Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22]>>[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[N:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:26][CH2:25]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1ccc(Nc2nc3c(Br)cccn3n2)cc1
Product: COc1ccc(Nc2nc3c(N4CCN(S(C)(=O)=O)CC4)cccn3n2)cc1

Procedure:
[8-(4-Methanesulfonyl-piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(4-methoxy-phenyl)-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(4-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and 1-methanesulfonyl-piperazine (29.0 mg, 0.176 mmol) in a manner analogous to example 30. The title compound was isolated as an off-white solid (0.021 g, 33%). MP=240-241° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (dd, J=6.5, 1.1 Hz, 1H), 7.51-7.46 (m, 2H), 6.93-6.88 (m, 2H), 6.77 (dd, J=7.7, 6.6 Hz, 1H), 6.73 (s, 1H), 6.71 (dd, J=7.7, 1.0 Hz, 1H), 3.81 (s, 3H), 3.59-3.54 (m, 4H), 3.50-3.45 (m, 4H), 2.83 (s, 3H). MS=403 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][C@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:35][CH2:36][OH:37]>>[CH3:33][N:2]([CH3:1])[C:3]([C:5]1[N:27]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][N:23]([CH2:35][CH2:36][OH:37])[C@H:22]([CH3:26])[CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OCCBr
Reactant: C[C@@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1
Product: C[C@@H]1CN(c2ccc(Nc3ncc4cc(C(=O)N(C)C)n(C5CCCC5)c4n3)nc2)CCN1CCO
Yield: 68.4 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-[5-((R)-3-methyl-piperazin-1-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (43 mg, 0.095 mmol) and 2-bromo ethanol (13 mg, 0.105 mmol) gave 7-cyclopentyl-2-{5-[(R)-4-(2-hydroxy-ethyl)-3-methyl-piperazin-1-yl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (32 mg, 68%). MS (ESI) m/z 493.3 (M+H)+
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[CH3:14].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[CH3:14])(=[O:19])[CH3:18]
Reactant: CCCC1Oc2c(C)c(C)c(O)c(C)c2S1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCC1Oc2c(C)c(C)c(OC(C)=O)c(C)c2S1
Yield: 95.6 %

Procedure:
A mixture of 1.6 g of 5-hydroxy-4,6,7-trimethyl-2-propyl-1,3-benzoxathiole (prepared as described in Example 42), 0.8 g of acetic anhydride and 10 ml of pyridine was reacted at room temperature for 15 hours and the reaction mixture was then treated with purified in the same manner as described in Example 4, to give 1.8 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[CH:17][N:16]=1>C(#N)C.C(Cl)Cl>[N+:21]([C:20]1[C:15]([N:1]2[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=[CH:2]2)=[N:16][CH:17]=[CH:18][CH:19]=1)([O-:23])=[O:22]
Reactant: C1CNCCNC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: O=[N+]([O-])c1cccnc1N1C=CC=NC=C1
Reaction time: 4 h

Procedure:
Homopiperazine (15.58 g) is dissolved in 100 ml of acetonitrile. Potassium carbonate (8.7 g) is added and then the 2-chloro-3-nitropyridine (5.0 g) dissolved in 25 ml of acetonitrile is added dropwise. The reaction is stirred at 20°-25° 4 hr, then diluted with methylene chloride, washed with water (2 ×), saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, NMR (300 MHz, CDCl3) 8.30, 8.08, 6.66, 3.60, 3.41, 3.10, 2.89 and 1.93 δ.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][CH2:10]Cl>>[CH3:7][O:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCCl
Reactant: C1CCNCC1
Product: COCCN1CCCCC1
Reaction time: 48 h

Procedure:
In an autoclave of 100 mL, piperidine (40.0 g, 470 mmol) was made reacted with chloroethyl methyl ether (22.0 g, 232 mmol) at 130 deg C. for 48 hours. Solid salt that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 25 cm. Then 1H-NMR measurement of obtained amine is performed, and it was confirmed that chemical shifts, δ (ppm), are 3.49-3.46 (t, 2H), 3.31(s, 3H), 2.51-2.48(t, 2H), 2.40-2.36(m, 4H), 1.59-1.53(m, 4H), and 1.42-1.36(m, 2H), and that N-2-methoxyethylpiperidine was synthesized.
Reaction SMILES: C([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:27]C(=O)C)[C:19]([O:23]C(=O)C)=[C:20]([S:21][CH3:22])[C:7]=2[CH2:6][CH2:5]1)(=O)C.C(OC(=O)C)(=[O:33])C.I([O-])(=O)(=O)=O.[Na+]>N1C=CC=CC=1.CO>[OH:23][C:19]1[C:18]([OH:27])=[CH:17][C:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[C:20]=1[S:21]([CH3:22])=[O:33]
Reactant: CSc1c2c(cc(OC(C)=O)c1OC(C)=O)C(c1ccccc1)CN(C(C)=O)CC2
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: c1ccncc1
Solvent: CO
Product: CS(=O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1

Procedure:
A solution of 8.6 g (20 mm) of 3-acetyl-7,8-diacetoxy-1-phenyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared by reacting the dihydroxy parent with an excess of acetic anhydride in pyridine at room temperature) in 40 ml of methanol at -5° is treated with 40 ml of 0.52 M sodium periodate (20.8 mm) dropwise over 15 minutes at 0°. The mixture is cooled overnight, then filtered to give a solid which is washed with methylene chloride. The organic extracts are combined, dried and evaporated in vacuo. The residue is heated at reflux in ethanolic hydrochloric acid overnight. The volatiles are removed and the residue taken up in water. Neutralization with ammonia and extraction with ethyl acetate gives the desired 7,8-dihydroxy-6-methylsulfinyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. The hydrochloride salt is formed by treatment with ethereal hydrogen chloride.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[C:6]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[N:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=O.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[N:16]1([C:6]2[C:5]3[N:10]([CH:1]=[N:3][CH:4]=3)[C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][N:7]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)nc2CNC=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: c1csc(-c2cnc(N3CCNCC3)c3cncn23)c1
Temperature: 90 °C
Yield: 87.6 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(3-(formamidomethyl)-5-(thiophen-2-yl)pyrazin-2-yl)piperazine-1-carboxylate (0.40 g, 1.0 mmol) and toluene (20 mL). To the above mixture was added dropwise POCl3 (0.76 g, 5.0 mmol). The resulting mixture was heated at 90° C. for 1 h. Work-up: the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was further purified by flash column chromatography on silica gel with 5% MeOH in dichloromethane, to afford 0.25 g (85%) of the product. 1H NMR (300 MHz, CDCl3) δ: 8.41 (s, 1H), 7.74 (s, 1H), 7.46 (dd, J=5.1, 1.2 Hz, 1H), 7.37 (dd, J=3.6, 1.2 Hz, 1H), 7.25 (s, 1H), 7.19 (dd, J=5.1, 3.6 Hz, 1H), 3.89 (t, J=5.1 Hz, 4H), 3.08 (t, J=5.1 Hz, 4H). MS m/z: 286 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[O:15][C:14]2[C:9](=[C:10]([OH:16])[CH:11]=[CH:12][CH:13]=2)[O:8]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][C:19]=1[C:41]#[N:42]>CN(C=O)C>[C:41]([C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:18]=1[O:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]3[O:15][CH2:7][O:8][C:9]=13)=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]1)[CH:23]=2)#[N:42]
Reactant: Oc1cccc2c1OCO2
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc4c3OCO4)c(C#N)cnc2cc1OCCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.3 %

Procedure:
Potassium carbonate-(0.055 g) was added to a solution of 2,3-methylenedioxyphenol (0.041 g) in DMF (3 ml) and the mixture was stirred at ambient temperature for 10 minutes. 4-Chloro-3-cyano-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline (0.1 g) was added and the mixture was stirred and heated to 95° C. for 2 hours. The resultant mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was purified by colum chromatography on silica using initially increasingly polar mixtures of methylene chloride and methanol followed by increasingly polar mixtures of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound as a solid (0.069 g); NMR Spectrum: (DMSOd6 and CF3CO2D) 2.3-2.4 (m, 2H), 3.0 (s, 3H), 3.2-4.0 (m, 8H), 3.5 (m, 2H), 3.95 (s, 3H), 4.4 (m, 2H), 6.05 (s, 2H), 6.8 (m, 1H), 6.9 (m, 2H), 7.6 (s, 1H), 7.62 (s, 1H), 9.1 (s, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([O:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:15]=2)=[CH:9][N:8]=1.[Cl-].[Ca+2].[Cl-].C(OCC)(=O)C.CCCCCC>C(O)C.O.[Fe]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:23][CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:15]=2)=[CH:11][CH:12]=1
Reactant: COCCOCc1ccc(Oc2ccc([N+](=O)[O-])c(OC3CCOCC3)c2)cn1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: COCCOCc1ccc(Oc2ccc(N)c(OC3CCOCC3)c2)cn1
Yield: 73.6 %

Procedure:
To a solution of 2-[(2-methoxyethoxy)methyl]-5-[4-nitro-3-(tetrahydro-2H-pyran-4-yloxy)phenoxy]pyridine (11.5 g) in ethanol (100 mL) and water (25 mL) were added iron powder (8 g) and calcium chloride (0.3 g), and the mixture was stirred with heating under reflux for 4 hr. The reaction mixture was cooled, and insoluble material was filtered off through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 50:50, volume ratio) to give the title compound (7.84 g, yield 74%) as an orange oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:19][C:18]=2[O:36][CH3:37])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:19][C:18]=2[O:36][CH3:37])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1COc1nn(Cc2ccccc2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(OCc2nc(-c3ccco3)oc2C)ccc1COc1nn(Cc2ccccc2)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture of {1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzyl)oxy]-1H-pyrazol-4-yl}methanol (0.17 g), activated manganese dioxide (0.50 g) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-2-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (0.12 g, yield 71%). Recrystallization from ethyl acetate-hexane gave colorless needle crystals. melting point: 147-148° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:10]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)=[O:12])[S:8][C:6]=2[N:7]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:29]([C:31]1[N:32]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:10]=[C:9]([C:11]([N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)=[O:12])[S:8][C:6]=3[N:7]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CC(C)(O)C1CCN(C(=O)c2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCC(C(C)(C)O)CC3)sc2n1
Temperature: 150 °C

Procedure:
A mixture of (5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-yl)-[4-(1-hydroxy-1-methylethyl)piperidin-1-yl]methanone (250 mg, 0.59 mmol), 2-ethylbenzimidazole (90 mg, 0.62 mmol), tris(dibenzylideneacetone)dipalladium (15 mg, 2.5 mol %), XPhos (25 mg, 10 mol %) and Cs2CO3 (270 mg, 0.83 mmol) in DMF (6 mL) was purged with argon then heated at 150° C. for 30 min in a microwave reactor. The reaction mixture was purified by column chromatography (Si-PCC, MeOH:DCM, 1-5%) followed by recrystallisation from Et2O and EtOAc affording 771 (109 mg, 35%). LCMS (method I): RT 3.96 min [M+H]+ 536.3. 1H NMR (CDCl3, 400 MHz): δ 8.06-8.05 (1 H, m), 7.76-7.75 (1 H, m), 7.32-7.28 (2 H, m), 5.22 (1 H, d, J=13.34 Hz), 4.84 (1 H, d, J=13.16 Hz), 4.41 (4 H, brd s), 3.89 (4 H, t, J=4.74 Hz), 3.37 (2 H, q, J=7.46 Hz), 3.17-3.15 (1 H, m), 2.84-2.82 (1 H, m), 1.94 (2 H, t, J=13.72 Hz), 1.72-1.62 (1 H, m), 1.49-1.40 (5 H, m), 1.23 (6 H, d, J=7.01 Hz)
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:35][CH2:36][CH:37]([OH:42])[C:38]([O:40]C)=[O:39].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(OCC)(=O)C.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:35][CH2:36][CH:37]([OH:42])[C:38]([OH:40])=[O:39])=[O:30])=[CH:32][CH:33]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: COC(=O)C(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)NCC(O)C(=O)O)cc1)C1CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
To a mixture of 4-[(cyclohexyl{2-methyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methyl)amino]benzoic acid (300 mg) synthesized in Example 280 (4), methyl 3-amino-2-hydroxypropanoate hydrochloride (118 mg), 1-hydroxybenzotriazole monohydrate (117 mg) and triethylamine (106 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (146 mg), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (70% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature overnight, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (1 mL) was added at 0° C., and the resulting precipitate was collected by filtration to give a white solid. The obtained solid was dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to give the title compound (190 mg, 53%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:46])([CH3:45])[O:6][C@H:7]([CH2:37][O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([OH:36])=O)[CH:29]=3)[CH:24]=2)[O:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])[CH3:3].[F:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][NH2:53])=[CH:50][CH:49]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][C:2]([Si:5]([CH3:45])([CH3:46])[O:6][C@H:7]([CH2:37][O:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([C:34]([NH:53][CH2:52][C:51]4[CH:54]=[CH:55][C:48]([F:47])=[CH:49][CH:50]=4)=[O:36])[CH:29]=3)[CH:24]=2)[O:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(-c3ccnc(C(=O)O)c3)ccc2O1
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](COc1ccccc1)CN(Cc1ccccc1)C[C@H]1CCc2cc(-c3ccnc(C(=O)NCc4ccc(F)cc4)c3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a solution of 4-((2R)-2-{[[(2S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-(phenyloxy)propyl](phenylmethyl)amino]methyl}-3,4-dihydro-2H-chromen-6-yl)-2-pyridinecarboxylic acid (Example 90, 82 mg, 0.13 mmol) in dichloromethane (2 mL) was added 4-fluorobenzylamine (33 mg, 0.26 mmol, 2.0 eq.), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol, 2.0 eq.), and 1-hydroxybenzotriazole (35 mg, 0.26 mmol, 2.0 eq.). The solution was stirred overnight at room temperature before being concentrated in vacuo to remove volatile components. The crude residue was purified by flash chromatography on silica gel eluted with 75:25 hexanes/ethyl acetate. The title compound was obtained as a yellow oil (34 mg, 35%): 1H NMR (300 MHz, CDCl3) δ8.47 (d, 1 H), 8.40 (s, 2 H), 7.55 (dd, 1 H), 7.44-7.39 (m, 2 H), 7.34-7.29 (m, 4 H), 7.25-7.20 (m, 4 H), 7.01 (t, 2 H), 6.93-6.80 (m, 4 H), 4.64 (d, 2 H), 4.22-4.16 (m, 1 H), 4.11-4.05 (m, 1 H), 3.83 (s, 2 H), 3.75 (dd, 1 H), 2.94-2.80 (m, 2 H), 2.73-2.67 (m, 4 H), 1.71-1.57 (m, 2 H), 0.86 (s, 9H), 0.09 (s, 3 H), 0.05 (s, 3 H); MS m/z 746.5 (M+).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[O:11])=[CH:6][C:5]=1[Cl:20].Cl>[OH-].[Na+]>[Cl:20][C:5]1[CH:6]=[C:7]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)=[O:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:21])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)Nc2cccc(O)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Reaction time: 2 h
Yield: 102.1 %

Procedure:
A solution of 2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]benzoic acid methyl ester (900 mg; 2.82 mmol) in an aqueous 0.5 N sodium hydroxide solution (20 mL) was stirred at room temperature under argon. After 2 hr, the solution was acidified with 1 N HCl (11 mL) and the resulting colorless solid was filtered, washed with water, and dried in vacuo to give 840 mg of 2-chloro-4-[[(3-hydroxyphenyl)amino]carbonyl]benzoic acid. FAB HRMS: (C15H12ClNO4) Obs. Mass 306.0548 Calcd. Mass 306.0533 (M+H).
Reaction SMILES: BrC1C=C(C#N)C=NC=1.[I-:10].[Na+].[CH3:12][NH:13][C@@H:14]1[CH2:19][CH2:18]CC[C@H:15]1[NH:20][CH3:21]>O1CCOCC1.[Cu]I>[I:10][C:18]1[CH:21]=[N:20][CH:15]=[C:14]([N+:13]#[C-:12])[CH:19]=1
Reactant: [I-]
Reactant: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cu]I
Agent: N#Cc1cncc(Br)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: [C-]#[N+]c1cncc(I)c1
Temperature: 120 °C

Procedure:
To the reaction mixture of 5-bromo-3-cyanopyridine (3 g, 15.9 mmol, 1 eq), sodium iodide (4.77 g, 2 eq), copper(I) iodide (303 mg, 0.1 eq) in anhydrous 1,4-dioxane (40 mL) under nitrogen atmosphere was added trans-N,N′-dimethylcyclohexane-1,2-diamine (0.52 mL, 0.2 eq). After the reaction mixture was heated at 120° C. for 16 hours, it was cooled to room temperature and partitioned between aqueous ammonium chloride and ethyl acetate. The organic layer was isolated, washed with saturated aqueous sodium bicarbonate, brine, and dried with anhydrous sodium chloride. The upper clear solution was decanted, concentrated, and the brown oily residue was subject to a column chromatography (EtOAc-Hex 1:15 to 1:4) yielding 3-iodo-5-isocyanopyridine as a white solid in the amount of 2.41 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.P(Cl)(Cl)(Cl)=O.O>ClCCCl>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([C:8]([C:11]([F:13])([F:14])[F:12])=[CH:9][CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1c(C(F)(F)F)ccc(Cl)c1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCCl
Product: N#Cc1c(C(F)(F)F)ccc(Cl)c1F
Temperature: 35 °C
Yield: 92.6 %

Procedure:
To a solution of 266 g of 3-chloro-2-fluoro-6-trifluoromethylbenzamide in 2.5 liters of 1,2-dichloroethane was added 339 g of phosphorus oxychloride and then the mixture was heated at reflux for 18.5 hours. After cooling, the solution was gradually added into 2 liters of water maintained at 30-40° C. to hydrolyze the excess amount of phosphorus oxychloride and was then separated. The aqueous layer was extracted with chloroform, and the extract was combined with the organic layer previously obtained, washed with IN aqueous solution of sodium hydroxide, water and saturated saline solution in series, and then dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the crude product obtained was washed with chilled n-hexane and then filtered to obtain 228 g of the title compound(mp. 43-44° C.).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:9](=[N:11][OH:12])[NH2:10])=[N:7][CH:8]=1.[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](Cl)=O>>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[O:12][N:11]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:8][N:7]=2)[N:10]=1
Reactant: NC(=NO)c1ccc(C(F)(F)F)cn1
Reactant: O=C(Cl)c1sccc1Cl
Product: FC(F)(F)c1ccc(-c2noc(-c3sccc3Cl)n2)nc1

Procedure:
The title compound was prepared from 5-trifluoromethyl-pyridine-2-amidoxime (516 mg, 2.52 mmol) and 3-chloro-thiophene-2-carbonyl chloride (455 mg, 2.51 mmol) similar to Example 16, and yielded 764 mg (92%) of off-white solid. 1H NMR (CDCl3): 9.09 (m, 1H), 8.36 (d, J=8.24 Hz, 1H), 8.14 (m, 1H), 7.66 (d, J=5.22 Hz, 1H), 7.16 (d, J=5.49 Hz, 1H).