Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(O)(C)C>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[NH:6][C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1cc2c(cc1N)C(C)(C)CCC(=O)N2
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)NC(=O)CCC3(C)C)ncc1Cl
Yield: 27.5 %

Procedure:
7-Amino-8-methoxy-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (59 mg, 0.25 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (75 mg, 0.25 mmol), and 10-Camphorsulfonic acid (58 mg, 0.25 mmol), in Isopropyl alcohol (4 mL) were irradiated at 120° C. for 40 min in a CEM microwave. The sample was cooled, treated with MP-carbonate resin, filtered and conc. in vacuo. Silica gel chromatography afforded the product as a yellow solid (34 mg, 27%). MP: 197-199° C.; LCMS 495 (M+H); 1H-NMR, CDCl3: 11.1 (s, 1H), 8.66 (d, 1H, J=8.4 Hz), 8.38 (s, 1H), 8.16 (s, 1H), 7.50 (d, 1H, J=7.9 Hz), 7.43 (dd, 1H, J=7.7, 7.7 Hz), 7.30 (m, 1H), 7.08 (m, 1H), 7.01 (s, 1H), 6.45 (s, 1H), 6.21 (s, 1H), 3.90 (s, 3H), 3.07 (d, 3H, J=4.9 Hz), 2.40 (t, 2H, J=7.0 Hz), 2.08 (t, 2H, J=7.0 Hz), 1.30 (s, 6H).
Reaction SMILES: [Na].[CH2:2]([N:9]=[N+:10]=[N-:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]([CH2:16][CH2:17][CH:18](C(OCC)=O)[C:19](OCC)=[O:20])([O:14]C)=[O:13]>C(O)C>[CH2:2]([N:9]1[C:19]([OH:20])=[C:18]([CH2:17][CH2:16][C:12]([OH:14])=[O:13])[N:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: CCOC(=O)C(CCC(=O)OC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCc1nnn(Cc2ccccc2)c1O

Procedure:
To a solution of 1.725 g. (75 mmol.) of sodium in 50 ml. of absolute ethanol is added 6.0 g. (45 mmol.) of benzylazide and 12.3 g. (50 mmol.) of diethyl 2-(carbomethoxyethyl)malonate. The reaction mixture is refluxed for 12 hours, then cooled and evaporated to dryness. Water (100 ml.) is added and the mixture is heated while maintaining the pH at 12. The aqueous mixture is extracted with ethyl acetate and the aqueous phase is acidified with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution is evaporated to dryness to give 1-benzyl-4-(2-carboxyethyl)-5-hydroxy-1,2,3-triazole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[OH-].[Na+].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>O>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of piperidine-4-carboxylic acid (1.29 g, 10.0 mmol) in water was added NaOH (800 mg, 20.0 mmol). When the reaction solution was clear, (BOC)2O (2.5 g, 11.0 mmol) was added, and the reaction mixture was stirred at rt for 12 h. The solvent was removed in vacuo, and the residue was diluted with 1N HCl and EtOAc. The organic layer was extracted with EtOAc, and the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The product was used without further purification.
Reaction SMILES: C(OC([N:11]1[CH2:22][CH2:21][C:14]2([CH2:19][C:18](=[O:20])[O:17][CH2:16][CH2:15]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[O:20]=[C:18]1[O:17][CH2:16][CH2:15][C:14]2([CH2:21][CH2:22][NH:11][CH2:12][CH2:13]2)[CH2:19]1
Reactant: O=C1CC2(CCO1)CCN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CCO
Product: O=C1CC2(CCNCC2)CCO1

Procedure:
2-oxo-3-oxa-9-azaspiro[5.5]undecane is prepared by catalytic hydrogenation of 9-benzyloxycarbonyl-2-oxo-3-oxa-9-azaspiro[5.5]undecane in ethanol in the presence of palladium on activated carbon (10% Pd) (the product must be reacted further immediately after careful evaporation). Mass spectrum (ESI+): m/z 170 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH:13]([OH:22])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[C:23]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1C(O)=O)(=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[OH:22][CH:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6](=[O:7])[C@@H:39]1[CH2:38][CH2:37][CH2:33][N:32]1[C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(O)COc1ccccc1
Reactant: CCCCCCCC(=O)N1CCC[C@H]1C(=O)O
Product: CCCCCCCC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COc1ccccc1
Yield: 55.2 %

Procedure:
By the same procedure as in Example 1-D), while using (2S)-1-(tert-butoxycarbonyl)-2-(1-hydroxy-2-phenoxyethyl)pyrrolidine (1.50 g) and N-octanoyl-L-proline (1.18 g), there was obtained 1.16 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH:8]([C:11]3([OH:24])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:25].O1CCOCC1>CO>[ClH:25].[F:1][C:2]1[C:10]2[O:9][CH:8]([C:11]3([OH:24])[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C2Cc3cccc(F)c3O2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: OC1(C2Cc3cccc(F)c3O2)CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(7-fluoro-2,3-dihydrobenzofuran-2-yl)-4-hydroxypiperidine-1-carboxylate (0.404 g, 1.197 mmol) in MeOH (7.04 mL) was added HCl in dioxane (4 M, 4.4 mL, 17.48 mmol). Upon completion of addition, the reaction mixture was stirred at room temperature for 5 hours. After this time, the solvent was removed under reduced pressure to afford Compound 1F as a light yellow solid (0.38 g, 100% yield). LC/MS (m/z)=238 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2OC)=[O:7])=[CH:4][CH:3]=1.[CH3:20]OC1C=C([N+]([O-])=O)C=CC=1N.CC1C=C([N+]([O-])=O)C=CC=1N>>[NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cc(N)ccc1NC(=O)c1ccc(N)cc1
Reactant: COc1cc([N+](=O)[O-])ccc1N
Agent: Cc1cc([N+](=O)[O-])ccc1N
Product: Cc1cc(N)ccc1NC(=O)c1ccc(N)cc1

Procedure:
By operating as described under (a) above, but using, instead of 202 parts of 2-methoxy-4-nitro-aniline, 183 parts of 2-methyl-4-nitro-aniline, high yields of 4,4'-diamino-2'-methyl-benzanilide were obtained (melting point: 111°-115° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:22][C:23]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CCO)CC1
Reaction time: 1 h
Yield: 65 %

Procedure:
50 g of 4-piperidine ethanol and 49.2 g of sodium hydrogencarbonate were dissolved in 480 ml of water, in which 55.2 ml of benzyloxycarbonyl chloride was gradually dropped under ice-cooling conditions, followed by agitation for 1 hour as it is. The reaction solution was extracted with chloroform and dried with anhydrous magnesium sulfate. The sulfate was filtered off and the solvent was distilled off, after which the resultant residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:hexane=30:70) to obtain 66.0 g of the captioned compound (yield: 65%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC1C=CC(S(O[CH:21]2[CH2:24][CH2:23][CH2:22]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:21]2[CH2:24][CH2:23][CH2:22]2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1cc(OC2CCC2)ccc1Br
Temperature: 60 °C

Procedure:
4-bromo-3-fluorophenol (315 mg, 1.648 mmol), cyclobutyl 4-methyl-benzenesulfonate (373 mg, 1.648 mmol), and cesium carbonate (1074 mg, 3.30 mmol) were dissolved in DMSO (1648 μl) and heated to 60° C. overnight. The reaction mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 2% to 50% EtOAc:Hexane. 1H NMR δ (ppm) 7.4 (t, 1H), 6.10 (dd, 1H), 6.53 (dd, 1H), 4.60 (quintet, 1H), 2.49-2.43 (m, 2H), 2.21-2.13 (m, 2H), 1.93 (m, 1H), 1.73 (sextet, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4].[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[C:13]([Br:34])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30])=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3C(F)(F)F)c(=O)n2Cc2ccccc2)c1O
Yield: 79 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(2-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (85 mg, 0.19 mmol) and N-bromosuccinimide (37 mg, 0.21 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH) to give 80 mg of the title compound as a yellow solid. MS: (−) m/z 531.17, 533.12 (M−1, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)CC(=O)C.[I-].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCCCCCl
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: N#CCCCCN1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 72.1 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)piperazine (0.1 mol), 5-chloropentanenitrile (0.13 mol), sodium carbonate (10 g) and potassium iodide (0.1 g) in 4-methyl-2-pentanone (280 ml) was stirred and refluxed for 10 hours. The reaction mixture was cooled, filtered and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 22.5 g (72%) of 4-(3,4-dichlorophenyl)-1-piperazinepentanenitrile (interm. 2).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][CH2:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[C:6]([OH:19])[CH:7]=2.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22]>>[C:21]([Si:24]([CH3:26])([CH3:25])[O:19][C:6]1[CH:7]=[C:8]2[C:3](=[CH:4][CH:5]=1)[N:2]([CH3:1])[C:14]1[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11][CH2:10][C:9]2=1)([CH3:23])([CH3:22])[CH3:20]
Reactant: Cn1c2c(c3cc(O)ccc31)CSc1ccccc1-2
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: Cn1c2c(c3cc(O[Si](C)(C)C(C)(C)C)ccc31)CSc1ccccc1-2

Procedure:
Following the procedure described in Example 80, using 11-methyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (1.15 g, 3.123 mmol) and TBSCl (562 mg, 3.75 mmol) as the starting material, the title compound was prepared as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([C@H:17]([NH2:19])[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:20][CH2:21][CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1.Cl>C(#N)C.C1(C)C=CC=CC=1.O>[ClH:20].[C:7]1([C@H:17]([NH:19][CH2:21][CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[CH3:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: FC(F)(F)c1cccc(C=CCCl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: C[C@@H](NCC=Cc1cccc(C(F)(F)F)c1)c1cccc2ccccc12
Reaction time: 0.29 h

Procedure:
Anhydrous potassium carbonate (64.0 g) and (R)-1-(1-naphthyl)ethylamine (39.0 g) was added to a solution of 1-[3-chloroprop-1-en-1-yl]-3-(trifluoromethyl)benzene (Example 6; 50 g) in acetonitrile (500 mL) at room temperature. The reaction mixture was refluxed for 12 hours at 80° C. to 85° C. After completion of the reaction, the mixture was quenched with de-ionized water (250 mL). The organic layer was separated and completely distilled off to remove acetonitrile to obtain oil. The oil obtained was dissolved in toluene (500 mL) and added to de-ionized water (250 mL). The pH of this mixture was adjusted to 0.1-0.5 by adding solution of hydrochloric acid (6 N; 100 mL). The mixture was stirred at 50° C. to 60° C. for 15-20 minutes, followed by the layer separation. The organic layer was acidified with hydrochloric acid (6N; 50 mL) and stirred at 50° C. to 60° C. for 15-20 minutes. The organic layer was completely distilled off to obtain N-[(1R)-1-(naphthalen-1-yl)ethyl]-3-[3-(trifluoromethyl)phenyl]prop-2-en-1-amine hydrochloride.
Reaction SMILES: [CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[N:11][OH:12])[C:7]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CCCCCC>[CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[N:11][OH:12])[C:7]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(C2=C(C3CCCC3)CCC2=NO)c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Product: ON=C1CCC(C2CCCC2)=C1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a stirred solution of 27 mg 3-cyclopentyl-2-(3-methoxyphenyl)-2-cyclopenten-1-one oxime (Example 7) in 5 ml dichloromethane at −78° C., was added 0.5 ml 1.0 M boron tribromide in hexane dropwise under inert atmosphere. The reaction mixture was stirred for 2 hours while being allowed to gradually warm to room temperature. Then the reaction mixture was poured into saturated aqueous sodium carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=1:1) to yield 12 mg of 3-cyclopentyl-2-(3-hydroxyphenyl)-2-cyclopenten-1-one oxime as a solid. mp=207-209° C.; 1H NMR (CDCl3, 300 MHz): δ 7.26-7.21 (m, 2H), 6.79-6.70 (m, 3H), 2.93 (m, 1H), 2.80 (m, 2H), 2.61 (m, 2H), 1.70 (m, 4H), 1.54 (m, 4H); APCI MS: m/z 258.1 (M+1).
Reaction SMILES: B(Br)(Br)Br.FC(F)(F)C(O)=O.[CH2:12]([N:14]([CH2:41][CH3:42])[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[C:33]3[CH2:39][CH:38]4[NH:40][CH:35]([CH2:36][CH2:37]4)[CH2:34]3)[C:22]3[C:27]([O:28][C:29]=2[CH:30]=1)=[CH:26][C:25]([O:31]C)=[CH:24][CH:23]=3)=[O:16])[CH3:13].[OH-].[NH4+]>ClCCl>[CH2:41]([N:14]([CH2:12][CH3:13])[C:15]([C:17]1[CH:18]=[CH:19][C:20]2[C:21](=[C:33]3[CH2:39][CH:38]4[NH:40][CH:35]([CH2:36][CH2:37]4)[CH2:34]3)[C:22]3[C:27]([O:28][C:29]=2[CH:30]=1)=[CH:26][C:25]([OH:31])=[CH:24][CH:23]=3)=[O:16])[CH3:42]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1cc(OC)ccc1C2=C1CC2CCC(C1)N2
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1cc(O)ccc1C2=C1CC2CCC(C1)N2
Temperature: 0 °C

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (2.14 mL, 2.14 mmol) was added to a solution of the trifluoroacetic acid salt of 9-(8-aza-bicyclo[3.2.1]oct-3-ylidene)-6-methoxy-9H-xanthene-3-carboxylic acid diethylamide (0.285 g, 0.535 mmol) in dichloromethane (10 mL) at 0° C. The resultant mixture was stirred at room temperature for 2 h. The mixture was cooled to 0° C., and treated with 10% aqueous ammonium hydroxide (˜20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residues was dissolved in DMSO and applied to reverse phase C18 column for purification via HPLC, using a gradient of acetonitrile (10% to 90%) in water with trifluoroacetic acid (0.1%) as the eluant. Fractions containing the title compound were combined and further purified via reverse phase HPLC to give the purified title compound (0.035 g). MS: m/z 405.1 (MH+). 1H NMR (DMSO-d6): δ 1.0-1.2 (br m, 6 H), 1.29 (d, 12H, J=8.1 Hz), 1.7-1.8 (br m, 2 H), 2.8-3.0 (br m, 4 H), 3.1-3.5 (br m, 4 H), 3.99 (br s, 2 H), 6.63-6.65 (m, 2 H), 7.13 (d, 1 H, J=7.9 Hz), 7.18-7.21 (m, 3 H), 7.41 (d, 1 H, J=7.9 Hz), 8.70 (br s, 1 H), 9.01 br d, 1 H) and 9.93 (br s 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11](OCC)[O:12]CC)[S:9][CH:10]=1)=[O:5])[CH3:2].Cl>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]=[O:12])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(C(OCC)OCC)n1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(C=O)n1
Temperature: 60 °C

Procedure:
2-(Diethoxymethyl)-4-thiazolecarboxylic acid ethyl ester (2.90 g, 11.8 mmol) synthesized according to Bull. Chem. Soc. Jpn., 58, 352 (1985), which is incorporated herein by reference in its entirety, was dissolved in acetone (37.3 mL), 1N aqueous hydrochloric acid solution (3.73 mL) was added, and the mixture was stirred with heating at 60° C. for 4 hours. After evaporation of the solvent, the mixture was worked up according to a conventional method to give the title compound as a crude product (2.13 g).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]2=[O:29])=[CH:2]1.[CH3:30][O:31]CCO>CN(C)C1C=CN=CC=1.CN(C)C(=O)C.[Zn]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([N:16]([CH3:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([C:24]([O:26][CH2:27][CH2:28][O:31][CH3:30])=[O:25])[C:12]2=[O:29])=[CH:2]1
Reactant: CCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Reactant: COCCO
Agent: CN(C)c1ccncc1
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: COCCOC(=O)C1=C(N(C)Cc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A solution of the compound (0.050 g, 0.12 mmol) of Example 108, 2-methoxyethanol (0.20 mL, 2.6 mmol), 4-dimethylaminopyridine (0.0030 g, 0.024 mmol) and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0058 g, 0.0061 mmol) in N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 3.5 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.0029 g, y. 5%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([C:27]3[N:31]=[CH:30][N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=3)=[O:26])[CH:18]=1)=[O:14])[NH:7][C:6]2=[O:51])#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH:24][C:25]([C:27]3[N:31]=[CH:30][NH:29][N:28]=3)=[O:26])[CH:18]=1)=[O:14])[NH:7][C:6]2=[O:51])#[N:2]
Reactant: N#Cc1ccc2nc(C(=O)NCc3cccc(CNC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)c3)[nH]c(=O)c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(CNC(=O)c4nc[nH]n4)c3)[nH]c(=O)c2c1
Yield: 42.1 %

Procedure:
A solution of 6-cyano-4-oxo-N-({3-[({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]carbonyl}amino)methyl]phenyl}methyl)-3,4-dihydroquinazoline-2-carboxamide (420 mg, 0.626 mmol), triethylsilane (0.105 mL, 0.657 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (10 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from IPE. The obtained powder was suspended in ethanol, and the suspension was stirred under heating for 2 hr to give the title compound as a white powder (113 mg, 42%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH2:11][C:12]([C:14]1[CH:15]=[CH:16][C:17](=[O:20])[NH:18][CH:19]=1)=[O:13].IC.[C:30](=O)([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27])[CH2:11][C:12]([C:14]1[CH:15]=[CH:16][C:17](=[O:20])[N:18]([CH3:30])[CH:19]=1)=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccccc2C)c(F)c1
Agent: [K+]
Solvent: CI
Product: COc1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)c(F)c1

Procedure:
In analogy to example 161, step 1, 5-[3-(2-fluoro-4-methoxy-phenyl)-3-o-tolyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=380.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH2:3][CH:4]=[CH2:5].[CH3:14][O:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[O:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=1)[CH2:3][CH:4]=[CH2:5]
Reactant: COc1ccc(O)cc1OC
Reactant: C=CCC(O)c1ccc(C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: C=CCC(Oc1ccc(OC)c(OC)c1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A cooled (0° C.) mixture of 4-(1-hydroxy-3-butenyl)benzonitrile (14.6 g, 84.3 mmol) and 3,4-dimethoxyphenol (19.5 g, 125.4 mmol) in toluene (500 mL) was treated with tributylphosphine (32.14 mL of 97% purity, 25.6 g, 126.4 mmol), followed by 1,1′-(azodicarbonyl)dipiperidine (31.8 g, 126.4 mmol). After addition was complete, the reaction mixture thickened and the temperature rose to 15° C. Additional toluene was added (500 mL), and the mixture stirred at rt overnight. The precipitate of tributylphosphine oxide was then removed by filtration and the filtrate concentrated in vacuo to give 65.8 g of crude product. This was purified by chromatography on silica gel, eluting with toluene:methanol (98:2), to yield 17.9 g of the sub-title compound.