Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[C:43]([CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:42]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][O:28][Si](C(C)C)(C(C)C)C(C)C)[C:18]=2[F:39])=[N:11]1)=[O:4].C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O>[CH3:1][O:2][C:3]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[C:43]([CH2:49][NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH:42]=2)[C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:39])=[N:11]1)=[O:4]
Reactant: COC(=O)c1ocnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)cc(OCCO[Si](C(C)C)(C(C)C)C(C)C)c2F)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ocnc1-n1nc(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2cc(OC)cc(OCCO)c2F)[nH]c1=O
Reaction time: 3 h
Yield: 117.9 %

Procedure:
To a mixture of 4-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-[2-fluoro-5-methoxy-3-(2-triisopropylsilanyloxyethoxy)phenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)oxazole-5-carboxylic acid methyl ester (41.1 mg) and THF (2 mL) there was added a 1M THF solution of tetrabutylammonium fluoride (0.100 mL). The mixture was stirred for 3 hours, and then ethyl acetate (30 mL) and water (15 mL) were added. The mixture was sufficiently shaken, and then the organic layer was separated off, washed with water (15 mL) and saturated aqueous sodium chloride (15 mL) in that order, and dried over anhydrous magnesium sulfate. The mixture was filtered to obtain a filtrate and the solvent in the filtrate was distilled off under reduced pressure to obtain the target compound (39.1 mg) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](Cl)=[C:29]([N+:34]([O-:36])=[O:35])[CH:30]=[N:31]2)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.O>[Br:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[C:29]([N+:34]([O-:36])=[O:35])[C:30]([NH:7][CH2:6][CH2:5][CH2:4][CH:3]([O:8][CH3:9])[O:2][CH3:1])=[N:31]2)=[CH:26][CH:25]=1
Reactant: COC(CCCN)OC
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COC(CCCNc1nc2cc(Br)ccc2cc1[N+](=O)[O-])OC
Temperature: 0 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
4-Aminobutyraldehyde dimethylacetal (29.41 g, 208.6 mmol), triethylamine (36.36 mL), and potassium carbonate (24.0 g, 173.9 mmol) were added sequentially to a solution of 7-bromo-4-chloro-3-nitroquinoline (50.1 g, 173.9 mmol) in chloroform (200 mL) cooled to 0° C. The reaction was allowed to warm to ambient temperature and was stirred for 4 hours. The reaction mixture was then diluted with water (100 mL) and the reaction was stirred for 10 minutes and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to afford 66.9 g of (7-bromo-3-nitroquinolin-yl)(4,4-dimethoxybutyl)amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[N:34]=[CH:35][S:36][CH:37]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][C:33]2[N:34]=[CH:35][S:36][CH:37]=2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2cscn2)c1F)OC1CCCCO1
Solvent: O
Solvent: CC(=O)O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCc2cscn2)c1F
Reaction time: 8 h
Yield: 51.6 %

Procedure:
[(2R)-3-(2-{2-Chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1133 g, 0.204 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir overnight. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-(2-{2-chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (0.0497 g, 52%). LCMS: (M+H)+=472.1.
Reaction SMILES: P(Cl)(C(C)(C)C)C(C)(C)C.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[K+]>O1CCOCC1.C(OCC)C.O>[C:18]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1ccccn1
Agent: CC(C)(C)P(Cl)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1COCCO1
Product: c1ccc(-c2ccccn2)cc1
Temperature: 25 °C

Procedure:
A 30 mL of reactor equipped with magnetic stir bar was charged with 54 mg (0.10 mmol) of (t-Bu)2PCl)2PdCl2, 0.50 g (4.4 mmol) of 2-chloropyridine, 0.65 g (5.33 mmol) of PhB(OH)2 and 0.40 g (7.13 mmol) of KOH in 2 mL of 1,4-dioxane. The reaction mixture was refluxed for 7 hours. The reaction mixture was cooled to room temperature, transferred to a separatory funnel, and diluted with 100 mL of diethyl ether and 20 mL of H2O. The layers were separated, and organic layer was washed with H2O (50 mL), brine (30 mL), and dried over MgSO4, filtered, and solvents removed from the filtrate by rotary evaporation. The resulting residue was chromatographed on silicon gel. The eluate was concentrated by rotary evaporation followed by high vacuum to give 2-phenylpyridine. LC-MS Found: 156.2 (M++1).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].[C:51]([O:54][CH2:55]Cl)(=[O:53])[CH3:52].C(N(CC)CC)C>C1COCC1>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([O:10][CH2:55][O:54][C:51](=[O:53])[CH3:52])=[O:9])[CH3:2]
Reactant: CC(=O)OCCl
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCc1nc(CC)c(C(=O)OCOC(C)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 45.2 %

Procedure:
0.37 g of 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylic acid was dissolved in 5 mL THF and 0.5 g chloromethyl acetate and 0.5 mL triethylamine were added. The resulting solution was stirred overnight. The solvent was evaporated and the residue dissolved in methanol with 0.25 mL acetic acid and stirred 8 hours with 10 g silica gel. The mixture was evaporated and the residue on the gel was flash chromatographed with MeOH/CH2Cl2 (1:9) to provide 0.124 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[CH3:9][C:7]1[CH:8]=[C:2]2[C:3](=[CH:5][C:6]=1[N+:10]([O-:12])=[O:11])[NH:4][N:13]=[CH:1]2
Reactant: O=N[O-]
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2cn[nH]c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
2,4-Dimethyl-5-nitroaniline (1.662 g, 10.00 mmol) was dissolved in glacial acetic acid (100 ml) and the mixture was cooled to 0° C. A solution of sodium nitrite (1 eq, 690 mg) in water (2 ml) was added while maintaining a temperature below 25° C. Stirring was continued for three hours and the mixture was filtered. The filtrate was allowed to stand for three days at room temperature, then was concentrate under reduced pressure. The residue was diluted with water and the resulting mixture was stirred vigorously. The solid product was collected by filtration, washed thoroughly with cold water, and dried. The product was purified by flash chromatography (99:1 dichloromethane/methanol) to give 1.030 g (58.1%) of 5-methyl-6-nitro-1H-indazole as a solid.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C@H:7]([CH3:26])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:21][CH2:20][C@H:19]([O:22][CH2:23][CH2:24]O)[CH2:18][C:16]3=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:45]=[N+:46]=[N-:47].[Na+]>C1COCC1>[N:45]([CH2:24][CH2:23][O:22][C@H:19]1[CH2:20][O:21][C:15]2=[CH:14][CH:13]=[C:12]3[C:17]([N:9]([CH2:8][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:27])[CH3:28])[CH3:26])[N:10]=[CH:11]3)=[C:16]2[CH2:18]1)=[N+:46]=[N-:47]
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCCO)CO3)O[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCCN=[N+]=[N-])CO3)O[Si](C)(C)C(C)(C)C
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a cooled (0° C.) solution of the product from Step A (1.40 g, 3.45 mmol) and triethylamine (1.39 g, 1.92 mL, 1.38 mmol, 4.0 equiv.) in anhydrous THF (50 mL) was added methanesulfonic anhydride (1.20 g, 6.90 mmol, 2.0 equiv.). The mixture was stirred for 30 min and sodium azide (2.24 g, 34.5 mmol, 10 equiv.) was added. THF was evaporated and anhydrous dimethyl sulfoxide (50 mL) was added to the residue; this mixture was heated at 85° C. for 2 h. After cooling, the mixture was poured into a saturated solution of sodium bicarbonate (100 mL) and extracted with EtOAc (3×80 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, gradient, 10% to 25% ethyl acetate in hexane) to give an oil (0.73 g, 49%): LC/MS (+ESI) m/z 432 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].[NH2:10][C@H:11]([C:13]([N:15]1[C:21](=[O:22])[CH:20]([CH3:23])[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=2[C:17]2[C:28]([NH2:32])=[CH:29][CH:30]=[CH:31][C:16]1=2)=[O:14])[CH3:12]>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([NH:10][C@H:11]([C:13]([N:15]1[C:21](=[O:22])[CH:20]([CH3:23])[C:19]2[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=2[C:17]2[C:28]([NH2:32])=[CH:29][CH:30]=[CH:31][C:16]1=2)=[O:14])[CH3:12])=[O:4]
Reactant: CCCCC(C)C(=O)O
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CCCCC(C)C(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21

Procedure:
Following General Procedure C-P above using 2-methylhexanoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 422 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5](OC)=[O:6].[NH2:13][NH2:14]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([NH:13][NH2:14])=[O:6]
Reactant: COC(=O)c1ccc(Cl)c(Br)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1ccc(Cl)c(Br)c1
Temperature: 70 °C
Yield: 25 %

Procedure:
Methyl 3-bromo-4-chlorobenzoate (120 mg, 0.481 mmol) was added to hydrazine (23.12 mg, 0.721 mmol) in methanol (8 mL) and refluxed for 12 h at 70° C. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography affording the title compound (30 mg). 1H NMR (400 MHz, CDCl3): δ 8.02 (d, 1H, J=1.6 Hz), 7.60 (dd, 1H, J=2.0 & 8.0 Hz), 7.52 (d, 1H, J=8.0 Hz), ESI-MS: 250.9 [M+H]+.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH2:16][NH2:17]>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:16][NH:17][C:14]([NH:13][C:7]2([N:6]=[N:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:15])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=O)CCCCC1
Reactant: NN
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=O)NNC(=O)NC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 9.27 grams (0.044 moles) of 1-t-butylazo-1-isocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 0.74 grams (0.022 moles) of 97% hydrazine. The reaction mixture rapidly became a solid and pentane was added to slurry the mixture. The slurry was then stirred for 60 minutes at room temperature and filtered. The filter cake was dried leaving 9.5 grams (95% crude yield) of a white powder. The product melted at 195°-197° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1665 cm-1 and a broad NH band at 3350 cm-1 and a weaker band at 3080 cm-1.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[CH:4][C:3](=[O:7])[CH2:2]1.[C:8](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9].O.O.O.O.O.[N+]([O-])([O-])=O.[Bi+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(Cl)Cl>[O:7]=[C:3]1[CH2:2][O:1][CH2:6][CH:5]([NH:9][C:8](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4]1
Reactant: O=C1C=CCOC1
Reactant: NC(=O)OCc1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Bi+3]
Solvent: ClCCl
Solvent: O
Product: O=C1COCC(NC(=O)OCc2ccccc2)C1
Yield: 73.5 %

Procedure:
2H-pyran-3(6H)-one (2.33 g, 23.75 mmol), benzyl carbamate (4.31 g, 28.5 mmol), and DCM (2.375 mL) were added to a small vial and stirred vigorously. To the thick syrup was added bismuth(III) nitrate pentahydrate (1.728 g, 3.56 mmol). The vial was capped and the reaction was stirred vigorously overnight. The reaction was diluted with DCM and filtered through a pad of celite. The filtrate was condensed and purified on a 100G SNAP Biotage column (10-100% ethyl acetate in hexane) to give benzyl 5-oxotetrahydro-2H-pyran-3-ylcarbamate (4.35 g, 17.45 mmol, 73.5% yield) as a pale yellow oil; 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.41 (m, 5H), 5.20-5.28 (m, 1H), 5.05-5.15 (m, 2H), 4.24-4.35 (m, 1H), 4.01-4.06 (m, 1H), 3.89-3.95 (m, 1H), 3.80-3.87 (m, 1H), 2.73 (d, J=5.47 Hz, 1H), 2.64-2.71 (m, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:15]([NH2:17])[CH3:16])[CH:6]=[N:7][C:8]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[Cl:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1>>[Cl:18][C:19]1[N:24]=[C:23]([C:25]([NH:17][CH:15]([C:5]2[CH:6]=[N:7][C:8]([O:9][CH2:10][C:11]([F:14])([F:12])[F:13])=[C:3]([CH3:2])[CH:4]=2)[CH3:16])=[O:26])[CH:22]=[C:21]([CH3:28])[N:20]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)(F)F
Reactant: Cc1cc(C(=O)O)nc(Cl)n1
Agent: Cl
Product: Cc1cc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)nc(Cl)n1
Yield: 69 %

Procedure:
The title compound is prepared in 69% yield (296 mg, clear colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.1 mmol, Amine-17, single enantiomer) and 2-chloro-6-methylpyrimidine-4-carboxylic acid (191 mg, 1.1 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([Cl:13])[N:12]=1)[C:6]([O:8]C)=[O:7].[C:14]([O-:17])(=[O:16])[CH3:15].[Na+]>CN(C)C(=O)C.O>[C:14]([O:17][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([Cl:13])[N:12]=1)[C:6]([OH:8])=[O:7])(=[O:16])[CH3:15]
Reactant: COC(=O)c1cc(Cl)nc(CBr)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1cc(C(=O)O)cc(Cl)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 2-(bromomethyl)-6-chloroisonicotinate and sodium acetate in N,N-dimethylacetamide is stirred at 120° C. for 2 hours. The mixture is cooled to room temperature and diluted with water (50 mL). The mixture is washed with ethyl acetate/toluene (2:1, 80 mL×2). Water layer is acidified (to pH 4) by the addition of 2M hydrochloric acid, extracted with ethyl acetate (80 mL×2), dried over sodium sulfate. The organic solvent is removed under reduced pressure to give the title compound as a crude product (590 mg, clear brown oil, include N,N-dimethylacetamide). This is used without purification in the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)(=[O:16])=[O:15])[CH:10]=[CH:9][C:8]=2[NH:25][C:26]([C:28]2[N:29](COCC[Si](C)(C)C)[CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([CH2:13][S:14]([N:17]3[CH2:18][C@H:19]([CH3:24])[NH:20][C@H:21]([CH3:23])[CH2:22]3)(=[O:15])=[O:16])[CH:10]=[CH:9][C:8]=2[NH:25][C:26]([C:28]2[NH:29][CH:30]=[C:31]([C:33]#[N:34])[N:32]=2)=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[C@@H]1CN(S(=O)(=O)Cc2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)C[C@H](C)N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: C[C@@H]1CN(S(=O)(=O)Cc2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCCCC3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
A solution of 163 mg (0.266 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(cis-3,5-dimethyl-piperazine-1-sulfonylmethyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (15 mL) was treated with EtOH (300 μL) and TFA (4.5 mL), and stirred at RT for 4 h. Solvents were evaporated in vacuo, and the residue was purified by reverse phase high pressure liquid chromatography (RP-HPLC) (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min to afford 8.8 mg (7%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.31 (d, 1H, J=8.4 Hz), 8.04 (s, 1H), 7.39 (dd, 1H, J=8.4, 2.0 Hz), 7.33 (d, 1H, J=2.0 Hz), 5.91-5.87 (m, 1H), 4.47 (s, 2H), 3.87-3.79 (m, 2H), 3.31-3.25 (m, 2H), 2.76-2.67 (m, 2H), 2.36-2.27 (m, 4H), 1.94-1.79 (m, 4H), 1.29 (d, 6H, J=6.4 Hz). Mass spectrum (ESI, m/z): Calcd. for C24H30N6O3S, 483.2 (M+H). found 482.9.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[CH:3]=1.[BH4-].[Na+].O.O.C(O)(=O)C(O)=O>COCCOCCOC>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]4[CH2:23][CH2:22][O:21][C:20]4=[O:24])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCN1CCN(C2=Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Agent: O=C(O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Sc3ccccc32)CC1
Temperature: 100 °C

Procedure:
750 mg of 3-[2-[4-(2-chloro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone, 0.6 g of sodium borohydride and 30 ml of diglyme are treated dropwise under an argon atmosphere at 20°-30° C over a period of 15 minutes with 2.7 g of oxalic acid dihydrate in 15 ml of diglyme. The mixture is heated for 4 hours at an internal temperature of 100° C and subsequently evaporated under reduced pressure. The residue is treated with chloroform and 2-N sodium hydroxide solution. After equilibration, the aqueous phase is separated and washed twice with chloroform. The combined chloroform extracts are washed with water, dried over potassium carbonate and active carbon, filtered and evaporated under reduced pressure. There is obtained 3-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone in the form of a brown oil. The maleate of melting point 173°-175° C is prepared by treatment with maleic acid in ethanol/ether.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=2[C:18]2[N:19]([CH3:24])[N:20]=[CH:21][C:22]=2[Br:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(N(C)C)=O.Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>CS(C)=O>[CH:35]([O:34][C:32](=[O:33])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]([C:18]2[N:19]([CH3:24])[N:20]=[CH:21][C:22]=2[Br:23])[CH:13]=1)([CH3:37])[CH3:36]
Reactant: CC(C)OC(=O)Cl
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCCCCC1
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CC(C)OC(=O)Nc1ccc(OCCN2CCCCCC2)c(-c2c(Br)cnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 4-(2-azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenylamine (0.06 g, 0.1539 mmol) 2.0 mL of DMA was added isopropyl chloroformate (0.021 g, 0.1687 mmol), and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and purified by RP-HPLC. The proper fractions were collected and evaporated to ¼ volume and the aqueous was neutralized with 1N NaOH to a pH 9.0. Next, the product was extracted with ethyl acetate (2×, 30 mL). The pooled organic layer was dried with sodium sulfate, filtered and evaporated to dryness to afford [4-(2-Azepan-1-yl-ethoxy)-3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-phenyl]-carbamic acid isopropyl ester as a colorless solid in 69% yield. LCMS m/z (%)=478 (M+H79Br, 100), 480 (M+H81Br, 98). 1H NMR (400 MHz, DMSO-d6) δ: 8.79 (bs, 1H), 8.69 (bs, 1H), 7.59 (s, 1H), 7.34 (d, J=2.62 Hz, 1H), 7.21-7.31 (m, 1H), 7.14 (d, J=9.04 Hz, 1H), 4.02-4.12 (m, 1H), 3.92-4.12 (m, 2H), 3.67 (s, 3H), 2.69-2.78 (m, 2H), 2.53-2.59 (m, 2H), 1.4-1.58 (bs, 8H), 1.26 (d, J=6.82 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][OH:24])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][O:24][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OCC1CCCN(Cc2ccccc2)C1
Product: Fc1ccc(COCC2CCCN(Cc3ccccc3)C2)cc1

Procedure:
Following the procedure for Example 139, 4-fluorobenzylbromide and 1-benzyl-3-(hydroxy-methyl)piperidine were reacted to give 1-benzyl-3-(4'-fluorobenzyloxymethyl) piperidine.