Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1=[CH:3][CH2:4][CH2:5][C:6]([CH3:15])=[CH:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[CH2:10][CH2:11]1>CCCCC>[CH3:14][CH:12]([C:9]1[CH2:8][CH2:7][C:6]([CH:5]=[CH2:4])([CH3:15])[CH:11]([C:2]([CH3:1])=[CH2:3])[CH:10]=1)[CH3:13]
Reactant: CC1=CC=C(C(C)C)CCC(C)=CCC1
Agent: C/C1=C\C=C(\C(C)C)CC/C(C)=C/CC1
Solvent: CCCCC
Product: C=CC1(C)CCC(C(C)C)=CC1C(=C)C
Temperature: 35 °C

Procedure:
Preliminary studies, in which leaf extracts were compared to steam distillates by standard GC-MS methods (hot injector) and by cool on-column injection, revealed that the target metabolite, germacrene C (FIG. 1), was prone to thermal rearrangement to a compound with shorter GC retention time but nearly identical mass spectrum. This compound was absent in the pentane leaf extract when analyzed by cool (35° C.) on-column injection, but was present when the same pentane extract was injected onto a hot (230° C.) injector (FIG. 2). Comparison of this compound with authentic δ-elemene (FIG. 1) from black pepper oleoresin yielded an identical retention time and mass spectrum. Heating purified germacrene C in a sealed container to 130° C. for 1 h resulted in complete conversion to δ-elemene which was confirmed by GC-MS. Conversion of germacrene C to δ-elemene has been reported previously (Morikawa and Hirose, Tetrahedron Lett. 22:1799-1801, 1969). The sesquiterpene fraction of ‘VFNT Cherry’ leaves (3.2% of total volatile olefins) contained germacrene C (66%), germacrene A (7%), guaia-6,9-diene (7%), germacrene B (6%), β-caryophyllene (6%), germacrene D (4%), α-humulene (4%), and β-elemene (1%). This is the first report of azulane (guaia-6,9-diene) and germacrane skeletal types in tomatoes. By contrast, the sesquiterpene fraction of leaves from the commercial tomato variety ‘Better Boy’ (3.3% of total volatile olefins) contained mostly β-caryophyllene (71%), germacrene C (15%), and α-humulene (9%). The sesquiterpene composition of ‘Better Boy’ agrees with previous reports on the content of L. esculentum leaf oil (Buttery et al., J. Agric. Food Chem. 35:1039-1042, 1987; and Lundgren et al., Nord. J. Bot. 5:315-320, 1985), except that no δ-elemene was found by on-column injection; germacrene C has not been previously observed in Lycopersicon.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:9]=[C:10]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1oc2ccc(C(C)(C)C)c(O)c2c1C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3ccccc3)cc(C(C)(C)C)c(O)c2c1C

Procedure:
To a solution of ethyl 3-methyl-4-hydroxy-5-tert-butylbenzofuran-2-carboxylate, compound 12a (1.00 g, 3.62 mmol) and benzoyl chloride (0.763 g, 5.43 mmol) in 1,2-dichloroethane (40 mL) at 0° C. was added aluminum chloride (0.720 g, 5.43 mmol) and the resulting mixture warmed to reflux for 3.5 hours. The reaction was allowed to cool, poured into 2N HCl (100 mL) and extracted with methylene chloride (4×25 mL). The combined extracts were washed with 5% NaHCO3 (25 mL), dried (Na2SO4), and concentrated. Flash chromatography using 25% ethyl acetate in hexane as eluant afforded ethyl 3-methyl-4-hydroxy-5-tert-butyl-7-benzoylbenzofuran-2-carboxylate, compound 15 as an oil sufficiently pure for further chemistry. 1H NMR d 1.34 (3H, t, J=6 Hz), 1.51 (9H, s), 2.89 (3H, s), 4.35 (2H, q, J=6 Hz), 7.56 (3H, m), 7.86 (3H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH:9]=[CH:8]2>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[CH2:9][CH2:8]2
Reactant: CCOC(=O)c1cc(OC)c2[nH]c(=O)ccc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(c(OC)c1)NC(=O)CC2
Reaction time: 1 h
Yield: 70.3 %

Procedure:
0.12 g of 10% Pd-C was added to 20 ml of an acetic acid solution containing 1.20 g of 8-methoxy-6-ethoxycarbonylcarbostyril. The mixture was subjected to hydrogenation at 90° C. at normal pressure for 1 hour. The catalyst in the reaction mixture was removed by filtration. The filtrate was subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (elutant: chloroform) and recrystallized from chloroform-diethyl ether to obtain 0.85 g of 8-methoxy-6-ethoxycarbonyl-3,4-dihydrocarbostyril as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[O:29][N:28]=1)([CH3:26])[CH3:25].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:33]([NH:32][C:30]2[O:29][N:28]=[C:27]([C:24]([F:23])([CH3:25])[CH3:26])[CH:31]=2)=[O:34])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(F)c1cc(NC(=O)Oc2ccccc2)on1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)F)no4)c3)c2cc1OC
Yield: 44.9 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) and phenyl 3-(2-fluoropropan-2-yl)isoxazol-5-ylcarbamate from Example 42A (95 mg, 0.36 mmol) were reacted according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-(2-fluoropropan-2-yl)isoxazol-5-yl)urea as a colorless solid (63 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 10.50 (brs, 1H), 9.15 (s, 1H), 8.56 (s, 1H), 7.57-7.58 (m, 2H), 7.40-7.45 (m, 2H), 7.32 (m, 1H), 7.00 (m, 1H), 6.14 (s, 1H), 3.99-4.00 (2×s, 6H), 1.67 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 468 (M+H)+.
Reaction SMILES: O[C@H](CO)COC1C2C(=CC(OC)=CC=2)C(C2C=CC=CC=2)=C(C#N)N=1.CC1(C)[O:32][C@H:31]([CH2:33][O:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:45][CH:46]([F:48])[F:47])=[CH:42][CH:43]=3)[C:38]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[CH:50]=3)=[C:37]([C:56]#[N:57])[N:36]=2)[CH2:30][O:29]1>>[F:48][CH:46]([F:47])[O:45][C:41]1[CH:40]=[C:39]2[C:44](=[CH:43][CH:42]=1)[C:35]([O:34][CH2:33][C@@H:31]([OH:32])[CH2:30][OH:29])=[N:36][C:37]([C:56]#[N:57])=[C:38]2[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[CH:50]=1
Reactant: CC1(C)OC[C@@H](COc2nc(C#N)c(-c3cccc(F)c3)c3cc(OC(F)F)ccc23)O1
Agent: COc1ccc2c(OC[C@H](O)CO)nc(C#N)c(-c3ccccc3)c2c1
Product: N#Cc1nc(OC[C@@H](O)CO)c2ccc(OC(F)F)cc2c1-c1cccc(F)c1

Procedure:
Following the procedure for 1-{[(2R)-2,3-dihydroxypropyl]oxy}-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using 1-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-(difluoromethoxy)-4-(3-fluorophenyl)isoquinoline-3-carbonitrile in place of 1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-6-methoxy-4-phenylisoquinoline-3-carbonitrile, the title compound was synthesized.
Reaction SMILES: Br[C:2]1[C:6]2[C:7]([NH:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[C:19]1([C:2]2[C:6]3[C:7]([NH:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)=[N:8][CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1csc2ccnc(NCc3ccccn3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: c1ccc(-c2csc3ccnc(NCc4ccccn4)c23)cc1
Temperature: 155 °C
Yield: 59.4 %

Procedure:
A microwave reaction vessel was charged with (3-bromo-thieno[3,2-c]pyridin-4-yl)-pyridin-2-ylmethyl-amine (50 mg, 0.158 mmol), phenylboronic acid (37.9 mg, 0.312 mmol), palladium (II) acetate (3.5 mg, 0.0158 mmol), triphenylphosphine (12.3 mg, 0.0467 mmol) and sodium carbonate (49.5 mg, 0.467 mmol). The reaction was solvated with DME (0.75 ml) and distilled water (0.25 ml), sealed, and set to stir in a Biotage microwave reactor. The reaction was heated at 150-160° C. for 1 h. At which point the reaction was allowed to cool to room temperature and further diluted with distilled water (10 ml). The aqueous phase was then extracted with DCM (2×20 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The crude residue was subjected to flash column chromatography (eluent petroleum spirit 40-60° C.:EtOAc, 1:1, Rf 0.1). This afforded the title compound as a yellow solid (29.8 mg, 60%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].CS(C)=O.[Br:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>O>[Br:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cc(N3CCN(C(=O)c4ccc(Br)cc4)CC3)ccc2N1
Yield: 17.2 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 1 g of sodium hydrogencarbonate was added to 50 ml of dimethyl sulfoxide and the mixture was stirred with ice cooling while slowly adding dropwise 20 ml of dimethyl sulfoxide solution containing 3.2 g of 4-bromobenzoyl chloride. After completion of addition the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 0.8 g of 6-[4-(4-bromobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 233°-234.5° C., colorless granules.
Reaction SMILES: C[O:2][C:3]1[NH:4][NH:5][C:6]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15]3)(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[CH2:21]([N:17]1[C:18]2[C:14](=[CH:13][C:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=3)(=[O:11])=[O:10])=[CH:20][CH:19]=2)[CH:15]=[CH:16]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC1=CC=C(S(=O)(=O)c2ccc3c(ccn3Cc3ccccc3)c2)NN1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1ccc(S(=O)(=O)c2ccc3c(ccn3Cc3ccccc3)c2)n[nH]1
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(N-benzylindole-5-sulfonyl)-2H-pyridazine (0.64 mmol, 245 mg), conc. HCl (0.5 mL), and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue and the resulting solid, 6-(N-benzylindole-5-sulfonyl)-2H-pyridazin-3-one, was collected (55%, 102 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:9]2[S:8][C:7]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[CH:10]=2)[CH:19]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: Cc1cccc2ccsc12
Product: Cc1cccc2cc(Cc3cc(Br)ccc3Cl)sc12

Procedure:
7-Methylbenzo[b]thiophene (see Tilak, B. D. Tetrahedron 9 (1960) 76-95) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:19]([CH3:21])[CH3:20])[C:7]([N:9]1[CH2:13][C:12](=[O:14])[CH2:11][C@H:10]1[C:15]([O:17][CH3:18])=[O:16])=[O:8])=[O:4].[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:19]([CH3:21])[CH3:20])[C:7]([N:9]1[C@H:10]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][C:12]2([O:24][CH2:23][CH2:22][O:14]2)[CH2:13]1)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CC(=O)C[C@H]1C(=O)OC)C(C)C
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1C(=O)OC)OCCO2)C(C)C
Temperature: 110 °C
Yield: 41.7 %

Procedure:
In a 50 mL round-bottomed flask, (S)-methyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-4-oxopyrrolidine-2-carboxylate (230 mg, 766 μmol, Eq: 1.00) and ethane-1,2-diol (238 mg, 214 μl, 3.83 mmol, Eq: 5) were combined with toluene (15 ml) to give a colorless solution. p-toluenesulfonic acid monohydrate (29.1 mg, 153 μmol) was added and the reaction mixture was heated to 110° C. with a Dean-Stark apparatus for 20 hr. After cooling, it was diluted with EtOAc (50 ml), washed with NaHCO3 (sat solution, 200 ml), dried and concentrated in vacuo. The crude mixture was purified on a silica gel column (CH2Cl2, 20%, 30%, 40% and 60% EtOAc/CH2Cl2) to afford (S)-methyl 7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylate as an oil (110 mg, 41.7%). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 0.95 (d, J=6.78 Hz, 8H) 1.05 (d, J=6.78 Hz, 7H) 1.57 (s, 2H) 2.22 (dd, J=13.18, 6.90 Hz, 3H) 2.37 (dd, J=13.05, 8.78 Hz, 2H) 3.62-3.70 (m, 11H) 3.71-3.87 (m, 10H) 3.93-4.03 (m, 11H) 4.25 (d, J=2.76 Hz, 4H) 4.59-4.78 (m, 2H) 5.23-5.51 (m, 2H) 5.26-5.51 (m, 2H)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:20]=2[C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>[OH-].[Pd+2].[OH-].[C].C(O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C:19]2[N:23]([CH3:24])[N:22]=[C:21]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:20]=2[C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)=[O:17])=[CH:11][CH:10]=1
Reactant: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1NC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cn1nc(-c2ccc(F)cc2)c(-c2ccncc2)c1NC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Under a stream of argon gas, 0.11 g of 5-(4-benzyloxyphenylacetylamino)-3-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole, 22.9 mg of palladium hydroxide-carbon, and 8 ml of cyclohexene were added to 15 ml of ethanol followed by heating under reflux for 23 hours. After the reaction mixture was cooled to room temperature, the catalyst was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 30 g of silica gel [with an elution solvent comprising chloroform-methanol (100:0-40:1)]. Thus, 61.3 mg (69% yield) of the title compound was obtained as white crystals.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].CCN(C(C)C)C(C)C.C[Al](C)C.[F:19][CH:20]([F:41])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([O:39]C)=O)=[N:29]1>C(Cl)Cl>[F:41][CH:20]([F:19])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31](=[O:36])[C:30]([C:37]([N:3]([O:4][CH3:5])[CH3:2])=[O:39])=[N:29]1
Reactant: CNOC
Reactant: COC(=O)c1nn(-c2ccccc2OC(F)F)cc(OC)c1=O
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cn(-c2ccccc2OC(F)F)nc(C(=O)N(C)OC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (5.27 g, 54.0 mmol) and iPr2NEt (9.40 mL, 54.0 mmol) in CH2Cl2 (60 mL) was added AlMe3 (1.8 M solution in toluene, 30.0 mL, 54.0 mmol) dropwise at 0° C. After stirring at 0° C. for 1 h, a solution of methyl 1-[2-(difluoromethoxy)phenyl]-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (5.87 g, 17.99 mmol) in CH2Cl2 (60 mL) was added dropwise, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (3/1) to give the title compound (4.79 g, 75% yield) as pale yellow crystals: NMR (300 MHz, CDCl3): δ ppm 3.38 (3H, s), 3.68 (3H, s), 3.89 (3H, s), 6.52 (1H, t, J=72.6 Hz), 7.37 (2H, m), 7.46-7.53 (1H, m), 7.62 (1H, dd, J=7.8, 1.5 Hz), 7.76 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CO[C:10](OC)([N:12]([CH3:14])[CH3:13])[CH3:11]>>[CH3:13][N:12]([CH3:14])[C:10](=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:11]
Reactant: Nc1ccccn1
Reactant: COC(C)(OC)N(C)C
Product: CC(=Nc1ccccn1)N(C)C

Procedure:
Compound 13 was obtained according to general procedure I with 2-aminopyridine in presence of dimethylacetamide-dimethylacetal instead of dimethylformamide-dimethyl-acetal, as an orange oil in a quantitative yield.
Reaction SMILES: [F:1][C:2]1([F:37])[CH2:3][CH2:4][N:5]([C:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:36])=[O:24])[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].C=O.[C:40](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(O)(=O)C>[F:37][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:23]([C:25]2[S:29][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:27][C:26]=2[CH3:36])=[O:24])[C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH3:40])[CH2:17][CH2:18]1)=[O:11]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NC2CCNCC2)c2ccccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NC2CCN(C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To a solution of 60 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-(4-piperidyl)acetamide in 5 ml of dichloromethane were added 70 μl of a 40% aqueous solution of formaldehyde, 74 μl of acetic acid and 30 mg of sodium triacetoxy borohydride, followed by stirring at room temperature for six hours. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, followed by evaporating the solvent therefrom. The residue was purified by silica gel column chromatography (eluting with chloroform) and crystallized from diethyl ether to give 53 mg of (Z)-[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-(1methyl-4-piperidyl)acetamide as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:13]([Mg]Cl)[CH2:14][CH2:15][CH2:16][CH3:17]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1
Reactant: CCCCC[Mg]Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Product: CCCCCC(O)c1ccc(C(=O)OC)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and n-pentylmagnesium chloride following the general method exemplified in Preparation 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8](OC)=[O:9])(=[O:4])=[O:3].O.[NH2:16][NH2:17]>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([NH:16][NH2:17])=[O:9])(=[O:4])=[O:3]
Reactant: COC(=O)c1cccc(S(C)(=O)=O)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1cccc(C(=O)NN)c1
Yield: 95.3 %

Procedure:
A stirred solution of compound 2 (2.1 g, 9.8 mmol) and hydrazine hydrate (2.4 mL, 49.0 mmol) in ethanol (70 mL) was heated to reflux for 8 h. On completion, solvent was removed, diluted with water (30 mL) and extracted with 10% methanol in dichloromethane (60 mL×4). The combined organic layer was washed with brine, dried over sodium sulphate and concentrated to afford the title compound 3 (2.0 g, 91%) which was used for further reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=O)[O:26][C:24](=[O:25])[C:23]2=[CH:29][CH:30]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:27](=[O:26])[C:22]3[C:23](=[CH:29][CH:30]=[C:20]([Br:19])[CH:21]=3)[C:24]2=[O:25])=[O:8])=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccccc2N2C(=O)c3ccc(Br)cc3C2=O)cc1
Temperature: 110 °C
Yield: 93.4 %

Procedure:
A pressure tube was charged with N1-(4-methoxybenzoyl)-1,2-benzenediamine (2.00 g, 8.26 mmol), 4-bromophthalic anhydride (1.88 g, 8.26 mmol), and tetrahydrofuran (8 mL). The resultant slurry was then placed in a bath heated to 110° C. for 16 h. After cooling to ambient temperature, the product was triturated with ethyl acetate/hexanes and collected by filtration. Recrystallization from ethyl acetate/hexanes yielded 3.48 g (93%) of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:31])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]#[N:30])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:29]#[N:30])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
Reactant: CCOC(=O)C1(N)Cc2ccc(C#N)cc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(C#N)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (377 mg, 1.94 mmol), 2-amino-5-cyano-indan-2-carboxylic acid ethyl ester (670 mg, 2.91 mmol), HATU (1.11 g, 2.91 mmol) in anhydrous DMF (15 mL) is added DIPEA (480 μL, 2.91 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-70% EtOAc in heptane) to give a pure product (110) as a white semisolid (680 mg, 86%).