Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH:25]=[C:24]([C:26]#[N:27])[N:23]=[CH:22]1.C(#N)C.C(N(CC)CC)C>O.CCCCCC>[C:7]([N:21]1[CH:25]=[C:24]([C:26]#[N:27])[N:23]=[CH:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a mixture containing triphenylmethyl chloride (1.647 g, 5.91 mmol), 1H-imidazole-4-carbonitrile (0.5 g, 5.37 mmol) and dry acetonitrile (17 ml), triethylamine (1.295 ml, 9.29 mmol) was added dropwise and the resulting mixture stirred overnight at RT. Hexane (1.6 ml) and water (17 ml) were poured into the mixture and the stirring was continued for another 30 min. The precipitate was filtered and dried with vacuum. 1H-NMR (400 MHz; CDCl3): δ 7.06-7.12 (m, 6H), 7.35-7.40 (m, 10H), 7.49 (d, 1H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]([CH3:36])[CH2:32][C:33](O)=[O:34].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]3[CH2:29][CH2:28][N:27]([C:33](=[O:34])[CH2:32][N:31]([CH3:36])[CH3:30])[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[C:22]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)CC1
Temperature: 25 °C
Yield: 50 %

Procedure:
A mixture of 3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.054 g, 0.00014 mol), 2-(dimethylamino)acetic acid (0.0018 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.033 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for eighteen hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(dimethylamino)-1-ethanone (0.031 g, 0.00007 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:23])=[N:14][C:15]4[C:20]([N:21]=3)=[CH:19][C:18]([F:22])=[CH:17][CH:16]=4)[CH:11]=[C:4]2[N:3]=1.[NH2:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:23])=[N:14][C:15]4[C:20](=[CH:19][C:18]([F:22])=[CH:17][CH:16]=4)[N:21]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: Cc1nc2ccc(F)cc2nc1-c1cc2nc(Cl)cc(Cl)n2n1
Reactant: CC(C)(O)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(F)cc2nc1-c1cc2nc(Cl)cc(NCC(C)(C)O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-2-yl)-6-fluoro-2-methylquinoxaline (157 mg, 0.451 mmol) in N,N-dimethylformamide (4.0 mL), 1-amino-2-methyl-propan-2-ol (48 mg, 0.541 mmol), and potassium carbonate (187 mg, 1.35 mmol) was stirred at room temperature for 2 h. The reaction mixture was poured into ice-cooled water, and the resulting precipitate was collected and washed with water to give 1-{[5-chloro-2-(7-fluoro-3-methylquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2-methylpropan-2-ol. MS (APCI): m/z 401/403 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](I)[C:3]=1[O:10][CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].C([O-])=O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CC#N.CC#N.Cl[Pd]Cl.CN(C=O)C>[CH2:13]([C:12]1[C:4]2[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([Br:1])[C:3]=2[O:10][CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(Br)c(OCC=Cc2ccccc2)c(I)c1
Agent: Cl[Pd]Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(Br)c2occ(Cc3ccccc3)c2c1
Temperature: 80 °C
Yield: 52.7 %

Procedure:
1-Bromo-3-iodo-5-methyl-2-(3-phenylallyloxy)-benzene (10.86 g, 25 mmol), tetrabutylammonium chloride (7.65 gm, 27.5 mmol), sodium carbonate (6.62 g, 62.46 mmol), sodium formate (1.7 g, 25 mmol), and bis(acetonitrile)dichloropalladium(II) (0.467 g, 1.8 mmol) was added to 50 ml DMF. The mixture was degassed and heated under nitrogen at 80° C. for 105 minutes, then cooled to room temperature. Water was added and the mixture was extracted with a hexanes/ethyl acetate (1:1) mixture. The solution was dried onto 20 gm silica gel, the silica gel was layered over 100 gm silica gel in a fritted funnel and eluted with four 400 ml portions of hexanes. The hexanes was removed under reduced pressure to give 3-benzyl-7-bromo-5-methyl-benzofuran (3.97 g, 52% yield). MS: (M+H)+ 302.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[C:9]([N+:20]([O-])=O)[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H][H]>O1CCCC1.[Pd]>[NH2:20][C:9]1[CH:8]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:19]=[CH:18][C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCOCC2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(N2CCOCC2)cc1N
Yield: 3.9 %

Procedure:
127 g (0.412 mol) of tert-butyl 4-morpholin-4-yl-2-nitrobenzoate (WO 2007/06837 A1) were dissolved in 1000 ml of tetrahydrofuran, 12.7 g of palladium/carbon (5%, water-moist) were added, and the mixture was stirred over hydrogen at room temperature for 5 h. Conventional work-up gave 4.5 g (Y=100%) of tert-butyl 2-amino-4-morpholin-4-ylbenzoate.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[Cl:28][C:29]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([O:39][CH3:40])=[CH:33][C:30]=1[CH2:31][OH:32].CCOC(C)=O>C(Cl)Cl>[Cl:28][C:29]1[C:36]([O:37][CH3:38])=[CH:35][C:34]([O:39][CH3:40])=[CH:33][C:30]=1[CH:31]=[O:32]
Reactant: COc1cc(CO)c(Cl)c(OC)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1cc(C=O)c(Cl)c(OC)c1
Reaction time: 0.25 h

Procedure:
To a suspension of Dess-Martin periodinane (1.38 g, 32.5 mmol) in CH2Cl2 (120 mL) was added tert-butanol (3.05 mL, 32.5 mmol). After stirring for 15 min, a sol. of 2-chloro-3,5-dimethoxybenzyl alcohol (H. Newman, R. B. Angier, J. Org. Chem., 1966, 31, 1462-1464, 5.06 g, 25.0 mmol) in CH2Cl2 (20 mL) was added. After stirring for 1 h, EtOAc (200 mL) was added and the mixture was washed with aq. 1M NaOH. The org. phase was evaporated, and the crude product was dissolved again in EtOAc (200 mL), and washed successively with aq. 1M NaOH (2×), water (2×) and brine. The org. phase was dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The aldehyde was used without further purification. LC-MS: tR=0.92 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.C(=O)([O-])[O-].[Na+].[Na+].[C:15]([O:19][C:20](=[O:30])[NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1Br)([CH3:18])([CH3:17])[CH3:16].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:1]1[CH:5]=[CH:4][C:3]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][NH:21][C:20](=[O:30])[O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:2]1
Reactant: OB(O)c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccccc1-c1cc[nH]n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 1H-pyrazol-3-ylboronic acid (156 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (242 mg, 0.21 mmol), and sodium carbonate (222 mg, 2.1 mmol) in dimethylformamide (2 ml), was added tert-butyl-2-bromobenzylcarbamate (200 mg, 0.699 mmol). The suspension was stirred at 100° C. for 2 h, cooled to room temperature, poured onto saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate and concentrated in vacuo. The crude material was passed through silica (ISCO, 0–30% ethyl acetate/hexane) to give tert-butyl 2-(1H-pyrazol-3-yl)benzylcarbamate; MS (ES+) M+1 274.1 for C15H19N3O2.
Reaction SMILES: [OH:1]O.[CH2:3]([NH:5][C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH2:19][OH:20])[CH2:16]3)=[CH:12][C:10]=2[N:11]=1)[CH3:4]>CC(O)=O.C([O-])(O)=O.[Na+]>[CH2:3]([NH:5][C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:18]=[C:17]3[C:13]([CH2:14][CH:15]([CH2:19][OH:20])[CH2:16]3)=[CH:12][C:10]=2[N+:11]=1[O-:1])[CH3:4]
Reactant: OO
Reactant: CCNc1nc2cc3c(cc2[n+]([O-])n1)CC(CO)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(CO)C3
Temperature: 50 °C
Reaction time: 20 h
Yield: 14.7 %

Procedure:
H2O2 (70%, 1.0 mL, ca. 20.0 mmol) was added dropwise to a stirred solution of 1-oxide 126 (71 mg, 0.27 mmol) in HOAc (3 mL) at 50° C. and the reaction was stirred at 50° C. for 20 h. The mixture was diluted with aqueous NaHCO3 solution and extracted with DCM (5×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-4%) of MeOH/DCM, to give 1,4-dioxide 127 (11 mg, 15%) as a red solid: mp (MeOH/DCM) 153-155° C.; 1H NMR δ 8.10 (s, 1H, H-9), 8.05 (s, 1H, H-5), 7.01 (br s, 1H, NH), 3.69 (d, J=6.5 Hz, 2H, CH2O), 3.59-3.67 (m, 2H, CH2N), 3.15-3.28 (m, 2H, CH2), 2.90-3.03 (m, 2H, CH2), 2.72-2.86 (m, 1H, CH), 1.35 (t, J=7.2 Hz, 3H, CH3), OH not observed; HRMS calcd for C13H16N4O3 (M+) m/z 276.1222, found 276.1222.
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][C:12](=[O:13])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(=O)C.S(=O)(=O)(O)O>O.C(O)(C)C>[CH2:1]([N:8]1[C:15](=[O:16])[C:14](=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12](=[O:13])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CC(=O)N(c2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: O=C1C(=Cc2ccccc2)C(=O)N(c2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 50 °C
Yield: 75 %

Procedure:
In a 300-ml glass flask equipped with a thermometer, a reflux condenser and a stirrer, 4.0 g of 1-benzyl-3-phenylbarbituric acid, 1.6 g of benzaldehyde, and 40 ml of acetic acid were put, the content was added with a drop of sulfuric acid, kept under stirring, the flask was heated so as to adjust the inner temperature to 100° C., and the content was continued to be stirred at 100° C. for 3 hours. The content was then cooled to 50° C., added with a mixed solution of 39 ml of isopropanol and 17 ml of water, stirred at 10° C. or below for one hour, filtered under suction to collect a deposited crystal, and the crystal was washed with methanol, to thereby obtain 3.9 g of 1-benzyl-5-benzylidene-3-phenylbarbituric acid as an intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1.N1C=CC=CC=1>O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:11](=[N:12][N:13]([C:33]4[C:28]([CH3:27])=[N:29][CH:30]=[CH:31][CH:32]=4)[C:14]=3[CH3:16])[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ncccc1B(O)O
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Product: Cc1ncccc1-n1nc2c(c1C)C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 4.4 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 81.1) (200 mg, 0.542 mmol) in CAN (4 mL) with molecular sieves (4 g) under Ar were added 2-methylpyridine-3-boronic acid (166 mg, 1.085 mmol), pyridine (0.088 mL, 1.085 mmol) and copper(II) acetate (148 mg, 0.813 mmol) and the reaction mixture was stirred 10 min at 65° C. 2-methylpyridine-3-boronic acid (1.485 g, 10.85 mmol) was added portionwise over a period of 1 hr. The reaction mixture was concentrated under reduced pressure, quenched with a saturated aq. NaHCO3 solution and the aq. layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 1.5-5%). followed by preparative achiral SFC (column 4-Ethyl-pyridine, gradient 13-18% in 6 min_total 11 min) and triturated in Hexane/Et2O (1:1) to afford the title product (11 mg, 0.024 mmol, 4% yield). tR: 3.20 min (HPLC 1); tR: 0.87 min (LC-MS 2); ESI-MS: 460 [M+H]+ (LC-MS 2); Rf=0.53 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6)6 ppm 1.89 (s, 3H) 1.93 (s, 3H) 2.18 (s, 3H) 3.37 (s, 3H) 6.23 (s, 1H) 7.28-7.49 (m, 6H) 7.77 (d, J=2.7 Hz, 1H) 7.88 (dd, J=7.8, 1.56 Hz, 1H) 8.63 (dd, J=4.9, 1.4 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][S:9][C:5]=2[CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:8][S:9][C:5]=2[CH:4]=1
Reactant: N#Cc1ccc2c(-c3ccccc3)csc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc2c(-c3ccccc3)csc2c1
Reaction time: 2 h

Procedure:
Dissolve 6-cyano-3-phenylbenzothiophene (0.27 g, 1.16 mmol) in anhydrous THF (6 mL) and add lithium aluminum hydride (3.45 mL, 1M solution in THF) at 0° C. After 2 h, add water (0.86 mL), 2N aqueous NaOH (0.86 mL) and water (1.24 mL). Filter off the solids and evaporate the residue. Purify by prep HPLC (Zorbax SB-Phenyl column 21.2×250 mm, 5% to 50% acetonitrile in 0.1% TFA-water solution) and obtain the free base by SCX chromatography to give the title compound that is used without further purification (187 mg, 68%). MS (ES+) m/z: 223 (M-NH2)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18]3(OCC[O:27]3)[CH:17]=[CH:16]4)[C@H:13]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[C@H:13]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCOCC
Product: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC2=O
Yield: 85.1 %

Procedure:
A solution of 32.8 g of 3-benzyloxy-17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraene in 328 ml of acetone and 32.8 ml of water is stirred at room temperature with 1.033 g of para-toluenesulfonic acid for 2 hours. Then, it is diluted with diethyl ether, washed with sodium bicarbonate and water, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane acetone. 25.4 g of 3-benzyloxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetra-en-17-one is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[CH2:22][O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])(=[O:12])=[O:11])=[C:5]([CH3:32])[CH:4]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15][C@H:14]2[CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])(=[O:12])=[O:11])=[C:5]([CH3:32])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(S(=O)(=O)N2c3ccccc3C[C@H]2COCC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of (S)-tert-butyl 2-((1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)indolin-2-yl)methoxy)acetate (0.5 mmol) in dichloromethane (6 ml) was added TFA (1.5 ml) and the reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the crude product was used in the next step.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[CH2:66]([N:73]1[CH2:77][CH2:76][C@H:75]([NH2:78])[CH2:74]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH2:66]([N:73]1[CH2:77][CH2:76][C@H:75]([NH:78][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:74]1)[C:67]1[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@H]2CCN(Cc3ccccc3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.021 g (0.12 mmole) of (S)-1-benzyl-pyrrolidin-3-ylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.051 g of N—((S)-1-benzyl-pyrrolidin-3-yl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-100) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][O:23][C:24]1[C:36]2[CH2:35][CH2:34][CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[C:28]=2[CH:27]=[CH:26][C:25]=1[O:37][CH3:38].C(N(CC)CC)C>C(Cl)Cl.O.C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]([N:31]2[CH2:30][CH:29]3[CH:33]([CH2:34][CH2:35][C:36]4[C:24]([O:23][CH3:22])=[C:25]([O:37][CH3:38])[CH:26]=[CH:27][C:28]=43)[CH2:32]2)=[O:12])=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: COc1ccc2c(c1OC)CCC1CNCC21
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc2c(c1OC)CCC1CN(C(=O)CCc3ccc([N+](=O)[O-])cc3)CC21
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A slurry of p-nitrocinnamic acid (1.9 g, 9.8 mmole, Aldrich) and 22 mL dry benzene was stirred under N2 at 0° C. as oxalyl chloride (2.2 mL, 25.2 mmole) was added dropwise. The reaction mixture was stirred at reflux for 11/4 hr, was cooled to room temperature and evaporated. Benzene was added and evaporated several times. The acid chloride was dissolved in ca 15 mL CH2Cl2, and was added dropwise to a 0° C. solution of the compound of example 5 (free base, 1.9 g, 8.2 mmole) in 25 mL CH2Cl2, and triethylamine (1.6 mL, 11.5 mmole). The reaction mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers were washed with 1N HCl, saturated aqueous NaHCO3, saturated aqueous NaCl, dried (MgSO 4), filtered, and evaporated (in-vacuo) to yield a tan solid which was triturated with Et2O to yield 2.68 g tan solid (80%); mp 231°-4°.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(C(C(C([O-])=O)O)O)([O-])=[O:28].[Na].[K]>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[CH2:11][OH:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CCCCCCCOc1cc(I)ccc1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K]
Solvent: Cc1ccccc1
Product: CCCCCCCOc1cc(I)ccc1CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
87.5 ml of a solution of diisobutylaluminum hydride (DiBAlH) is added at 0° C. to a solution of methyl 2-heptyloxy-4-iodobenzene (14 g, 43.7 mmol) previously obtained, in toluene (450 ml). The solution is stirred for 2 hours at 0° C., and then a saturated solution of mixed tartrate of sodium and potassium is added.