Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][C:15]2([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])[CH2:16][C:15]3([CH3:24])[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC(=O)Nc2ccc(-c3cccc(F)c3)cc21

Procedure:
Prepared by coupling 3-fluorophenylboronic acid with an equivalent amount of 6-bromo-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one using a catalytic amount of tetrakis(triphenylphosphine)palladium(0) with overnight refluxing in toluene containing an equivalent amount of potassium carbonate dissolved in water. Work up in the usual manner followed by recrystallization from ethanol gave a gray solid: mp 190-192° C. 1H-NMR (DMSO-d6) δ 10.27 (s, 1H), 7.57 (s, 1H), 7.50 (m, 4H), 7.15 (m, 1H), 6.95 (d, 1H J=8.2 Hz), 2.39 (s, 2H), 1.29 (s, 6H); MS (APCI(−)) m/z 268 [M−H]− Anal. Calc. For C17H16FNO 0.25 H2O: C, 74.57, H, 6.07, N, 5.12. Found: C, 74.86, H, 5.97, N, 5.06.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:30][O:31][CH3:32])[O:5][C:6]1[CH:7]=[C:8]([O:19][C:20]2[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11]2.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][O:2][CH2:3][CH:4]([CH2:30][O:31][CH3:32])[O:5][C:6]1[CH:7]=[C:8]([O:19][C:20]2[CH:21]=[N:22][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][CH:25]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)OC)[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 58.8 %

Procedure:
To a solution of methyl 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (1.79 g) in a mixture of tetrahydrofuran (20 mL) and methanol (15 mL) was added 1M aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at 50° C. for 30 min. The mixture was concentrated under reduced pressure and the residue was dissolved in water. The mixture was washed with diethyl ether three times. The diethyl ether layers were combined and extracted with water. The aqueous layers were combined and 1M hydrochloric acid (15 mL) was added to the mixture. The resulting white suspension was filtered to give the title compound (1.02 g, 69%) as a pale orange solid. MS 451 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4,4-difluoropiperidin-1-yl)quinolin-7-yl]ethanone (20 mg, 0.06 mmol) and ammonium acetate (47.5 mg, 0.616 mmol) in methanol (0.35 mL) and acetonitrile (0.35 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (7.7 mg, 0.12 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude amine was used directly in the next step. LCMS calculated for C16H19ClF2N3 (M+H)+: m/z=326.1; Found: 326.0.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]O)[CH3:3].[ClH:13].[NH2:14][CH2:15][CH2:16][SH:17]>Cl>[ClH:13].[ClH:13].[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][S:17][CH2:16][CH2:15][NH2:14])[CH3:3]
Reactant: CN(C)Cc1cccc(CO)c1
Reactant: NCCS
Agent: Cl
Product: CN(C)Cc1cccc(CSCCN)c1

Procedure:
Equimolar quantities of 3-(dimethylaminomethyl)benzyl alcohol and cysteamine hydrochloride were heated under reflux for 5 hours in 12N aqueous hydrochloric acid and the mixture was evaporated to give 2-[3-(dimethylaminomethyl)benzylthio]ethylamine dihydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[CH3:37])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH:36]([CH:38]5[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]5)[CH3:37])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(Oc1cccc(Br)n1)C1CCCCC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC(C)C5CCCCC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 134, Step 3, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-(1-cyclohexyl-ethoxy)-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18](=O)[CH3:19])=[C:12]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:32][O:33][NH2:34].O.O.O.C([O-])(=O)C.[Na+]>O.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][C:18](=[N:34][O:33][CH3:32])[CH3:19])=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:25][CH:26]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CON
Reactant: CC(=O)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CON=C(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 14.4 %

Procedure:
A mixture of 2-(3,4-difluorophenyl)-4-(2-oxo-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone from Example 460 (150 mg, 0.3 mmol) in H2O (10 mL) and dioxane (20 mL) was treated with methoxyamine hydrochloride (84 mg, 1 mmol) and sodium acetate trihydrate (138 mg, 1 mmol). The mixture was stirred at room temperature for 6 hours. The reaction mixture was extracted with ethyl acetate and purified by column chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the title compound (yield: 20 mg, 15%). mp 143-145° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H), 3.30 (s, 3H), 3.74 (s, 3H), 4.93 (s, 2H), 7.54 (m, 1H), 7.65 (q, J=10 Hz, 1H), 7.82 (m, 1H), 7.92 (d, J=9 Hz, 2H), 8.07 (d, J=9 Hz, 2H), 8.24 (s, 1H); MS (APCI+) m/z 464 (M+H)+; (APCI−) m/z 498 (M+Cl)−. Anal. calc. for C21H19F2N3OS: C, 54.42; H, 4.13; N, 9.06. Found: C, 54.33; H, 3.93; N, 8.92.
Reaction SMILES: C(O)=[O:2].[CH:4]1([N:10]=[C:11]=[N:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:11]([NH:10][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:2]
Reactant: O=CO
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of formic acid (0.026 g, 0.556 mmol) in chloroform (1.5 mL) was added dropwise dicyclohexylcarbodiimide (DCC) (0.114 g, 0.56 mmol) in chloroform (1.5 mL) at 0° C. After 5 min the above solution was added to the compound 9 (0.10 g, 0.28 mmol) in pyridine (2 mL). The mixture was then stirred for 1 hours at room temperature. Evaporation of solvent was followed by addition of ether gave dicyclohexylurea which was removed via filtration and the solid was washed with ether. The combined filtrate was concentrated and purified by flash column chromatography to give the product 11, (EM 347) (0.075 g, 70%); 1H NMR (CDCl3): δ 0.66 (s,3H), 0.74-1.42 (m, 11H), 1.2-2.08 (m, 19H), 2.37-2.48 (m, 2H), 2.87 (s, 3H), 3.04 (dd, 1H, J=4, 13 Hz), 3.2-3.4 (m, 3H),8.12 (s, 0.8H), 8.24 (s, 0.2H); 13C NMR (CDCl3) δ 170.56, 164.54, 162.97, 68.59, 65.62, 51.99, 51.71, 44.11 ,36.85, 36.40, 34.12, 32.88, 30.64, 29.68, 29.04, 28.96, 25.20, 24.37, 22.86, 20.55, 20.21, 13.77, 12.34:. HRMS: calcd for C24H40N2O2, 388.3089; found 388.3147. ##STR12##
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])[C:9]1=[CH:15][C:16](=[O:20])[NH:17][C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:20])[N:17]([CH3:23])[C:18](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)-c1cc(=O)n(C)c(=O)n1CC2
Temperature: 25 °C

Procedure:
A mixture of 9,10-dimethoxy-3,4,6,7-tetrahydro-2H-pyrimido(6,1-a)isoquinolin-2,4-dione (4.11 g), oil-free sodium hydride (0.75 g) and dimethylformamide (100 ml) is heated for 15 minutes to 100° C. and then cooled to room temperature. Methyl iodide (10 ml) is added and the reaction mixture is heated for 12 hours to 100° C. The solvent is removed under reduced pressure and the residue treated with cold water. The solid matter is filtered off and recrystallized from ethyl acetate/methylene chloride. Yield 4.0 g, melting point 260°-262° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=1>C(OCC)(=O)C.C(O)C.[Pd]>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2]1
Reactant: CCOC(=O)C=Cc1cnc2ccccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCC1CNc2ccccc2C1
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A mixture of ethyl β-(3-quinolyl)acrylate (100 mg, 0.44 mmol) and 50 mg of 10% Pd/C in ethyl acetate/ethanol (3 ml/1 ml) was hydrogenated under hydrogen (55 psi) for 1 h. The mixture was filtered through celite, the residue was washed with methylene chloride, and the combined organic layer was concentrated in vacuo. Upon chromatographic purification on 20 cm silica column (ethyl acetate/hexane, 1/8-1/2), 49 mg (50%) of ethyl 3-(3-quinolyl)propionate (KUO-1953-136B) and 27 mg (26%) of ethyl 3-(1,2,3,4-tetrahydro-3-quinolyl)propionate was isolated.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:15]([OH:17])=[O:16])=[C:10]([O:13][CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+]>C(O)C.O>[N:20]([CH2:2][C:3]([NH:5][C@@H:6]1[C:18](=[O:19])[N:8]2[C:9]([C:15]([OH:17])=[O:16])=[C:10]([O:13][CH3:14])[CH2:11][S:12][C@H:7]12)=[O:4])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CBr)[C@H]2SC1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CN=[N+]=[N-])[C@H]2SC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution, prepared at 30° C., of 7β-bromoacetylamino-3-methoxy-3-cephem-4-carboxylic acid (about 0.15 mmol), prepared according to the process described in Example 43, in 10 ml of ethanol and 0.3 ml of water is mixed with a solution of 0.03 g of sodium azide in 0.5 ml of water. The reaction mixture is stirred for 15 hours at room temperature with exclusion of light and is then worked up according to the process described in Example 41. 7β-Azidoacetylamino-3-methoxy-3-cephem-4-carboxylic acid is thus obtained, which in a thin layer chromatogram (silica gel; system: n-butanol/pyridine/acetic acid/water, 42:24:4:30) shows an Rf value of 0.40; ultraviolet absorption spectrum (in ethanol): λmax at 264 mμ; infrared absorption spectrum (in mineral oil): characteristic bands at 4.65μ and 5.64μ.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CS(O[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)(=O)=O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)OCc1ccc(F)cc1
Reactant: CC(C)CCN(c1ccc(O)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)CCN(c1ccc(OCc2ccc(F)cc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.13 h
Yield: 90.6 %

Procedure:
4-[(4-hydroxy-phenyl)-(3-methyl-butyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (In, 1.18 g, 3.26 mmol) was dissolved in DMF (7 mL), treated with NaH (0.26 g, 6.52 mmol, 60% dispersion in mineral oil), and stirred for 8 minutes. 4-Fluorobenzyl methanesulfonate (Ie, 0.93 g, 4.56 mmol) was added and the reaction was stirred for 5 minutes, then diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate solution and with brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 4:1 hexane/EtOAc to give 1.39 g (91%) of the desired product.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH:2]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:3]([O:5][CH3:6])=[O:4])=[CH:8][CH:9]=1
Reactant: COC(=O)C(Br)c1ccc(OC)cc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: COC(=O)C(c1ccc(OC)cc1)N1CCCCC1
Yield: 71.2 %

Procedure:
To a solution of methyl 2-bromo-2-(4-methoxyphenyl)acetate (2.5 g, 9.65 mmol) in THF (50 ml), was added piperidine (1.64 g, 19.3 mmol) and the mixture reacted for 2 hours at room temperature. The solvent was evaporated and the resulting crude was portioned between water and EtOAc. The aqueous phase was extracted with EtOAc, the organic phases were combined, dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (petroleum ether/EtOAc=85/15) to obtain (methyl 2-(4-methoxyphenyl)-2-(piperidin-1-yl)acetate (1.81 g, 71.4% yield).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])C.C(Cl)(Cl)Cl>O1CCOC1>[C:1]([O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH2:11][C@@H:10]1[CH:29]1[O:32][CH2:33][CH2:34][O:31]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)C(=O)OC[C@@H]1C=CC(=O)O1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1COCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Yield: 93 %

Procedure:
A solution containing 29.0 mg (0.146 mmol) compound (2d) and 3.0 mg (0.016 mmol) benzophenone in 20 mL [1,3]-dioxolane was irradiated at 0° C. for 1.5 hours according to the general procedure. Column chromatography (silica gel 15 g, ethyl acetate in hexanes 40%) gave compound (3d) (37 mg. 93%) as a colorless solid, Rf=0.21, [α]25D 23.8°, c 1.0, CHCl3, IR (neat) 1785, 1740, 1210, 740 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 1.21 (s, 9H), 2.57-2.60 (m, 1H), 2.67-2.75 (m, 2H), 3.91-3.93 (m, 2H), 4.01-4.04 (m, 2H), 4.37 (dd, 1H, J=4.2 Hz, J=12.2 Hz), 4.38 (dd, 1H, J=2.9 Hz, J=12.2 Hz), 4.69 (mc, 1H), 4.92 (d, 1H, J=3.6 Hz). 13C-NMR (100.6 MHz, CDCl3, Dept) δ: 27.14 (+), 29.75 (−), 38.70 (+) (quat), 65.26 (−), 65.43 (−), 65.58 (−), 77.37 (+), 103.30 (+), 175.47 (quat), 178.02 (quat). C13H20O6; Exact Mass: 272.13; Mol. Wt.: 272.29; C, 57.34, H, 7.40, O, 35.25.
Reaction SMILES: Cl.[CH3:2][N:3](C)[CH:4]1[CH2:18][C:7]2[C:8]3[NH:9][C:10](=[O:17])[C:11](=[O:16])[NH:12][C:13]=3[CH:14]=[CH:15][C:6]=2[CH2:5]1.[N+:20]([O-])([OH:22])=[O:21]>FC(F)(F)C(O)=O>[CH3:2][NH:3][CH:4]1[CH2:18][C:7]2[C:8]3[NH:9][C:10](=[O:17])[C:11](=[O:16])[NH:12][C:13]=3[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[C:6]=2[CH2:5]1
Reactant: CN(C)C1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8-dimethylamino-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione hydrochloride (0.39 g) in trifluoroacetic acid was cooled in an ice bath and then treated with fuming nitric acid (1 mL). After stirring for 1 h, the mixture was warmed to room temperature for 3 h. The solvent was evaporated and the residue suspended in methanol. The resulting yellow solid was collected by filtration and dried. Calc'd for C12H12 N4O4.CH4O3S: C, 41.93; H, 4.33; N, 15.05; found: C, 39.56; H, 4.11; N, 13,61. Ms M+1 (277).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]Br)#[N:2].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1.CN(C)C=O>O>[C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)#[N:2]
Reactant: CCCCC(C#N)(CCCCCBr)c1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(C#N)(CCCCCn1ccnc1)c1ccc(Cl)cc1Cl
Yield: 47.8 %

Procedure:
A mixture of 6-cyano-6-(2,4-dichlorophenyl)decyl bromide (14.2g., 0.036 mole) imidazole (10g., 0.15 mole) and 5 ml. N,N-dimethylformamide is heated at 120° C. for 24 hours. The reaction mixture is poured into water and extracted with ether. The combined ether extracts are dried over magnesium sulfate and filtered. Into the ethereal solution is bubbled dry hydrogen chloride gas until no more oily precipitate forms. The solvent is then decanted and the oily residue is taken up in acetone and neutralized with dilute ammonium hydroxide solution. The purified free base is extracted into ether and dried over magnesium sulfate. When the solvent is evaporated, a total of 6.5 g. (47.8%) of product is obtained, which is identified by nmr.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])[CH2:16][C:17]([CH3:19])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH3:21]>>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:20])/[CH:16]=[C:17](\[NH2:21])/[CH3:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)CC(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: N
Product: C/C(N)=C/C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
12.5 g (45.7 mmoles) of acetoacetic acid N-[4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-phenyl]-amide in 225 ml of aqueous concentrated ammonia are heated under reflux for 2 hours. After cooling, the product if filtered off with suction and washed with water until it is neutral.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:8]=[C:7]([N:21]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:48][C:49]([CH3:51])=[CH2:50]>C1COCC1>[CH3:1][O:2][C:3](=[O:36])[CH:4]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=2)[N:8]=[C:7]([N:21]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)[CH:6]=1)[CH2:50][C:49]([CH3:51])=[CH2:48]
Reactant: C=C(C)CBr
Reactant: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)CC(C(=O)OC)c1cc(-c2ccc(C(F)(F)F)cc2)nc(N(CC(C)C)c2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.5 h
Yield: 47.2 %

Procedure:
To a solution of [2-[isobutyl-(4-trifluoromethyl-phenyl)-amino]-6-(4-trifluoromethyl-phenyl)-pyridin-4-yl]-acetic acid methyl ester (75 mg, 0.15 mmol) in THF (5 mL) at −78° C. under argon was added potassium bis(trimethylsilyl)amide (0.5 M solution in toluene, 300 μL, 0.15 mmol). After stirring for 30 minutes, 3-bromo-2-methylpropene (20 mg, 0.15 mmol) was added and stirred for an additional 30 minutes The reaction mixture was allowed to warm up slowly and stirred for another 30 minutes at 0° C. The mixture was then concentrated and purified by column chromatography on silica gel (0-30% methylene chloride in heptane) to give the product as a white solid (40 mg, 47%). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=8.29 Hz, 2H), 7.71 (d, J=8.29 Hz, 2H), 7.57-7.68 (m, 2H), 7.38 (d, J=8.29 Hz, 2H), 7.19 (s, 1H), 6.55 (s, 1H), 4.61-4.79 (m, 2H), 3.96 (d, J=7.54 Hz, 2H), 3.67 (s, 3H), 2.68-2.85 (m, 1H), 2.31-2.47 (m, 1H), 2.07-2.26 (m, 1H), 1.70 (s, 3H), 0.89-1.05 (m, 6H). MS m/e 565.3 (M+H).