Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([OH:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl.CCOCC>[CH:11](=[O:27])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCC/C=C\CCCCCCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC/C=C\CCCCCCCCCC=O
Temperature: 25 °C
Yield: 95 %

Procedure:
DMSO (0.11 mL, 1.6 mmol) was added dropwise to a solution of oxalyl chloride (0.080 mL, 0.96 mmol) in CH2Cl2 (5 mL) at −78° C., and after 5 minutes a solution of alcohol 5 (0.21 g, 0.87 mmol) in CH2Cl2 (0.9 mL) was added. After stirring for 15 minutes at the same temperature, triethylamine (0.61 mL, 4.4 mmol) was added. The mixture was warmed to room temperature, diluted with Et2O, washed sequentially with 1M HCl, saturated aqueous NaHCO3, brine, dried with Na2SO4, and the solvent was removed in vacuo. Flash chromatography of the residue (SiO2, 10% EtOAc in hexanes) provided 6 (0.20 g, 95% yield, 86% Z as determined by 1H-NMR) as a colorless oil; 1H NMR (CDCl3): δ 9.76 (1H, t, J=1.9 Hz), 5.36 (2H, m), 2.42 (2H, td, J=7.4, 1.9 Hz), 2.02 (4H, m), 1.63 (2H, m), 1.24-1.36 (16H, m), 0.90 (3H, t, J=7.2 Hz); 13C NMR (CDCl3): δ 202.9, 129.9, 129.8, 43.9, 32.0, 29.8, 29.5, 29.4 (2C), 29.3, 29.2, 27.2, 26.9, 22.4, 22.1, 14.0; HRMS (FAB): 237.2209, [C16H30O−H]+ requires 237.2218.
Reaction SMILES: C1(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O[C:33]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)[CH:34]=[CH2:35])(=O)C.[CH3:49][NH:50][CH3:51]>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Pd+2]>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C:33]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[CH:34][CH2:35][N:50]([CH3:51])[CH3:49])=[CH:43][CH:44]=1
Reactant: C=CC(OC(C)=O)(c1ccc(Cl)cc1)c1cccnc1
Reactant: CNC
Agent: [Pd+2]
Agent: CC(=O)/C=C(/C)[O-]
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CC=C(c1ccc(Cl)cc1)c1cccnc1
Temperature: 55 °C
Yield: 79 %

Procedure:
Palladium acetylacetonate (9.3 mg, 0.03 mmol), 1,2-bis-(diphenylphosphino)ethane (17.5 mg, 0.04 mmol) and 3-acetoxy-3-(4-chlorophenyl)-3-(3-pyridyl)-1-propene (0.211 g, 0.73 mmol) was dissolved in tetrahydrofuran (2.2 ml) at room temperature under nitrogen. A solution of dimethylamine in tetrahydrofuran (3.2 ml of a 2.5 M solution) was added. The resulting solution was warmed to 55° C. and allowed to react for 1 h and 40 min. Evaporation of the solvent and work-up by preparative TLC (SiO2, ethyl acetate/hexane/triethylamine 49/49/2) gave 0.158 g (79%) of a Z/E mixture of the title compound. The Z/E ratio was determined by 1H NMR to 55/45.
Reaction SMILES: CCCCCC.[H-].[Na+].[C:9]([C:13]1[NH:17][N:16]=[CH:15][N:14]=1)([O:11][CH3:12])=[O:10].[CH3:18][N:19]1[N:23]=[N:22][C:21]([C:24]2[CH:34]=[C:33]([CH3:35])[C:27]([O:28][CH2:29][CH2:30][CH2:31]Br)=[C:26]([CH3:36])[CH:25]=2)=[N:20]1>CN(C=O)C>[C:9]([C:13]1[N:14]=[CH:15][N:16]([CH2:31][CH2:30][CH2:29][O:28][C:27]2[C:26]([CH3:36])=[CH:25][C:24]([C:21]3[N:22]=[N:23][N:19]([CH3:18])[N:20]=3)=[CH:34][C:33]=2[CH3:35])[N:17]=1)([O:11][CH3:12])=[O:10]
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCBr
Reactant: COC(=O)c1ncn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COC(=O)c1ncn(CCCOc2c(C)cc(-c3nnn(C)n3)cc2C)n1
Reaction time: 1 h
Yield: 39.8 %

Procedure:
Hexane washed 60% NaH (22 mg, 0.55 mmol) in 0.5 ml of DMF was added at 20° C. to a solution of 5-carbomethoxy-1,2,4-triazole (63.5 mg, 0.5 mmol) in 0.5 ml of DMF and the mixture was stirred for 1 h. To the above mixture was added at 20° C. 3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propylbromide (163 mg, 0.5 mmol) in 0.5 ml of DMF and the mixture was stirred at 20° C. for 18 h. The mixture was partitioned between ice/water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×), and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/5-1/0; methylene chloride/acetone) to afford 74 mg (40%) of 5-carbomethoxy-2-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].N1C=CN=C1.[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1COCC1.CC(OC)(C)C>[CH3:9][C:3]1[CH:4]=[C:5]([O:8][Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Cc1cc(O)ccc1N
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1N
Temperature: 0 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a solution of 4-amino-3-methylphenol (75.0 g, 609 mmol) in THF (1.5 L) was added imidazole (83 g, 1.22 mol). The reaction was cooled to 0° C. and triisopropylsilyl chloride (123 mL, 579 mmol) was added. The reaction mixture was allowed to warm to room temperature, stirred for 3 h, diluted with MTBE (1.5 L) and filtered. The filtrate was washed with water (1.0 L). The aqueous phase was back-extracted with MTBE (500 mL). The organics were combined, washed with 0.5 N NaOH (2×500 mL), brine (500 mL), and dried over MgSO4. The organics were filtered and concentrated to give 2-methyl-4-(triisopropylsilyloxy)aniline (135 g, 482 mmol, 83% yield) as a red oil. Exact mass calculated for C16H29NOSi: 279.2, found: LCMS m/z=280.5, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.09 (d, J=7.0 Hz, 18 H), 1.21 (m, 3 H), 2.12 (s, 3 H), 3.31 (bs, 2 H), 6.53 (d, J=8.4 Hz, 1 H), 6.57 (dd, J1=8.4, J2=2.7 Hz, 1 H), 6.62 (d, J=2.7 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C@@:16]2([CH3:21])[C:3]1=[CH:4][CH2:5][C@@H:6]1[C@@H:15]2[CH2:14][CH2:13][C@@:11]2([CH3:12])[C@H:7]1[CH2:8][CH2:9][C@@H:10]2[C:22]([OH:24])=O.[C:25]1([CH:31]([NH2:39])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:31]([NH:39][C:22]([C@H:10]2[CH2:9][CH2:8][C@H:7]3[C@H:6]4[C@H:15]([CH2:14][CH2:13][C@:11]23[CH3:12])[C@:16]2([CH3:21])[C:3]([N:2]([CH3:1])[C:19](=[O:20])[CH2:18][CH2:17]2)=[CH:4][CH2:5]4)=[O:24])[CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(Cc1ccccc1)c1ccccc1
Reactant: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC[C@@H]12
Product: CN1C(=O)CC[C@@]2(C)C1=CC[C@H]1[C@@H]3CC[C@H](C(=O)NC(Cc4ccccc4)c4ccccc4)[C@@]3(C)CC[C@@H]12
Yield: 78 %

Procedure:
The title compound was prepared in a yield of 78% in a similar manner to that described in Example 1 by reacting 4-methyl-3-oxo-4-azaandrost-5-ene-17β-carboxylic acid (prepared as described in Preparation 5) and 1,2-diphenylethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:26][N:27]([CH3:37])[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13]C)[CH:5]=[CH:6][CH:7]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(ON1C(=O)CCC1=O)(OCC[Si](C)(C)C)=O.C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].[Cl-].[Na+].O.C(Cl)Cl.O.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:26][N:27]([CH3:37])[C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:35])[CH3:36])=[O:29])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)CN(C)C(=O)OCC[Si](C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCO)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Reaction time: 4 h
Yield: 25.5 %

Procedure:
A 100 mL round-bottom flask was charged with of (3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide (0.6557 g, 1.0 mmol, 1.0 equiv), n-Bu4NI (3.765 g, 10 mmol, 10 equiv), and CH3CN (15 mL). To the flask was added AlCl3 (1.345 g, 10 mmol, 10 equiv) at 0° C. After 4 h, the reaction mixture was quenched with 10% aq Na2CO3 (18 mL) and 1 N aq NaOH (10 mL) and extracted with CH2Cl2 (3×). The combine organic extracts were dried over Na2SO4 and the solvent was removed in vacuo. The crude product was treated with Teoc-OSu (0.534 g, 2.06 mmol), K2CO3 (4.080 g, 29.5 mmol), water (5 mL) and CH2Cl2 (50 mL) at rt for 2.5 h. The mixture was diluted with brine, extracted with CH2Cl2 and dried over Na2SO4. After the solvent was removed in vacuo, the crude product was purified by prep HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 10 min, flow rate 25 mL/min) to give (3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (0.1625 g). LC-MS (3 min) tR=2.29 min, m/z 660, 662 (MNa+), 638, 640 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:8][C:4]1[N:3]=[C:2]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Clc1cncc(NC2CCC2)n1
Yield: 80 %

Procedure:
A solution of 2,6-dichloropyrazine (4.47 g), cyclobutanamine (3.8 mL) and potassium carbonate (6.20 g) in DMA (30 mL) was stirred at 80° C. for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→15% ethyl acetate/hexane) to give the title compound (4.42 g, 80%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][SH:8])[CH2:4][CH3:5])[CH3:2].[CH:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17](Br)[CH3:18])[CH2:13][CH2:12]1)=[O:10]>CO.[OH-].[K+]>[CH:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([S:8][CH2:7][CH2:6][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:18])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(Br)C1CCN(C=O)CC1
Reactant: CCN(CC)CCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCSC(C)C1CCN(C=O)CC1
Temperature: 40 °C

Procedure:
To a solution of N,N-diethylaminoethylmercaptan (4 g, 0.03 mole) in methanol (10 ml), 5 N potassium hydroxide in methanol (5 ml) was added, followed by (B) (5.5 g, 0.025 mole). The mixture was heated to 40° C. for 20 hours. After removal of the solvent in vacuo, the residue was diluted with ether (50 ml) and filtered. The filtrate was washed with two 5 ml portions of 2 N sodium hydroxide followed by water and dried. The solvent was stripped in vacuo, and the residue was chromatographed on "Florisil" (100 g), eluting with ether followed by ethyl acetate-methanol (8:2) to give (C) as a faintly yellow oil.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10]Cl.[OH:12][C:13]1[C:22]([C:23]#[N:24])=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH3:25])=[N:20]2)=[CH:15][CH:14]=1>CC(C)=O>[CH3:8][O:9][CH2:10][O:12][C:13]1[C:22]([C:23]#[N:24])=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([CH3:25])=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc2ccc(O)c(C#N)c2n1
Reactant: COCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1ccc2ccc(C)nc2c1C#N
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Referring to FIG. 20, under a nitrogen atmosphere, triethylamine (0.034 mL, 0.235 mmol) and chloromethyl methyl ether (0.018 mL, 0.235 mmol) were added to a solution of 5b (0.0200 g, 0.109 mmol) in acetone (8 mL). The reaction was stirred for 1 h. The solvent was evaporated and the remaining residue was dissolved in chloroform, which was washed with brine, dried over Na2SO4, and evaporated to afford 8b (0.0236 g, 0.106 mmol, 97%) as a white solid: 1H NMR (CDCl3) δ 8.02 (1H, d, J=8.0 Hz), 7.93 (1H, d, J=9.2 Hz), 7.48 (1H, d, J=9.2 Hz), 7.29 (1H, d, J=8.4 Hz), 5.43 (2H, s), 3.58 (3H, s), 2.79 (3H, s); 13C NMR (CDCl3) δ 162.4, 161.8, 148.7, 135.9, 133.4, 121.8, 121.7, 114.6, 114.9, 95.1, 56.9, 25.7; FTIR (neat) 2924, 2216, 1612, 1504, 1248, 1161, 1143, 1061, 984, 924, 839 cm−1; MS (ESI) m/z calculated for (C13H12N2O2+H)+ 229, found 229; HRMS (ESI) m/z calculated for (C13H12N2O2+H)+ 229.0978, found 229.0996.
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[C:9]([CH2:13][O:14][CH3:15])=[CH:8][N:7]3[C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>>[OH:12][C@@H:11]1[C:10]2[C:9]([CH2:13][O:14][CH3:15])=[CH:8][N:7]3[C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=[C:6]3[C:5]=2[NH:4][C@H:3]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@H:2]1[OH:1]
Reactant: COCc1cn2c(C)c(C)nc2c2c1C(=O)[C@H](O)[C@@H](c1ccccc1)N2
Agent: [BH4-]
Agent: [Na+]
Product: COCc1cn2c(C)c(C)nc2c2c1[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N2

Procedure:
0.4 g of (8R, 9R)-8-hydroxy-6-methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h]-[1,7]naphthyridin-7-one are reacted with sodium borohydride analogously to Example 15. After purification on silica gel (mobile phase: methylene chloride/methanol=100/3), 120 mg of the title compound [Rf=0.44 (methylene chloride/methanol=13/1)] of melting point 202-5° C. (decomp.) are obtained.
Reaction SMILES: C(OC([NH:11][CH:12]([CH3:30])[CH:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[Si:23]([O:22][CH:13]1[CH:12]([CH3:30])[NH:11][C:15](=[O:16])[C:14]1([CH3:21])[CH3:20])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)(C)C(O[Si](C)(C)C(C)(C)C)C(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1NC(=O)C(C)(C)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.7 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-(tert-butyldimethylsilyloxy)pentanoate (2.73 g) in methanol (13 mL) was added 10% palladium carbon (containing 50% water, 170 mg), and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethanol (20 mL). A 20% solution (4 mL) of sodium ethoxide-ethanol was added thereto, and the mixture was refluxed for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1→1/2) to give the title compound (yield: 700 mg, 44%) and (4RS,5RS)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethylpyrrolidin-2-one (yield: 380 mg, 24%), each as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:34][C:35]1[CH:47]=[C:46]2[C:38]([C:39]3[CH:40]=[C:41]([C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=4)[CH:42]=[C:43]([C:48]([NH2:50])=[O:49])[C:44]=3[NH:45]2)=[CH:37][CH:36]=1>CN(C=O)C.CO>[CH3:58][O:57][C:53]1[CH:52]=[C:51]([C:41]2[CH:42]=[C:43]([C:48]([NH2:50])=[O:49])[C:44]3[NH:45][C:46]4[C:38]([C:39]=3[CH:40]=2)=[CH:37][CH:36]=[C:35]([NH:34][C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:10])[CH:47]=4)[CH:56]=[CH:55][CH:54]=1
Reactant: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(N)ccc4c3c2)c1
Reactant: CN1CCC(C(=O)O)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(NC(=O)C5CCN(C)CC5)ccc4c3c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69 %

Procedure:
To a solution of 1-methylpiperidine-4-carboxylic acid (25.9 mg, 0.181 mmol) in DMF (0.5 mL), were successively added N,N′-diisopropylethylamine (0.053 mL, 0.302 mmol), EDC (23.14 mg, 0.121 mmol) and HOBt (18.49 mg, 0.121 mmol). After stirring at room temperature for 5 min, 7-amino-3-(3-methoxyphenyl)-9H-carbazole-1-carboxamide (20 mg, 0.060 mmol, Example 138) was added. After stirring for 16 h, the reaction was diluted with MeOH, and the product was isolated by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=90:10 and ending with A:B=30:70 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min). The HPLC fractions that contained the product were applied onto a PHENOMENEX® Strata-X-C 33 um cation mixed-mode polymer cartridge. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents gave 18.9 mg of 3-(3-methoxyphenyl)-7-(1-methylpiperidine-4-carboxamido)-9H-carbazole-1-carboxamide as a white solid. MS (ESI) m/z 457.2 (M+H). 1H NMR (MeOD) δ ppm 8.43 (1H, s), 8.13 (1H, d, J=1.22 Hz), 8.08 (1H, d, J=8.55 Hz), 8.04 (1H, s), 7.30 -7.43 (3H, m), 7.27 (1H, dd, J=8.39, 1.68 Hz), 6.92 (1H, dd, J=5.49, 2.14 Hz), 3.90 (3H, s), 3.00 (2H, d, J=11.60 Hz), 2.38-2.51 (1H, m), 2.33 (3H, s), 2.06-2.20 (2H, m), 1.85-2.04 (4H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH:7]2[O:8][CH:6]2[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[NH3:27]>C(O)C>[NH2:27][C@@H:6]1[C:5]2[CH:9]=[C:10]([S:13]([N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:15])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:1])([CH3:26])[C@H:7]1[OH:8]
Reactant: N
Reactant: CC1(C)Oc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2C2OC21
Solvent: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)N3CCCc4ccccc43)cc2[C@@H](N)[C@@H]1O
Temperature: 90 °C

Procedure:
Intermediate 2a (3.49 g, 9.4 mmol) is treated with a saturated solution of ammonia in ethanol (60 mL) and heated at 90° C. in an autoclave for 15 hours. The solvent is evaporated off under reduced pressure to yield the crude product which is purified by chromatography on silica gel, eluent 25% aqueous NH3 --MeOH--tBuOMe (1:5:94) to give the title compound as a foam, having the following physical characteristics:
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:8][S:9]([O:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(CO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At r.t. to a solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (0.41 g, 4.2 mmol) in methylene chloride (10 mL) was added methanesulfonyl chloride (490 uL, 6.3 mmol), followed by triethylamine (1.5 mL, 10.0 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol). The mixture was stirred at r.t. for 3 h. It was diluted with methylene chloride, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield the crude product which was used in the next step reaction without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=3[CH3:24])[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[Cl:25][C:26]1[C:27]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:28][C:29]([CH3:41])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>>[Cl:25][C:26]1[C:27]([S:42]([CH3:45])(=[O:43])=[O:44])=[CH:28][C:29]([CH3:41])=[C:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=4[CH3:24])[C:15]([NH:17][CH:18]4[CH2:19][CH2:20]4)=[O:16])=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)[CH:31]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(Cl)nncc2c1
Reactant: Cc1cc(S(C)(=O)=O)c(Cl)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(-c3cc(Cl)c(S(C)(=O)=O)cc3C)nncc2c1

Procedure:
This material was prepared according to the procedure similar to that described in Method A-Example 3a, using 3-(1-chlorophthalazin-6-yl)-N-cyclopropyl-4-methylbenzamide and 2-(5-chloro-2-methyl-4-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. MS (ESI, pos. ion) m/z: 506.9 (M+1).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:9]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1.C(Cl)Cl.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[F:3][C:4]1[C:9]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:26](=[O:28])[CH3:27])[CH2:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ncccc1C1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCC(c2cccnc2F)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To an ice cooled solution of 2-fluoro-3-(piperidin-3-yl)pyridine dihydrochloride (612 mg, 2.418 mmol), DCM (20 mL) and triethylamine (2022 μL, 14.51 mmol) was added acetic anhydride (229 μL, 2.418 mmol) dropwise. After 1 hour, the reaction was poured into water and the aqueous mixture back extracted once with DCM (10 mL). The combined organics were washed with 0.5M NaOH and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 100% EtOAc in hexane, to provide 1-(3-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone (100 mg, 0.450 mmol) as a light yellow syrup. [M+1]=223.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:31]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=4)=[O:32])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(CNC(=O)c4ccnc(Cl)c4)cc3)ccc2n1
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 27 mg (0.05 mmol) 4-Amino-N-[4-(aminomethyl)phenyl]-2-methyl-6-quinolinecarboxamide, 9 mg (0.1 mmol) 2-chloropyridine-4-carboxylic acid, and 0.07 ml (0.5 mmol) triethylamine in 2 ml dichloromethane was added 90 mg (2.0 mmol) PyBrop and stirred at room temparature for 1 d. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 17 mg (74%) of the title compound. MS 446.3 (M+1)+, 1H-NMR (DMSO-d6) δ: 2.60 (s, 3H), 4.47 (d, 2H), 6.64 (s, 1H), 7.34 (d, 2H), 7.73 (d, 2H), 7.81 (dd, 1H), 7.87 (d, 1H), 7.91 (s, 1H), 8.35 (dd, 1H), 8.57 (d, 1H), 8.95 (s, 1H), 9.00 (br. 2H), 9.41 (t, 1H), 10.47 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]CC2C=CC=CC=2)[CH:5]=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19]>[Pd].CCO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:2]([CH3:1])[CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)cc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(O)cc1C
Temperature: 25 °C
Reaction time: 19 h
Yield: 63.9 %

Procedure:
To a flask containing 10% Pd/C catalyst under nitrogen was added ethyl (2E)-3-{2-methyl-4-[(phenylmethyl)oxy]phenyl}-2-propenoate (1.22 g, 4.12 mmol) in EtOH (15 mL) washing in with more EtOH (2×4 mL). The reaction vessel was placed under an atmosphere of hydrogen and stirred rapidly at ambient temperature for 19 h. The mixture was then filtered through a pad of celite washing with EtOH and the filtrate reduced under vacuum. The residue was the purified by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 10:1 to 2:1) to afford the title compound (548 mg).