Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]=[C:3]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([CH:14]=[CH:15][CH2:16][CH2:17][C:18]3([CH3:23])OCC[O:19]3)[CH:12]=[CH:13][C:6]=2[O:5][CH2:4]1.CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.CC#N.CC#N.Cl[Pd]Cl>[Cl:1][CH:2]=[C:3]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:11]([CH:14]=[CH:15][CH2:16][CH2:17][C:18](=[O:19])[CH3:23])[CH:12]=[CH:13][C:6]=2[O:5][CH2:4]1
Reactant: CC1(CCC=Cc2ccc3c(c2)C=CC(=CCl)CO3)OCCO1
Agent: Cl[Pd]Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CC#N
Product: CC(=O)CCC=Cc1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
6 mg (0.023 mmol) of bis(acetonitrile)palladium(II) chloride are added to 79 mg (0.237 mmol) of 3-(chloromethylene)-7-[4-(2-methyl-1,3-dioxolan-2-yl)-1-butenyl]-2,3-dihydro-1-benzoxepin, prepared according to example 74, in solution in 1.5 ml of dichloromethane. After stirring at ambient temperature for 3 hours, 0.5 ml of acetone and a catalytic amount of para-toluenesulfonic acid are added. The reaction medium is then stirred for 30 minutes. The crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 10/90) to provide 55 mg (80%) of 6-[3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-yl]-5-hexen-2-one in the form of a mixture of isomers in an EZ/EE ratio (85/15) for the chloromethylene functional group; 1H NMR (300 MHz, CDCl3) EZ isomer: 2.18 (s, 3H), 2.45 (m, 2H), 2.61 (m, 2H), 4.86 (s, 2H), 6.10 (m, 1H), 6.33 (m, 4H), 6.96 (m, 3H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:15]([O:17]C)=[O:16])=[N:6][O:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C>CO>[CH:1]1([C:4]2[C:5]([C:15]([OH:17])=[O:16])=[N:6][O:7][C:8]=2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1noc(-c2ccccc2)c1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1noc(-c2ccccc2)c1C1CC1
Yield: 77.4 %

Procedure:
A solution of methyl 4-cyclopropyl-5-phenylisoxazole-3-carboxylate (170 mg, 0.699 mmol) and 1N aqueous sodium hydroxide (1 mL, 1.05 mmol) in methanol (6 mL) was heated to 80° C. in a sealed tube for 1 hr. The reaction mixture was acidified with acetic acid until the pH was ˜4. The mixture was concentrated, and the residue was purified by preparative HPLC to give 4-cyclopropyl-5-phenylisoxazole-3-carboxylic acid (124 mg). The compound had an HPLC ret. time=2.81 min.−Column. YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90%
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].S(Cl)([Cl:28])=O>>[Cl:28][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
6-Bromonicotinic acid (200 mg, 0.99 mmol) was heated at reflux in thionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in DCM (2 ml), p-anisidine (123 mg, 0.10 mmol) and sodium carbonate (500 mg) were added to the solution. The reaction was stirred at room temperature for 4 hrs, filtered and the filtrate reduced to dryness under vacuum to give 6-chloro-N-(4-methoxyphenyl)nicotinamide. NMR: δH [2H6]-DMSO 10.37,(1H, b), 8.94,(1H, d), 8.34,(1H, dd), 7.70,(1H, d), 7.66,(2H, m), 6.95,(2H, m), 3.75,(3H, s).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:21])[C:11]([OH:20])([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][CH:13]=[CH2:14])[CH2:2]2.[O:22]([CH2:29][CH2:30][CH2:31][Br:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C.C(Cl)(Cl)Cl>[Br-:32].[OH:20][C:11]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([CH2:12][CH:13]=[CH2:14])[C:10]([O:9][C@@H:3]1[CH:4]2[CH2:5][CH2:6][N+:1]([CH2:31][CH2:30][CH2:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH2:8][CH2:7]2)[CH2:2]1)=[O:21]
Reactant: BrCCCOc1ccccc1
Reactant: C=CCC(O)(C(=O)O[C@H]1CN2CCC1CC2)c1cccs1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C=CCC(O)(C(=O)O[C@H]1C[N+]2(CCCOc3ccccc3)CCC1CC2)c1cccs1
Product: [Br-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
250 mg (0.81 mmol) of 2-Hydroxy-2-thien-2-ylpent-4-enoic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester, Intermediate I-3, were dissolved in 5 ml of acetonitrile and 7.5 ml of chloroform. To this solution were added 0.63 ml (4.1 mmol) of phenoxypropylbromide. After stirring for 48 h at room temperature under a N2 atmosphere, solvents were evaporated. Ether was added and the mixture stirred. The solid obtained was filtered and washed several times with ether. The yield was 0.3 g (71%) of the title compound as a mixture of diastereomers; mp: 157° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[C:24](N1C=CN=C1)([N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)=O.CN(C)CCN>O1CCCC1>[CH3:24][N:26]([CH3:27])[CH2:30][CH2:29][NH:28][C:19](=[O:21])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:23])[F:22])=[CH:4][CH:5]=1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
A suspension of 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0156 mole), 1,1'-carbonyldiimidazole (3.0 g, 0.0185 mole) and dry tetrahydrofuran (125 ml) was stirred at room temperature for 2 hours with nitrogen bubbling through it. The reaction mixture was then heated at 50° C. under nitrogen for 2 hours. The solution was cooled and a solution of N,N-dimethylethylenediamine (4.2 g, 0.047 mole) in tetrahydrofuran (5 ml) was added. The reaction mixture was stirred at room temperature overnight under nitrogen and evaporated under reduced pressure. The residue was triturated in water, and the solid was collected by filtration, washed once with water, twice with 5% potassium hydroxide solution and then twice again with water to yield 3.0 g (49%) of product. A 0.7-g sample of the solid was dissolved in hot isopropyl ether with a little isopropyl alcohol added to aid solubility, filtered, and cooled to room temperature to yield 0.4 g of a white solid, mp 196°-197.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[NH2:21]C1C=CC(C(O)=O)=CC=1[N+]([O-])=O.OC1C=CC(C(O)=O)=CC=1>>[Br:1][C:2]1[C:3]2[C:5](=[N:10][N:21]([C:16]3[CH:15]=[C:14]([CH3:13])[CH:19]=[CH:18][C:17]=3[OH:20])[N:4]=2)[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Cc1ccc(O)cc1
Reactant: Nc1c(Br)cc(Br)cc1[N+](=O)[O-]
Agent: O=C(O)c1ccc(O)cc1
Product: Cc1ccc(O)c(-n2nc3cc(Br)cc(Br)c3n2)c1
Yield: 60 %

Procedure:
Example 1 was repeated except that 59.2 g (200 mmoles) of the 2,4-dibromo-6-nitroaniline and 21.6 g (200 mmoles) of p-methylphenol were used instead of 36.4 g (200 mmoles) of 4-amino-3-nitrobenzoic acid and 27.6 g (200 mmoles) of p-hydroxybenzoic acid respectively to obtain 4,6-dibromo-2-(2'-hydroxy-5'-methylphenyl)benzotriazol. The yield was 60%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH3:13])[CH2:11][CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC.CO>O1CCCC1>[OH:15][CH2:14][C@@H:9]1[CH2:10][CH2:11][C@H:12]([CH3:13])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: C[C@H]1CC[C@@H](C(=O)O)N1C(=O)OC(C)(C)C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1CC[C@@H](CO)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
To a solution of (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (5.91 g, 25.8 mmol) in tetrahydrofuran at 0° C., was added borane in dimethylsulfide (1.0 M, 3.4 mL, 34 mmol) dropwise. The reaction was stirred for 4 hours at 0° C. then 18 hours at room temperature. The mixture was then cooled to 0° C. and methanol (70 mL) was added dropwise. The reaction was warmed to room temperature and the solvents were removed in vacuo. The residue was taken up in dichloromethane (200 mL) and extracted with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-tert-butyl 2-(hydroxymethyl)-5-methylpyrrolidine-1-carboxylate as a clear oil (5.15 g, 23.9 mmol, 93%) and was used directly in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[O:10]=[C:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2([OH:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Cl[Mg]c1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 1 h

Procedure:
Slowly add 4-chlorophenylmagnesium chloride (5.9 mL of 1M solution) to a solution of ethyl 4-oxo-cyclohexanecarboxylate (1.0 g) in Et2O at 0° C. After 1 h, pour the reaction mixture into 1N HCl and extract with Et2O. Separate the organic layer, wash with water, brine and concentrate to give ethyl 4-(4-chlorophenyl)-4-hydroxy-cyclohexanecarboxylate (1.75 g) which is used without purification in the next step.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[N:20]=1)[C:3]([C:5]1[C:6]([F:18])=[C:7]([NH:11][C:12](=[O:17])[O:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[CH:9][CH:10]=1)=O.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29].O>CC(N(C)C)=O>[Cl:25][C:21]1[N:20]=[C:19]([C:2]2[O:29][C:28]([C:27]([CH3:32])([CH3:31])[CH3:26])=[N:30][C:3]=2[C:5]2[C:6]([F:18])=[C:7]([NH:11][C:12](=[O:17])[O:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)C(Br)c2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)C(N)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)oc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Yield: 19.7 %

Procedure:
A stirring mixture of 2-propen-1-yl {3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (6.1 g, 14.23 mmol) and 2,2-dimethylpropanamide (2.16 g, 21.35 mmol) in DMA (200 ml) was heated to 80° C. for 2 days. Upon cooling, the reaction mixture was poured into water (500 ml) and extracted with EtOAc (100 ml×5). The combined organic layers were washed with brine, separated, dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with petroleum ether with EtOAc (10% to 16%) and collected fractions to obtain title compound as yellow solid (1.21 g, 19%). MS (ES): 431 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH:11](OC)(OC)OC.[F:18][C:19]1[CH:20]=[C:21]([NH2:25])[CH:22]=[N:23][CH:24]=1>CCCCCC>[F:18][C:19]1[CH:20]=[C:21]([NH:25][CH:11]=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[CH:22]=[N:23][CH:24]=1
Reactant: COC(OC)OC
Reactant: Nc1cncc(F)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCCCCC
Product: CC1(C)OC(=O)C(=CNc2cncc(F)c2)C(=O)O1
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A 150 mL sealed tube was charged with 2,2-dimethyl-1,3-dioxane-4,6-dione (6.0 g, 41.6 mmol) and trimethyl orthoformate (41.6 mL, 41.6 mmol). This was heated to 100° C., and stirred at this temperature for 2 hours. Reaction then cooled to 30° C. and 5-fluoropyridin-3-amine (4.7 g, 41.6 mmol) added portion-wise. Reaction vessel resealed and mixture stirred at 100° C. for 3 hours. LC/MS shows completion. Reaction mixture was cooled to room temperature, diluted with hexane, filtered, and air dried to yield 5-((5-fluoropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (9.1 g, 82% yield) as a bright yellow solid. MS [M+H]=267.2. Calc'd for C12H11FN2O4=266.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[N:10]=[C:11]([NH:18][CH2:19][CH:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>CS(C)=O>[NH2:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][C:5]2[CH:4]=[C:3]([C:9]3[N:10]=[C:11]([NH:18][CH2:19][CH:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:29][CH2:28]1
Reactant: NC(=O)c1ncc(-c2cc(F)ncc2Cl)nc1NCC1CCOCC1
Reactant: NC1CCC(N)CC1
Solvent: CS(C)=O
Product: NC(=O)c1ncc(-c2cc(N[C@H]3CC[C@H](N)CC3)ncc2Cl)nc1NCC1CCOCC1
Temperature: 100 °C

Procedure:
5-(5-chloro-2-fluoropyridin-4-yl)-3-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazine-2-carboxamide (0.035 g, 0.096 mmol) was dissolved in DMSO (2 ml). This was treated with 1,4-diaminocyclohexane (0.109 g, 0.957 mmol). The reaction mixture was then heated at 100° C. for 4 hr. The material was purified by preparative reverse-phase HPLC to give 0.0053 g of 5-(2-(trans-4-aminocyclohexylamino)-5-chloropyridin-4-yl)-3-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazine-2-carboxamide as the TFA salt. LCMS (m/z): 460.1 (MH+), retention time=0.54 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]([CH:22]([OH:37])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[C:15]([O:17]C(C)(C)C)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH:14]([CH:22]([OH:37])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1)[C:15]([OH:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(CCNC(=O)OCc1ccccc1)C(O)CCc1ccc(-c2ccccc2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCC(C(=O)O)C(O)CCc1ccc(-c2ccccc2)cc1)OCc1ccccc1
Reaction time: 4 h
Yield: 70.3 %

Procedure:
To a solution of the compound (40 mg) obtained from step 2 above in dry dichloromethane (10 ml) at 0° C. was added trifluoroacetic acid (0.5 ml) and anisole (0.05 ml) and stirred for 4 hours. The solvent and excess reagents were evaporated under reduced pressure and the residue thus obtained was purified by column chromatography using 60% ethyl acetate in hexane as eluant to furnish the title compound (25 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][NH:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Nc2ccc(CO)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CNc2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 13 g of N-[4-(hydroxymethyl)phenyl]-4-(tetradecyloxy)benzamide in 250 ml of tetrahydrofuran is added dropwise with stirring under argon 59.14 ml of 1 molar lithium aluminum hydride in tetrahydrofuran. The mixture is stirred at room temperature for 0.5 hours and refluxed for 5 hours. Ethyl acetate is added dropwise followed by water. The mixture is filtered and the cake washed with ether. The filtrate is evaporated to a residue which is purified by chromatography on silica gel with 2:1 chloroform:hexane to give the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][N:10]1[C:19]1[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=[C:21]([Cl:29])[N:20]=1>CN(C)C=O>[ClH:29].[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:21]1[N:20]=[C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[N:22]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc2c(c(N3CCc4ccccc4C3)n1)CCCC2
Solvent: CN(C)C=O
Product: CN(c1ccccc1)c1nc2c(c(N3CCc4ccccc4C3)n1)CCCC2
Product: Cl
Yield: 39.3 %

Procedure:
After N-methylaniline(0.70 ml, 6.3 mmol) was added to a mixture solution of 4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloro-5,6,7,8-tetrahydroquinazoline(0.90 g, 3.0 mmol) and dimethylformamide(5 ml), 0.48 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[S:7].Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=O.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][CH:2]([CH3:9])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)[N:8]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)CCNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 27.3 %

Procedure:
A solution of N-(3-methylbutyl)thiourea (3.00 g, 20.5 mmol), 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone (5.45 g, 20.5 mmol), sodium acetate (2.19 g, 26.7 mmol) in ethanol (50 mL) was stirred at 90° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was recrystallized from dichloromethane-hexane to give the title compound (1.76 g, yield 27%) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH2:12]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:12][CH2:13]1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CCC(NCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
A solution of 4-fluorobenzylamine (5.48 g, 43.8 mmol) in a mixture of methanol and acetic acid (5:1, 60 mL) was added dropwise to a solution of benzyl 4-oxo-1-piperidine carboxylate (10.2 g, 43.8 mmol) in methanol (150 mL) at rt. To this mixture sodium cyanoborohydride (5.50 g, 87.5 mmol) was slowly added. After 20 hours stirring at rt the reaction mixture was neutralized and the solvent was removed by evaporation under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness. Purification of the residue by silica gel column chromatography, eluting with 7% methanol in dichloromethane, afforded the desired compound (9.0 g, 60%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.FC(F)(F)S(O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]2[O:17][CH:1]3[C:10]4[C:5]([CH:4]=[CH:3][N:2]3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]2=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc2cnccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(C2OC3c4ccccc4C=CN3c3ccccc32)cc1
Yield: 92 %

Procedure:
Following the general procedure, treatment of isoquinoline (0.064 g, 59 μL, 0.50 mmol) and 4-fluorobenzaldehyde (0.093 g, 80 μL, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=93/07) of the crude reaction mixture afforded 6-(4-fluorophenyl)-4bH,6H-benzo[4,5][1,3]oxazino[2,3-a]isoquinoline as inseparable mixture of diastereomers as a yellow solid (0.151 g, 92% yield, dr determined by 1H NMR analysis of crude reaction mixture is 3:2).
Reaction SMILES: CO[CH2:3][CH2:4][C:5](=[O:7])[CH3:6].[CH2:8]([C:10]([CH2:12][CH3:13])=[O:11])[CH3:9].C[O-].[Na+].[C:17](O)(=O)[CH3:18]>CO>[CH3:3][C:4]1[C:5](=[O:7])[CH:6]([CH3:17])[CH2:9][CH2:8][C:10]=1[CH3:12].[CH3:3][CH:4]1[CH2:13][CH2:12][C:10](=[O:11])[CH:8]=[C:9]1[CH2:17][CH3:18]
Reactant: CC(=O)O
Reactant: CCC(=O)CC
Reactant: COCCC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC1=C(C)C(=O)C(C)CC1
Product: CCC1=CC(=O)CCC1C

Procedure:
152 g of 1-methoxybutan-3-one is dripped in the course of one hour into a boiling mixture of 400 g of diethyl ketone and 5 g of a 30% by weight solution of sodium methylate in methanol. The whole is then heated under reflux for another hour. The reaction mixture is neutralized with glacial acetic acid and then fractionated. 70 g of 2,3,6-trimethyl-2-cyclohexen-1-one and 9 g of 4-methyl-3-ethyl-2-cyclohexen-1-one is obtained. The total yield of cyclohexenone is 57% with reference to 1-methoxybutan-3-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.C([Li])CCC.Br[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)[OH:8])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2cc(Br)cs2)cc1
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
Under a nitrogen stream, to a solution of 4-bromo-2-thiophenecarboxaldehyde (10.0 g, 52.3 mmol) in anhydrous THF (100 ml), a hexane solution of n-butyllithium (1.6 M, 34.35 ml, 55.0 mmol) was added dropwise at −78° C. over 5 minutes. After stirring at the same temperature for 10 minutes, a solution of 1-bromo-4-ethylbenzene (10.2 g, 55.0 mmol) in THF (50 ml) was added dropwise. The reaction mixture was stirred at −78° C. for 2 hours and, after addition of saturated aqueous ammonium chloride, was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:10)) to give the titled compound (7.1 g, 45%).