Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]2[NH:13][CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCC2NCC(c3c[nH]c4cc(F)ccc34)C21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2c1ncccn1
Temperature: 70 °C
Reaction time: 16 h
Yield: 46.3 %

Procedure:
A solution containing 34 (370 mg, 1.07 mmol), DIPEA (163 mg, 1.26 mmol), and 2-chloropyrimidine (135 mg, 1.17 mmol) in anhydrous DMF (6 mL) was warmed to 70° C. After 16 h, the reaction mixture was cooled to ambient temperature and diluted with water and subsequently extracted with diethyl ether. The organic extract was washed successively with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 210 mg (46%) of 70 as a white solid. Mass spectrum, m/z [424] (M+H)+.
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:23]([NH:22][CH2:20][CH3:21])=[O:24])#[N:3]
Reactant: CCN=C=O
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCNC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 95 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and ethyl isocyanate in 95% yield as a light yellow solid. MS 319 (MH+).
Reaction SMILES: [N:1]1([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[ClH:18].[OH-].[Na+]>C1COCC1>[ClH:18].[N:1]1([C:10]2[CH:11]=[C:12]([CH2:13][NH2:14])[CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1cccc(N2CCc3ccccc32)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCc1cccc(N2CCc3ccccc32)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A solution of 7.1 g (32.3 mmole) of 3-(1-indolinyl)benzonitrile of Example 3a in 44 ml THF was added dropwise over 30 minutes to an ice cold solution of 129 ml (129 mmole, 4 equivalents) of 1M BH3.THF complex under nitrogen. After heating at reflux for 1 hour, the reaction mixture was cooled to 0°-5° C. and treated dropwise with 50 ml concentrated HCl. The resulting suspension was heated at reflux for 1 hour, permitted to stand at room temperature overnight (about 16 hours) and then made basic using 50% NaOH (60 ml). The reaction mixture was partitioned between water-CH2Cl2 (300 ml each) and the organic phase was washed with brine (300 ml), dried over MgSO4 and concentrated to give 8.9 g of crude free base. Conversion as in Example 1 to the HCl salt (ethanol/ethereal HCl) and recrystallization from hot acetonitrile-methanol afforded 2.86 g (34% overall) of 3-(1-indolinyl)benzenemethanamine hydrochloride, m.p. 170.5°-173.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[C:9]2[O:10][CH2:12][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(O)c(O)c(F)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(F)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol) and BrClCH2 (4.9 g, 38.5 mmol) in dry DMF (50 mL) was added Cs2CO3 (12.6 g, 39 mmol). The mixture was stirred at 60° C. overnight and was then poured into water. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to afford 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 49%). 1H NMR (300 MHz, CDCl3) δ 9.78 (d, J=0.9 Hz, 1 H), 7.26 (dd, J=1.5, 9.3 Hz, 1H), 7.19 (d, J=1.2 Hz, 1 H), 6.16 (s, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].CI>CS(C)=O.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of 6-bromo-1H-indole (1.530 mmol) in dimethyl sulfoxide (10 mL) was treated with potassium carbonate (4.59 mmol) and was stirred at room temperature for 30 min. The solution was then treated with methyl iodide (1.683 mmol) and was stirred at room temperature overnight. The solution was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (hexanes) to provide the title compound as a yellow oil (62%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.70 (s, 1H) 7.50 (d, J=8.34 Hz, 1H) 7.35 (d, J=3.03 Hz, 1H) 7.14 (dd, J=8.34, 1.77 Hz, 1H) 6.44 (d, J=3.03 Hz, 1H) 3.78 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[S:26][C:10]3[N:11]=[C:12]([CH3:25])[N:13]=[C:14]([CH2:15][N:16]4[C:21](=[O:22])[CH:20]5[CH2:23][CH2:24][CH:17]4[CH2:18][NH:19]5)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1(CO)C2C=CC=C[C:30]=2N=N1.[Cl:38]CCCl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[ClH:38].[CH:1]1([C:7]2[S:26][C:10]3[N:11]=[C:12]([CH3:25])[N:13]=[C:14]([CH2:15][N:16]4[C:21](=[O:22])[CH:20]5[CH2:23][CH2:24][CH:17]4[CH2:18][N:19]5[CH3:30])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCn1nnc2ccccc21
Reactant: ClCCCl
Reactant: Cc1nc(CN2C(=O)C3CCC2CN3)c2cc(C3CCCCC3)sc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Product: Cc1nc(CN2C(=O)C3CCC2CN3C)c2cc(C3CCCCC3)sc2n1
Product: Cl
Reaction time: 5 h

Procedure:
To a mixture of 2-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-2,5-diazabicyclo[2.2.2]octan-3-one (67 mg), 1H-benzotriazole-1-methanol (54 mg), and DCE was added NaBH(OAc)3 (115 mg) at room temperature, followed by stirring at the same temperature for 5 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) and the obtained purified product was dissolved in EtOAc. An excess amount of 4 M HCl/EtOAc was added thereto, followed by concentration under reduced pressure. To the residue was added Et2O, followed by stirring, and the precipitate was collected by filtration to obtain 2-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-5-methyl-2,5-diazabicyclo[2.2.2]octan-3-one hydrochloride (57 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I>C1COCC1.CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@H:13]2[C@H:12]([N:20]([CH3:30])[C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(Cl)ncn3)[C@@H]2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(c1cc(Cl)ncn1)[C@@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a mixed solution of N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloropyrimidin-4-amine (405 mg, 0.98 mmol) in THF (10.0 mL) and DMF (2.50 mL) was added sodium hydride (47.0 mg, 1.17 mmol) under an atmosphere of Argon, and the mixture was stirred for 15 minutes. Methyl iodide (0.08 mL, 1.27 mmol) was added to the mixture, and the resulting mixture was stirred for 1 h. After quenching by addition of brine (20.0 mL), the mixture was extracted with ethyl acetate (3×40.0 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 5 to 15% ethyl acetate in DCM to afford the title compound (381 mg, 91%) as a colorless oil. LC/MS: Rt=2.55 min, ES+ 428.3 (AA standard).
Reaction SMILES: Cl.NC[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([OH:15])[CH:5]=1.[CH:16]([N:19](CC)C(C)C)(C)C.C1(=O)N(O[C:31](=[O:45])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])C(=O)CC1>CN(C)C=O.C(OCC)(=O)C>[C:41]([O:40][C:38]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][C:31]([NH:19][CH2:16][C:5]1[C:6]([OH:15])=[C:7]([CH:13]=[CH:14][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:45])=[O:39])([CH3:42])([CH3:43])[CH3:44]
Reactant: CCOC(=O)c1ccc(CN)cc1O
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)ON1C(=O)CCC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(CNC(=O)CCCCCNC(=O)OC(C)(C)C)c1O
Reaction time: 18 h
Yield: 128.1 %

Procedure:
Ethyl 4-aminomethyl-2-hydroxybenzoate hydrochloride (0.52 g, 1.28 mmoles) was suspended in anhydrous N,N-dimethylformamide (25 mL), and N,N-diisopropylethylamine (0.79 mL, 4.53 mmoles) was added, followed by N-tert-butoxycarbonyl-6-aminohexanoic acid succinimidyl ester (0.74 g, 2.26 mmoles). The mixture was stirred under dry nitrogen for 18 hours, during which time all solids dissolved. The reaction mixture was diluted with ethyl acetate (100 mL) and extracted with 1 N aqueous hydrochloric acid (100 mL). The layers were separated, and the ethyl acetate solution was washed with water (100 mL) and saturated aqueous sodium chloride (500 mL). The ethyl acetate solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to afford an amorphous off-white solid. Finally, the solid was crystallized from ethyl acetate, filtered, and dried in vacuo to afford 0.67 g (73% yield) of ethyl (N-tert-butoxycarbonyl-6-aminohexanoyl)aminomethyl-2-hydroxybenzoate (m.p. 120-121° C., open capillary, uncorrected).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5](C1CCOCC1)[C:6]([N:8]1[CH2:12][C:11](F)(F)[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]5[NH:37][C:38]([CH:41]6[CH2:45][CH2:44][CH2:43][N:42]6[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:48]6[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=6)=[N:39][CH:40]=5)[CH:32]=4)[CH:27]=3)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7].COC(N[CH:72]([CH:76]1CCOCC1)[C:73](O)=O)=O.[CH2:82](OC(N1C(C2NC(C3C=CC(B4OC(C)(C)C(C)(C)O4)=CC=3)=CN=2)CC2(CC2)C1)=O)[C:83]1C=CC=CC=1.C(OC(N1CC(F)(F)CC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)C1C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:66])[NH:4][CH:5]([C:6]([N:8]1[CH:9]([C:15]2[NH:16][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:36]6[NH:37][C:38]([CH:41]7[CH2:45][CH2:44][CH2:43][N:42]7[C:46](=[O:59])[CH:47]([NH:54][C:55]([O:57][CH3:58])=[O:56])[C:48]7[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=7)=[N:39][CH:40]=6)[CH:32]=5)[CH:27]=4)=[CH:22][CH:21]=3)=[CH:18][N:19]=2)[CH2:10][C:11]2([CH2:83][CH2:82]2)[CH2:12]1)=[O:7])[CH:72]([CH3:76])[CH3:73]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(F)(F)CN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Reactant: COC(=O)NC(C(=O)O)C1CCOCC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(C4CC5(CC5)CN4C(=O)OCc4ccccc4)[nH]3)cc2)OC1(C)C
Agent: CC1(C)OB(c2ccc(-c3cnc(C4CC(F)(F)CN4C(=O)OCc4ccccc4)[nH]3)cc2)OC1(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)c1ccccc1
Yield: 34 %

Procedure:
[1-(6-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.10 g, 34%) was prepared following the procedure for [2-(4,4-Difluoro-2-{5-[4-(6-{2-[1-(2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-pyran-4-yl)-ethyl]-carbamic acid methyl ester, substituting 2-Methoxycarbonylamino-3-methyl-butyric acid for Methoxycarbonylamino-(tetrahydro-pyran-4-yl)-acetic acid and 6-{5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester for 4,4-Difluoro-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid benzyl ester. LCMS-ESI+: calc'd for C49H52N8O6: 848.40 (M+); Found: 849.96 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([F:21])[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.CCOC(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>[NH2:18][C:17]1[CH:19]=[CH:20][C:14]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:15][C:16]=1[F:21]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1F
Temperature: 95 °C

Procedure:
A mixture of 3-nitrobenzeneboronic acid (0.70 g, 4.2 mmol), 4-bromo-2-fluoroaniline (730 mg, 4.0 mmol), (PPh3)4Pd (93 mg, 0.08 mmol), and K2CO3 (0.69 g, 5.0 mmol) in toluene (20 mL) and water (2 mL) was heated at 95° C. for 16 h and the mixture was diluted with EtOAc (20 mL). The mixture was washed with water (10 mL) and brine (10 mL), concentrated and purified by silica gel chromatography to afford the 4-amino-3-fluoro-3'-nitrobiphenyl (structure 82 of Scheme XXI, where R1 =R3-7 =H, R8 =F) (0.4 g, 41%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl.[NH2:28][OH:29].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22](/[CH:25]=[N:28]\[OH:29])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22](/[CH:25]=[N:28]/[OH:29])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: NO
Reactant: CCN1CCN(c2nc(-c3ccc(C=O)cc3)cc3ccccc23)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN(c2nc(-c3ccc(/C=N/O)cc3)cc3ccccc23)CC1
Product: CCN1CCN(c2nc(-c3ccc(/C=N\O)cc3)cc3ccccc23)CC1

Procedure:
1-(4-Ethylpiperazin-1-yl)-3-(4-formylphenyl)isoquinoline (3.00 g) obtained in Example 17-5 was reacted with hydroxylamine hydrochloride (0.90 g) and sodium acetate (1.10 g) in ethanol (50 ml) at 60° C. for 2 hr. The reaction solution was evaporated, and then the resulting residue was extracted in methylene chloride, washed with brine and dried. The solvent was removed, and the resulting residue was isolated and purified by silica gel column chromatography (methylene chloride/methanol system), to give (Z)-1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyiminomethylphenyl)isoquinoline (1.01 g) and (E)-1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyiminomethylphenyl)isoquinoline (1.52 g), both as yellow solids. 0.30 g each of the compounds was converted into a hydrochloride in a conventional manner, to give the hydrochlorides of the title compounds as yellow powders (0.32 g and 0.35 g, respectively).
Reaction SMILES: Cl.C[O:3][C:4](=O)[CH:5]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:6][C:7]1[C:8]([CH2:16]Cl)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.[CH2:30]([NH2:34])[CH:31]([CH3:33])[CH3:32].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[NH:18][CH:5]1[C:4](=[O:3])[N:34]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:16][C:8]2[C:9]3[CH:10]=[N:11][NH:12][C:13]=3[CH:14]=[CH:15][C:7]=2[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(Cc1ccc2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Reactant: CC(C)CN
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)CN1Cc2c(ccc3[nH]ncc23)CC(NC(=O)OCc2ccccc2)C1=O

Procedure:
In a manner similar to [9-(2,2-dimethyl-propyl)-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-(R)-cyclohepta[e]inden-7-yl]-carbamic acid benzyl ester, the title compound was prepared by treating 2-benzyloxycarbonylamino-3-(4-chloromethyl-1H-indazol-5-yl)-propionic acid methyl ester, hydrochloride with isobutylamine followed by treatment with acetic acid in refluxing toluene to give (9-Isobutyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohepta[e]inden-7-yl)-carbamic acid benzyl ester in 91% yield. MS (ESI) 407 (M+H); Rf=1.58.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[N:29]1([CH2:35][CH2:36][OH:37])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([N:32]1[CH2:33][CH2:34][N:29]([CH2:35][CH2:36][OH:37])[CH2:30][CH2:31]1)=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: OCCN1CCNCC1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)N2CCN(CCO)CC2)c(=O)n(C)c1=O

Procedure:
Example 44 was synthesized following a similar procedure described in the synthesis of Example 5 by reaction of compound 2A and 2-(piperazin-1-yl)ethanol. 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H) 6.95 (t, J=8.0 Hz, 1H) 4.17 (br, 1H) 3.86 (br, 3H) 3.54 (br, 5H) 3.33 (br, 1H) 3.28 (br, 5H) 3.10 (br, 2H) 2.37 (br, 1H). [M+H] calc'd for C19H23FIN5O4, 532. found, 532.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:9](=[NH:11])[NH2:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O.O=[C:23]([CH3:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]1[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:23]([CH3:30])[NH:10][C:9]([C:4]2[C:3]([F:2])=[CH:8][CH:7]=[CH:6][N:5]=2)=[N:11]1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)c1ncccc1F
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2ncccc2F)=NC1c1ccc(Cl)cc1Cl
Yield: 54 %

Procedure:
3-fluoropicolinimidamide hydrochloride (5.53 g, 31.5 mmol) was reacted with 2,4-dichlorobenzaldehyde (5.51 g, 31.5 mmol) and ethyl 3-oxobutanoate (4.1 g, 31.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (6.94 g, 54%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[CH:15](N)=[NH:16].[H-].[Na+].C([O-])(O)=O.[Na+].CC([N:28](C)C)=O>>[F:10][C:8]1[CH:9]=[C:2]2[C:3]([C:4]([NH2:28])=[N:5][CH:15]=[N:16]2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC(=O)N(C)C
Reactant: N=CN
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncnc2cc(F)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A suspension of 2,4-difluorobenzonitrile (1 g, 7.17 mmol), formamidine acetate (2.98 g, 28.68 mmol), and NaH (60% suspension in mineral oil, 2.29 g, 57.36 mmol) in dimethylacetamide (50 mL) is stirred at 120° C. for overnight. The reaction mixture is poured onto a saturated solution of NaHCO3 (100 mL), and the aqueous phase is extracted with EtOAc (3×). The combined organic layers is washed with brine, dried over MgSO4, and evaporated to dryness. Purification of the crude material by column chromatography (10% MeOH in CH2Cl2) affords 7-Fluoro-quinazolin-4-ylamine (0.2874 g, 25%). LC/MS m/z=164 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:21])[CH2:16][NH:17][CH2:18][CH2:19][NH2:20])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([N:24]=[C:25](SC)SC)#[N:23]>C(O)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:21])[CH2:16][N:17]3[CH2:18][CH2:19][NH:20][C:25]3=[N:24][C:22]#[N:23])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSC(=NC#N)SC
Reactant: COc1ccc(C(C)CNCCN)cc1OC1CCCC1
Solvent: CCO
Product: COc1ccc(C(C)CN2CCNC2=NC#N)cc1OC1CCCC1
Yield: 12.9 %

Procedure:
A mixture of intermediate 22 (0.0068 mol) and dimethyl cyanocarbonimidodithioate (0.0068 mol) in ethanol (20 ml) was stirred and refluxed for 2 days. The solvent was evaporated and the residue was first purified by short open column chromatography over silica gel (eluent: CH2Cl2, CH2Cl2 /CH3OH 96/4 and 90/10), then twice by HPLC (1 eluent: CH2Cl2 /CH3OH 90/10 and 2. Eluent: CH2Cl2 /CH3OH 96/4). The pure fractions were collected and the solvent was evaporated, yielding 0.3 g (13%) of (±)-[1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl]-2-imidazolidinylidene] cyanamide (compound 1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C1COCC1.C(Cl)(Cl)Cl.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>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL)/CHCl3 (40 mL) in a dry flask, under nitrogen. Triethylamine (8.14 mL, 58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5% HCl (2×40 mL), dried (MgSO4) and concentrated to a brown oily-solid (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluting with 10% EtOAc/hexane (1 L) followed by 15% EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91%) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H: 249.0947, found 249.0947 (M+H)+.