Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:34][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2cc(N3CCCCC3)ccc2O)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1ccc(C(=O)O)c(NC(=O)c2cc(N3CCCCC3)ccc2O)c1
Yield: 86.1 %

Procedure:
A trifluoroacetic acid (3.0 mL) solution of the obtained tert-butyl 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(2-methylphenyl)benzoate (0.063 g) was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and water and ethanol were added thereto. After adjusting the pH to 5.5 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 0.048 g of 2-(2-hydroxy-5-(piperidin-1-yl)benzamido)-4-(2-methylphenyl)benzoic acid as a yellow solid.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)C.[Li][CH2:9][CH2:10][CH2:11][CH3:12].[CH:13]([Si:16]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:17][CH2:18][CH2:19][CH:20]1CC(C=O)=[CH:23][CH2:22][CH2:21]1)([CH3:15])[CH3:14]>C1COCC1>[C:11]([C:10]1[CH2:9][CH:20]([CH2:19][CH2:18][O:17][Si:16]([CH:31]([CH3:32])[CH3:33])([CH:28]([CH3:30])[CH3:29])[CH:13]([CH3:14])[CH3:15])[CH2:21][CH2:22][CH:23]=1)#[CH:12]
Reactant: [Li]CCCC
Reactant: CC(C)[Si](OCCC1CCC=C(C=O)C1)(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Product: C#CC1=CCCC(CCO[Si](C(C)C)(C(C)C)C(C)C)C1

Procedure:
A solution of TMS-diazomethane (4.61 mL, 9.22 mmol) in THF (60 mL) was reacted with n-BuLi (5.0 mL, 7.99 mmol) at −78 EC for 0.5 h. 5-(2-triisopropylsilanyloxy-ethyl)-cyclohex-1-enecarbaldehyde (Intermediate R13) was added via cannula. The mixture was reacted at −78 EC for 1 h and at 0 EC for 1 h. After work-up and chromatographic purification, [2-(3-ethynyl-cyclohex-3-enyl)-ethoxy]-triisopropyl-silane (Intermediate R14) was isolated, 1.44 g (77%). To Intermediate R14 in THF (70 mL) at 0 EC was injected tetrabutyl ammonium fluoride (TBAF). After 2 h at rt the mixture was subjected to an aqueous work-up. The material was purified by chromatography to give the alcohol, 2-(3-ethynyl-cyclohex-3-enyl)-ethanol 0.68 g, (98%). The alcohol was oxidized by a Swern reaction to the aldehyde stage and aldehyde was subjected to the applicable step of Method A to yield 4-(3-ethynyl-cyclohex-3-enylmethyl)-1H-imidazole (Intermediate R15).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[CH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][O:4][N:3]=1.[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:26]=[CH:27][C:28]([C:11]3[CH:16]=[CH:15][C:14]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[C:6]=4[CH:7]=[CH:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:13][CH:12]=3)=[CH:29][CH:30]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: Cc1nocc1C=CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using 5-4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4]Cl.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>O1CCOCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCl
Reactant: c1c[nH]cn1
Solvent: C1COCCO1
Product: CC(C)=CCCC(C)=CCCC(C)=CCn1ccnc1
Yield: 88 %

Procedure:
72.3 parts by weight of 3,7,11-trimethyldodeca-2,6,10-trienyl chloride and 40.8 parts by weight of imidazole are dissolved in 500 parts by weight of dioxane. The reaction mixture is then refluxed for 6 hours. After the mixture has cooled it is filtered and the filtrate is concentrated in vacuo. Distillation of the residue from the filtrate under an oil pump vacuum gives 72 parts by weight (88% of theory) of 1-(3,7,11-trimethyldodeca-2,6,10-trienyl)-imidazole; b.p. (0.01 mm Hg): 155° C.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9](Cl)(=[O:12])[CH2:10][CH3:11].Cl>>[C:9]([O:7][C:6]1[C:1]([CH3:8])=[CH:2][CH:3]=[CH:4][CH:5]=1)(=[O:12])[CH2:10][CH3:11]
Reactant: Cc1ccccc1O
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)Oc1ccccc1C
Yield: 98 %

Procedure:
Into a spherical flask equipped with a condenser, a dropping funnel and containing 2 mols of o-cresol are introduced, in 15 minutes, 2.2 mols of propionyl chloride. The mixture as obtained is heated at 110° C. for about 2 hours, until the discharge of hydrochloric acid ceases. The o-cresol propionate which is obtained is distilled under vacuum:
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([N+:28]([O-])=O)=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)C>[NH2:28][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH2:10][CH2:11]2)=[CH:20][C:19]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(C(=O)c3ccccc3)CC2)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A suspension of 5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (0.8 g, 2.0 mmol), and palladium on carbon (40 mg, 5%) in 40 ml ethanol was stirred at room temperature under hydrogen atmosphere overnight. The mixture was filtered with the aid of celite. (4-(4-amino-3-(phenylamino)phenyl)piperazin-1-yl)(phenyl)methanone (0.60 g, 80%) was obtained by flash column chromatograph (60% ethyl acetate in hexanes), ant its hydrochloride was made by bubbling HCl gas in ether solution. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.24 (s, br, 4H), 3.53 (s, br, 2H), 3.80 (s, br, 2H), 6.81 (d, J=8.1 Hz, 1H), 6.87 (t, J=7.3 Hz, 1H), 7.26-7.49 (m, 11H), 8.56 (s, br, 1H). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 49.4, 107.5, 110.4, 116.6, 120.1, 124.9, 127.0, 128.4, 129.3, 129.6, 135.5, 137.6, 143.1, 169.0.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C@H:10]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.BrC1C=C(CC2C=C[C:42]([O:45]CC)=CC=2)C(Cl)=C(OC)C=1OC>>[Cl:1][C:2]1[C:3]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=2)=[CH:4][C:5]([C@H:10]2[C@H:15]([OH:16])[C@@H:14]([OH:17])[C@H:13]([OH:18])[C@@H:12]([CH2:19][OH:20])[O:11]2)=[C:6]([O:45][CH3:42])[C:7]=1[O:8][CH3:9]
Reactant: CCOc1ccc(Cc2cc(Br)c(OC)c(OC)c2Cl)cc1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2Cl)cc1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OC)c(OC)c2Cl)cc1

Procedure:
Similar procedure with preparation of 75 proceeded except for using compound 160 to obtain the compound E151.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCO>C1COCC1.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].C1(C)C=CC=CC=1.O>[F:18][C:17]([F:20])([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:6]2[CH:21]=[C:2]([C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH:3]=[N:4][CH:5]=2)=[O:8])=[CH:11][CH:12]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cccnc2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 42.1, 5 g, 13.85 mmol), 3-pyridylboronic acid (1.872 g, 15.23 mmol), PdCl2(dppf) (0.507 g, 0.692 mmol), K3PO4 (8.82 g, 41.5 mmol), EtOH (9.33 mL), water (14 mL) and toluene (70 mL) was stirred at 100° C. for 2 h. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 500 g, EtOAc/MeOH from 0 to 2% MeOH). Fractions containing the pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in THF, stirred overnight with Si-Thiol (1 g), filtered and the filtrate was evaporated off under reduced pressure to give the title compound as a white solid. UPLC-MS (Condition 7) tR 0.95 min, m/z=358 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.41 (d, J=8.56 Hz, 2H) 7.59 (dd, J=7.95, 4.77 Hz, 1H) 7.91 (m, J=9.00 Hz, 2H) 8.29 (dt, J=7.83, 1.96 Hz, 1H) 8.65 (t, J=2.20 Hz, 1H) 8.68 (dd, J=4.77, 1.59 Hz, 1H) 9.08 (d, J=1.96 Hz, 1H) 9.13 (d, J=1.96 Hz, 1H) 9.16 (d, J=2.20 Hz, 1H) 10.69 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10](Cl)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2ccc(F)cc2)nc1
Yield: 51.9 %

Procedure:
2-(4-Fluorophenyl)-5-cyano-6-chloropyridine (8.6 g) prepared in Example 1 was dissolved in ethyl acetate (300 ml), followed by adding to the solution, Pd-C (1 g) and triethylamine (12 ml), subjecting the above pyridine derivative to catalytic reduction at ordinary temperature and ordinary pressure, thereafter adding water (100 ml), filtering, withdrawing the ethyl acetate layer separated from the filtrate, twice washing it with water, distilling off ethyl acetate, and recrystallizing the residue from ethanol to obtain the objective 2-(4-fluorophenyl)-5-cyanopyridine (3.8 g). M.P.: 149.0° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[C:10]1([C:8]2[S:9][C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=3[CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: S=C(Cc1ccccc1)c1ccccc1
Solvent: O
Product: c1ccc(-c2cc3ccccc3s2)cc1
Temperature: 190 °C
Yield: 55.7 %

Procedure:
2-Phenylthioacetophenone (63.8 g) was added to 450 g of polyphosphoric acid at 100° C. and then heated further to 190° C. for three hours. The reaction was allowed to cool below 100° C. before pouring it into a mixture of ice and water. The aqueous solution was extracted with ether. The ether layer was dried with magnesium sulfate and evaporated to yield a tan, amorphous solid. The residue was crystallized from acetone-ethanol to give 35.2 g of the title compound. mp 171° C.-172° C.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=[O:14])=[CH:5][CH:4]=1)=[O:2].[CH:15]([Mg]Cl)([CH3:17])[CH3:16]>C1COCC1>[CH:13]([C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([CH:1]([OH:2])[CH:15]([CH3:17])[CH3:16])=[CH:4][CH:5]=1)=[O:14]
Reactant: O=Cc1ccc(C=O)c2ccccc12
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(C=O)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 14 %

Procedure:
To a solution of 1,4-diformylnaphthalene (490 mg, 2.66 mmol) in THF (12 mL) was added dropwise at 0° C. isopropyl magnesium chloride (1.3 mL of a 2 M solution in THF). The mixture was stirred at room temperature for 3 hr, diluted with satd. NH4Cl (10 mL), and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (silicagel, hexane:ethyl acetate, 5:1) provided the title compound (81 mg, 14%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[N:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:16]1([C:22]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=Cc1ccc(OC(=O)N2CCOCC2)cc1
Temperature: 25 °C
Yield: 74.8 %

Procedure:
To a 250 mL dry round bottom flask were added 4-hydroxybenzaldehyde (6.11 g, 50.0 mmol), anhydrous CH2Cl2 (80 mL) and pyridine (4.86 mL, 60.0 mmol). The mixture was stirred in an ice-water, then 4-morpholinecarbonyl chloride (6.12 mL, 52.5 mmol) was added. The mixture was stirred and warmed slowly to room temperature, then stirred at room temperature overnight. An aqueous solution of 5% NaHCO3 (100 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. Removal of the solvent gave 4-formylphenyl morpholine-4-carboxylate (8.80 g) as white solid. Yield: 75%. 1H NMR (CDCl3, 300 MHz): δ=9.97 (s, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.30 (d, J=9.0 Hz, 2H), 3.77-3.57 (m, 6H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): δ=191.0, 156.0, 152.6, 133.6, 131.1, 122.3, 66.5, 66.4, 45.0, 44.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH:11]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccnc(Cl)n1
Reaction time: 14 h
Yield: 90 %

Procedure:
To a solution of 2-chloropyrimidine-4-carboxylic acid (1.0 g, 6.31 mmol) in 1:1 benzene (5 mL) and MeOH (5 mL) at 0° C. was added trimethylsilyl-diazomethane (2.0 M solution in hexanes, 3.78 mL, 7.57 mmol) dropwise. The solution was left to stir for 14 hr and concentrated to dryness. Flash chromatography on silica (0-100% EtOAc/hexanes) afforded methyl 2-chloropyrimidine-4-carboxylate (980 mg, 5.68 mmol, 90% yield) as a yellow oil. MS ESI: [M+H]+ m/z 173.0. 1H NMR (500 MHz, CDCl3) δ 8.88 (dd, J=1.5, 4.9, 1H), 7.96 (dd, J=1.5, 4.9, 1H), 4.04 (d, J=1.5, 3H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O1[C:7]23[C@:23]([CH3:28])([CH2:24][CH2:25][C:26](=[O:27])[CH:6]12)[C@@H:22]1[C@H:10]([C@H:11]2[C@:19]([CH3:29])([CH2:20][CH2:21]1)[C@@H:14]([C@H:15]([CH3:18])[CH2:16][OH:17])[CH2:13][CH2:12]2)[CH2:9][CH2:8]3.[N-:30]=[N+:31]=[N-:32].[Na+].S(=O)(=O)(O)O.O>CS(C)=O>[C:1]([OH:4])(=[O:3])[CH3:2].[N:30]([C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17])=[N+:31]=[N-:32]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a vigorously stirred solution of the (20S)-4,5-epoxy21-hydroxy-20-methylpregnan-3-one acetate (3.0 g, 7.72 mmole) obtained in the preceding example, in dimethyl sulfoxide (100 mL), there was added sodium azide (8.2 g) and then concentrated sulfuric acid (0.55 mL). The mixture was heated at 60° C. for 1.5 hours and the cooled mixture was poured into cold water (700 mL). After stirring for 30 minutes, the solids were collected by filtration, washed with water and dried by suction. The resulting solid was purified by flash chromatography on silica gel to give (20S)-4-azido-21-hydroxy-20-methylpregn-4-en-3-one acetate as a white solid (1.6 g, 50.1%), melting at 137°-138° C., with decomposition, after recrystallization from aqueous acetone. IR 2110, 1736, 1670, 1588 (m), 1254 cm-1 ; MS (CI) 386 (3%, M +1 -N2), 326 (100%, M+1 -N2 -AcOH); 1H NMR (CDCl3) δ 0.72 (3H, s, C18 -Me), 1.01 (d, C22 -Me), 1.14 (s, C19 -Me), 2.06 (s, Ac-Me), 3.02 (1H, dq, C6 -H), 3.77 (1H, dd, 1/2 C21 -CH2), 4.08 (1H, dd, 1/2 C21 -CH2).
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])([O-:9])=[O:8].[ClH:19].[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[ClH:19].[N+:7]([C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][C:28]1[CH:27]=[CH:26][C:25]2[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=2)[C:29]=1[CH2:33][C:34](=[O:36])[NH2:35])=[O:13])([O-:9])=[O:8]
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccccc3[N+](=O)[O-])ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
50 Milliliters of anhydrous pyridine and 20 ml of DMF were added to 5.0 g of 2-nitrobenzoic acid, 3.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 4.4 g of DCC and 218.2 mg of DMAP, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. Then, the precipitate was filtered and washed with 100 ml of warm DMF. This wash liquid and the filtrate were combined, and the solvent was distilled off under reduced pressure. To the residue was added 20 ml of DMF, and the resulting solution was added dropwise to 600 ml of acetone, followed by stirring for 2 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using chloroformmethanol-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To 1/2 of the residue were added 20 ml of methanol and 1.4 ml of concentrated hydrochloric acid to suspend the residue. The suspension was added dropwise to a mixed liquid of 200 ml of ether and 200 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 2.42 g of 6-amidino-1-carbamoylmethyl-2-naphthyl 2-nitrobenzoate.hydrochloride.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]([O:13][CH2:14][CH2:15][F:16])=[O:12].ClCCl.Cl.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[CH:39]=[C:38]([O:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[N:37]=[CH:36][N:35]=1)[CH2:29][CH2:28]2)(=[O:24])=[O:23]>O>[CH3:21][S:22]([C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([C:34]1[N:35]=[CH:36][N:37]=[C:38]([O:40][CH:41]3[CH2:46][CH2:45][N:44]([C:11]([O:13][CH2:14][CH2:15][F:16])=[O:12])[CH2:43][CH2:42]3)[CH:39]=1)[CH2:29][CH2:28]2)(=[O:24])=[O:23]
Reactant: O=C(Cl)OCCF
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OCCF)CC2)ncn1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 36.2 %

Procedure:
Diisopropylethylamine (178 μL, 0.997 mmol) and (2-fluoroethyl) chloroformate (33 μL, 0.350 mmol) were added at 0° C. to a dichloromethane (2 mL) suspension of the 5-(methylsulfonyl)-1-[6-(piperidin-4-yloxy)pyrimidin-4-yl]indoline hydrochloride (188 mg, 0.396 mmol) produced in Reference Example 27, and the mixture was stirred at room temperature for 80 minutes. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [(i) hexane:dichloromethane=1:1, V/V; (ii) hexane:ethyl acetate:dichloromethane=2:1:2-1:1:1-2:2:1, V/V; (iii) ethyl acetate:dichloromethane=1:1, V/V] to obtain the title compound as white powder (58.8 mg, yield: 38%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][C:31]([NH:33][CH3:34])=[O:32])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][C:31]([NH:33][CH3:34])=[O:32])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)Cn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(methylamino)-2-oxoethyl)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (69.0 mg, 115 μmol) in dichloromethane (3.00 mL) under Ar, trifluoroacetic acid (372 mg, 0.25 mL, 3.26 mmol) was added at 25° C. After 18 h, the solvent was removed and the residue was dissolved in a mix of dichloromethane/methanol/NH3OH (3:2:0.25, 5.25 mL) and stirred. After 2.5 h, the reaction was concentrated and dried in vacuo (200 mTorr, 25° C.). The solid residue was triturated with water (50 mL) and isolated by filtration. The solid was washed with water and hexanes and dried in vacuo (200 mTorr, 40° C.) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(2-(methylamino)-2-oxoethyl)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (45.6 mg, 91.9 μmol, 80%) as a light brown solid. MS (M)'=472; 1H NMR (DMSO-d6) δ: 12.83 (br. s, 1H), 9.04 (s, 1H), 8.39 (d, J=2.8 Hz, 1H), 8.21 (m, 2H), 7.89 (s, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.40 (dd, J=2.0, 9.0 Hz, 1H), 7.20 (t, J=74.3 Hz, 1H), 5.24 (s 2H), 2.65 (m, 3H), 1.51 (s, 9H).