 10 mL dichloromethane. The organic phase was separated, washed with water and brine and dried over anhydrous MgSO4 and concentrated to give the title compound (16 mg) as a white solid.