Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][NH2:16]>ClCCl>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:14]=1[CH2:15][NH:16][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:11]
Reactant: COc1cccc(N=C=O)c1
Reactant: NCc1c(F)cccc1F
Solvent: ClCCl
Product: COc1cccc(NC(=O)NCc2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 3-methoxyphenyl isocyanate (1.0 g, 6.7 mmol) in anhydrous dichloromethane (10 mL) was treated with 2,6-difluorobenzylamine (960 mg, 6.7 mmol) and stirred at ambient temperature for 1 hour. The reaction mixture was filtered, and washed with dichloromethane to give a white solid (1.47 g, 50.3%), MS (CI) m/z 293.0 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:3]=1.O.[NH2:14][NH2:15].C(O)C>C1COCC1>[NH:14]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:3]=1)[NH2:15]
Reactant: OC1CN(c2cc(Cl)ncn2)C1
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CC(O)C2)ncn1
Reaction time: 1 h

Procedure:
960 mg (5.2 mmol) 1-(6-chloropyrimidin-4-yl)azetidin-3-ol and 2.5 ml (51.7 mmol) hydrazine hydrate are initially introduced into a mixture of 10 ml ethanol and 10 ml THF. The reaction is carried out at 130° C. for 1 h in a single mode microwave (CEM Explorer). The mixture is concentrated to approx. 20-50% of the original volume of liquid and is left to stand at RT for 48 h. The supernatant is decanted off from the solid formed and the solid is washed three times with 1.5 ml cold ethanol each time. It is dried under a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21](C(F)(F)F)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:31][CH3:32])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.O[Li].O>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:31][CH3:32])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccc(Nc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1)C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(Nc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.8 %

Procedure:
To a solution of ethyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-3,3,3-trifluoropropanoate (0.130 g, 0.28 mmol) in dioxane (11 mL) and water (7 mL) was added LiOH.H2O (0.035 g, 0.84 mmol) and the mixture was stirred at rt for 12 h. After this time, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.053 g, 53%) as a white solid. MW=395.88. 1H NMR (DMSO-d6, 500 MHz) δ 9.60 (s, 1H), 8.34-8.27 (m, 2H), 7.67 (d, J=8.5 Hz, 2H), 7.59-7.52 (m, 2H), 7.27 (d, J=8.5 Hz, 2H), 6.60 (s, 1H), 4.09 (q, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); APCI MS m/z 396 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone (example 22) was reacted with 4-trifluoromethoxy-phenyl boronic acid to give the title compound as light yellow solid. MS: 477.2 (MH+).
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[N:21]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: C=Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Product: C=Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 44 %

Procedure:
2-Chloro-1-(4-vinylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 2-(piperazin-1-yl)-1-(4-vinylphenyl)-1H-indole-3-carboxaldehyde (44% yield) as a yellow solid. ESI/MS 332 (M+H), RT=2.57 min; NMR (CDCl3) 10.29 (1H, s); 8.28 (1H, d, J=6 Hz); 7.62 (2H, d, J=6 Hz); m); 7.00 (1H, d, J=9 Hz); 6.85 (1H, dd); 5.89 (1H, d, J=15 Hz); 5.42 (1H, 3.38 (4H, m); 2.77 (4H, m).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[N:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([O:20][C:21](=O)[O:22]CC)C.[Li+].[OH-]>C1COCC1>[CH3:17][C:10]1[CH:11]=[C:12]([CH2:16][C:21]([OH:22])=[O:20])[CH:13]=[C:14]([CH3:15])[N:9]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1cc(C)nc(C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)O)cc(C)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of lithium diisopropylamide (2M in THF/Hept/ethylbenzene, 5 mL) was added a solution of 2,4,6-collidine (1.26 mL) in THF (5 mL). The reaction mixture was stirred at RT for 4 h and added dropwise to a solution of diethylcarbonate (1.38 mL) in THF (5 mL) over 15 min. The resulting mixture was stirred at RT for 20 h. A LiOH solution (1M in water, 28 mL) was added, the mixture was stirred at RT for 2 h and filtered off. The filtrate was evaporated in vacuo. The residue was purified by preparative LC-MS (X) to afford 30 mg of yellow oil as mixture of two regioisomers. LC-MS (E): tR=0.17 min; [M+H]+: 165.97.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[CH2:14][C:15]1[O:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:23]([O:22][C:20]([C:18]1[O:19][C:15]([CH2:14][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[Cl:1])=[CH:16][CH:17]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Cn2c(Cl)nc3ccccc32)o1
Reaction time: 24 h

Procedure:
Alternately, combine 2-chlorobenzimidazole (20 mmol) and sodium hydride (20 mmol) in dimethylformamide (30 mL). After gas evolution ceases, add ethyl 5-chloromethyl-2-furoate (20 mmol) and stir. After 1 day, evaporate in vacuo to give a residue. Combine the residue and ethyl acetate. Extract with water and brine. Dry the the organic layer over Na2SO4, filter, and evaporate in vacuo to give 1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]([C:7]([O-:9])=O)[C:2]=1[C:10]([O:12]C)=O.[CH2:14]([CH2:16][NH2:17])[OH:15]>CCO>[OH:15][CH2:14][CH2:16][NH:17][C:7]([C:3]1[C:2]([C:10]([NH:1][CH2:2][CH2:10][OH:12])=[O:12])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: COC(=O)c1nccnc1C(=O)[O-]
Reactant: NCCO
Solvent: CCO
Product: O=C(NCCO)c1nccnc1C(=O)NCCO
Yield: 131.1 %

Procedure:
Methyl pyrazine-2,3-dicarboxylate (2 g, 10.2 mmol) was dissolved in EtOH (3 mL). Ethanolamine (1.25 g, 20.4 mmol) was added and the mixture was heated under reflux for 6 h. After cooling the solvent was evaporated and the residue was purified by silica gel chromatography (EtOAc/MeOH, 3:1) to afford the title compound (1.7 g, 65.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1F.[CH2:20]([NH2:23])[CH2:21][NH2:22].O>CN(C)C(=O)C>[NH2:22][CH2:21][CH2:20][NH:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[N:9]([CH:12]1[CH2:14][CH2:13]1)[CH:8]=[C:7]([C:15]([OH:17])=[O:16])[C:6]2=[O:18]
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: NCCN
Solvent: O
Solvent: CC(=O)N(C)C
Product: NCCNc1cc2c(=O)c(C(=O)O)cn(C3CC3)c2cc1Cl
Temperature: 115 °C
Reaction time: 8.5 h
Yield: 10 %

Procedure:
7-Chloro-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-quinoline-3-carboxylic acid (56.3 g) and ethylenediamine (36 g) were dissolved in N,N-dimethylacetamide (650 mL) at 100° C. and stirred for 8.5 h at 115° C. Water (700 mL) was added to the reaction mixture cooled at room temperature. The reaction mixture was stirred at room temperature for 2 h, cooled at 0-5° C. and stirred for 1 h. The precipitate obtained was filtered, washed with cold water, cold EtOH, and dried at 110° C. under reduced pressure for 1 h. The crude product was treated with HCl (6% aqueous solution) heating for 1 h in the presence of charcoal. After filtration, the solution was cooled to 35-40° C. and a first precipitation happened. The precipitate was filtered, washed with water and dried at 110° C. for 1 h. The title compound (6.4 g) was obtained as the hydrochloride salt. The hydrochloride salt was then converted to the free base using standard conditions; ESMS m/z 320 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[NH2:26][CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:18])([CH3:19])[C:15]([NH:26][CH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])=[O:16])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(C)(CN)CO
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NCC(C)(C)CO)c2c1N

Procedure:
Prepared as in Example 24a from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example 47b) and 3-amino-2,2-dimethylpropan-1-ol as a brown solid (40%). MS 432 (MH+).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]([CH2:26][CH:27]([CH:33]([CH3:35])[CH3:34])[C:28]([O:30]CC)=[O:29])[C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:13]=2)=[N:4][N:3]=[N:2]1>[OH-].[Na+]>[C:28]([CH:27]([CH:33]([CH3:34])[CH3:35])[CH2:26][N:19]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[NH:4][N:3]=[N:2][N:1]=2)=[CH:17][CH:16]=1)([OH:30])=[O:29]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)CC(C(=O)OCC)C(C)C
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)CC(C(=O)O)C(C)C

Procedure:
980 mg of ethyl rac-N-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-N-valeryl-2-(aminomethyl)-3-methylbutanoate in 3.1 ml of 2N NaOH are heated at 100° for 72 hours. Neutralization with 3.1 ml of 2N HCl and extraction with CH2Cl2 yields the product, Rf =0.30 (system N8).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][Cl:30]>CC(CC(C)C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:20])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:28][CH2:29][Cl:30])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:4][CH2:3]1
Reactant: ClCCBr
Reactant: COc1cc(CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: COc1cc(CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl

Procedure:
Using 1.5 g of N-(trans-4-methylcyclohexyl)-2-(4-hydroxy-3-methoxyphenyl)acetamide (Example 127), 100 ml of methylisobutylketone, 5 g of potassium carbonate, and 4 ml of 1-bromo-2-chloroethane, a reaction similar to that conducted in Example 106 was carried out. As a result, 1.38 g of N-(trans-4-methylcyclohexyl)-2-[4-(2-chloroethoxy)-3-methoxyphenyl]acetamide (a compound of the present invention) was obtained as a pale yellowish white crystal, which had the following physiochemical properties:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1.[Cu][C:18]#[N:19].CCOC(C)=O>CN1C(=O)CCC1>[C:18]([C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1)#[N:19]
Reactant: CCSc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCSc1c(C(N)=O)cnn2cc(C#N)cc12
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A solution of 6-bromo-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (200 mg, 0.666 mmol) and copper(I) cyanide (119 mg, 1.333 mmol) in NMP (3 mL) was heated to 180° C. for 1.5 hrs, and then 200° C. for 1.5 hrs under microwave oven (CEM). To the reaction mixture was added 50 mL of EtOAc. The mixture was washed with 30 mL of 10% LiCl solution, 30 mL of saturated NH4Cl solution, and 30 mL of brine and dried over Na2SO4. Filtration and concentration yielded 6-cyano-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (140 mg, 77% yield). MS (ES+) m/z: 247.08 (M+H); HPLC retention time: 1.902 min (analytical HPLC Method F).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:24].[K+].[K+].OO>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH2:22])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2)CC1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 4-(4-cyano-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester Example 9, step 1, 215 mg, 0.71 mmol) and potassium carbonate (49 mg, 0.36 mmol) in DMSO (35 mL) at 0° C. Then add dropwise hydrogen peroxide (213 μL). Then stir at room temperature for 1 h. Quench the reaction with water (10 mL) and extract with EtOAc/hexanes (2/1, 3×20 mL). Combine the organic layers, dry over magnesium sulfate, filter and concentrate to give the title compound.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C@H:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+]>O.Cl>[NH:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C@H:13]([CH3:19])[CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1)[NH2:1]
Reactant: O=N[O-]
Reactant: C[C@@H]1CC(=O)NN=C1c1ccc(N)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: C[C@@H]1CC(=O)NN=C1c1ccc(NN)cc1
Reaction time: 0.08 h

Procedure:
A slight modification on the procedure described in J.Med.Chem. (1990), 33(10), 2870-2875 was used as follows. A solution of sodium nitrite (1.7 g) in water (12.5 ml) was added slowly at 0-5° C. to a solution of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one (5 g) in 1 M hydrochloric acid (75 ml). The resulting solution was stirred on ice bath for five minutes and then added slowly to a solution of tin(II)chloride dihydrate (17 g) in 1 M hydrochloric acid (150 ml) keeping the reaction temperature below 5° C. This solution was stirred on ice for forty minutes and then a solution of 50% NaOH (75 ml) was quickly added. The resulting mixture was stirred on ice bath until the temperature reached zero degrees Celsius. The crystals were filtered and washed with dilute ammonia. Yield: 5.0 g, 93%.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]2[C:8]3=[C:9]([C:11]([O:13][C:14](=[O:15])[C:7]3=[CH:6][CH:5]=[CH:4]2)=O)[CH:10]=1.[NH2:16][CH:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1>C(O)CCC>[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[CH:17]([N:16]1[C:11](=[O:13])[C:9]3[CH:10]=[CH:1][CH:2]=[C:3]4[C:8]=3[C:7](=[CH:6][CH:5]=[CH:4]4)[C:14]1=[O:15])[CH2:18]2
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: NC1CN2CCC1CC2
Solvent: CCCCO
Product: O=C1c2cccc3cccc(c23)C(=O)N1C1CN2CCC1CC2
Yield: 83.7 %

Procedure:
A solution of 1,8-naphthalic anhydride (1.9 g, 9.6 mmol) and (RS)-3-amino-1-azabicyclo[2.2.2]octane (1.2 g, 9.5 mmol) in n-butanol (100 mL) was stirred for 3 hours at reflux temperature and the solution concentrated to dryness. Purification of the remaining solid by column chromatography (silica-gel; 5-10% gradient methanol in CH2Cl2 and approximately 1% aqueous NH4OH) gave (RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dihydro-1H-benz[de]isoquinoline-1,3-dione (2.45 g, 7.95 mmol), m.p. 206°-207° C.
Reaction SMILES: [CH:1]1([CH3:15])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:2]1.C(Cl)(=O)C(Cl)=O.O[CH:23]1[CH2:27][C:26](=[O:28])[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:24]1[CH:38]=[CH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>C1C=CC=CC=1.N1C=CC=CC=1.O>[CH:1]1([CH3:15])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:8])[CH3:9])[CH:3]([O:10][CH2:11][C:12]([O:14][CH:23]2[CH2:27][C:26](=[O:28])[C:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:24]2[CH:38]=[CH:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[O:13])[CH2:2]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)O)C1
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC1CCC(C(C)C)C(OCC(=O)OC2CC(=O)C(CCCCCCC(=O)O)=C2C=Cc2ccccc2)C1
Reaction time: 1 h

Procedure:
5 Parts of (-)-menthoxyacetic acid is dissolved in 8.79 parts of benzene and treated with 5.95 parts of oxalyl chloride. The resulting solution then is heated at about 60° for 2 hours and allowed to stand for 1 hour at room temperature. After that time, the solvent is removed under reduced pressure, and the remaining residue is dissolved in benzene and again concentrated to dryness. The crude (-)-menthoxyacetyl chloride thus obtained is dissolved in 8.79 parts of benzene and that solution added to a cold solution of 7.5 parts of 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid dissolved in 9.82 parts of pyridine. That mixture is allowed to stand for about 16 hours at room temperature, then poured into a cold solution of 50 parts of d-tartaric acid in 1,500 parts of water. The solution is extracted with ethyl acetate and the organic extracts are washed with water, dried over anhydrous sodium sulfate and concentrated to dryness. The oily residue which remains is dissolved in benzene and chromatographed on silicic acid to yield, after elution with 10% ethyl acetate-90% benzene, crude product. The pure material is obtained upon recrystallization from benzene-hexane to give 3-((-)-menthoxyacetoxy)-5-oxo-2-styrylcyclopent-1-eneheptanoic acid, melting at about 103°-104°, and displaying an optical rotation of about -42.1°. That compound is characterized by infrared absorption maxima, in chloroform, at about 1754, 1710, 1627 and 1124 reciprocal centimeters, an ultraviolet absorption band, in methanol, at about 326 millimicrons with a molecular extinction coefficient of about 37,000, and represented by the following structural formula ##SPC21##
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH3:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH:9]=O>>[CH3:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[C:2]([C:1]#[N:5])[C:3]#[N:4]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: N#CCC#N
Product: Cc1ccc(C=C(C#N)C#N)c(C)c1

Procedure:
This material was prepared from malononitrile and 2,4-dimethylbenzaldehyde according to the procedure of M. Boehringer et al., WO 03/068748.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCC(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4-hydroxymethyl-cyclohexane carboxylic acid methyl ester (300 mg, 1.74 mmol; CAS Reg. No. 13380-85-3) in dichloromethane (10 ml) under nitrogen was added triethylamine (0.5 ml, 3.48 mmol) and p-toluenesulfonyl chloride (664 mg, 3.48 mmol; CAS Reg. No. 98-59-9) at 25° C. and the mixture was stirred for 16 h. The reaction mixture was evaporated under reduced pressure, and the crude product was purified by column chromatography over silica gel (ethyl acetate/n-hexane) to give the desired compound. Colorless powder (62%). MS (Turbo Spray): m/z=327.1 (M+H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[CH2:11][C:12]([OH:14])=[O:13]>C(O)(=O)C.C1CCCCC1>[Br:1][C:7]1[C:6]([CH3:10])=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[C:4]([CH3:3])=[CH:9][CH:8]=1
Reactant: Cc1cccc(C)c1CC(=O)O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1ccc(Br)c(C)c1CC(=O)O
Temperature: 45 °C
Reaction time: 16 h

Procedure:
At 45° C., a solution of 8.5 kg [53.2 mol] of bromine in 10 l of glacial acetic acid is added dropwise to a solution of 6.86 kg [40.45 mol] of 2,6-dimethylphenylacetic acid in 401 of glacial acetic acid. The reaction mixture is then stirred at 45° C. for another 16 hours and concentrated on a rotary evaporator. The solid obtained is stirred in 10 l of cyclohexane at room temperature. After filtration, the residue is washed a little at a time with 10 l of cyclohexane and then dried. This gives 8.43 kg of a solid.
Reaction SMILES: [OH-].[Na+].CO[C:5]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:6]=1[CH:7]=[CH:8][C:9]([OH:11])=[O:10].Cl[CH:19](Cl)[CH3:20].B(Br)(Br)Br>>[CH2:17]([O:16][C:13]1[CH:12]=[C:6]2[C:5](=[CH:15][CH:14]=1)[O:11][C:9](=[O:10])[CH:8]=[CH:7]2)[C:20]1[CH:19]=[CH:7][CH:6]=[CH:5][CH:15]=1
Reactant: CC(Cl)Cl
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccc2cc(OCc3ccccc3)ccc2o1
Temperature: 82 °C
Yield: 127 %

Procedure:
Equip a 5-L, three-neck, round-bottom flask with a large blade mechanical stirrer, thermocouple, an addition funnel, Claisen adapter, reflux condenser, and a sodium hydroxide scrubber. Charge the flask with 2,5-dimethoxycinnamic acid (182.3 g, 865 mmol, 1.0 equiv) and dichloroethane (2.5 L). Add boron tribromide (163.5 mL, 433.2 g, 1.73 mol, 2.0 equiv.) dropwise over 1 h, keeping the temperature below 35° C. Gas evolution can be monitored as the temperature of the reaction is gradually increased to reflux (82° C.). Reflux for 12 h, cool to 5° C., and quench by the careful addition of water (1.0 L). Filter the resulting yellow-red suspension/emulsion through a glass frit and wash with dichloroethane (1.0 L) and heptane (1.0 L) to afford a brown solid. Dry the wet material in a vacuum oven (30 in., 35° C.) for 18 h, to afford the coumarin (180.3 g, 127% theory) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=9.6 Hz, 1H), 7.22 (d, J=9.9 Hz, 1H), 7.05 (m, 2H), 6.43 (d, J=9.6 Hz, 1H).