Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CO>[C:14]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:13][C:6]=2[CH2:7][CH2:8][CH2:9][C:10]1=[O:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CCCc2cc(I)ccc2N1
Solvent: CO
Product: CC(=O)N1C(=O)CCCc2cc(I)ccc21

Procedure:
10 gms. of the 7-iodo-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine from part (a) of this example are refluxed for 6 hours with 160 ml. of acetic anhydride. The solution is evaporated under vacuum following which a thick oil is obtained, which when admixed with methanol gives crystalline N-acetyl-7-iodo-2 oxo-2,3,4,5-tetrahydro-1-H-1-benzazepine with a melting point of 116° to 117° C. Yield 9.5 gm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=CC(C(O)=O)=C[C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH:35]([CH3:39])[C:36]([NH2:38])=[O:37]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:39][C:35]([C:36]([NH:38][C:24](=[O:31])[CH:23]([CH3:28])[CH3:17])=[O:37])=[CH:34][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: CC(C)C(N)=O
Solvent: CC#N
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)C(C)C)ccc1C(C)(C)C)c1ccc(OC)cc1OC

Procedure:
Following a similar procedure to that described in Example 139, but using N-(2-t-butyl-5-carboxyphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Preparation 7) and 2-methylpropanamide, the title compound was obtained as crystals, melting at 157-159° C. (from acetonitrile).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH3:16]I.O>CN(C)C=O>[CH3:16][O:1][C:2]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(C(F)(F)F)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)ccc1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.5 g of 2-hydroxy-4-(trifluoromethyl)benzaldehyde was dissolved in 20 ml N,N-dimethylformamide. 1.0 g of sodium hydride (60% oily) was added, followed by stirring at room temperature for 30 minutes. 1.8 ml methyl iodide was added dropwise thereinto, follwed by reacting for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was subjected to silica gel column chromatography, to give 3.0 g of 2-methoxy-4-(trifluoromethyl)benzaldehyde as a colorless oil from fractions eluted with hexane-ethyl acetate (9:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:16]3[C:17](=[C:19]([C:23]([O-:25])=O)[CH:20]=[CH:21][CH:22]=3)[N:18]=2)[CH2:10][CH:9]1[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.Cl.[CH3:30][N:31]1[CH:36]2[CH2:37][CH2:38][CH2:39][CH:32]1[CH2:33][CH:34]([NH2:40])[CH2:35]2>>[CH3:26][CH:9]1[CH2:10][N:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:25])[NH:40][CH:34]4[CH2:33][CH:32]5[N:31]([CH3:30])[CH:36]([CH2:37][CH2:38][CH2:39]5)[CH2:35]4)[C:17]=3[N:18]=2)[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7]
Reactant: CN1C2CCCC1CC(N)C2
Reactant: CC1CN(c2nc3c(C(=O)[O-])cccc3o2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Product: CC1CN(c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cccc3o2)CCN1C(=O)OC(C)(C)C

Procedure:
Following general procedure GP-C1, lithium 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)benzoxazole-4-carboxylate and 9-methyl-9-azabicyclo[3.3.1]nonan-3-amine dihydrochloride were coupled to provide tert-butyl 2-methyl-4-(4-(9-methyl-9-azabicyclo[3.3.1]nonan-3-ylcarbamoyl)benzoxazol-2-yl)piperazine-1-carboxylate. MS consistent.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[C:11]=1[CH3:27]>C1COCC1>[CH3:16][C:14]1[N:13]=[C:12]([NH:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[C:11]([CH3:27])=[C:10]([O:1][CH:2]2[CH2:6][CH2:5][O:4][CH2:3]2)[N:15]=1
Reactant: OC1CCOC1
Reactant: Cc1cc(C)c(Nc2nc(C)nc(Cl)c2C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Nc2nc(C)nc(OC3CCOC3)c2C)c(C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 3-hydroxy-tetrahydrofuran (0.5 ml) and sodium hydride (60% in oil, 53 mg, 1.33 mmol) in dry THF was stirred at room temperature for 5 minutes, (6-chloro-2,5-dimethyl-pyrimidin-4-yl)-(2,4,6-trimethylphenyl)-amine (107 mg, 0.388 mmol) was added. The mixture was heated at reflux for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a yellow oil. The oil was purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give 48 mg of the title compound as off-white crystals, mp 126-128° C. 1H NMR (CDCl3) δ6.89 (s, 2H), 5.60 (brs, 2H), 3.8-4.0 (m, 4H), 2.27 (s, 6H), 2.13 (s, 6H), 2.1-2.25 (m, 2H), 1.93 (s, 3H) ppm.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15](OC(C)=O)=[O:16]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:15]([O:13][CH:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:16])[CH3:14]
Reactant: OC1CCC(c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a mixture of 20.3 g (0.115 mol) of 4-phenylcyclohexanol, 14.2 ml (O.1S mol) of acetanhydride and 29 ml of triethylamine are added, with stirring and at ambient temperature, 2.3 g (0.02 mol) of 4-dimethylaminopyridine, a clear solution being produced in an exothermic reaction. This is heated to 80° C. for 3 hours and the reaction mixture is then poured into ice water. The crystalline product precipitated is suction filtered, dissolved in ether, washed with sodium bicarbonate solution, dried and evaporated down in vacuo. 23 g (92% of theory) of O-acetyl-4-phenylcyclohexanol are obtained. The product is obtained initially as an oil but crystallises when left to stand. Melting point: 43-45° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([B:20]([O:22]C12CC(C1(C)C)CCC2(O)C)[OH:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([B:20]([OH:21])[OH:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(O)CCC2CC1(OB(O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C2(C)C
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccccc1)B(O)O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 2.93 g. (7 mmol) of (+)-pinanediol-1-benzyloxycarbonylamino-2-phenylethane boronate (IV) in 20 ml of CH2Cl2 at −78° C. is added 24 ml of boron trichloride. The mixture is kept at 20° C. for 2 hrs., then concentrated under vacuum and the residue is washed with ether, treated with methanol, concentrated and dissolved in water. The solution is then neutralized with Dowex 1-x8 ion exchange resin bicarbonate, concentrated and crystallized from THF/water to give (R)-1-benzyloxycarbonylamino-2-phenylethane boronic acid and its anhydride.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1.C(Cl)(Cl)Cl.[Br:19]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:19][C:11]1[S:10][C:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:14])[N:3]=[C:2]([CH3:1])[N:7]=2)=[N:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Nc2nccs2)nc(C)n1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2ncc(Br)s2)nc(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a round bottomed flask were added 50 mg of (2,6-dimethyl-pyrimidin-4-yl)-thiazol-2-yl-amine (23-2), chloroform (3.0 mL) and 47 mg of N-bromosuccinimide. The reaction was allowed to stir at room temperature for 2 hours. The chloroform was diluted with ethyl acetate and washed with saturated sodium bisulfite solution. The ethyl acetate was dried (MgSO4) and the solvent removed under high vac to give the desired product. The title compound was used as is. 1H-NMR (400 MHz, DMSO-d6) 11.05 (1H, s), 7.53 (1H, s), 6.69 (1H, d), 6.69 (1H, s), 2.54 (3H, s), 2.35 (3H, s). MS(M+1)=285.
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1.Cl[C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32]>C(Cl)Cl>[CH3:12][S:9]([C:7]1[CH:8]=[CH:3][C:4]([NH:13][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:25][CH2:26][N:27]([C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32])[CH2:28][CH2:29]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c2OCCN3C2CCNCC2)c(F)c1
Reactant: CC(OC(=O)Cl)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CC(OC(=O)N1CCC(N2CCOc3c(Nc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1)C(F)(F)F
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC (C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1 H), 8.31 (brs, 1 H), 8.14 (s, 1 H), 7.59-7.78 (m, 2 H), 5.18-5.34 (m, 1 H), 4.78-4.93 (m, 1 H), 4.22-4.41 (m, 4 H), 3.47-3.55 (m, 2 H), 3.04 (s, 3 H), 2.88-3.07 (m, 2 H), 1.79 (m, 2 H), 1.60-1.75 (m, 2 H), 1.42 (d, J=6.60 Hz, 3 H).). LRMS (ESI) 548 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([F:10])[C:7]=1[CH:8]1[O:14][CH2:13][CH2:12][O:9]1
Reactant: O=Cc1c(Br)ccc(O)c1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1ccc(Br)c(C2OCCO2)c1F
Yield: 93.6 %

Procedure:
A solution of 6-bromo-2-fluoro-3-hydroxybenzaldehyde (1.61 g, 7.35 mmol), ethylene glycol (2 mL, 36.8 mmol), para-toluenesulfonic acid (0.27 g, 0.147 mmol), and toluene (150 mL) was refluxed with a dean-stark head for 16 hours. An aqueous solution of sodium bicarbonate was added and the solution was extracted with ethyl acetate. The aqueous layer was extracted five more times with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to give 4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenol (1.81 g, 94% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1.Br[CH2:15][CH2:16][CH:17]1[O:21][CH2:20][CH2:19][O:18]1.O>CC(C)=O>[O:18]1[CH2:19][CH2:20][O:21][CH:17]1[CH2:16][CH2:15][S:7][C:8]1[N:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Sc1ncccn1
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: c1cnc(SCCC2OCCO2)nc1

Procedure:
Potassium carbonate (0.766 g) was added to a stirred solution of 2-mercaptopyrimidine (0.622 g) in acetone (10 cm3) at ambient temperature. 2-(2-Bromoethyl)-1,3-dioxolane (1 g) was added to the resulting mixture and the reaction heated under reflux for 3.5 hours. The reaction mixture was left to cool overnight, then poured into water and extracted with diethyl ether. The organic phase was dried with magnesium sulfate and evaporated under reduced pressure to give a yellow oil. This material was used in step 2 without further purification. M+ =212; 1H NMR (CDCl3): δ2.25 (2H,m); 3.25(2H,t); 3.90 (2H,m); 4.00 (2H,m); 5.05 (1H,t); 6.96 (1H,t); 8.52 (2H,d).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[BH4-].[Na+]>CO>[CH2:31]([NH:39][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][C:12]2[N:13]=[CH:14][C:9]([C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])=[CH:10][CH:11]=2)=[CH:17][CH:18]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)N3CCCCC3)cn2)cc1
Reactant: NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)nc1)N1CCCCC1
Reaction time: 72 h
Yield: 82.7 %

Procedure:
Combine 4-[5-(Piperidine-1-carbonyl)-pyridin-2-yloxy]-benzaldehyde (72.0 mg, 0.23 mmol), MeOH (2.3 mL), Trimethylorthoformate (1.6 mL), and Phenethylamine (26 uL, 0.21 mmol). After the reaction stirs for 72 hours at room temperature under a Nitrogen atmosphere, add NaBH4 (10.5 mg, 0.28 mmol). After 5 hours, concentrate the reaction under reduced pressure and add the mixture to a 2 g SCX column. Wash with MeOH and then 1N NH3MeOH to afford 72.2 mg (75% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5-1.8 (6H, m), 2.8-3.0 (4H, m), 3.3-3.8 (4H, m), 3.85 (2H, s), 6.8 (1H, d), 7.1-7.4 (9H, m), 8.0 (1H, d), 8.2 (1H, s); MS m/z 416 (M+1).
Reaction SMILES: [CH:1](Br)([CH3:3])[CH3:2].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH:1]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:24][CH3:25])([CH3:3])[CH3:2]
Reactant: CC(C)Br
Reactant: COc1cc2c(Nc3cccc(C)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cccc(C)c3)ncnc2cc1OC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Isopropyl bromide (0.246 g) was added to a stirred mixture of 7-hydroxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.281 g), potassium carbonate (0.414 g) and DMA (3 ml). The mixture was stirred at ambient temperature for 30 minutes and then heated to 70° C. for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated to give 7-isopropoxy-6-methoxy-4-(3'-methylanilino)quinazoline (0.28 g), m.p. 218°-221° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:32]=[CH:31][C:12](/[CH:13]=[CH:14]/[C:15]2[N:23]([CH3:24])[C:22]3[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH3:30])[C:17]=3[N:16]=2)=[CH:11][CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[OH-].[Na+]>O1CCCC1>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:13]=[CH:14]/[C:15]2[N:23]([CH3:24])[C:22]3[C:21](=[O:25])[N:20]([CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH3:30])[C:17]=3[N:16]=2)=[CH:31][CH:32]=1
Reactant: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN=[N+]=[N-])cc3)n2C)n(CC)c1=O
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2c(nc(/C=C/c3ccc(OCCCCN)cc3)n2C)n(CC)c1=O

Procedure:
Compound 187 (75 mg, 0.17 mmol) obtained in Reference Example 184 was dissolved in 7.5 ml of tetrahydrofuran. To the solution was added 90 mg (0.34 mmol) of triphenylphosphine, and the mixture was heated under reflux for 3 hours. Water (5 ml) was added thereto and the mixture was heated under reflux for further one hour. After cooling, a 2N aqueous solution of sodium hydroxide was added thereto, and the mixture was extracted with chloroform and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol/triethylamine) to give 74 mg (yield quant.) of Compound 188. The obtained crude crystals were further recrystallized from 2-propanol/water.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[N:5][C:6]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][C:8]=1[S:9]([CH3:11])=O)#[N:2].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]CS.C1CCN2C(=NCCC2)CC1>COCCOC>[C:1]([C:3]1[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[N:5][C:6]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][C:8]=1[S:9][CH2:11][CH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=1)#[N:2]
Reactant: CS(=O)c1nc(NC(=O)c2ccccc2)nc(-c2ccco2)c1C#N
Reactant: SCCc1ccccn1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(SCCc2ccccn2)nc(NC(=O)c2ccccc2)nc1-c1ccco1

Procedure:
From N-(5-cyano-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl)-benzamide, 2-pyridylethylmercaptan and DBU in DME. ES-MS m/e (%): 428 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][CH2:29][C@H:30]([OH:57])[CH2:31][O:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][Si](C(C)(C)C)(C5C=CC=CC=5)C5C=CC=CC=5)=[CH:35][CH:34]=4)=[CH:22][CH:21]=3)[CH2:15][CH2:14]1)=[O:12])=[CH:5]2>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][NH:28][CH2:29][C@H:30]([OH:57])[CH2:31][O:32][C:33]4[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=4)=[CH:24][CH:25]=3)[CH2:17][CH2:18]1)=[O:12])=[CH:5]2
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)c4cc5cc(Br)ccc5[nH]4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(c1cc2cc(Br)ccc2[nH]1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 35.5 %

Procedure:
(5-Bromo-1H-indol-2-yl){4-[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-1-piperidinyl}methanone (0.119 g, 0.141 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.031 g, 0.05 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13](Cl)=[O:14].[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][NH:20]1.C(N(CC)CC)C.Cl>ClCCl>[CH3:16][O:17][CH2:18][C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:13]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:14]
Reactant: COC[C@@H]1CCCN1
Reactant: COc1ccc2ccccc2c1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC[C@@H]1CCCN1C(=O)c1c(OC)ccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methoxy-naphthalene-1-carbonyl chloride (0.50 g, 2.27 mmol) in dry dichloromethane (5 mL) at 0° C. under a N2 atmosphere was added 2-(S)-methoxymethylpyrrolidine (0.32 g, 2.75 mmol) and triethylamine (0.47 mL, 3.39 mmol). The mixture was allowed to warm to rt and stirred overnight, after which time it was poured into N HCl (50 mL) and extracted with dichloromethane (3× 50 mL). The combined organic layers were dried over Na2SO4, and the crude product was purified by column chromatography on silica gel using a solvent gradient of 10-30% ethyl acetate in hexane. The title compound was obtained as a colorless solid (0.374 g, 55%). 1H NMR (300 MHz, CDCl3) δ 1.90 (m, 6H), 2.99 (m, 1H), 3.21 (m, 1H), 3.48 (m, 3H), 3.95 (m, 3H), 4.59 (m, 1H), 7.29 (m, 1H), 7.37 (m, 1H), 7.48 (m, 1H), 7.76 (m, 3H); MS (ESI) m/z=300 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]=[C:11]=[S:12])=[O:9])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[S:12])=[C:30]([CH3:35])[CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 56%).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:15])[CH:6]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26](O)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([O:15][C:7]2[CH:6]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(OCCF)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCF)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 102.9 %

Procedure:
Using a procedure similar to that of Example 6-D, methyl 4-(2-fluoroethoxy)-2-hydroxybenzoate (3.6 g, 17.8 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (3.58 g, 17.8 mmol), and triphenylphosphine (5.60 g, 21.4 mmol) in THF (75 mL) is treated with diethyl azodicarboxylate (3.60 g, 17.8 mmol) in THF (15 mL) to afford the crude product (7.28 g) which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15](O)=[O:16])([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)=[O:16])([O-:11])=[O:10]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Yield: 88.6 %

Procedure:
Using p-toluidine (1.19 g, 11.0 mmol) and 3-nitrobenzoic acid (1.76 g, 10.0 mmol), the procedure of Reference Example 16 was repeated to obtain 2.27 g (88.3%) of the title compound in the form of colorless needle crystals.