Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:12](=[O:16])[O:13][C:14](=[O:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[BH4-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:11]2[C:12](=[O:16])[O:13][CH2:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[Cl:1][C:2]1[C:11]2[CH2:12][O:13][C:14](=[O:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: O=C1OC(=O)c2c1c(Cl)nc1ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OCc2c(Cl)nc3ccccc3c21
Product: O=C1OCc2c1c(Cl)nc1ccccc21
Reaction time: 2 h

Procedure:
To a well stirred mixture of 4-Chloro-furo[3,4-c]quinoline-1,3-dione (1.9 g) in tetrahydrofuran (10 mL) was added sodium borohydride (400 mg) at 0° C. and stirring was continued for 2 h. The reaction was then quenched with excess 6N HCl and water, and concentrated in vacuo to afford 4-Chloro-furo[3,4-c]quinolin-3(1H)-one as a pink solid along with a small quantity of 4-Chloro-furo[3,4-c]quinolin-1(3H)-one which could be isolated by column chromatography on silica gel.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=1)(=[O:7])=[O:6].[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C.[Li]CCCC>C1COCC1>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][O:4][S:5]([C:8]1[CH:9]=[C:10]([B:17]([OH:22])[OH:18])[CH:11]=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)COS(=O)(=O)c1cccc(B(O)O)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Step 2) To a solution of the above prepared 3-bromo-benzenesulfonic acid 2,2-dimethyl-propyl ester (9.83 g, 32 mmol) and triisopropyl borate (13.4 mL, 58 mmol) in THF (45 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 20 mL, 32 mmol) keeping the internal temperature below −65° C. Stirring was continued at −78° C. for 1 h, then more n-BuLi (4.0 mL, 6.4 mmol) was added and stirring was continued at −78° C. for 30 min. The reaction mixture was quenched with 1 M H2SO4-sol. (40 mL), allowed to quickly (waterbath) warm to ca. 20° C. and stirred for 10 min. Diluted with EtOAc, layers were separated, washed organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left the title compound as white solid (9.00 g, 103%). MS (ISN) 271.4 [(M−H)−].
Reaction SMILES: [CH2:1]([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=[O:15])[CH3:14].[Cl:16][CH2:17][C:18]1[O:23][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([F:32])([F:31])[F:30])[C:20]=2[N:19]=1.Cl>CCCCCC.O1CCCC1.O>[Cl:16][CH:17]([CH3:1])[C:18]([NH:19][C:20]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](=[O:24])[CH2:14][C:13]([NH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=1)=[O:15])=[O:23]
Reactant: CC(=O)Nc1ccccn1
Reactant: [Li]CCCC
Reactant: O=c1oc(CCl)nc2c(C(F)(F)F)cccc12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(Cl)C(=O)Nc1c(C(=O)CC(=O)Nc2ccccn2)cccc1C(F)(F)F
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
14 ml of a solution of butyllithium in hexane were added under argon at -5° to 0° C. over 30 minutes to a solution of 1.36 g of N-(2-pyridinyl)-acetamide in 27.2 ml of tetrahydrofuran and the mixture was stirred under argon at -5° C. for 15 minutes and was then cooled to -70° C. A solution of 1.38 g of 2-(1-chloromethyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one [prepared in Step A of Example 14 of U.S. patent application Ser. No. 262,952] in 13.8 ml of tetrahydrofuran was added at -70° C. under argon over 30 minutes to the mixture which was stirred at -70° C. for one hour and was poured into a mixture of 200 ml of iced water and 10 ml of concentrated hydrochloric acid. The mixture was stirred at room temperature for 30 minutes and was extracted three times with 100 ml of ethyl acetate. The combined organic phases were washed twice with 75 ml of water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an 8-2 ethyl acetate-cyclohexane mixture. The product was taken up in ether and the mixture was filtered. The product was dried to obtain 1.2 g of 2- [(2-chloro-1-oxo-propyl)-amino]-β-oxo-N-(2-pyridinyl)-3-trifluoromethyl-benzene-propanamide melting towards 150° C.
Reaction SMILES: C([N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2([CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[N:3]1([C:28]([CH:25]2[CH2:26][CH2:27][C:20]3([CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH2:22][CH2:21]3)[CH2:23][CH2:24]2)=[O:30])[CH2:4][CH2:6][CH2:9][CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)O)CC2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)N3CCCC3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Ethyl-diisopropylamine (4 eq.) was added to a solution of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (commercially obtainable from Anthem, Order No. A1106) (0.35 g, 1.18 mmol, 1 eq.) in methylene chloride. The reaction mixture was cooled to 0° C. and N-ethyl-N′-3-(dimethylamino)-propyl-carbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (0.2 eq.) were then added. The mixture was stirred at this temperature for 15 min, before the amine (1.1 eq.) was finally added. The reaction mixture was then stirred at room temperature overnight. For working up, the reaction mixture was washed in each case 1× with 10% strength NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica; ethyl acetate/ethanol) in order to obtain the desired product. Yield: 0.23 g (56%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.[CH:13]([NH2:16])([CH3:15])[CH3:14]>>[CH:13]([NH:16][C:2]1[N:7]=[C:6]([NH:16][CH:13]([CH3:15])[CH3:14])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:9][CH:5]([CH3:6])[CH3:4])[N:3]=1)([CH3:15])[CH3:14]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1c(Cl)nc(Cl)nc1Cl
Product: CC(C)Nc1nc(NC(C)C)c([N+](=O)[O-])c(NC(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 148.5 %

Procedure:
1.15 g (0.005 mol) of 2,4,6-trichloro-5-nitropyrimidine are dissolved in 50 ml of alcohol and the solution is then treated with 2.9 g (0.05 mol) of isopropylamine. The mixture is stirred for 3 hours at room temperature after the temperature has first risen to 35° C, and then it is evaporated. The residue is treated with 100 ml of water and extracted twice with ether. The ethereal extract is dried over MgSO4 for 4 hours, filtered, and evaporated, to yield 1.1 g of 2,4,6-tri-isopropylamino-5-nitro-pyrimidine as an oil; b.p. 185° C at 0.001 Torr.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([OH:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:11]([O:13][C:14](=[O:27])[C@@H:15]([O:24][CH2:25][CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1)[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:11]([O:13][C:14](=[O:27])[C@@H:15]([O:24][CH2:25][CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:9][C@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[CH3:8])=[CH:19][CH:18]=1)[CH3:12]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(O[C@@H](C)C(=O)OC(C)(C)C)cc1)OCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
To a solution of 2-(R)-hydroxypropionic acid tert-butyl ester (1.23 g, 8.44 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.01 g, 8.44 mmol) in THF (100 ml) was added the triphenyl phosphine (2.21 g, 8.44 mmol). The mixture was cooled to 0° C. and added the DIAD (diisopropyl azodicarboxylate) (1.70 g, 8.44 mmol) dropwise over 5 minutes. The reaction mixture was stirred for 18 hours while warmed to room temperature. The reaction was quenched with water (2 ml) and concentrated to a residue, purified by silica gel chromatography with 20% EtOAc/Hexanes to afford product (0.99 g, 32%) and recovered starting material ((S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester, 0.85 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O>C(#N)C.CCOCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:1][CH2:2][CH2:3][CH2:4]2
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOCC
Product: Brc1ccc2c(c1)CCCN2
Temperature: 0 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
1,2,3,4-tetrahydroquinoline (1.7 g, 12.8 mmol) was dissolved in acetonitrile (25 mL) and cooled to 0° C. N-Bromosuccinimide (2.16 g, 12.2 mmol) was added in 4 portions over 30 minutes and the mixture was stirred for 3 hours. The mixture was diluted with ether and washed with sodium bisulfite, water, brine, dried over anhydrous magnesium sulfate, and concentrated. Purification via Isco chromatography (the Redisep® column, silica, gradient 5%-30% ethyl acetate in hexane) afforded 6-bromo-1,2,3,4-tetrahydroquinoline (1.5 g). MS (ES) m/z 211.8; HPLC purity 100.0% at 210-370 nm, 10.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammonium formate buffer pH=3.5 acetonitrile+MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](N(OC)C)=[O:10].[Li][CH2:16][CH2:17][CH2:18][CH3:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:10])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Cl
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirring hazy solution of 2,4-dichloro-N-methoxy-N-methylbenzenecarboxamide (1 g, 4.27 mmol), in THF (20 ml) is added BuLi (2.051 ml, 5.13 mmol) in portions. The reaction is stirred for 4 hours at RT and the partitioned between 1M HCl (100 ml) and EtOAc (140 ml). The organic portion is washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography eluting with 0 to 100% EtOAc/iso-hexane on a 40 g silica-column to yield 1-(2,4-dichloro-phenyl)-pentan-1-one as a brown oil; 1H NMR (400 MHz, CDCl3) δ 7.45 (1H, d, J 2.0), 7.43 (1H, d, J 7.3), 7.32 (1H, dd, J 7.3, 2.0), 2.94 (2H, t, J 7.4), 1.70 (2H, m), 1.40 (2H, m), 0.95 (3H, t, J 7.3).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]2[C:21]3[CH:22]=[C:23]([C:26]#[N:27])[CH:24]=[CH:25][C:20]=3[O:19][C:18]([CH3:29])([CH3:28])[CH2:17]2)=[N+:13]([O-:15])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[C:26]([C:23]1[CH:24]=[CH:25][C:20]2[O:19][C:18]([CH3:29])([CH3:28])[CH2:17][CH:16]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N+:13]=3[O-:15])[C:21]=2[CH:22]=1)#[N:27]
Reactant: CC1(C)CC(c2ccc(OCc3ccccc3)c[n+]2[O-])c2cc(C#N)ccc2O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)CC(c2ccc(O)c[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 31.1 %

Procedure:
0.21 g of 5-benzyloxy-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide in 90 ml of methanol was hydrogenated over 10% palladium-on-carbon at room temperature and under atmospheric pressure for 30 minutes. The catalyst was removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (19:1) for the elution to give 0.05 g of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-hydroxypyridine N-oxide in the form of an off-white solid of melting point 224° C (from ethyl acetate).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]=3)=[CH:11][C:3]=12.[F:35][C:36]1[CH:37]=[CH:38][C:39]([O:45][CH3:46])=[C:40](B(O)O)[CH:41]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CN(C)C=O.O>[Cl:8][C:7]1[C:2]([C:38]2[CH:37]=[C:36]([F:35])[CH:41]=[CH:40][C:39]=2[O:45][CH3:46])=[C:3]2[CH:11]=[C:10]([C:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH:13]=3)[N:9]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:4]2=[N:5][CH:6]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Cc1ccc(S(=O)(=O)n2c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1-c1c(Cl)cnc2c1cc(C1=CCN(C(=O)OC(C)(C)C)CC1)n2S(=O)(=O)c1ccc(C)cc1
Temperature: 110 °C

Procedure:
A mixture of Example 229C (0.16 g, 0.306 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (0.062 g, 0.368 mmol) and sodium hydrogencarbonate (0.103 g, 1.225 mmol) in degassed N,N-dimethylformamide (2.55 mL) and water (0.851 mL) was treated with 1,1′-bis(di-t-butylphosphino)ferrocenepalladium dichloride (TCI, 0.014 g, 0.021 mmol) under nitrogen and the mixture was heated at 110° C. for 10 minutes in a Biotage Initiator microwave reactor. Water and ethyl acetate was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography on silica gel (AnaLogix IntelliFlash 280) eluting with a gradient of 0-45% ethyl acetate in heptanes afforded the title compound. MS (ESI+) m/z 612.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:24](=[O:25])[N:22]([CH:23]=1)[CH2:21][C@@H:20](O)[CH2:19][NH:18][C:17](=[O:27])[C:16]1=[C:28]3[N:29]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1.COCCN(S(F)(F)[F:40])CCOC.C(O)C.C([O-])(O)=O.[Na+]>CS(C)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:24](=[O:25])[N:22]([CH:23]=1)[CH2:21][C@H:20]([F:40])[CH2:19][NH:18][C:17](=[O:27])[C:16]1=[C:28]3[N:29]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1NC[C@H](O)Cn2cc(F)cc(c2=O)[C@H]2CCCN2c2ccn3ncc1c3n2
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C1NC[C@@H](F)Cn2cc(F)cc(c2=O)[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.9 %

Procedure:
A solution of (6R,13S)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.17,11.02,6.020,24]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione (Example 5; 10 mg, 0.0251 mmol) in a mixture solvent of DCM (0.3 mL) and 3 drops of DMSO was treated with bis(2-methoxyethyl)amino-sulfur trifluoride (7.87 μL, 0.0427 mmol) at 0° C., followed by addition of a DCM (0.1 mL) solution of ethanol (0.231 mg, 0.00502 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was poured into saturated NaHCO3 and extracted with DCM, then dried (Na2SO4), filtered, and concentrated. The crude material was purified by reverse phase column chromatography (Biotage SP4 system C18 12+M cartridge, acetonitrile/water 5 to 50%) to give the title product as beige solid (1.3 mg, 12% yield). MS (apci) m/z=401.2 (M+H).
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)([O-:7])=[O:6].[N+:13]([O-])([OH:15])=[O:14]>O>[N+:13]([N:11]1[CH:12]=[C:8]([N+:5]([O-:7])=[O:6])[N:9]=[CH:10]1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Reaction time: 1 h

Procedure:
430 mL of acetic acid and 188 g of 4-nitroimidazole were charged into a 2 L-volume reactor and stirred. While stirring the mixture, 100% nitric acid(137 mL) was slowly added dropwise to the mixture at the reaction temperature of 35° C. Anhydrous acetic acid(318 mL) was added dropwise thereto at 25° C. over 1 hour. After stirring the reaction mixture at 25° C. for 2 days, 1,4-dinitroimidazole was synthesized. Then, the resultant was poured in 2 L cold water, and extracted three times with 500 mL of methyl chloride for each time. The obtained methylene chloride solution was dried over MgSO4 so as to completely remove the water therefrom, resulting in methylene chloride extract solution containing 1,4-dinitroimidazole. The structure of the obtained 1,4-dinitroimidazole was as same as that of the comparative example.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 5-trimethylsilanylethynyl-pyridin-2-ylamine (26 mg, 137 mmol) described in Manufacturing Example 28-1-2 in tetrahydrofuran (1 mL) and methanol (1 mL) was added potassium carbonate (37.9 mg, 274 mmol) at room temperature, which was stirred for 1 hour at room temperature. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (16 mg, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6](Cl)[C:3]=1[C:4]#[N:5].[CH3:14][CH:15]([C:21]([CH3:23])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([NH2:1])[C:3]=1[C:4]#[N:5])([CH3:14])[C:21](=[O:22])[CH3:23])[CH3:20]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(C)=O)c1ccc([N+](=O)[O-])c(N)c1C#N
Reaction time: 24 h
Yield: 45.5 %

Procedure:
To a solution of 2-amino-6-chloro-3-nitrobenzonitrile (1.97 g, 10 mmol) and ethyl 2-methylacetoacetate (3.6 g, 25 mmol) in DMF (10 mL) was added finely powdered K2CO3, and the mixture stirred vigorously for 24 h. The deep red mixture was diluted with EtOAc and washed in turn with 2M HCl, water and brine. The residue after evaporation was purified by flash chromatography in hexane/EtOAc 3:1 to yield 2-(3-amino-2-cyano-4-nitrophenyl)-2-methyl-3-oxobutyric acid ethyl ester as an oil (1.39 g, 46%), MS (NH3 CI) 323 (M+NH4+), 293 (M+NH4—NO+).
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].[N+:36]([C:39]1[C:48]2[N:47]=[C:46]([C:49]([F:52])([F:51])[F:50])[O:45][C:44](=[O:53])[C:43]=2[CH:42]=[CH:41][CH:40]=1)([O-:38])=[O:37].[OH-].[Na+]>O1CCOCC1>[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[NH:1][C:44](=[O:53])[C:43]1[CH:42]=[CH:41][CH:40]=[C:39]([N+:36]([O-:38])=[O:37])[C:48]=1[NH:47][C:46](=[O:45])[C:49]([F:51])([F:52])[F:50])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1N
Reactant: O=c1oc(C(F)(F)F)nc2c([N+](=O)[O-])cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc([N+](=O)[O-])c1NC(=O)C(F)(F)F
Temperature: 100 °C
Reaction time: 4 h
Yield: 114.8 %

Procedure:
To a solution of 4-amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (6.0 g) in 1,4-dioxane (200 ml) was added 8-nitro-2-trifluoromethyl-3,1-benzoxazin-4-one (3.24 g) and the mixture was stirred at 100° C. for 4 hours. To the mixture was added 8-nitro-2-trifluoromethyl-3,1-benzoxazin-4-one (3.24 g). and the solution was stirred at 100° C. for additional 3 hours. To the mixture was added 1N sodium hydroxide solution (90 ml) and the resulting solution was stirred at 60° C. for 1 hour. After being concentrated in vacuo, the residue was diluted with chloroform and the organic solution was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate and the solvent was concentrated in vacuo to give 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(3-nitro-2-trifluoroacetylaminobenzoyl)aminobenzamide as a yellow powder (10.6 g). The crude product was used for next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([N:15]3[CH2:20][CH2:19][CH:18]([O:21]C4CCCCO4)[CH2:17][CH2:16]3)(=[O:14])=[O:13])=[CH:8][C:7]=2[C:28]2[C:29]3[CH:38]=[CH:37][NH:36][C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:3][CH2:2]1.C(O)(=O)C.O1CCCC1>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([N:15]3[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)(=[O:13])=[O:14])=[CH:8][C:7]=2[C:28]2[C:29]3[CH:38]=[CH:37][NH:36][C:30]=3[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2cc(S(=O)(=O)N3CCC(OC4CCCCO4)CC3)ccc2OCC2CC2)c2cc[nH]c2c1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2cc(S(=O)(=O)N3CCC(O)CC3)ccc2OCC2CC2)c2cc[nH]c2c1=O
Yield: 65.6 %

Procedure:
A solution of Example 354e (54 mg, 0.10 mmol), acetic acid (4 mL, 69.9 mmol), tetrahydrofuran (2 mL) and water (1 mL) was stirred at 45° C. for 2.5 hours. The reaction mixture was concentrated to dryness and the residue was dried overnight (in-vacuo). The crude product was triturated with diethyl ether, filtered and dried (in-vacuo) to afford the title compound (30 mg, 66% yield). 1H NMR (300 MHz, DMSO-d6) ppm 0.25-0.31 (m, 2H) 0.44-0.51 (m, 2H) 1.08-1.17 (m, 1H) 1.38-1.51 (m, 2H) 1.70-1.80 (m, 2H) 2.70-2.80 (m, 2H) 3.10-3.18 (m, 2H) 3.51-3.56 (m, 1H) 3.57 (s, 3H) 3.97 (d, J=6.78 Hz, 2H) 4.66 (d, J=4.07 Hz, 1H) 6.12 (t, J=2.71, 2.03 Hz, 1H) 7.27-7.32 (m, 2H) 7.36 (s, 1H) 7.64-7.70 (m, 2H) 12.04 (brs, 1H). MS (ESI+) m/z 458 [M+H]+.
Reaction SMILES: [O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C@@H:23]2[OH:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([O:26][C@H:23]1[CH2:22][CH2:21][C@@:20]2([CH3:27])[C:25]3[C@:2]4([O:1][C:24]1=3)[O:29][C@H:3]4[C@@H:4]1[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:28])[C@H:5]1[CH2:6][CH2:7][C@@H:8]2[CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4OC(C)=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 14 h
Yield: 83 %

Procedure:
To a mixture of 0.202 g (0.50 mmole) of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3β-ol, 0.5 ml (6.18 mmoles) of dry pyridine and 10 ml of methylene chloride was gradually added 0.1 ml (1.06 mmoles) of acetic anhydride dropwise at a temperature of 0° C. and the resulting solution was stirred at room temperature for 14 hours. The reaction mixture was then worked up in the same manner as Example 10 to recover 0.185 g of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-ene-3β-yl acetate (yield: 83%).