Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14].O>C1C=CC=CC=1>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:13](=[O:14])[CH2:12][Cl:11])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)CCl)n[nH]1
Yield: 71.9 %

Procedure:
28 g (0.2 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 as dissolved in 200 ml of benzene, and 23 g of monochloroacetyl chloride was added dropwise thereto at 30° to 40° C. while cooling with water. After completion of the dropwise addition, the mixture was further allowed to react under reflux conditions for 5 hours. Thereafter, the resulting product was cooled and stirred whereby crystals were precipitated. The crystals were collected by filtration and washed with water and benzene to obtain 31 g of 5-t-butyl-3-monochloroacetylaminopyrazole.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH:20]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[CH:21]([N:24]([CH3:26])[CH3:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:25][N:24]([CH3:26])[CH:21]([CH2:22][CH3:23])[CH:20]([C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=3)[S:12][C:13]=2[CH:19]=1)[N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CCC(C(c1ccc2nc(Oc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C(c1ccc2nc(Oc3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)oxy)benzoate (65 mg, 0.14 mmol) and lithium hydroxide monohydrate (30 mg, 0.72 mmol) in 4 mL of dioxane and 2 mL of water was heated together with stirring at 50° C. for 4 hr. The mixture was concentrated in vacuo and the residue dissolved in about 2 mL of water. The solution was neutralized with 1N HCl then concentrated again in vacuo. The residue was purified by PTLC using two, 2 mm silica plates eluting with 20% MeOH/DCM to give the title compound. MS (ESI+) m/z 437.21 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Temperature: 100 °C
Yield: 77.5 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (5.4 g, 0.0194 mol) in toluene (25 mL) was added to a suspension of activated manganese dioxide (27 g) in toluene (325 mL) which was previously concentrated with a Dean Stark water separator at reflux for one hour. The suspension was heated at 100° C. for 17 hours. The solids were filtered and the filtrate concentrated and flash chromatographed over silica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole-5-carboxaldehyde as an oil. NMR and IR were consistent with the structure.
Reaction SMILES: [CH2:1]([C:3](=[CH:18][CH:19]([CH3:21])[CH3:20])[CH:4]=[CH:5][CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)[CH3:2].O.NN>C(O)C>[CH2:1]([C:3](=[CH:18][CH:19]([CH3:20])[CH3:21])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:2]
Reactant: CCC(C=CCN1C(=O)c2ccccc2C1=O)=CC(C)C
Agent: NN
Solvent: O
Solvent: CCO
Product: CCC(C=CCN)=CC(C)C

Procedure:
A mixture of N-(4-ethyl-6-methyl-2,4-heptadiene-1-yl)phthalimide (17.62 g), hydrazine monohydrate (9.9 g), and ethanol (700 ml) was refluxed for 90 minutes under nitrogen atmosphere. The reaction mixture was evaporated in vacuo. The residue was dissolved in 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give 4-ethyl-6-methyl-2,4-heptadiene-1-ylamine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:30][CH3:31])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23]S(C)(=O)=O)[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:32].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:30][CH3:31])[C:10](=[O:29])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[C:16](=[O:28])[C:12]3=2)[C:7]1=[O:32]
Reactant: C1COCCN1
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCS(C)(=O)=O)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1c2c(c3n(c1=O)CCCCN(CCN1CCOCC1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-(2-methane-sulfonylethyl)-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(1H)-trione (97 mg, 0.17 mmol), morpholine (30 mg, 0.35 mmol), and diisopropylethylamine (006 mL, 0.355 mmol) in THF (1.7 mL) was stirred at 40° C. overnight. The product mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with gradient mixture of methanol in dichloromethane. Collection and concentration of appropriate fractions afforded the title compound. 1H NMR (400 MHz, CDCl3) δ 7.37 (dd, J=2.0, 7.0 Hz, 1H), 7.21 (m, 1H), 7.12 (t, J=8.8 Hz, 1H), 4.80 (dd, J=6.2, 13.9 Hz, 1H), 4.74 (d, J=15.0 Hz, 1H), 4.62 (d, J=14.8 Hz, 1H), 4.12-4.07 (m, 4H), 3.69-3.64 (m, 4H), 3.45-3.30 (m, 5H), 3.20-3.13 (m, 1H), 2.90-2.83 (m, 1H), 2.66-2.42 (m, 7H), 2.08 (br m, 1H), 1.91-1.72 (br m, 3H). (ES MS M+1=547.4)
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH2:44])[CH:38]=1>>[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH:44][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:24]=[CH:25][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:27][CH:28]=2)=[O:10])[CH:38]=1
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: NCc1cccnc1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCc4cccnc4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and (3-pyridyl)methylamine according to Procedure K: mp 211-215° C.; Anal. Calcd for C21H18N6O4S.H2O: C, 53.84; H, 4.30; N, 17.94. Found: C, 54.29; H, 4.03; N, 17.82.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].CO[CH:17]([N:20]([CH3:22])[CH3:21])OC.CN(C=O)C>O>[F:1][C:2]1[C:3]([N+:12]([O-:14])=[O:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=[CH:17][N:20]([CH3:22])[CH3:21])[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C=Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 62.7 %

Procedure:
A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol), dimethoxymethyl-dimethylamine (11.9 g, 100 mmol) and DMF (50 mL) was heated at 100° C. for 4 h. The solution was cooled and poured into water. The red precipitate was collected via filtration, washed with water adequately and dried to give [2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine (8 g, 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.Cl.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(CCC(=O)O)cc1

Procedure:
A mixture of 5.0 g. of 4-nitrocinnamic acid and 100 mg. of 10% palladium-on-carbon in 200 ml. of ethanol containing 5 drops of 5.5 N ethanolic hydrogen chloride is treated with hydrogen in a Parr apparatus at room temperature for 3 hours. The mixture is then filtered through celite and the filtrate is concentrated, affording 4-aminohydrocinnamic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:33])[O:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([C:22]([O:23][CH2:24][C:25]2[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=2)=[O:33])[CH2:11]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCC1CNCCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture comprising of t-butyl(2-morpholin-2-ylethyl)carbamate (3 g, 13.03 mmol) in DCM (100 ml), was added saturated aqueous sodium bicarbonate solution (100 ml, 13.03 mmol), followed by 3,5-dichlorobenzyl carbonochloridate (3.43 g, 14.33 mmol). The biphasic mixture was stirred at room temperature for 2 hours. The resulting mixture was treated with 2M NaOH solution (50 ml). The reaction mixture was separated and the organic portion was dried over MgSO4 and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)[C@H:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:24][C:18](=[O:19])[NH:17]2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccnc(Br)c1)[C@H](O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@H](c2ccnc(Br)c2)[C@@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Optically-enriched tert-butyl (1R,2R)-1-(2-bromopyridin-4-yl)-2-hydroxy-2-phenylethylcarbamate (1.85 g, 2.35 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 40 mL) and stirred at room temperature for 1 h. LC/MS shows clean conversion to product. The reaction was concentrated, dissolved in methanol, and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. The resulting residue was suspended in tetrahydrofuran (50 mL), cooled to 0° C., and treated with carbonyldiimidazole (0.763 g, 4.70 mmol) in a single portion. The resulting suspension was stirred at 0° C. for 5 min. The ice bath was removed and stirring continued for 1 h. The reaction was re-cooled to 0° C., and treated with an additional portion of carbonyldiimidazole (160 mg) and stirred at room temperature for 2 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was purified by column chromatography (25%-->50% EtOAc/Hex) to give the optically-enriched product. The minor enantiomer was removed by SFC Prep HPLC (Chiralpak AS-H, 25% MeOH in CO2) to give 452 mg (30%). 1H-NMR (CDCl3, 500 MHz) δ 8.42 (d, J=5.2, 1H), 7.40-7.56 (m, 4H), 7.33 (m, 2H), 7.19 (dd, J=5.2, 1.2, 1H), 6.95 (bs, 1H), 5.21 (d, J=7.3, 1H), 4.81 (d, J=7.3, 1H). 13C-NMR (CDCl3, 126 MHz) δ 158.9, 151.1, 150.6, 143.3, 136.4, 129.9, 129.4, 126.2, 125.6, 120.3, 85.3, 63.4. Mass spec.: 319.04 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12](O)=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26].[CH:28]1([S:31]([NH2:34])(=[O:33])=[O:32])[CH2:30][CH2:29]1>CN(C)C1C=CN=CC=1.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([NH:34][S:31]([CH:28]3[CH2:30][CH2:29]3)(=[O:33])=[O:32])=[O:13])[CH:11]=1)[NH:8][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=1)[CH2:6][C:5]2([CH3:27])[CH3:26]
Reactant: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)O)cc(F)cc21
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(N3CCCC3)c2)Nc2c(C(=O)NS(=O)(=O)C3CC3)cc(F)cc21
Yield: 25.6 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (150 mg, 0.32 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), 4-dimethylaminopyridine (59 mg, 0.48 mmol), cyclopropane sulfonic acid amide (149 mg, 1.23 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [6-fluoro-4,4-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-amide (38.6 mg, 20%) as a light yellow solid: MS (ESI) M+1=472.3.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:8][CH3:9])[CH2:7][CH2:6][NH:5][CH2:4]1.[F:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1F)[N:17]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])[CH:16]=[C:15]([C:30]([OH:32])=[O:31])[C:14]2=[O:33].C(N(CC)CC)C>>[CH3:1][O:2][C:3]1([O:8][CH3:9])[CH2:7][CH2:6][N:5]([C:20]2[CH:19]=[C:18]3[C:13]([C:14](=[O:33])[C:15]([C:30]([OH:32])=[O:31])=[CH:16][N:17]3[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:12][C:11]=2[F:10])[CH2:4]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2cc(F)c(F)cc2c1=O
Reactant: COC1(OC)CCNC1
Solvent: CCN(CC)CC
Product: COC1(OC)CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccc(F)cc2F)C1
Temperature: 45 °C

Procedure:
Into an oven-dried glass flask flushed with dry N2, and containing 6 mL of dry pyridine were placed 0.116 g (0.88 mmol) of 3,3-dimethoxypyrrolidine, from Step 4, then 0.150 g (0.44 mmol) of 6,7-difluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (preparation described by H. Tone et al., Eur. Pat. Appl. EP 181521, May, 1986), and 180 mL (1.3 mmol) of triethylamine. This reaction solution was maintained under N2 and heated to 45° C. for 41 hours. The pyridine was then removed by azeotropic distillation with toluene, the residue triturated with water, the pH adjusted to pH 5 to 6 with acetic acid, and the solution filtered. The solid was washed with hot ethanol:water (3:1), which was refiltered and dried to afford the title compound, mp 228°-230° C.; MS(DCl) M/Z: 449 (M+H), 404 (M-COOH); NMR d 2.13 (dd, 2H, J=7.5 Hz), 3.41 (dd, 2H, J=1.5 Hz, J=7.5 Hz), 3.62 (d, 2H, J=3.6 Hz), 3.27 (s, 6H), 5.87 (d, 1H, J=7.5 Hz), 7.30 (m, 2H), 7.65 (m, 1H), 7.95 (d, 1H, J=13.5 Hz), 8.60 (s, 1H). Analysis calculated for C22H19F3N2O5 ·0.5 H2O: C, 59.77; H, 4.41; N, 6.12. Found: C, 58.28; H, 4.34; N, 6.21.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:16]1([CH:4]([NH:3][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (140 mg, 0.42 mmol) in DCM (5 ml), were sequentially added triethylamine (175 μl, 1.26 mmol) and pivaloyl chloride (62.1 μl, 0.50 mmol). The reaction was stirred at RT for 2 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine, dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-pivalamidoacetate (95 mg; 66% yield).
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][C:15]([C:21]([O:23]CC)=[O:22])=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][CH:13]=4)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1ccc2c(c1)[nH]c(=O)c1cnc(C3CCCCC3)n12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)[nH]c(=O)c1cnc(C3CCCCC3)n12

Procedure:
Ethyl 1-cyclohexyl-4-oxo-4,5-dihydroimidazo[1,5-a]-quinoxaline-7-carboxyate as synthesized in the above Example 57, 3.33 g, ethanol 14 mL and 1N aqueous sodium hydroxide solution 29.4 mL were mixed, and heated under reflux for an hour in nitrogen atmosphere. The reaction liquid was allowed to cool off, and its pH was adjusted to 7 by addition of diluted hydrochloric acid. The precipitated crystals were recovered by filtration, washed with water and dried by heating under reduced pressure to provide 2.96 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=[O:10])=[O:6].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(CCCCl)NC(C(=O)O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(c1ccccc1)N1CCCC1=O
Temperature: 0 °C
Yield: 63.2 %

Procedure:
2-(4-Chlorobutanamido)-2-phenylacetic acid (650 mg, 2.54 mmol) was dissolved in dry THF (8.5 ml) and the solution was cooled to 0° C. with an ice-bath stirring under nitrogen atmosphere. Potassium tert-butoxide (599 mg, 5.34 mmol) was added in three portions and a white suspension was obtained. The mixture was stirred at the same temperature for 15 minutes. 1N HCl was added dropwise till pH 2-3 and than the mixture was diluted with water (10 ml) and extracted three times with EtOAc (15 ml×3). The organic phase was dried (Na2SO4) and evaporated to obtain the title compound (352 mg, 63.2% yield) as a pale yellow spongy sticky solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][N:10]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[CH:11][C:12]([CH2:13][OH:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(COC2CCCCO2)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(COC2CCCCO2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
Methyl 6-((tetrahydro-2H-pyran-2-yloxy)methyl)nicotinate (1.5 g, 6.0 mmol) was dissolved in THF (30 mL) and cooled to 0° C. under nitrogen. DIBAL-H (1.0 M in THF, 21 mL, 21 mmol) was added dropwise, via a syringe over 5 min, and stirred for 90 min. The reaction mixture was warmed to room temperature, and quenched with water (25 mL), followed by saturated NH4Cl (10 mL). After stirring for 10 minutes, the mixture was basified with solid KOH, extracted with CH2Cl2 (2×100 mL), washed with brine (100 mL), dried (MgSO4), filtered, and concentrated, to afford (6-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-3-yl)methanol as a yellow oil (1.3 g, 97%).
Reaction SMILES: [Na].[CH2:2]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:21][C:22]([NH2:24])=[O:23]>C(O)C>[CH2:2]([CH:10]1[C:11](=[O:13])[NH:24][C:22](=[O:23])[NH:21][C:16]1=[O:18])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: NC(N)=O
Reactant: CCCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCC1C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of sodium (5.32 g) in 400 ml of anhydrous ethanol is added a solution of diethyl 2-octylmalonate (31.5 g) in 50 ml of ethanol and successively 10.27 g of urea, then the mixture is refluxed for 2 hours 30 minutes. The mixture is rapidly cooled to room temperature and the solid which was formed is recovered by filtration and washed with diethyl ether. The solid is then dissolved in 200 ml of water and acidified with 6 N hydrochloric acid until pH 1.5-2 is reached. A solid separates. The mixture is added with 200 ml of ethyl acetate and it is stirred for 2 hours, then it is added with additional 800 ml of warm ethyl acetate. The organic phase is separated and the aqueous phase is washed with 200 ml of ethyl acetate. The pooled organic phases are washed with 250 ml of saturated aqueous solution of sodium chloride dried over sodium sulfate and concentrated to dryness. 21.03 g of the product are obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:7]=1.[C:15]([NH:18][NH2:19])(=O)[CH3:16]>C(O)CCC>[CH3:16][C:15]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1
Reactant: CC(=O)NN
Reactant: Fc1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(F)c3)nn12

Procedure:
As in Example 36, a mixture of 3.0 g. of 3-chloro-6-(m-fluorophenyl)pyridazine, 2.14 g. of acetylhydrazine and 50 ml. of n-butanol is refluxed 48 hrs. to give 2.0 g. of the product as crystals, m.p. 184°-186° C.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Br:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14](Br)[CH:13]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([NH:4][C:1](=[O:3])[CH3:2])[CH:15]=[C:16]([F:18])[CH:17]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: ClCCl
Product: CC(=O)Nc1cc(F)cc(Br)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
A mixture of acetamide (2.8 g, 47.2 mmol), palladium acetate (0.50 g, 0.80 mmol), XANTPHOS (0.68 g, 1.2 mmol) and cesium carbonate (18 g, 55.2 mmol) was degassed and purged with nitrogen twice. Dry dioxane (50 mL) was added followed by 1,3-dibromo-5-fluorobenzene (10 g, 39.4 mmol). The reaction was heated to 105° C. overnight and then allowed to cool to room temperature. Dichloromethane was added and the mixture was stirred vigorously for 1 hr. The mixture was filtered. The filtrate was concentrated to dryness. Chromatography on silica gel with 25% ethyl acetate in hexanes gave 4.0 g (44%) of the product as a colorless solid.