Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1.P(Cl)(Cl)([Cl:22])=O.C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:9]=[CH:8][N:7]=1
Reactant: O=c1[nH]cnc2cc(F)cc(OC3CCOCC3)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Temperature: 80 °C

Procedure:
A first portion (0.25 g) of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was added to a stirred mixture of phosphoryl chloride (1.76 ml), diisopropylethylamine (3.95 ml) and acetonitrile (10 ml) that had been heated to 80° C. The resultant mixture was heated to 80° C. for 3 hours. A second portion (0.25 g) of 7-fluoro-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one was added and the mixture was heated to reflux for a further 90 minutes. There was thus obtained a solution of 4-chloro-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline which was used without being isolated. A solution of 6-chloro-2,3-methylenedioxyaniline (0.32 g) in acetonitrile (3 ml) was added and the reaction mixture was heated to 80° C. for 2.5 hours. As the required conversion was incomplete, the reaction mixture was evaporated and toluene (15 ml) was added as reaction solvent. A second portion of 6-chloro-2,3-methylenedioxyaniline (0.32 g) was added and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between methylene chloride and an aqueous sodium chloride solution. The organic phase was washed with water, dried over magnesium sulphate and evaporated. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoline as a foam (0.73 g); NMR Spectrum: (DMSOd6) 1.9-2.05 (m, 2H), 2.1-2.2 (m, 2H), 3.5-3.6 (m, 2H), 3.8-3.95 (m, 2H), 5.1 (m, 1H), 6.1 (s, 2H), 7.0 (d, 1H), 7.1 (d, 1H), 7.3 (d, 1H), 7.4 (m, 1H), 8.6 (s, 1H), 9.3 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:32]=[CH:33][C:34]=2[F:35])[CH2:25][CH2:24]1>C(Cl)(Cl)Cl>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:32]=[CH:33][C:34]=3[F:35])[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1ccc(C(C(=O)O)c2ccc(C)cc2)cc1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(C(=O)NCCCN2CCC(c3cc(NC(=O)C(C)C)ccc3F)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 132 was prepared from bis(4-methylphenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.36–7.31 (m, 1H), 7.28–7.21 (m, 1H), 7.12–7.07 (m, 3H), 7.03–6.99 (m, 5H), 6.86–6.80 (m, 1H), 6.79–6.75 (m, 1H), 4.74 (s, 1H), 3.33–3.25 (m, 2H), 2.85–2.77 (m, 2H), 2.72–2.62 (m, 1H), 2.40 (septet, 1H, J=6.7 Hz), 2.28 (t, 2H, J=6.6 Hz), 2.21 (m, 6H), 1.94–1.84 (m, 2H), 1.65–1.52 (m, 6H), 1.71 (d, 6H, J=6.6 Hz); ESMS m/e: 544.3 (M+H)+; Anal. Calc. for C34H42FN3O2.HCl.0.10 CHCl3: C, 70.17; H, 7.35; N, 7.10. Found: C, 70.35; H, 6.99; N, 7.10.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C([Li])CCC.[CH:27](=[O:29])[CH3:28].Cl>O1CCCC1>[CH:1]([O:4][C:5]1[CH:21]=[CH:20][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[S:16][C:17]([CH:27]([OH:29])[CH3:28])=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(Oc2nnc(-c3cccs3)s2)cc1
Reactant: CC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2nnc(-c3ccc(C(C)O)s3)s2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 185.6 %

Procedure:
A solution of Example 24D (0.35 g, 1.1 mmol) in tetrahydrofuran (14 mL) was cooled to −78° C. under a nitrogen atmosphere and was treated with n-butyllithium (2.5M in hexanes, 0.925 mL, 2.31 mmol) drop wise over 5 minutes. After stirring at −78° C. for 10 min, acetaldehyde (0.309 mL, 5.5 mmol) was added and the reaction was allowed to warm to −30° C. The reaction was stirred for 10 min at −30° C. and 1N HCl (20 mL) was added. The resulting bilayer was stirred at 25° C. for 5 min and was extracted with ethyl ether (80 mL). The organic phase was washed with brine (20 mL), dried (Na2SO4), filtered, and evaporated to provide 0.74 g of a light brown oil. The residue was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 35% ethyl acetate in hexanes to provide 0.34 g (86%) of the title compound as a pale green oil. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.48 (d, J=3.68 Hz, 1H) 7.39 (d, J=9.19 Hz, 2H) 7.02 (d, J=9.19 Hz, 2H) 6.96 (dd, J=3.68, 0.74 Hz, 1H) 5.78 (d, J=5.15 Hz, 1H) 4.88-5.06 (m, 1H) 4.63 (heptet, J=5.88 Hz, 1H) 1.43 (d, J=6.25 Hz, 3H) 1.28 (d, J=5.88 Hz, 6H); MS (ESI) m/z 363 (M+H)+.
Reaction SMILES: CS(C1C=CC(OC2C3CC(C)(C)OC=3C=C(C(O)=O)C=2)=CC=1)(=O)=O.C[O:27][C:28]([C:30]1[CH:40]=[C:39]([O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48](=[O:52])[N:49]([CH3:51])[CH3:50])=[C:44]([F:53])[CH:43]=2)[C:33]2[CH2:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=2[CH:31]=1)=[O:29]>>[CH3:51][N:49]([CH3:50])[C:48]([C:45]1[CH:46]=[CH:47][C:42]([O:41][C:39]2[C:33]3[CH2:34][C:35]([CH3:38])([CH3:37])[O:36][C:32]=3[CH:31]=[C:30]([C:28]([OH:29])=[O:27])[CH:40]=2)=[CH:43][C:44]=1[F:53])=[O:52]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)c(F)c2)c2c(c1)OC(C)(C)C2
Agent: CC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2O1
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 15a, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (142a). 1H NMR (400 MHz, CDCl3)) δ 7.40 (t, J=7.96 Hz, 1 H) 7.27-7.33 (m, 2 H) 6.80 (dd, J=8.34, 2.02 Hz, 1 H) 6.70 (dd, J=10.61, 2.27 Hz, 1 H) 3.10-3.18 (m, 3 H) 3.00 (br. s., 3 H) 2.92 (s, 2 H) 1.49 (s, 6 H); LCMS for C20H20FNO5 m/z 374.00 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:25])[CH2:17][C:18]([O:20][CH:21]1[CH2:24][CH2:23][CH2:22]1)=[O:19].[NH2:26]/[C:27](/[CH3:31])=[CH:28]\[C:29]#[N:30].C(O)(=O)C>CC(O)C>[C:29]([C:28]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]([C:18]([O:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)=[O:19])=[C:16]([CH3:25])[NH:26][C:27]=1[CH3:31])#[N:30]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: C/C(N)=C/C#N
Reactant: CC(=O)CC(=O)OC1CCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2cccc3c(=O)cc(C)oc23)C(C(=O)OC2CCC2)=C(C)N1

Procedure:
60 mg (0.32 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 49.7 mg (0.32 mmol) of cyclobutyl 3-oxobutanoate, 26.2 mg (0.32 mmol) of 3-aminocrotononitrile and 19.1 mg (0.32 mmol) of acetic acid in 5 ml of 2-propanol and heated under reflux under argon for 4 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 64 mg (51% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([O:25]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:24])=[C:12]([C:15]3[S:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH3:1][O:2][N:3]=[C:4]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:5]([NH:7][CH:8]1[C:39](=[O:40])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([C:15]3[S:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][N:19]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3nnc(N(C)C)s3)CS[C@H]12)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(c3nnc(N(C)C)s3)CS[C@H]12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
A mixture of 0.11 g of benzhydryl 7-(2-methoxyimino-2-phenylacetamido)-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (obtained in Example 48), 2 ml of anisole and 4 ml of trifluoroacetic acid is stirred for 30 minutes at room temperature. After removal of the solvent under reduced pressure, the residue is triturated with the addition of absolute ether. The precipitates are filtered, and washed with ether to give 0.058 g of 7-(2-methoxyimino-2-phenylacetamido)-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].[CH:19]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10])[CH3:19]
Reactant: COC(=O)Cc1nc(-c2ccc(Br)cc2)oc1C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1nc(-c2ccc(Br)cc2)oc1C
Temperature: 50 °C
Yield: 46 %

Procedure:
[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (11.6 g, 37.4 mmol) is dissolved in anhydrous tetrahydrofuran (150 mL) and allowed to stir under nitrogen. Lithium diisopropyl amide solution in tetrahydrofuran (28 mL of 2M soln., 56.1 mmol) is slowly added to the solution at room temperature. This is then heated to 50° C. for 6 hours. The solution is allowed to cool to room temperature and methyl iodide (7.0 mL, 112 mmol) is added in one portion. The mixture is allowed to stir under nitrogen at room temperature overnight. The solution is quenched with a saturated solution of ammonium chloride, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl]-propionic acid methyl ester (5.57 g, 17.19 mmol) is isolated in 46% yield after column chromatography. The racemic 2-[2-(4-Bromo-phenyl)-5-methyl-oxazol-4-yl)-propionic acid methyl ester is resolved on a Chiralcel OJ column (4.6×250 mm). Eluted with 40% isopropanol in heptane with 0.2% dimethy-ethylamine at 1 mL per minute with detection at 260 nM and concentrated the fractions to provide the pure enantiomer esters (isomer 1, 99.8% ee; isomer 2, 99.4% ee).
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13])=[CH2:2].C1(=O)N(C(C)[CH:20]=[O:21])C(=O)C2=CC=CC=C12>>[C:7]1(=[O:8])[N:3]([CH2:1][CH2:2][CH:20]=[O:21])[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: CC(C=O)N1C(=O)c2ccccc2C1=O
Product: O=CCCN1C(=O)c2ccccc2C1=O
Yield: 78 %

Procedure:
Starting from N-vinylphthalimide, a 78% yield of the 3-phthalimidopropanaldehyde and 2-phthalimidopropanaldehyde in a ratio of 2.5:1 was obtained. The Rh-related catalyst afforded a relatively reverse selectivity.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1>C1COCC1>[N:35]1([C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=3)[C:8]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[C:7]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:6]=2)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: C1CCNCC1
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: C1CCOC1
Product: Fc1ccc(Oc2nc(N3CCCCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (from Example 20) (30 mg, 0.06 mmol) was reacted with excess piperidine (0.5 mL) in THF in a sealed tube at 60° C. overnight by general procedure described in Example 103 to afford the title compound: HPLC/MS: m/e=546 (M++1); Rt=5.36 min. 1H-NMR 400 MHz (CDCl3); δ 0.85-0.95 (m, 2H), 1.71-1.59 (m, 2H), 1.60-1.69 (m, 2H), 3.55-3.65 (s, 4H), 6.89-6.94 (m, 1H), 7.08-7.21 (m, 8H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([C:25]([S:28]CCC(OC)=O)([CH3:27])[CH3:26])[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH:2]=[CH2:3].C[S-].[Na+].S(=O)(=O)(O)[O-].[Na+]>CS(C)=O>[CH2:1]([O:4][C:5](=[O:35])[C@@H:6]([C:25]([SH:28])([CH3:26])[CH3:27])[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[CH:15][CH:16]=1)(=[O:9])=[O:10])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1)C(C)(C)SCCC(=O)OC
Agent: C[S-]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CCOC(=O)[C@H](NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1)C(C)(C)S
Reaction time: 3.5 h
Yield: 75 %

Procedure:
To a stirred solution of N-[4-(4-fluorophenoxy)benzenesulfonyl]--S--[2-(methoxycarbonyl)ethyl]-D-penicillamine allyl ester (0.100 g., 0.19 mmol) in DMSO(1 ml.) at room temperature was added sodium thiomethoxide (0.053 g., 0.762 mmol). After 3.5 hours, the reaction was then acidified with 1N aqueous sodium bisulfate to pH=4 and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica eluting with 20% ethyl ethyl acetate in hexane to give N-[4-(4-fluorophenoxy)benzenesulfonyl]-D-penicillamine allyl ester as a colorless oil in 75% yield. 1H--NMR (δ, CDCl3) δ 1.43 (s, 6H), 1.93 (s,1H), 3.82-3.86 (d, 1H, J=11 Hz),4.25-4.38 (m, 2H), 5.23-5.29 (m, 2H), 5.49-5.53 (d, 1H, J=11 Hz), 5.63-5.78 (m,1H), 6.96-7.79 (m, 8H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1(C(O)=O)(C(O)=O)CC1.FC1C=CC([NH2:31])=CC=1.[CH3:34][O:35][C:36]1[CH:62]=[CH:61][C:39]([CH2:40][N:41]2[C:45]3=[N:46][CH:47]=[CH:48][C:49]([O:50][C:51]4[C:56]([Cl:57])=[CH:55][C:54](N)=[CH:53][C:52]=4[Cl:59])=[C:44]3[C:43]([CH3:60])=[N:42]2)=[CH:38][CH:37]=1>>[Cl:59][C:52]1[CH:53]=[C:54]([N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([C:11]2([C:14]([NH2:31])=[O:16])[CH2:12][CH2:13]2)=[O:10])[CH:55]=[C:56]([Cl:57])[C:51]=1[O:50][C:49]1[CH:48]=[CH:47][N:46]=[C:45]2[N:41]([CH2:40][C:39]3[CH:61]=[CH:62][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[N:42]=[C:43]([CH3:60])[C:44]=12
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4c(Cl)cc(N)cc4Cl)ccnc32)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: O=C(O)C1(C(=O)O)CC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4c(Cl)cc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4Cl)ccnc32)cc1
Yield: 7 %

Procedure:
Prepared from 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (0.1354 g, 0.3762 mmol; prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836) and 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3,5-dichlorobenzenamine (0.170 g, 0.1505 mmol) according to the procedure of Example 13, Step C. The crude product was purified preparative TLC (0.5 mm) eluting with EtOAc. Product (12 mg, 7%) was obtained as a orange solid. LRMS (esi pos) m/e 634 (M+1).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]#[CH:12])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([SnH:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[C:1]([Si:5]([CH3:6])([CH3:7])[O:8][CH2:9][CH2:10][CH:11]=[CH:12][Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])([CH3:3])([CH3:4])[CH3:2]
Reactant: C#CCCO[Si](C)(C)C(C)(C)C
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: CCCC[Sn](C=CCCO[Si](C)(C)C(C)(C)C)(CCCC)CCCC
Yield: 95 %

Procedure:
A solution of Example 31A (1.08 g, 5687 mmol), tri-(n-butyl)tin hydride (1.43 mL, 5.31 mmol), and AIBN (cat.) in benzene (10 mL) was stirred at 80° C. for 3 hours. Volatiles were removed under reduced pressure to provide the title compound as a colorless oil (>95% E-isomer). 1H NMR (300 MHz, CDCl3): δ 0.05 (s, 6H), 0.80-0.98 (m, 15H), 0.90 (s, 9H), 1.23-1.38 (m, 6H), 1.42-1.53 (m, 6H), 2.34-2.40 (m, 2H), 3.66 (d, J=6 Hz, 2H), 5.94-5.98 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][CH2:8]1.C(OCC)(=[O:16])C>>[O:4]1[CH2:5][CH2:6][N:1]([CH:8]([CH2:9][C:10]([OH:16])=[O:11])[C:7]([OH:12])=[O:13])[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)O1
Reactant: C1COCCN1
Reactant: CCOC(C)=O
Product: O=C(O)CC(C(=O)O)N1CCOCC1

Procedure:
Morpholine (8.9 g) and succinic anhydride (10.1 g) were dissolved in ethyl acetate (50 mL) and refluxed for 2 hours, and then the solvent was evaporated to obtain a crude product of monomorpholinosuccinic acid. By using the resulting crude product and the 1,3-diacylglycerol compound, Compound 1A-4-1 was obtained in the same manner as that used for Compound 1A-1-3.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1Cl.[CH2:13]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:21][NH2:22])[CH2:14][CH2:15][CH3:16].O1CCOCC1>O>[Cl:1][C:2]1[C:3](=[O:12])[NH:4][N:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]=1
Reactant: CCCCOc1cc(CN)ccc1OC
Reactant: CCOc1n[nH]c(=O)c(Cl)c1Cl
Solvent: O
Solvent: C1COCCO1
Product: CCCCOc1cc(CNc2c(OCC)n[nH]c(=O)c2Cl)ccc1OC
Reaction time: 15 h

Procedure:
A mixture comprising 7.32 g of 4,5-dichIoro-6-ethoxy-3(2H)pyridazinone prepared in Reference Example 2, 21.95 g of 3-n-butoxy-4-methoxybenzylamine, 60 ml of 1,4-dioxane and 60 ml of water, was refluxed under stirring for 15 hours. Then, most 1,4-dioxane was distilled off under reduced pressure, and dilute hydrochloric acid was added for acidification. Then, chloroform was added thereto, and the mixture was vigorously shaked. The precipitated crystals were separated by filtration, and the chloroform layer of the filtrate was subjected to liquid separation and washed with water and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light yellow oily substance. The product was crystallized from n-propanol-di-i-propyl ether (1:9 v/v), to obtain 10.48 g of the above identified compound having a melting point of from 117° to 118° C. as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.C(N(CC)C(C)C)(C)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN2C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of 5-methoxyindoline (202 mg, 1.35 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) in 4.0 mL of dry dichloromethane was added benzoyl chloride (0.23 mL, 2.0 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate. The solution was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 70/30) to obtain 5-methoxy-1-benzoylindoline (224 mg, 65%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:27][CH2:28][CH3:29])[C:5](=[O:26])[CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:2].[Cl:30][C:31]1[C:32]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH:48]=O)[CH:42]=2)=[N:33][N:34]([CH3:40])[C:35]=1[O:36][CH:37]([F:39])[F:38]>CN(C)C=O>[Cl:30][C:31]1[C:32]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([CH:48]=[CH:6][C:5](=[O:26])[CH:4]([O:27][CH2:28][CH3:29])[O:3][CH2:1][CH3:2])[CH:42]=2)=[N:33][N:34]([CH3:40])[C:35]=1[O:36][CH:37]([F:38])[F:39]
Reactant: CCOC(OCC)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1nc(-c2ccc(Cl)c(C=O)c2)c(Cl)c1OC(F)F
Solvent: CN(C)C=O
Product: CCOC(OCC)C(=O)C=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)ccc1Cl
Temperature: 85 °C

Procedure:
5.1 g of (3,3-diethoxy-2-oxopropylidene)(triphenyl)phosphorane were added to a solution of 2 g (6.2 mmol) of 4-chloro-3-(4-chloro-3-formylphenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 20 ml of dimethylformamide, and the mixture was hen heated at 80-90° C. for 5 hours. The mixture was then concentrated and the crude product thus obtained was purified by chromatography on silica gel (eluent: hexane/ethyl acetate=4:1). Yield: 2.1 g.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C.C(OCC)(=O)C>C1(C)C(C)=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccncc2)CC1

Procedure:
4.0 g (26.6 mmol) of 4-chloropyridine hydrochloride, 4.2 g (26.6 mmol) of ethyl piperidine-4-carboxylate and 7.4 ml (53.2 mmol) of triethylamine were stirred in 100 ml of xylene at 130° C. for 24 hours. The reaction mixture was treated with ethyl acetate as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:13]=O.[CH3:19][C:20]1([CH3:28])[CH2:25][CH2:24][C:23](=O)[CH2:22][C:21]1=[O:27]>>[Cl:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:22]3[C:21](=[O:27])[C:20]([CH3:28])([CH3:19])[CH2:25][CH2:24][C:23]=3[NH:1][C:2]3[N:6]([CH3:7])[NH:5][C:4](=[O:8])[C:3]2=3)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)C(C)(C)CC1)C2c1ccc(Cl)c(Cl)c1
Yield: 68 %

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (0.08 g, 0.75 mmol), 3,4 dichlorobenzaldehyde (0.13 g, 0.75 mmol), and 4,4-dimethyl-1,3-cyclohexanedione (0.10 g, 0.75 mmol) were processed as described in Example 22 to provide 0.2 g (67%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (s, 3H), 0.99 (s, 3H), 1.78 (t, 2H), 2.65 (m, 2H), 3.45 (s, 3H), 4.83 (s, 1H), 7.08 (dd, 1H), 7.29 (d, 1H), 7.42 (d, 1H), 9.52 (s, 1H), 9.68 (s, 1H); MS (ESI−) m/z 390 (M−H)−; Anal. calcd for C19H19N3Cl2O2: C, 58.16;H, 4.84; N, 10.71. Found: C, 58.23;H, 4.75; N, 10.68.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13]Cl.[CH:15]([O-:17])=[O:16].[Na+].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH2:13][O:17][CH:15]=[O:16]
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=COCc1c(Cl)ccc2cc(Cl)cnc12
Yield: 84 %

Procedure:
24.5 parts by weight of 3,7-dichloro-8-chloromethylquinoline and 13 parts by weight of sodium formate in 220 parts by weight of dimethylsulfoxide are heated for 6 hours at 100° C. The mixture is then cooled, water is added and the precipitated product is filtered off under suction and recrystallized from toluene. 21.5 parts by weight (84% of theory) of 3,7-dichloro-8-formyloxymethylquinoline of melting point 146° C. are obtained.