Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:11]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[OH:23])[C:16]([O:18][CH3:19])=[O:17])=O.Cl>C1COCC1>[OH:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[CH:11]=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1cc(C(=O)OC)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
To a stirred solution of lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran) (8 mL) in a 0° C. ice bath is added methyl triphenylphonium bromide (1.92 g, 5.38 mmol). The mixture is allowed to warm to rt and stir for 10 min. A solution of methyl 3-formyl-4-hydroxybenzoate (200 mg, 1.11 mmol) in THF (3 mL) is added to the above solution. The mixture is stirred at rt for 5 h. The reaction mixture is acidified to pH=5 with 1N HCl, and extracted with ether (3×). The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated to a yellow oil. The crude product is purified by chromatography on SiO2. Elution with hexanes-EtOAc (80:20) gives 130 mg (66%) of methyl 4-hydroxy-3-vinylbenzoate as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.12, 7.86, 6.93, 6.85, 5.84, 5.50, 5.46, 3.92.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C\NC(C)(C)C)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@@]4(C)C3CC[C@@H]4O)[C@]21C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 49 μL (0.46 mmol) tertbutylamine. The reaction mixture is stirred at room temperature overnight. CH2Cl2 is removed in vacuo. The residue is triturated with Et2O to give 58 mg (50%) product as an orange powder. MS (ESI) m/z 504 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH3:29][O:30][NH2:31].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:29][O:30][NH:31][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: CON
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-methyl-hydroxylamine hydrochloride (15 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 21.6 mg (67%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.23 (1H, s), 8.71 (1H, d, J=2.2), 8.05 (4H, m), 7.51 (5H, m), 7.25 (1H, s), 7.10 (1H, d, J=7.7 Hz), 6.91 (1H, m), 5.98 (1H, m), 4.31 (1H, d, J=14.3), 7.20 (1H, d, J=7.3),4.42 (2H, d, J=3.2). ESIMS (M+H+): 412.1.
Reaction SMILES: [F:1][B-](F)(F)F.[H+].[CH2:7]([C:11]1[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14](N)[N:15]=1)[CH2:8][CH2:9][CH3:10].N([O-])=O.[Na+]>O>[CH2:7]([C:11]1[N:12]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:14]([F:1])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1nc(N)c(C(=O)OCC)n1Cc1ccccc1Cl
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CCCCc1nc(F)c(C(=O)OCC)n1Cc1ccccc1Cl
Temperature: 0 °C

Procedure:
The 4-amino product was fluorinated using the procedure of K. L. Kirk and L. J. Cohen, JACS, 95 (14), 4619 (1973). Fluoroboric acid (48%, 150 mL) was added to 2-n-butyl-1-{(2-chlorophenyl)methyl}-4-amino-5-carboethoxyimidazole (10.75 g, 0.032 mol) in a quartz flask. The resulting solid mass was sonicated and stirred vigorously to form a suspension. This suspension was cooled to 0° C. and then sodium nitrite (2.80 g, 0.0406 mol) in 5 mL of water was added slowly. The ice bath was removed and then the reaction mixture was irradiated for 20 hours with a 450-watt mercury vapor lamp placed in a quartz immersion well, cooled by circulating 1 water. The reaction mixture was cooled to -20° C. and the pH was adjusted to 6.4 with 50% aqueous sodium hydroxide. The product was extracted into ethyl acetate (3x) and the combined extracts were washed with water and saturated sodium chloride solution. The organic extract was dried with anhydrous sodium sulfate and concentrated to give 8.43 g of a crude product, which was chromatographed on silica gel eluting with chloroform to give 4.31 g of 2-n-butyl-1-{(2-chlorophenyl)methyl}-4-fluoro-5-carboethoxyimidazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([F:18])([F:17])[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:2].[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([N+:28]([O-:30])=[O:29])=[CH:23][N:22]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([F:18])([F:17])[CH2:6][N:7]([C:23]1[C:24]([N+:28]([O-:30])=[O:29])=[CH:25][N:26]=[C:21]([Cl:20])[N:22]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C(F)(F)CNCc1ccc(OC)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(Cc1ccc(OC)cc1)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.2 %

Procedure:
A solution of 1.2 g (0.0044 mole) of 2,2-difluoro-3-(4-methoxy-benzylamino)-propionic acid ethyl ester) in 4 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 0.85 g (0.0044 mole) of 2,4-dichloro-5-nitro-pyrimidine, 1.5 g (0.018 mole) of sodium bicarbonate and 10 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.9 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-benzyl)-amino]-2,2-difluoro-propionic acid ethyl ester (IV-291) as a yellow thick oil. This material was used directly in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:32]([O:39]CC)([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35]>C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][P:32]([O:36][CH2:37][CH3:38])(=[O:39])[O:33][CH2:34][CH3:35])[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Solvent: Cc1ccccc1C
Product: CCOP(=O)(CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1)OCC
Yield: 34.7 %

Procedure:
A mixture of 2,4,5-triphenyl-1-(7-bromoheptyl)-imidazole (0.95 g) and triethyl phosphite (1.66 g) in xylene (5 ml) was heated at reflux temperature for 20 hours. The mixture was evaporated to an oil and chromatographed on silica gel (ethyl acetate/ethanol) to give diethyl 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonate (0.37 g, 35%) as a light brown oil. NMR μ(CDCl3) 0.9-1.7 (18H, m, 6×CH2 +2×CH3), 3.9 (2H, t, CH2N), 4.1 (4H, m, 2×CH20), 7.1-7.7 (15H, m, 3×Ph) ppm. Diethyl 7-(2,4,5-triphenylimidazol-l-yl)heptane-phosphonate (0.35 g) was dissolved in dry chloroform, cooled to -40° C and to it was added trimethylsflyl iodide (0.66 g) over 2 minutes under an atmosphere of nitrogen. The cooling bath was removed and the reaction mixture was stirred for 3 hours at room temperature then evaporated to an oil and re- evaporated from methanol and water respectively. The oil was taken up in methanol, treated with excess aqueous sodinto bicarbonate, evaporated to dryness then taken up in ethanol, filtered and the flitrate evaporated to an oil. This was taken up in water, filtered and dilute hydrochloric acid added to pH4. The precipitated oil was washed with water, taken up in methanol and precipitated with ether to give 7-(2,4,5-triphenylimidazol-1-yl)heptane-phosphonic acid (0.16 g, 51%) as a light brown oil. Found: C, 68.12; H, 6.39, N, 5.60% C28H31N2O3P+4% H2O requires: C, 68.03; H 6.76; N, 5.66%.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[S:13])[CH2:6][CH2:5]2.Cl[C:15]1[S:16][C:17]([C@@:20]2([OH:27])[CH2:25][CH2:24][O:23][C@@H:22]([CH3:26])[CH2:21]2)=[CH:18][N:19]=1>>[OH:27][C@:20]1([C:17]2[S:16][C:15]([S:1][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[S:13])[CH2:6][CH2:5]4)=[N:19][CH:18]=2)[CH2:25][CH2:24][O:23][C@@H:22]([CH3:26])[CH2:21]1
Reactant: C[C@H]1C[C@@](O)(c2cnc(Cl)s2)CCO1
Reactant: CN1C(=S)CCc2cc(S)ccc21
Product: C[C@H]1C[C@@](O)(c2cnc(Sc3ccc4c(c3)CCC(=S)N4C)s2)CCO1
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 3, 6-mercapto-1-methyl-2-thioxo-1,2,3,4-tetrahydroquinoline was reacted with (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1-methyl-2-thioxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thiazol-5-yl]tetrahydropyran as a foam (0.365 g, 45%);
Reaction SMILES: C([O:5][C:6](=[O:33])[CH:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([Cl:25])=[CH:16][N:17]=[C:18]2[NH:21][C:22]([NH2:24])=[NH:23])=[CH:13][CH:12]=1)=[O:10])(C)(C)C.[C:34]([C:38]([OH:40])=[O:39])([F:37])([F:36])[F:35]>C1(C)C=CC=CC=1>[F:35][C:34]([F:37])([F:36])[C:38]([OH:40])=[O:39].[Cl:25][C:15]1[C:14]2[C:19](=[CH:20][C:11]([C:9]([NH:8][CH:7]([C:6]([OH:33])=[O:5])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:10])=[CH:12][CH:13]=2)[C:18]([NH:21][C:22]([NH2:24])=[NH:23])=[N:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccccc1)NC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NC(Cc3ccccc3)C(=O)O)cc12

Procedure:
A solution of N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-phenylalanine t-butyl ester (210 mg, 0.48 mmol) in CF3CO2H (1 mL) was stirred at room temperature for 1 h. The solution was diluted with PhMe, evaporated in vacuo, and the residue was triturated with Et2O to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-DL-phenylalanine trifluoroacetate (196 mg, 0.37 mmol).
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:3][N:2]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=O)CC(=O)COc1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(COc2ccccc2)[nH]n1
Yield: 54.7 %

Procedure:
Hydrazine hydrate (0.197 mL, 4.06 mmol) was added to a stirring room temperature solution of 40 (1.0163 g, 4.06 mmol) in EtOH (4.1 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC. The reaction was concentrated and purified by silica gel chromatography (Combiflash column, 92:4:4 Hexanes:CH2Cl2: 2N NH3 in EtOH): Only pure fractions were combined and concentrated to obtain 0.5474 g (54.7%) of 41. 1H (CDCl3, 400 MHz): δ 12.12 (1H, broad s), 7.28 (2H, t, J=7.8 Hz), 7.01-6.94 (3H, m), 6.91 (1H, s), 5.17 (2H, s), 4.36 (2H, q, J=7.0 Hz), 1.36 (3H, t, J=7.1 Hz) ppm. Partial 13C (CDCl3, 100 MHz): δ 158.11, 129.48, 121.26, 114.71, 107.83, 62.61, 61.31, 14.17 ppm. HPLC: 9.505 min.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9](=[CH:12]N(C)C)[C:10](=O)[C:4]=2[CH:3]=1.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34]([NH2:36])=[NH:35])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9]3[CH:12]=[N:36][C:34]([NH:33][C:27]4[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=4)=[N:35][C:10]=3[C:4]=2[CH:3]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Reactant: COc1ccc(NC(=N)N)cc1OC
Solvent: O=[N+]([O-])O
Product: COc1ccc(Nc2ncc3c(n2)-c2cc(Cl)ccc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for method I, 7-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-d) and N-(3,4-dimethoxyphenyl)guanidine nitrate were converted to I-24 (67%): HRMS Calcd. for C20H17ClN4O3: 397.1067, Found 397.1059.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([C:20]3([CH3:31])[CH2:30][CH:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1)=O)(C)(C)C>ClCCl>[NH2:15][C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([C:20]3([CH3:31])[CH2:30][CH:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1c(NC(=O)OC(C)(C)C)ccc2c1OCC1CC21C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(N)ccc2c1OCC1CC21C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
Trifluoroacetic acid (4 mL) was added to a solution of methyl (1aRS,7bSR)-5-(tert-butoxycarbonylamino)-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 51, 0.6 g) in dichloromethane (4 mL) and the resultant dark solution was stirred at room temperature for 1 hour. The solution was evaporated to dryness and the residue was partitioned between water and ethyl acetate and treated with a small amount of solid sodium bicarbonate until the pH of the aqueous layer was >7. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl (1aRS,7bSR)-5-amino-7b-methyl-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.402 g) as a red/orange solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:32])[C:19]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[CH:20][O:21][CH:22]([F:24])[F:23])=[CH:11][C:10]=1[O:33][CH3:34])C1C=CC=CC=1.Br.C(O)(=O)C>O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:19](=[CH:20][O:21][CH:22]([F:23])[F:24])[C:18]([NH:17][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:33][CH3:34])[CH:11]=2)=[O:32])=[CH:26][CH:27]=1
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)ccc1OCc1ccccc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)ccc1O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 74.5 %

Procedure:
1.45 g (2.97 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-chlorophenyl)-3-difluoromethoxyacrylamide, 751 mg (4.46 mmol) of 48% hydrobromic acid and 15 ml of acetic acid were mixed and stirred at 80° C. for 1.5 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) to give 880 mg of 2-(4-chlorophenyl)-3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]acrylamide (the present compound 1454).
Reaction SMILES: [Cl:1][C:2]([Cl:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH3:6].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].O.[Cl-].[Li+].Cl>O.C(OCC)(=O)C>[C:9]([C:11]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:4]([CH:3]=[C:2]([Cl:8])[Cl:1])[C:5]1([CH3:7])[CH3:6])#[N:10]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C#N)C(C=C(Cl)Cl)C1(C)C
Temperature: 80 °C
Yield: 63.4 %

Procedure:
151 Parts of 1,1-dichloro-4-methylpenta-1,3-diene, 113 parts of ethyl cyanoacetate, 200 parts of cupric acetate monohydrate, 148 parts of cupric chloride, 62.6 parts of lithium chloride monohydrate and 900 parts of ethyl acetate are stirred in an atmosphere of nitrogen. The temperature is raised to 80° C. and maintained at 80°-81° C. for 5 hours. After cooling, the reaction mixture was stirred with 1180 parts of hydrochloric acid (s.g. 1.18) and 1500 parts of water for 10 minutes. The organic layer was separated and extracted twice with 590 parts of hydrochloric acid (s.g. 1.18) in 500 parts of water. The ethyl acetate solution was diluted with 900 parts of ethyl acetate and the solution washed four times with 500 parts of water. The ethyl acetate solution is evaporated by heating to 87° C. at 20 mm Hg pressure to yield 201 parts of ethyl 1-cyano- 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylate (estimated strength 82.7% equivalent to 63.4% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](B(O)O)=[CH:3][N:2]=1.[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23](Br)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:4]3[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=[N:2][CH:3]=3)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: OB(O)c1cncc2ccccc12
Reactant: Brc1ccc(Cn2ccnc2)cn1
Product: c1ccc2c(-c3ccc(Cn4ccnc4)cn3)cncc2c1

Procedure:
Synthesized using 4-isoquinolinylboronic acid (218 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 97 mg, 0.34 mmol, 54%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.26 (s, 2H), 7.00 (t, J=1.3 Hz, 1H), 7.16 (brs, 1H), 7.58-7.66 (m, 4H), 7.70-7.73 (m, 1H), 8.04 (d, J=8.2 Hz, 1H), 8.17 (dd, J=8.5, 0.6 Hz, 1H), 8.62 (s, 1H), 8.71 (d, J=1.6 Hz, 1H), 9.30 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.1, 119.1, 124.5, 125.0, 127.4, 128.0, 128.5, 130.0, 130.4, 130.8, 131.1, 133.6, 135.7, 137.4, 143.5, 148.5, 153.4, 156.6; MS (ESI): m/z=287.10 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([CH3:18])[CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([NH2:17])[C:13]([O:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C@@H:28]2[C@@H:33]3[CH2:34][C@@H:30]([CH:31]=[CH:32]3)[C@@H:29]2[C:35]([NH2:37])=[O:36])=[N:26][C:21]([NH:17][C:12]2[C:13]([O:15][CH3:16])=[CH:14][C:7]3[CH2:6][CH2:5][N:4]([CH2:3][C:2]([F:1])([F:19])[CH3:18])[CH2:10][CH2:9][C:8]=3[CH:11]=2)=[N:22][CH:23]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc2c(cc1N)CCN(CC(C)(F)F)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(CC(C)(F)F)CC2

Procedure:
The title compound was prepared from 3-(2,2-Difluoro-propyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.060 g, 67%). MP: 120-134° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.18 (s, 1H), 7.89 (s, 1H), 7.39 (s, 1H), 6.63 (s, 1H), 6.56-6.50 (m, 1H), 6.34-6.29 (m, 2H), 5.53 (br s, 1H), 5.26 (br s, 1H), 4.48-4.42 (m, 1H), 3.86 (s, 3H), 3.09-3.05 (m, 1H), 2.90 (m, 12H), 2.54-2.49 (m, 1H), 2.29-2.24 (m, 1H), 1.68 (t, 3H, J=18.7 Hz). MS: 533 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:50]>>[Cl:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[O:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: Clc1ccccc1OCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4Cl)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.062 g of 1-(3-bromopropoxy)-2-chlorobenzene are used to prepare the title compound. Rf=0.27 (2:1 EtOAc-heptane); Rt=6.07.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:11][C:12]([F:15])([F:14])[F:13])=[O:10])=[CH:4][C:3]=1[OH:16].[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:17][C:18]([F:29])([F:30])[O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][O:16][C:3]2[CH:4]=[C:5]([S:9]([CH2:11][C:12]([F:14])([F:15])[F:13])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[CH:24][CH:25]=1
Reactant: OCCc1ccc(OC(F)(F)F)cc1
Reactant: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1OCCc1ccc(OC(F)(F)F)cc1
Reaction time: 16 h
Yield: 40.1 %

Procedure:
In 30 ml of tetrahydrofuran were dissolved 0.3 g (1.19 mmol) of 2,4-dimethyl-5-(2,2,2-trifluoroethylsulfinyl)phenol, 0.29 g (1.41 mmol) of 2-(4′-trifluoromethoxyphenyl)ethanol and 0.41 g (1.56 mmol) of triphenylphosphine. Thereto was added 0.31 g (1.53 mmol) of diisopropyl azodicarboxylate at room temperature, and stirred for 16 hours. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=5:1), and the residue was washed with n-hexane, to obtain 0.21 g (yield: 40%) of an intended product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C)C=O.S(Cl)([Cl:30])=O>>[Cl:30][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCC1CCN(C)CC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Yield: 98 %

Procedure:
A solution of 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-3,4-dihydroquinazolin-4-one (2.8 g, 9.24 mmol) in thionyl chloride (28 ml) containing dimethylformamide (0.28 ml) was heated at reflux for 1 hour. The reaction was cooled, the volatiles were removed in vacuo and the resultant solid was triturated with diethyl ether, filtered, washed with diethyl ether and dried in vacuo. The solid was dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate, water and brine. Evaporation of the solvent and drying in vacuo yielded 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (2.9 g, 98% yield):