Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:48])[CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[C:28]2[C:32]([NH:33][C:34](=[O:47])[CH2:35][NH:36]C(OCC3C=CC=CC=3)=O)=[N:31][O:30][N:29]=2)=[CH:13][CH:12]=1)C1C=CC=CC=1.[ClH:50].O1CCOCC1>O1CCCC1.CO.[Pd]>[ClH:50].[NH2:36][CH2:35][C:34]([NH:33][C:32]1[C:28]([C:20]2[N:19]([CH2:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH2:10])=[CH:12][CH:13]=3)=[O:48])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)=[N:29][O:30][N:31]=1)=[O:47]
Reactant: O=C(CNC(=O)OCc1ccccc1)Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NCC(=O)Nc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of 0.2 g of [4-(2-{2-[4-(2-benzyloxycarbonylamino-acetylamino)-furazan-3-yl]-benzoimidazol-1-yl}-acetyl)-phenyl]-carbamic acid benzyl ester (0.29 mmol; 1 eq.) in 2 mL of tetrahydrofuran and 2 mL of methanol containing 0.19 mL of a solution of 4M HCl in 1,4-dioxane (0.86 mmol; 3 eq.) and 0.046 g of 10% Pd/C (0.04 mmol; 0.14 eq.) is stirred for 7 hours under hydrogen atmosphere at room temperature. Then the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is suspended in 2 mL of a mixture of dichloromethane/diisopropylether (1/1, v/v) and the suspension is filtered. The solid is washed with 2 mL of diisopropylether and dried under reduced pressure to give the crude product. The solid is purified by MCI gel column chromatography (eluent water/acetonitrile=75/25 to 65/35, containing 0.1% of HCl) to afford 0.02 g of the desired product as a light brown powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:40]1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[C:36]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1)(=[O:37])[NH2:40]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Yield: 50.1 %

Procedure:
A solution of (3R,5S)-1-(tert-butoxycarbonyl)-5-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (540 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (345 mg) and WSC.HCl (383 mg) in DMF (10 ml) was stirred at room temperature for 24 hr, and the mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object product (270 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CCOCC.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:19]
Reactant: Brc1ccccn1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(=O)c1ccccn1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 20 mL (210 mmol) of 2-bromopyridine in 500 mL of dry ether at −78° C. under Ar was added 85 mL of a 2.5 M solution of n-butyllithium in hexane in a slow stream. After stirring in the cold for 30 min, the solution was transferred over a 5 min period via two cannula into a 0° C. stirred solution of 100 mL (736 mmol) of diethyl oxalate in 1.0 L of dry ether under Ar. After stirring for 2 h in the cold, the reaction mixture was washed with 600 mL of sat. NaHCO3, water, and brine. The solution was dried over MgSO4 and the solvents concentrated at reduced pressure to give a red oil that was purified by SiO2 chromatography (10×15 cm) using 1:4 to 35:65 EtOAc-hexanes. The product-containing fractions were concentrated at reduced pressure to afford 6-1 as a reddish oil: 1H NMR (CDCl3) δ 1.42 (t, 3H), 4.45-4.55 (m, 2H), 7.55-7.6 (m, 1H), 7.9-7.95 (m, 1H), 8.11 (d, 1H), 8.78 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1.[H][H]>C1COCC1.CO.[Ni]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1
Reactant: COc1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cn1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Nc2c(N)cnc3ccc(Br)cc23)cn1

Procedure:
6-bromo-N-(6-methoxypyridin-3-yl)-3-nitroquinolin-4-amine (compound of step 2, 13.3 mmol) was hydrogenated using Raney-Ni (1 g) in THF-MeOH [(1:1), 50 mL] under 40 psi of hydrogen for 4 h at RT. After completion of the reaction, the reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated and purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.93 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.7 Hz, 3H), 7.47 (dd, J=2.1, 9.0 Hz, 2H), 6.93 (dd, J=3.0, 8.7 Hz, 1H), 6.65 (d, J=9.0 Hz, 1H), 5.42 (s, 2H), 3.85 (s, 3H); MS (m/z): 345.0 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH:3]=1>CO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([NH2:8])[N:5]=2)=[N:11][CH:12]=1
Reactant: Cc1cc(Nc2ccc([N+](=O)[O-])cn2)nc(N)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Nc2ccc(N)cn2)nc(N)n1
Reaction time: 20 h
Yield: 1 %

Procedure:
Compound 9 (634 mg, 246 mmol) was hydrogenated in MeOH (50 mL) with 10% Pd/C (100 mg) at 45 Hg mm. for 20 h. The reaction mixture was filtered and evaporated to dryness to give 10 (550 mg, 99%); mp (MeOH) 230-233° C.; 1H NMR [(CD3)2SO] δ 8.96 (s, 1 H, NH), 7.70 (d, J=8.7 Hz, 1 H, H-3′), 7.65 (d, J=2.5 Hz, 1 H, H-6′), 6.95 (dd, J=8.8, 2.9 Hz, H-4′), 6.30 (s, 1 H, H-5), 5.94 (s, 2 H, NH2), 4.84 (s, 2 H, NH2), 2.07 (s, 3H, CH3); HRMS (FAB+) calc. for C10H13N6 (M+1) m/z 217.1202, found 217.1202; Anal. calc. for C10H12N6; C, 55.5; H, 5.6; N, 38.9; found C, 55.3; H, 5.7; N, 38.6%.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38](B(O)O)[CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]=2[N:3]1[C:38]1[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(c3cccnc3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.5 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol), pyridin-3-ylboronic acid (52 mg, 0.424 mmol), copper(II)acetate (58 mg, 0.318 mmol) and 5 Å molecular sieves (60 mg) in anhydrous dichloromethane (2 ml). To this was added anhydrous pyridine (34 μl, 0.424 mmol) and the resulting blue suspension stirred at room temperature under air for 24 hours. Further pyridine (1 mL) was added and the resulting deep blue solution stirred at room temperature for 24 hours. Further pyridin-3-ylboronic acid (52 mg, 0.424 mmol) and copper(II)acetate (58 mg, 0.318 mmol) were added and the mixture stirred at room temperature for 72 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 88:12 to 0:100) to give the desired product as an off-white solid (32 mg 28% yield). 1H-NMR (500 MHz, CDCl3) δ 8.50-8.80 (2H, br m), 7.71 (1H, d), 7.50 (1H, br s), 7.09-7.26 (7H, m), 6.92-7.02 (2H, d), 6.71 (1H, s), 5.00 (3H, s), 2.10-2.55 (4H, m), 1.92-2.05 (1H, m), 1.66-1.80 (1H, m), 1.00-1.45 (9H, br m). LCMS (Method A) RT=6.61 min, M+H+=549.09.
Reaction SMILES: FC(F)(F)S([C:6]1[CH:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=O)=O.[C-:25]#[N:26].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCCCCC>C(#N)C.[Zn].C(OCC)(=O)C>[C:25]([C:6]1[CH:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[CH:9]=[CH:10][CH:11]=1)#[N:26]
Reactant: [C-]#N
Reactant: O=S(=O)(c1cccc(-c2cc(-c3ccccn3)no2)c1)C(F)(F)F
Agent: [K+]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1cccc(-c2cc(-c3ccccn3)no2)c1
Temperature: 60 °C
Yield: 23.3 %

Procedure:
A mixture of 5-[3-trifluoromethanesulfonylphenyl]-3-[pyridin-2-yl]-1,2-oxazole (98 mg, 0.26 mmol), KCN (230 mg, 4 mmol), NiBr2(PPh3)2 (52.4 mg, 0.07 mmol), and PPh3 (42 mg, 0.16 mmol) in acetonitrile (1 mL) was treated with zinc powder (20 mg, 0.3 mmol) and the mixture was heated overnight at 60° C. Silica gel chromatography of the resulting mixture using a gradient of hexane to ethyl acetate afforded 15 mg (23%) of 5-[3-cyanophenyl]-3-[pyridin-2-yl]-1,2-oxazole as a white solid.
Reaction SMILES: [Mg].[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6]Cl.[O:9]=[C:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][C:12]2[CH:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:24][C:11]1=2.[Cl-].[NH4+].Cl>O1CCCC1.BrC(Br)C>[CH3:2][N:3]([CH3:8])[CH2:4][CH2:5][CH2:6][C:10]1([OH:9])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][C:12]2[CH:21]=[CH:22][C:23]([CH2:25][CH2:26][O:27][C:28]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:24][C:11]1=2
Reactant: O=C1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Reactant: CN(C)CCCCl
Agent: CC(Br)Br
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CN(C)CCCC1(O)c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
To a solution of 3-dimethylaminopropyl magnesium chloride obtained by reacting 0.2 g of magnesium with 1.0 g of 3-dimethylaminopropyl chloride in 10 ml of tetrahydrofuran under a nitrogen atmosphere using dibromoethane as a catalyst, is dropwise added a solution obtained by dissolving 2.0 g of 11-oxo-2-(2-triphenylmethyloxyethyl)-6,11-dihydrodibenz[b,e]oxepin in 10 ml of tetrahydrofuran under ice cooling and the mixture is stirred at room temperature for one day. Aqueous ammonium chloride solution is added thereto and the pH of the mixture is adjusted to 7.0 with aqueous 4N-hydrochloric acid solution. The solvent is distilled away under reduced pressure. The mixture is extracted with 200 ml of methylene chloride and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution in order. After drying the extract over anhydrous sodium sulfate, the solvent is distilled away under reduced pressure. The resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate:triethylamine=10:10:1 ) to obtain 1.2 g of the desired product as a colorless amorphous.
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:30]C)[CH:25]=2)=[CH:18][N:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3].Cl>C(O)C>[CH2:1]([N:4]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[NH:21][C:20](=[O:22])[C:19]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([OH:30])[CH:25]=2)=[CH:18][N:17]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH2:2][CH3:3]
Reactant: CCCN(CCCCNc1ncc(Cc2ccnc(OC)c2)c(=O)[nH]1)c1ccccn1
Agent: Cl
Solvent: CCO
Product: CCCN(CCCCNc1ncc(Cc2ccnc(O)c2)c(=O)[nH]1)c1ccccn1

Procedure:
2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]-5-(2-methoxy pyrid-4-ylmethyl)pyrimid-4-one (1.8 g) in ethanol (50 ml) saturated with hydrogen chloride was heated under reflux for 40 hrs. After stripping, the residue was triturated with ether. The residue was taken up in water, basified and extracted with ether, acidified to neutral pH and extracted with chloroform. After stripping, the residue was crystallized from methanol to give 2-[4-(N-propyl-N-pyrid-2-ylamino)butylamino]-5-(2-hydroxypyrid-4-ylmethyl)pyrimid-4-one 1.4 H2O, 0.80 g (43%) m.p. 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[C:9]([CH3:18])=[N:8]2)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][CH2:40][C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[S:39][C:40](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]=3[C:21]([F:24])([F:22])[F:23])[N:8]=[C:9]4[CH3:18])[C:41](=[O:43])[N:42]=2)[CH2:34][C@@H:33]1[CH2:44][OH:45])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=O)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Product: Cc1nn(Cc2ccc(Cl)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCN(C(=O)OC(C)(C)C)[C@@H](CO)C4)=NC3=O)cc12

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(4-Chloro-2-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehyde and 2-(R)-Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][CH2:25][CH2:26][OH:27])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:35]([Si:39](Cl)([CH3:41])[CH3:40])([CH3:38])([CH3:37])[CH3:36].O>C1COCC1>[Si:39]([O:27][CH2:26][CH2:25][NH:24][CH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNCCO)C1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNCCO[Si](C)(C)C(C)(C)C)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution (13.2 mL) of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-{[(2-hydroxyethyl)amino]methyl}-1,4-oxazepane-4-carboxylate (1.65 g) and triethylamine (0.605 mL) in THF was added, under ice-cooling, tert-butylchlorodimethylsilane (654 mg), and the mixture was stirred at room temperature overnight. Then, tert-butylchlorodimethylsilane (654 mg) and triethylamine (0.605 mL) were added, and the mixture was stirred at 50° C. for 1 hr. Distilled water was added, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.96 g).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][N:20]([CH2:28][CH2:29][O:30][CH3:31])C(=O)OC(C)(C)C)=[CH:17][N:18]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:49])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:32])[C:16]([CH2:19][NH:20][CH2:28][CH2:29][O:30][CH3:31])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COCCNCc1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 47 (400 mg, 0.568 mmol) in toluene (10 mL) was added TFA (0.874 mL, 11.35 mmol) and the reaction mixture was stirred at RT overnight. The mixture was concentrated to dryness and the residue was purified by Gilson Reverse Phase HPLC (Aquasil C18, elient a linear gradient of 35% MeOH in water to 95% MeOH in water with 0.05% of formic acid, 60 min run) to afford 48 as a white solid, (305 mg, 65% yield) as the TFA salt. MS (m/z): 605.3 (M+H).
Reaction SMILES: [C:1]([O:11][CH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([N+:22]([O-])=O)[CH:14]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>>[C:1]([O:11][CH2:12][C:13]1[CH:14]=[C:15]([NH2:22])[CH:16]=[C:17]([NH2:19])[CH:18]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Product: CCCCCCCCC(=O)OCc1cc(N)cc(N)c1
Yield: 100.1 %

Procedure:
39.6g (0.2 mol) of3,5-dinitrobenzyl alcohol, 23.7 g (0.3 mol) of pyridine and 200 ml of methyl ethyl ketone were introduced into a reactor and dissolved by stirring under a nitrogen gas stream at about 70° C. 35.3 g (0.2 mol) of pelargonic acid chloride was dissolved in 100 ml of methyl ethyl ketone and the resultant solution was added dropwise into the reactor as described above. After the completion of the addition, the mixture was refluxed and stirred under nitrogen for about 2 hours. Then the reactor was cooled by allowing to stand and pyridine hydrochloride was removed by filtration. The filtrate was concentrated and purified by using a column to give 50.8 g of 3,5-dinitrobenzyl pelargonate. 33.8 g of 3,5-dinitrobenzyl pelargonate and 4 g of a catalyst (5% palladium carried on active carbon) were introduced into a hydrogenation apparatus and reduced with hydrogen. After filtration and concentration, 27.8 g (0.1 mol) of 3,5-diaminobenzyl pelargonate was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[CH:9]=[C:8]([CH3:10])[S:7][C:6]=2[C:11]=1[Cl:12].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC(=O)CC.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][O:13][C:3]1[C:2]([Cl:1])=[C:11]([Cl:12])[C:6]2[S:7][C:8]([CH3:10])=[CH:9][C:5]=2[CH:4]=1)[CH3:20]
Reactant: Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(C)sc2c(Cl)c1Cl
Yield: 93.9 %

Procedure:
A mixture of 2.1 g of 6,7-dichloro-5-hydroxy 2-methylbenzo[b]thiophene, 1.88 g of ethyl bromoacetate, 20 ml of 2-butanone, 2 ml of dimethylformamide and 4.0 g of sodium bicarbonate is refluxed for 16 hours. The cooled mixture is diluted with ice, extracted 3 times with ether and the ether solution is washed, dried and concentrated. The crude oil after removal of solvent is purified by passing it through an alumina column. Elution with ether gives 2.7 g of ethyl[ (6,7-dichloro-2-methylbenzo[b]thien-5-yl)oxy]acetate as off-white crystals, mp 91°-92°. An analytical sample is recrystallized twice from hexane and dried at 80°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][CH3:27])=[O:25].FC(F)(F)C(O)=O>CC(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([NH:26][CH3:27])=[O:25])[CH:7]=3)[CH2:9]2)=[CH:14][CH:15]=1
Reactant: CNC(=O)c1cccc(N)c1
Reactant: Fc1ccc(OC2CN(c3ccnc(Cl)c3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2cc(N3CC(Oc4ccc(F)cc4)C3)ccn2)c1
Temperature: 92 °C
Yield: 58.1 %

Procedure:
To 2-chloro-4-(3-(4-fluorophenoxy)azetidin-1-yl)pyridine (90 mg, 0.323 mmol) and 3-amino-N-methylbenzamide (72.7 mg, 0.484 mmol) in 2-propanol (3.00 mL) in a disposable sealed tube at RT was added trifluoroacetic acid, (0.075 mL, 0.969 mmol). The resulting reaction mixture was heated at 84° C. for 5 days and 92° C. for 20 days, cooled to RT, concentrated, purified using MPLC (5 g cartridge, 12 g column, 0 to 100% 90/10 CH2Cl2-MeOH in CH2Cl2) giving 3-(4-(3-(4-fluorophenoxy)azetidin-1-yl)pyridin-2-ylamino)-N-methylbenzamide (73.6 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15]O.Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N)CC1

Procedure:
1-t-Butoxycarbonyl piperidine-4-one (commercially available from Lancaster Chem) (39.9 g, 0.20 mol), THF (150 mL), H2O (300 mL), and H2NOH HCl (55.2, 0.80 mol) were dissolved together and Na2CO3 (55.2 g, 0.53 mol) was added in small portions. The mixture was stirred at 23° for 14 h, most of the THF was evaporated in vacuo, adjusted to pH>10 with 50% aq NaOH, extracted with EtOAc(5×50 mL) and concentrated to a white foam. Triturated with hexane, filtered and the solid was dried in vacuo to afford 40.31 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[F:25][C:26]([F:31])([F:30])[CH2:27][NH:28][NH2:29]>>[F:25][C:26]([F:31])([F:30])[CH2:27][NH:28][NH:29][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[CH:5]=1
Reactant: NNCC(F)(F)F
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NNCC(F)(F)F)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2,2,2-trifluoroethylhydrazine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.