Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]([NH2:15])=O)[NH:8][C:9]2=O)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2)[CH:6]=[C:7]([C:13]#[N:15])[N:8]=1
Reactant: NC(=O)c1cc2ccc(Cl)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2ccc(Cl)cc2c(Cl)n1
Yield: 81.8 %

Procedure:
A solution of 7-chloro-1-oxo-1,2-dihydroisoquinoline-3-carboxamide (550 mg, 2.46 mmol) in POCl3(10 mL) was heated to reflux for 6 hours. The solvent was subsequently removed in vacuo and the crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EA=30:1) to give the title compound (450 mg, 81.8%). 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.80 (dd, J=1.6 Hz and 8.0 Hz, 1H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C([O-])(O)=O.[Na+].[NH2:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1>CO>[CH2:1]([NH:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1cccc(O)c1
Reactant: CCCCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCNc1cccc(O)c1
Yield: 62 %

Procedure:
0.11 mol of n-heptyl bromide and 0.1 mol of NaHCO3 are added to 0.1 mol of m-aminophenol in 150 ml of methanol, and the mixture is refluxed for 5 h. After cooling, it is filtered and the solvent is removed in vacuo. The oil which remains is fractionated in vacuo, to give 3-(n-heptyl-amino)phenol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([SH:22])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]([S:22][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:14]=[C:13]2[CH2:23][CH2:24][CH3:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: CCOC(=O)CCCCBr
Reactant: CCCc1nc(S)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2
Product: CCCc1nc(SCCCCC(=O)OCC)c(C(=O)OCC)n1Cc1cc2c(cc1Cl)OCO2

Procedure:
The operation is carried out as in Stage 7 of Example 1 starting with the product obtained in Stage 6 of Example 1 and ethyl 5-bromo-pentanoate instead of ethyl 4-bromocyclohexaneacetate. In this way the expected product is obtained.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH:12]([NH:14][CH2:15][CH2:16][CH2:17][C@H:18]3[O:22][C:21](=[O:23])[N:20]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)[CH2:19]3)[CH2:13][N:9]3[C:10]=2[C:5]([CH:6]=[CH:7][C:8]3=[O:35])=[CH:4][CH:3]=1.[Si:36]([O:43][CH2:44][CH:45]=O)([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>>[C:39]([Si:36]([CH3:38])([CH3:37])[O:43][CH2:44][CH2:45][N:14]([CH2:15][CH2:16][CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1)[CH:12]1[C:11]2=[C:10]3[C:5](=[CH:4][CH:3]=[C:2]2[F:1])[CH:6]=[CH:7][C:8](=[O:35])[N:9]3[CH2:13]1)([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C1CSc2ccc(N3C[C@@H](CCCNC4Cn5c(=O)ccc6ccc(F)c4c65)OC3=O)cc2N1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Product: CC(C)(C)[Si](C)(C)OCCN(CCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1)C1Cn2c(=O)ccc3ccc(F)c1c32
Yield: 43 %

Procedure:
Starting from the compound of Example 13 and tert-butyldimethylsilyloxy-acetaldehyde and using procedure E, the title compound was obtained as a yellow foam (57 mg; 43% yield).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]([OH:12])[CH:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:19]([O:12][CH:11]1[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]=[CH:10]1)(=[O:21])[CH3:20]
Reactant: OC1C=CCC1(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC1C=CCC1(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 5,5-diphenyl-2-cyclopenten-1-ol (0.70 g) in pyridine (5 ml) were added acetic anhydride (0.84 ml) and catalytic amount of 4-dimethylaminopyridine at room temperature. After being stirred for 30 minutes, the pH of the reaction mixture was adjusted to 1.0 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 5,5-diphenyl-2-cyclopentenyl acetate (0.82 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][CH:18]=[C:17]3[C:13]=1[CH:14]=[N:15][NH:16]3)=[N:7][C:6]([CH3:24])=[C:5]2[CH:25]=O.Cl.[CH3:28][C:29]1([CH3:35])[O:34][CH2:33][CH2:32][NH:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH3:28][C:29]1([CH3:35])[O:34][CH2:33][CH2:32][N:31]([CH2:25][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]([C:12]3[C:20]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[N:15][NH:16]4)=[N:7][C:6]=2[CH3:24])[CH2:30]1
Reactant: Cc1nc(-c2c(C(C)C)ccc3[nH]ncc23)c2ccc(O)cc2c1C=O
Reactant: CC1(C)CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1nc(-c2c(C(C)C)ccc3[nH]ncc23)c2ccc(O)cc2c1CN1CCOC(C)(C)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.6 %

Procedure:
A mixture of 6-hydroxy-1-(5-isopropyl-1H-indazol-4-yl)-3-methyl-isoquinoline-4-carbaldehyde (246 mg, 0.71 mmol), 2,2-dimethyl-morpholine hydrochloride (216 mg, 1.4 mmol), NaB(OAc)3H (451 mg, 2.1 mmol), and AcOH (30 uL) in DCM (10 ml) is stirred for 6 h at room temperature. 1N—NaOH (5 ml) is added and the mixture is extracted with DCM. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel eluting with DCM/MeOH (10:1) to give 207 mg of 4-(2,2-dimethyl-morpholin-4-ylmethyl)-1-(5-isopropyl-1H-indazol-4-yl)-3-methyl-isoquinolin-6-ol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11](Cl)[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH:14][C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1nc(-c2ccc(Br)cc2)ns1
Reactant: CC(C)(N)CO
Solvent: CCOC(C)=O
Product: CC(C)(CO)Nc1nc(-c2ccc(Br)cc2)ns1
Temperature: 125 °C
Yield: 35 %

Procedure:
3-(4-Bromophenyl)-5-chloro-1,2,4-thiadiazole (2.0 g, 7.3 mmol), prepared in the previous step, was dissolved in 2-amino-2-methylpropanol and heated to 125° C. for 16 h. The mixture was cooled, diluted with ethyl acetate, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone in hexane) afforded 2-{[3-(4-bromophenyl)-1,2,4-thiadiazol-5-yl]amino}-2-methylpropan-1-ol (0.85 g, 35%) as a pale yellow solid. HRMS: calcd for C12H14BrN3OS+H+, 328.01137; found (ESI, [M+H]+), 328.0113; Analytical HPLC: purity 100% at 210-370 nm, 10.0 min; 100% at 252 nm, 10.0 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH 3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][C@H:3]2[CH2:7][C:8]3[C:13]([C@@H:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3.[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].O>CN(C=O)C>[CH2:18]([N:1]1[C:5](=[O:6])[CH2:4][C@H:3]2[CH2:7][C:8]3[C:13]([C@@H:2]12)=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: O=C1C[C@H]2Cc3ccccc3[C@H]2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1C(=O)C[C@H]2Cc3ccccc3[C@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a solution of (3aR,8bS)-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one (1.00 g, 5.77 mmol) in DMF (10 mL) was added at 0° C. sodium hydride (60% in mineral oil, 0.254 g, 6.35 mmol). The solution was stirred for 1 h at 0° C. and allyl bromide (1.41 g, 2 equiv., 1.01 mL, 11.5 mmol) was added. The solution was stirred for 18 h at room temperature and water was added. The mixture was extracted with ethyl acetate and washed with water and brine. The solvents were removed in vacuo and the residue was purified by flash chromatography eluting with cyclohexane and ethyl acetate (50:50) to give (3aR,8bS)-1-allyl-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrol-2-one F22 (0.910 g, 0.910 g, 4.27 mmol, 73.9% Yield) as a colourless oil. LCMS (method A) 1.51 min; ES+: 214 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:24][C:18]=2[N:17]=1)[C:3]([CH3:15])([CH3:14])[C:4]([O:6]CC1C=CC=CC=1)=O.[NH3:29]>C1COCC1>[NH2:1][C@H:2]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:24][C:18]=2[N:17]=1)[C:3]([CH3:14])([CH3:15])[C:4]([NH2:29])=[O:6]
Reactant: N
Reactant: CC(C)(C)c1ccc2[nH]c([C@@H](N)C(C)(C)C(=O)OCc3ccccc3)nc2c1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc2[nH]c([C@@H](N)C(C)(C)C(N)=O)nc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30 %

Procedure:
To a solution of benzyl (3S)-3-amino-3-(5-tert-butyl-1H-benzimidazol-2-yl)-2,2-dimethylpropanoate (Preparation 13, 150 mg, 0.312 mmol) in THF (10 mL) was added freshly condensed liquid NH3 (20 mL) at −78° C. and the reaction was stirred at room temperature for 24 hours. The reaction mixture was evaporated and purified by preparative TLC eluting with 70% EtOAc in petroleum ether. The residue was dissolved in dioxane (6 mL), cooled to 0° C. and treated with 2N HCl in dioxane (4 mL). The reaction was stirred at room temperature for 4 hours before concentrating in vacuo. The residue was purified through an SCX cartridge to afford the title compound (25 mg, 30%).
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([C:24](O)([CH3:26])[CH3:25])=[CH:20][CH:19]=2)[C:8]2[NH:17][C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:8]2[NH:17][C:11]3=[N:12][CH:13]=[C:14]([F:16])[CH:15]=[C:10]3[CH:9]=2)[C:18]2[CH:19]=[CH:20][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(C(CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 50 °C
Yield: 4 %

Procedure:
A mixture of 2-{4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (prepared as in Example 119, 150 mg, 0.41 mmol) and 10% palladium on activated carbon (0.2 g) in methanol (50 mL) was heated at 50° C. under hydrogen (50 psi) for 5 h. After cooling to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 2-[2-cyclopentyl-1-(4-isopropyl-phenyl)-ethyl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine as a white solid (5.7 mg, 4%): LC/MS m/e calcd for C23H27FN2 [M+H]+ 351.48, observed 351.26; 1H NMR (400 MHz, CD3OD) δ ppm 1.19 (m, 2H), 1.22 (d, J=6.8 Hz, 6H), 1.48 (m, 2H), 1.57-1.87 (m, 5H, H), 2.06 (m, 1H), 2.17 (m, 1H), 2.86 (m, 1H), 4.11 (t, J=7.8 Hz, 1H), 6.29 (s, 1H), 7.16 (d, J=8.3 Hz, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.60 (dd, J=2.5 Hz, 3JHF=9.2 Hz, 1H), 7.95 (brm, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[C:17]([Cl:25])[N:18]3[CH3:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cnc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 107.3 %

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (7.3 g) was dissolved in N,N-dimethylformamide (70 mL), and then N-chlorosuccinimide (2.9 g) was added to this solution. The reaction solution was stirred at room temperature for 23 hours. Water (260 mL) was added to the reaction solution, and this was stirred at room temperature for one hour. A white precipitate was then collected by filtration. The white solid obtained was washed with water and hexane to give the title compound (8.6 g).
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]#[C:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[N:14]=1>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.[Pd]>[NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)[N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(F)cc4CC(N)=O)n3)cc2)CC1
Reaction time: 16 h

Procedure:
A suspension of 10% Pd/C (0.175 g) and tert-butyl 4-(4-((4-((2-(2-amino-2-oxoethyl)-4-fluorophenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A36) (0.191 g, 0.320 mmol) in DMF (10 mL) and Et3N (1 mL) was stirred under an atmosphere of hydrogen for 16 hours. The resulting mixture was diluted with EtOAc (60 mL), filtered through Celite and the volatiles were removed under reduced pressure. The residue was adsorbed onto silica gel, then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A37 as a yellow solid (0.168 g, 87%); 1H NMR (400 MHz, d6-DMSO) δ 10.14 (s, 1H), 8.65 (s, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.48 (s, 1H), 7.23-7.15 (m, 3H), 7.08 (dd, J=10.2, 2.8 Hz, 1H), 7.00 (td, J=8.4, 2.7 Hz, 2H), 4.07 (d, J=11.8 Hz, 2H), 3.50 (s, 2H), 3.13-3.04 (m, 2H), 3.04-2.95 (m, 2H), 2.79 (brs, 2H), 2.69-2.57 (m, 1H), 1.74 (d, J=12.9 Hz, 2H), 1.54-1.43 (m, 2H), 1.42 (s, 9H). LCMS-A: rt 6.612 min; m/z 602 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:9]=3[C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8](=[O:17])[NH:7][C:6]3[CH:18]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]=2[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)NC(=O)c1ccc(Cl)cc1N2

Procedure:
A mixture of Example 7C (30 mg, 0.11 mmol) and CH3SO2Cl (13 mg, 0.112 mmol) in pyridine (4 mL) was stirred overnight at room temperature. The excess pyridine was removed under reduced pressure and the residue was washed with hexanes and filtered. The filter cake was dried in a vacuum oven to provide the desired product. MS (DCI) m/e 338 (M+H)+, 355 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([CH2:20]O)[CH:17]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:15]=2)=[C:8]([O:30][CH3:31])[CH:7]=1.[CH3:33][O:34][C:35](=[O:49])/[C:36](/[C:47]#[N:48])=[CH:37]/[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[C:40]([O:45][CH3:46])[CH:39]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH3:33][O:34][C:35](=[O:49])/[C:36](/[C:47]#[N:48])=[CH:37]/[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH2:20][C:18]2[CH:19]=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:32])=[CH:7][C:8]=3[O:30][CH3:31])[CH:15]=[C:16]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][Cl:29])[CH:17]=2)=[C:40]([O:45][CH3:46])[CH:39]=1
Reactant: COC(=O)/C(C#N)=C/c1ccc(O)c(OC)c1
Reactant: COC(=O)/C=C/c1ccc(OCc2cc(CO)cc(OCCCCCCCl)c2)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(OCc2cc(COc3ccc(/C=C(\C#N)C(=O)OC)cc3OC)cc(OCCCCCCCl)c2)c(OC)c1
Temperature: 0 °C
Yield: 73.7 %

Procedure:
1 g (2.2 mmol) (E)-3-[4-[3-[(6-chlorohexyl)oxy]-5-[hydroxymethyl]benzyloxy]-3-methoxyphenyl]acrylic acid methyl ester was added to a solution of 0.62 g (2.7 mmol) 2-cyano-(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid methyl ester and 0.73 g (2.7 mmol) triphenylphosphine in 10 ml tetrahydrofuran. The solution was cooled to 0°C. and then 1.1 ml (2.7 mmol) of a solution of azodicarboxlic acid diethyl ester in toluene were added dropwise. The mixture was allowed to react for 1 hour at 0° C. and then it was poured into an ice cold 1 M solution of HCl. The mixture was extracted three times with tert.-butyl-methylether/ethyl acetate. The organic phase was washed with a saturated sodium bicarbonate solution and repeatedly with water, dried over magnesium sulfates filtered and concentrated in vacuum. The solid residue was first treated with diethylether, filtered and then it was recrystallized twice from tert.-butyl-methylether to give 1.1 g (79%) of (E)-3-[4-[[3-[(6-Chlorohexyl)oxy]-5-[[2-methoxy-4-[(E)-2-(methoxycarbonyl)vinyl]phenoxy]methyl]benzyl]oxy)-3-methoxyphenyl]-2-cyanoacrylic acid methyl ester in form of slightly yellow crystals.
Reaction SMILES: [NH3:1].C([O:4][C:5]([C:7]1[O:8][C:9]2[C:17]([CH2:18][CH:19]=[CH2:20])=[CH:16][CH:15]=[C:14]([O:21][CH2:22][CH:23]3[O:27][CH2:26][CH2:25][CH2:24]3)[C:10]=2[C:11](=[O:13])[CH:12]=1)=O)C>C(O)C>[CH2:18]([C:17]1[C:9]2[O:8][C:7]([C:5]([NH2:1])=[O:4])=[CH:12][C:11](=[O:13])[C:10]=2[C:14]([O:21][CH2:22][CH:23]2[O:27][CH2:26][CH2:25][CH2:24]2)=[CH:15][CH:16]=1)[CH:19]=[CH2:20]
Reactant: N
Reactant: C=CCc1ccc(OCC2CCCO2)c2c(=O)cc(C(=O)OCC)oc12
Solvent: CCO
Product: C=CCc1ccc(OCC2CCCO2)c2c(=O)cc(C(N)=O)oc12
Temperature: 0 °C

Procedure:
Anhydrous ammonia gas was passed through a stirred solution of 38.4 parts of 8-allyl-5-tetrahydrofurfuryloxy-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester in 600 parts of anhydrous ethanol at 45° C for 3 hours. The resulting dark, reddish brown solution was cooled to 0° C. A white crystalline solid was formed, which was collected and dried in vacuo. 24.7 Parts of 8-allyl-5-tetrahydrofurfuryloxy-4-oxo-4H-1-benzopyran-2-carboxamide were obtained, melting point 211.5°-213.5° C.
Reaction SMILES: [C:1]([NH:4][CH:5](P(OC)(OC)=O)[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].C1CCN2C(=NCCC2)CC1.[O:27]1[CH:31]=[CH:30][C:29](C=O)=[C:28]1C=O>C(Cl)(Cl)Cl>[O:27]1[C:31]2[CH:30]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[N:4]=[CH:1][C:2]=2[CH:29]=[CH:28]1
Reactant: COC(=O)C(NC(C)=O)P(=O)(OC)OC
Reactant: O=Cc1ccoc1C=O
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc2occc2cn1
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
Methyl (acetylamino)(dimethoxyphosphoryl)acetate (2.34 g, 9.8 mmol) is dissolved in CHCl3 (40 mL), treated with DBU (1.46 mL, 9.8 mmol), stirred for 5 min then added dropwise to a 0° C. solution of furan-2,3-dicarbaldehyde (1.65 g, 8.9 mmol) in CHCl3 (80 mL). The mixture is stirred for 2.5 h as the cooling bath expires then 5.5 h at RT and finally 24 h at 50° C. The mixture is concentrated in vacuo to a yellow oily-solid (6.66 g). The crude material is chromatographed over a standard 100 g slurry-packed silica gel, eluting with 65% EtOAc/hexane. The appropriate fractions are combined and concentrated in vacuo to afford 1.30 g (82%) of methyl furo[3,2-c]pyridine-6-carboxylate as a yellow solid. MS (EI) m/z: 177 (M+).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[C:4]2C(O[C:8](=O)[C:3]=12)=O>[Cu]=O.CN1C(=O)CCC1>[F:13][C:10]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][C:8]=1[C:3]1[CH:4]=[C:10]([F:13])[CH:11]=[CH:12][C:2]=1[F:1]
Reactant: O=C1OC(=O)c2c(F)ccc(F)c21
Agent: O=[Cu]
Solvent: CN1CCCC1=O
Product: Fc1ccc(F)c(-c2cc(F)ccc2F)c1
Temperature: 150 °C

Procedure:
Using the procedure above, 0.5 g of 3,6-difluorophthalic anhydride, 0.1 g of copper (II) oxide and 10 mL of NMP were combined and heated to 150° C. for 12 h. GCMS analysis of the reaction mixture indicated complete consumption of the starting material and formation of 1,4-difluorobenzene as the major product. A small amount of 2,2',5,5'-tetrafluorobiphenyl was formed as a by-product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][N:18]3C(=O)C4=CC=CC=C4C3=O)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.O.NN>>[NH2:18][CH2:17][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][C:9](=[C:8]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:10][CH2:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: NN
Solvent: O
Product: NCCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 20 %

Procedure:
The title compound was prepared in a yield of 20% in a similar manner to that described in Preparation 15' by reacting 4-[bis(4-fluorophenyl)methylene]-1-(3-phthalimidopropyl)piperidine (prepared as described in Preparation 48') and hydrazine hydrate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:25]=[CH:26][CH:27]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:23][CH3:24])=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:29][CH2:30][C:31]([N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][C:12]=2[O:23][CH3:24])[N:9]=[CH:8][N:7]=[C:6]3[NH:5][C:4]2[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=2[F:28])[CH2:18]1)=[O:32]
Reactant: O=C(Cl)CCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCCN(C(=O)CCl)C1
Yield: 91.6 %

Procedure:
The 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline material was prepared as follows: —4-(3-chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-3-yloxy)quinazoline (430 mg, 1.07 mmol) (Prepared as described in Example 22 under preparation of starting material), chloroacetyl chloride (126 mg, 1.12 mmol) and N,N-diisopropylethylamine (519 mg, 4.02 mmol) in methylene chloride (15 ml) was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (92/8) solvent, Removal of the solvent under vacuum gave 6-[1-(chloroacetyl)piperidin-3-yloxy]-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline as a yellow gum (470 mg). This material was used without any further purification); Mass Spectrum: (M+H)+ 479.