Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:15]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:22][CH2:23][CH2:24][N:25]3[C:29](=[O:30])[C:28]4=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]4[C:26]3=[O:35])[CH2:10][CH2:9]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(C(c2ccccc2)N2CCCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
To a mixture of 1-(diphenylmethyl)hexahydro-1H-1,4-diazepine (2.0 g), N-(3-bromopropyl)phthalimide (2.01 g) and anhydrous potassium carbonate (3.1 g) was added acetone (10 ml) and then stirred for 6 hours at 50° C. The reaction mixture was filtered and the filtrate was concentrated in vacuo and then the resultant oily residue was subjected to a column chromatography on silica gel using a mixture of ethyl acetate and chloroform (2:3) for elution to give N-[3-{4-(diphenylmethyl)hexahydro-1H-1,4-diazepin-1-yl}propyl]phthalimide (2.2 g) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[CH:19]([F:21])[F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.O>CN(C)C=O>[F:20][CH:19]([F:21])[C:11]1[N:10]([C:4]2[CH:3]=[C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:7]=[C:6]([S:8][CH3:9])[N:5]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: C1COCCN1
Reactant: CSc1nc(Cl)cc(-n2c(C(F)F)nc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (2.2 g) in N,N-dimethylformamide (11 mL) were added potassium carbonate (1.4 g) and morpholine (0.88 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 2-(difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.1 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:28][OH:29]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH:18]([NH:28][OH:29])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=3)(=[O:15])=[O:16])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=S(=O)(/C=C/CCc1cncc(Cl)c1)N1CCN(c2ccc(Cl)cc2)CC1
Solvent: C1CCOC1
Product: O=S(=O)(CC(CCc1cncc(Cl)c1)NO)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-4-{[(1E)-4-(5-chloropyridin-3-yl)but-1-enyl]sulfonyl}piperazine (crude from previous step), in THF (10 mL) at RT was added a solution of hydroxylamine (2 mL, 50% aqueous solution in water). The reaction was stirred for 3 hours at RT before being quenched with saturated aqueous ammonium chloride solution (5 mL).The layers were separated and the aqueous phase extracted with ethyl acetate (3×10 mL). The combined organic extracts were then dried, (MgSO4), filtered and concentrated in vacuo. The residue was then purified by flash chromatography (silica, 100% ethyl acetate) to give the title compound (100 mg, 0.22 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>ClCCl>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([CH:23]2[CH2:24][CH:19]([NH:18][C:10]3[N:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:20][CH2:21][N:22]2[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Fc1ccc(Cn2c(NC3CCN(C4CCNCC4)CC3)nc3ccccc32)cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1CC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CCN1C1CCNCC1
Reaction time: 1 h

Procedure:
To a stirred mixture of 4 parts of N-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-[1,4'-bipiperidine]-4-amine, 1 part ofN,N-diethylethanamine and 91 parts of dichloromethane was added dropwise a solution of 1.6 parts of 4-fluorobenzoyl chloride in 39 parts of dichloromethane: slightly exothermic reaction, the temperature rises from 25° C. to 30° C. Upon completion, stirring was continued for one hour at room temperature. The reaction mixture was purified by high performance liquid chromatography using a mixture of trichloromethane, hexane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 1.8 parts (34%) of 1'-(4-fluorobenzoyl-N-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-[1,4'-bipiperidine]-4-amine; mp. 194.3° C.; (compound 18).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Zn].C(COC)OC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:15]([C:14]2[CH:18]=[CH:19][C:11]([Cl:10])=[CH:12][CH:13]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Zn]
Solvent: COCCOC
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 91 %

Procedure:
To dimethoxyethane (100 mL) was added 4-chlorobenzylbromide (4.1 g), 4-chlorobenzoylchloride (2.56 mL), bis(triphenylphosphine)palladium dichloride (702 mg) and zinc powder (2.6 g) and the mixture was stirred for 2 hours under nitrogen gas atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=49/1 to 9/1) to obtain (4-chlorobenzyl) (4-chlorophenyl)methanone (4.85 g, yield: 91%) as a powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:34].CCOCC>>[ClH:34].[CH2:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][S:16][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:23][CH:22]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(OCc3ccccc3)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=C(SCc1ccc(OCc2ccccc2)cc1)N1CCNCC1

Procedure:
A solution of 86 mg (0.19 mmol) 4-(4-benzyloxy-benzylsulfanylcarbonyl)-piperazine-1-carboxylic acid tert-butyl ester in 2.2 ml 1.5M HCl/Et2O and 0.45 ml abs. MeOH was stirred at rt for 4 h. Evaporation of the reaction mixture provided 64 mg product as colourless powder. 1H-NMR(d6-DMSO): 3.03–3.17 m, 4H and 3.58–3.73 m, 4H; 4.09 s, 2H; 5.08 s, 2H; 6.95 d, J=7.5 Hz, 2H and 7.26 d, J=7.5 Hz, 2H (AB-system) and 7.30–7.50 m, 5H; 9.2 br, 2H. MS (ISP): 343.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[C:19]([CH2:21][NH:22]C(=O)OC(C)(C)C)[CH:18]=[CH:17][N:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:22][CH2:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:13]([N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:31][CH:30]=3)[CH2:8][CH2:9]2)=[O:14])[CH:20]=1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of tert-butyl ((2-(4-(4-chlorophenoxy)piperidine-1-carbonyl)pyridin-4-yl)methyl)carbamate (165 mg, 0.37 mmol, Step-1), trifluoroacetic acid (2 mL), and dichloromethane (2 mL) was stirred at room temperature for 1 hour. After removal of the solvent, the residue was purified by a strong cation exchange cartridge (BondElute(registered trademark) SCX) to give 128 mg (>99%) of the title compound as colorless syrup. 25 mg of this material was further purified by preparative LC-MS to give 16.9 mg (68% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:15]([NH:25][C:12]([C@@H:9]1[CH2:10][CH2:11][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCN
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCNC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-(tert-Butoxycarbonyl)-(S)-(−)-2-azetidinecarboxylic acid (1) (90 mg; 0.447 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. n-Decylamine (72 mg; 0.470 mmol), N,N-diisopropylethylamine (116 mg; 0.895 mmol) and PyBOP (244 mg; 0.470 mmol) are added sequentially. The reaction is stirred for 4 days at room temperature, then concentrated under reduced pressure. The crude product is purified via silica gel chromatography using a gradient elution (10%→60% ethyl acetate in hexanes) affording the desired product (285). ISMS: MH+ 341.4
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11](P(=O)(OCC)OCC)[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:28]([N:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1>[C:14]1(/[CH:13]=[CH:12]/[CH:11]=[C:38]2[CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:36][CH2:37]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOP(=O)(CC=Cc1ccccc1)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C/C=C/c2ccccc2)CC1
Yield: 100.1 %

Procedure:
Lithium bis(trimethylsilyl)amide (1M sol. in THF, 2.63 mL, 2.63 mmol) was added at −60° C. under nitrogen atmosphere to a solution of diethyl cinnamylphosphonate (0.629 mL, 2.64 mmol). After 15 min. under stirring at the same temperature, N-Boc-4-piperidone (500 mg, 2.51 mmol) dissolved in THF (5 ml) was added. Stirring and cooling was maintained for 30 min and, after 2 h, the reaction mixture was quenched with water and with EtOAc. The combined extracts were washed, dried over Na2SO4 and evaporated to dryness affording the title product (752 mg), that was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([NH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 55.1 %

Procedure:
Using cyclohexyl{3-methyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.59 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.55 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.50 g, 55%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23](O)[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:9]=1)([CH3:4])[CH3:3].CCN(S(F)(F)[F:37])CC.O>C1(C)C=CC=CC=1>[CH3:3][C:2]([Si:5]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[C:10]([CH:23]([F:37])[C:24]([CH3:26])([CH3:25])[CH3:27])[CH:9]=1)([CH3:29])[CH3:30])([CH3:1])[CH3:4]
Reactant: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(O)C(C)(C)C)c1
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2C(F)C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 66.30B (0.400 g, 0.925 mmol) in toluene (10 mL) at −78° C. was added DAST (0.209 g, 1.29 mmol) dropwise. The reaction was stirred at −78° C. for 30 minutes and then warmed to 23° C. and stirred for an additional 2 hours. Water was added to quench the reaction mixture. The reaction was then extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.30C as a colorless oil (0.400 g, 99% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)([O-])=O.[H][H]>CO.[Pd].[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:22]=[CH:23][CH:24]=1)[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2cccc([N+](=O)[O-])c2)CC1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CCc2cccc(N)c2)CC1
Reaction time: 2.5 h
Yield: 63 %

Procedure:
A Parr glass liner was charged with tert-butyl 4-(3-nitrophenethyl)piper-azine-1-carboxylate (7C, 1.0 eq) and methanol (about 0.2 M 7C in MeOH). To this solution was added a slurry of 12.5 wt eq of 10% Pd/C in methanol. The reaction mixture was sealed in a Parr hydrogenation vessel and subjected to 3 pressurization/venting cycles with H2. The reaction mixture was allowed to proceed at room temperature and 45 psi H2 for 2.5 h. The reaction mixture was then charged with 12.5 wt eq of Pd(OH)2/C and the vessel was repressurized with hydrogen (45 psi). After 1 hr, the reaction mixture was filtered through a pad of diatomaceous earth, the diatomaceous earth washed with MeOH, and the combine organic layers concentrated in vacuo to provide the desired tert-butyl 4-(3-aminophenethyl)piperazine-1-carboxylate (7D, 63%), which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].O>CS(C)=O>[CH2:14]([O:13][CH2:12][CH2:11][C:5]1[C:6]2[N:7]([N:8]=[CH:9][N:10]=2)[C:2]2[N:3]([N:22]=[N:23][N:24]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]
Reactant: CCOCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOCCc1c(-c2ccccc2)n2nnnc2n2ncnc12
Reaction time: 5 h

Procedure:
To a solution containing 30.2 g of 5-chloro-8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine (0.1 moles) dissolved in 200 ml of dimethylsulfoxide is added 20 g of sodium azide (0.3 moles). The resulting reaction mixture is heated to 65°-70° C. and then stirred for 5 hours. The reaction mixture is then stirred overnight at room temperature. The reaction mixture is then stirred into 1 liter of water and a precipitate forms. The mixture is filtered and the precipitate is washed with water and dried yielding a crude product. The crude product is chromatographed on silica gel and recrystallized from diethylether to yield 6-(2-ethoxyethyl)-5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidine having the structural formula ##STR20## and the azido tautomer thereof as a white solid having a melting point of 114° C. and the following elemental analysis:
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH2:12](O)[CH3:13]>>[CH2:12]([O:4][C:3](=[O:5])[C:2]([NH2:1])([CH3:7])[CH3:6])[CH3:13]
Reactant: CCO
Reactant: CC(C)(N)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)N
Temperature: 0 °C
Yield: 63 %

Procedure:
2-Amino-2-methyl-propionic acid (1.0 g, 9.69 mmol) was dissolved in ethanol (15 ml) and cooled to 0° C. Thionyl chloride (1.7 g, 14.53 mmol, 1.5 eq) was added to the reaction mixture, which was then heated to reflux overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and dried to give 2-amino-2-methyl-propionic acid ethyl ester (0.8 g, 63%). The crude compound was used in the next stage without purification.
Reaction SMILES: COC[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:43](OC)=[O:44]>C(Cl)Cl>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:17]3[C:12]([CH:9]4[CH2:10][CH2:11][N:6]([C:4]([O:44][CH3:43])=[O:5])[CH2:7][CH2:8]4)=[N:13][CH:14]=[CH:15][N:16]=3)=[CH:20][CH:21]=2)=[N:27][CH:28]=1
Reactant: COC(=O)Cl
Reactant: COCC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 5-methyl-N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine (0.278 g, 0.548 mmol) (See step 3, Example 282), and diisopropylethylamine (0.502 mL, 2.88 mmol) in DCM (5 mL) was added methyl chloroformate (0.051 mL, 0.658 mmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was purified by ISCO column (40% EtOAc/Hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 420.2 (M+1). IC50 (uM) 0.000107.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:44])[NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:43][CH2:42][O:41][CH2:40][CH2:39]5)[CH2:33]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47])(=O)C.C1COCC1.[OH-].[Na+]>CO>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:46])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:45])[CH2:12][CH2:13][C@@:14]3([C:30]([NH:31][C@@H:32]4[CH2:36][CH2:35][C@H:34]([CH2:37][N:38]5[CH2:39][CH2:40][O:41][CH2:42][CH2:43]5)[CH2:33]4)=[O:44])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:48])[CH3:47]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCOCC4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.9 %

Procedure:
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((1R,3S)-3-(morpholinomethyl)cyclopentylcarbamoyl)-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-yl acetate (Example 20, 0.22 g) in MeOH:THF (8:8 ml) and cooled the contents to 0° C. then sodium hydroxide (0.05 g in 4 ml water) was added and the contents were stirred for about 6 hours at room temperature then completion of the reaction was monitored by TLC. The reaction mixture was evaporated under reduced pressure, the residue was taken in water and extracted with DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 5% methanol in DCM as an eluent to furnish the title compound (0.14 g) as a white solid. 1H NMR (300 MHz, CDCl3): 0.88-0.96 (m, 9H); 1.25-1.39 (m, 11H); 1.43-1.88 (m, 24H) 2.21-2.47 (m, 8H); 2.86-3.10 (m, 3H); 3.15-3.72 (m, 7H); 4.60 (s, 1H); 4.74 (s, 1H); ES Mass: 622 (100%), [M+Na] 645; HPLC: 98.6%.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)=[O:11])=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10]([CH:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[O:11])=[O:7])=[C:2]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]([F:32])([F:45])[F:44])[CH:24]=1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)N(NC(=O)C1CCSCC1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)C1CCSCC1)C(=O)COc1ccc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 45.1 %

Procedure:
A solution of tetrahydro-thiopyran-4-carboxylic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (116 mg, 0.27 mmol) in DME (2.5 ml)/2M Na2CO3 (0.468 ml, 0.94 mmol) was treated with 2-trifluoromethoxyphenylboronic acid (83 mg, 0.40 mmol) and Pd[PPh3]4 (62 mg, 0.053 mmol) in a microwave oven at 150° C., for 10 min. 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 adsorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexane gradient to afford the product as a solid (62.6 mg, 45%). MS m/e 515.48 (M+H+)
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:14][O-:15].[Na+].[Na]>CO.O>[C:1]([C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:15][CH3:14])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: C[O-]
Reactant: COc1c([N+](=O)[O-])ccnc1C#N
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CO
Product: COc1ccnc(C#N)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
3 g (0.017 moles) of 2-cyano-3-methoxy-4-nitropyridine obtained in Example a) and a sodium methoxide solution prepared from 0.77 g (0.033 moles) of sodium and 65 ml of methanol are stirred at ambient temperature for 4 hours. There is added 100 ml of water, the methanol is eliminated and the aqueous phase is extracted with dichloromethane. The organic phase is washed with water, dried, concentrated and the residue chromatographed (ethyl acetate/heptane, 1:1) to obtain 1.96 g (72% yield) of a white solid (MP=133° C.).