Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C:12]([CH3:33])([C:14]([NH:16][CH2:17][CH:18]1[O:32][C:21]2=[C:22]3[C:27](=[C:28]([CH3:30])[CH:29]=[C:20]2[CH2:19]1)[NH:26][C:25](=[O:31])[CH:24]=[CH:23]3)=[O:15])[CH3:13])(OCC1C=CC=CC=1)=O.[H][H]>CN(C)C=O.CO.[Pd]>[CH3:30][C:28]1[CH:29]=[C:20]2[CH2:19][CH:18]([CH2:17][NH:16][C:14](=[O:15])[C:12]([CH3:13])([CH3:33])[NH2:11])[O:32][C:21]2=[C:22]2[C:27]=1[NH:26][C:25](=[O:31])[CH:24]=[CH:23]2
Reactant: [H][H]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)C2
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)N)C2
Yield: 95.5 %

Procedure:
2-(N-Carbobenzyloxy-α-methylalanyl]aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.46 g, 5.48 mmol) was dissolved in dimethylformamide (190 ml). To the obtained solution, 10% palladium-on-carbon (2.46 g) was added, followed by stirring at room temperature for 3 hours in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed. The resultant residue was dissolved in methanol (70 ml). To the obtained solution, 1.37 N-HCl--methanol (4.39 ml) was added at room temperature, followed by condensing under reduced pressure. The resultant residue was submitted to a recrystallizing procedure using methanol to obtain 1.65 g of the title compound as pale yellow powdery crystals (85.6%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([CH:16]=[O:17])[CH:3]=1.O1CCC[CH2:19]1.C[Mg]I>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[C:4]([CH:16]([OH:17])[CH3:19])[CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C=O
Agent: C[Mg]I
Solvent: CCOCC
Product: CC(O)c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To an ice-cooled solution of tert-butyl 6-chloro-4-formylpyridin-3-ylcarbamate (1.0091 g, 3.9313 mmol) in tetrahydrofuran (20 mL, 200 mmol) in an oven-dried flask was added 3.0 M of methylmagnesium iodide in ether (3.4 mL). The reaction mixture was stirred at 0° C. for one hour and then quenched with 10 mL saturated aqueous NH4Cl. The resulting mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3, and the organic layer was dried with brine and MgSO4 and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (40 g silica, solvent gradient: 0-40% ethyl acetate in heptane) to yield 0.870 g (81%) of tert-butyl 6-chloro-4-(1-hydroxyethyl)pyridin-3-ylcarbamate. LCMS (ESI): M+H=273.2; 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.43 (s, 1H), 7.45 (s, 1H), 5.76 (s, 1H), 4.95 (d, J=6.4 Hz, 1H), 1.46 (s, 9H), 1.28 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:20][CH3:21])([CH3:19])[C:16](O)=[O:17])[N:13]=2)=[N:6][CH:7]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:57]([NH:60][NH2:61])(=[O:59])[CH3:58]>C(Cl)Cl.CN(C=O)C>[C:57]([NH:60][NH:61][C:16](=[O:17])[C:15]([O:20][CH3:21])([CH3:19])[CH2:14][C:12]1[N:13]=[C:9]([NH:8][C:5]2[C:4]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:11]=1)(=[O:59])[CH3:58]
Reactant: CC(=O)NN
Reactant: COC(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(C)(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)NNC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
In a 20 mL scintillation vial, 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)-2-methoxy-2-methylpropanoic acid (0.087 g, 0.187 mmol) was dissolved in CH2Cl2 (5 mL) and DMF (2 mL) and N-methylmorpholine (0.0309 mL, 0.281 mmol), followed by addition of HOBT. The mixture was cooled to 0° C. and EDCI (0.047 g, 0.244 mmol) was added. The resulting mixture was agitated for 30 minutes and acetohydrazide (0.021 g, 0.28 mmol) was added. The mixture was then agitated overnight, diluted with 50 mL of CH2Cl2 and washed with citric acid solution, sodium bicarbonate solution twice, dried and evaporated to give the title compound (0.0975 g, quantitative yield). Crude product was used in the next step.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>CC#N>[Br-:23].[C:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:26][CH2:25][CH2:24][N+:1]23[CH2:6][CH2:5][C:4]([C:9]([OH:10])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)([CH2:3][CH2:2]2)[CH2:7][CH2:8]3)=[CH:29][CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(OCCCBr)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Solvent: CC#N
Product: N#Cc1ccc(OCCC[N+]23CCC(C(O)(c4ccccc4)c4ccccc4)(CC2)CC3)cc1
Product: [Br-]
Yield: 76.9 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0520 g, 0.177 mmol) and 4-[(3-bromopropyl)oxy]benzonitrile (0.156 g, 0.652 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0726 g, 76.8%). EI-MS m/z 453(M+) Rt (1.86 min).
Reaction SMILES: [P:1]([O-:5])([O-:4])([OH:3])=[O:2].[K+].[K+].C([O-])(=O)C.[Ca+2:12].C([O-])(=O)C>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Ca+2:12].[Ca+2:12]
Reactant: O=P([O-])([O-])O
Agent: CC(=O)[O-]
Agent: [Ca+2]
Agent: [K+]
Product: O=P([O-])([O-])[O-]

Procedure:
This example illustrates the preparation of a catalyst suitable for use in the invention hydrogenation process. The catalyst, referred to as catalyst A in Example II below, was prepared by adding an aqueous solution of dipotassium hydrogen phosphate (1.0 mole) with vigorous stirring to an aqueous solution of calcium acetate (1.67 moles) to obtain a calcium phosphate gel having a Ca:P atomic ratio of 1.67. The gel was allowed to stand overnight and was recovered by filtration and was washed by slurrying in a 3500 mL portion of water 3 times, with filtering after each wash. The filter cake was additionally washed by pulling 10 liters of distilled water through it. About one quarter of the wet cake was reslurried in 1000 mL of distilled water, and to the stirred slurry was added 16 grams of barium nitrate dissolved in 300 mL of distilled water. The mixture was allowed to stand for 2 days with occasional stirring. Then to the well-stirred slurry was slowly added a mixture of 145 g nickel nitrate and 16 g barium nitrate dissolved in 600 mL of hot distilled water and 100 g potassium carbonate dissolved in 250 mL of distilled water. The resulting mixture was filtered to obtain a cake which was reslurried in about 3500 mL of distilled water and filtered. This operation was repeated and then about 3 liters of distilled water was pulled through the filter cake. The cake was dried overnight at 220° F., crushed to pass a 40-mesh screen and calcined in air at 800° F. for 3 hours. The cooled product was mixed with 3 weight percent polyethylene powder and pilled to 1/8-inch size at 100 psig. The pills were heated at about 800° F. in hydrogen for about 20 minutes to obtain the finished catalyst. The catalyst, as analyzed, contained 16.3 weight percent barium and 26.9 weight percent nickel based on the total weight of the catalyst. The surface area of the catalyst was about 80 square meters per gram, as determined by nitrogen absorption, the pore volume was about 0.2 mL per gram as determined by water absorption, and the apparent bulk density was 0.94 gram per mL.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[N:18]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:17])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:21]2[CH2:20][CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(C)cc(=O)n(CCN3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 5 mL of chloroform, (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde was dissolved, thereto were added 135 mg of tert-butyl piperazine-1-carboxylate and 43.6 mg of acetic acid, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was added with 231 mg of sodium triacetoxyborohydride, and stirred for 1 hour. Thereto was added an aqueous saturated sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Silica gel 60N manufactured by Kanto Chemical Co., Inc., eluent; ethyl acetate] to obtain 173 mg of a yellow oily substance, tert-butyl 4-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=2)[N:3]=1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:32][CH2:33][N:34]([C:2]3[C:11]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:19]([O:21][CH3:22])=[O:20])[CH:8]=4)[N:3]=3)[CH2:35][CH2:36]2)=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc2nc(Cl)c(-c3ccc(F)cc3)nc2c1
Reactant: Clc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(N3CCC(c4ccc(Cl)cc4)CC3)c(-c3ccc(F)cc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed a solution of methyl 2-chloro-3-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 4-(4-chlorophenyl)piperidine hydrochloride (219 mg, 0.94 mmol, 2.00 equiv), potassium carbonate (326 mg, 2.36 mmol, 5.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with dichloromethane/methanol (10:1) and the organic layers were combined. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 200 mg (89%) of methyl 2-(4-(4-chlorophenyl)piperidin-1-yl)-3-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].C([OH:9])C>>[CH3:1][CH:2]([CH2:3][CH2:4][OH:5])[CH2:6][OH:9].[CH3:1][C:2]([OH:9])([CH3:6])[CH2:3][CH2:4][OH:5]
Reactant: CC(C)CCO
Reactant: CCO
Product: CC(C)(O)CCO
Product: CC(CO)CCO
Yield: 75 %
Yield: 12.4 %

Procedure:
A similar experiment, carried out in 5 ml of anhydrous ethanol, produced 75% 2-methyl-1,4-butanediol, 11.6% 3-methylbutanol, and 12.4% 3-methyl-1,3-butanediol.
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C[N+]([O-])=O>[C:1]1([CH2:11][CH:21]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:29])[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2ccccc12
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Solvent: C[N+](=O)[O-]
Product: O=C(c1ccccc1)C(Cc1cccc2ccccc12)C(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of naphthalen-1-ylmethanol (XXII) (0.75 mmol) in CH3NO2 (1 mL) was added slowly over a period of 45 min to a solution of dibenzoylmethane (XXI) (2.27 mmol) and Bi(OTf)2 (0.008 mmol) in CH3NO2 heated at 100° C. The solution was further stirred at 100° C. for 2 h. The solution was cooled and the solvent was removed under vacuum. The residue was purified by column chromatography to produce 2-(naphthalen-1-ylmethyl)-1,3-diphenylpropane-1,3-dione 19 as a yellow solid (75% yield). 1H NMR (DMSO-d6, 400 MHz): δ ppm 3.75 (d, J=7 Hz, 2H), 6.23 (t, J=7 Hz, 1H), 7.24-7.38 (m, 6H), 7.50-7.55 (m, 4H), 7.57 (m, 1H), 7.81-7.87 (m, 5H), 8.14 (m, 1H); ESIMS found C26H20O2 m/z 365 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2=[O:13])=[CH:4][CH:3]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([OH:18])=[C:9]3[C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: O=C1CNCCN1Cc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-fluorobenzyl)piperazin-2-one (10.0 g, 48.0 mmol) and diethyl ethoxymethylenemalonate (10.9 g, 50.4 mmol) in toluene (250 mL) was heated in a sealed tube at 80° C. for 4 hours. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous DMF (350 mL), cooled to 0° C. under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 57.4 mL, 57.4 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with diethyl ether, and the solid precipitated was filtered to provide the titled compound.
Reaction SMILES: Br.[Br:2][C:3]1[S:4][C:5]([Br:11])=[C:6]2[CH2:10][NH:9][CH2:8][C:7]=12.[C:12]1([C:18]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]2[CH:23]=[C:22]([CH2:24]Cl)[N:21]=[CH:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:2][C:3]1[S:4][C:5]([Br:11])=[C:6]2[CH2:10][N:9]([CH2:24][C:22]3[N:21]=[CH:20][N:19]([C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[CH2:8][C:7]=12
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Brc1sc(Br)c2c1CNC2
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1sc(Br)c2c1CN(Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn1)C2
Reaction time: 2 h
Yield: 32.2 %

Procedure:
1.5 g (4.1 mmol) of 1,3-dibromo-5,6-dihydro-4H-thieno[3,4-c]pyrrole hydrobromide, 2.12 g (5.9 mmol) of 1-triphenylmethyl-4-chloromethylimidazole, 30 ml of dimethylformamide and 1.54 ml (9 mmol) of N,N-diisopropylethylamine are introduced into a 50 ml round-bottomed flask. The reaction mixture is subjected to ultrasound for 2 hours and is then poured onto ice. The precipitate obtained is filtered, washed with water, taken up in 50 ml of ethyl acetate, dried over sodium sulphate, filtered and evaporated to dryness. The residue is purified by chromatography on silica gel using the 1/1 ethyl acetate/hexane eluent mixture. 0.8 g of a white solid is obtained. Yield 32%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Br[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@@H:15]3[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[N:10]1[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)CCBr
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 120 °C
Yield: 27.7 %

Procedure:
A mixture of (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 600 mg, 1.97 mmol), tetrabutylammonium iodide (770 mg, 2.1 mmol) and 1-bromo-3-methyl-butane (2 mL, 16.7 mmol) in dimethylformamide (6 mL) was heated in an oil-bath at 120° C. for 18 h. The solvent was evaporated and dichloromethane (75 mL) was added. The solution was washed with water (5×20 mL) and aqueous sodium thiosulfate (20 mL), dried (magnesium sulfate), filtered, and evaporated. The residue was purified using an ISCO 40 g column, eluting with 20-90% ethyl acetate/hexanes to give (4S,7R)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1-(3-methyl-butyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (204 mg, 28%) as a white solid. ES(+)-MS (M+H) 375.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].CCOC(C)=O>C1COCC1.C(N(CC)CC)C.[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][Si:13]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C#C[Si](C)(C)C(C)(C)C
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere 0.80 g (4.20 mmol) of CuI and 2.90 g (4.13 mmol) of bis(triphenylphosphane)palladium (II) chloride were added to a solution of 49.90 g (201.0 mmol) of 2,5-dibromopyridine and 43.0 mL (225.6 mmol) of tert-butylethynyldimethylsilane in 500 mL of dry THF and 120 mL of triethylamine at −7° C. and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was stirred for a further 3.5 hours at RT, then filtered and the filtrate was evaporated down in vacuo. The residue was dissolved in 1 L of EtOAc, the organic phase was washed with water and saturated NaCl solution, dried over sodium sulfate, and evaporated down in vacuo. The crude product was reacted further without purification. Yield: 59.5 g (quant. yield); C13H18BrNSi (M=296.278); calc.: molpeak (M+H)+: 296/298 (Br); found: molpeak (M+H)+: 296/298 (Br); Rf value: 0.75 (silica gel, cyc/EtOAc 8:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:25]=[O:26])=[C:11]([CH:22]([CH3:24])[CH3:23])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[O-:27]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:25]([OH:27])=[O:26])=[C:11]([CH:22]([CH3:23])[CH3:24])[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ccccn3)c2c1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure D, ethyl3-formyl-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-6-carboxylate (Compound 36, 287 mg, 0.82 mmol) in t-BuOH (6 ml), 2-methyl-2-butene (2.29 ml) was added a solution of NaH2PO4 (1.97 g, 16.4mmol) and NaClO2 (80%, 1.48 g, 16.4 mmol) in H2O (6 ml). The mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a light yellow solid.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([OH:10])(=[O:9])C>>[C:7]([OH:10])(=[O:9])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:5].[C:1]([OH:6])(=[O:5])/[C:2](=[CH:4]\[C:7]([OH:10])=[O:9])/[CH3:3]
Reactant: CC(=O)O
Reactant: C=C(C)C(=O)O
Product: C/C(=C/C(=O)O)C(=O)O
Product: O=C(O)/C=C\C(=O)O

Procedure:
After an operating time of 90 days, and at the same bath temperature, the conversion is 59.5 mole %, and the selectivities with respect to methacrylic acid and acetic acid are 90.8 mole % and 1.1 mole % respectively. Maleic acid and citraconic acid are formed in a total amount of 0.82%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1O)=[CH:13][C:12]([Cl:17])=[CH:11][N:10]=2)=[O:5])[CH3:2].C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:37]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:27])[N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[C:14]([C:15]=1[Cl:37])=[CH:13][C:12]([Cl:17])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(Cl)c2cc(Cl)cnc2n(Cc2ccc(OC)cc2)c1=O
Yield: 85 %

Procedure:
A solution of 6-chloro-4-hydroxy-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (75) (6.0 g, 15.43 mmol) and triethylamine (5.36 mL, 38.57 mmol) was heated in neat POCl3 at 90° C. for 3 h. The solution was cooled and the excess POCl3 was distilled under vacuum. The residue was suspended in saturated NaHCO3 solution, sonicated briefly and filtered. The solids were dissolved in dichloromethane, washed subsequently by saturated NaHCO3 solution, water and brine. The organic phase was dried over MgSO4 and evaporated to yield 6.2 g (85%) of 4,6-dichloro-1-(4-methoxy-benzyl)-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (77) as yellow waxy solids. 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.2 Hz, 3H), 3.69 (s, 3H), 4.38 (q, J=7.2 Hz, 2H), 5.50 (s, 2H), 6.82 (m, 2H), 7.24 (m, 2H), 8.48 (d, J=2.4 Hz, 1H), 8.87 (d, J=2.4 Hz, 1H); EIMS: 407 (M).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=O>C(O)C>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[NH:16][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=1)=[C:19]2[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 77.5 °C

Procedure:
4-Benzyloxy phenyl hydrazine hydrochloride (1.0 g, 4 mmol), 4-benzyloxy propiophenone (0.96 g, 4 mmol) were suspended in 15 ml of ethanol and mixture was refluxed for 12 hrs at a temperature of 75-80° C. Then the mixture was cooled to 10-15° C. within 1 hr. The white product was filtered and washed with chilled ethanol (3 ml). The title compound 5-benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-1H-indole (formula-1) melting at 152-153° C. and purity by HPLC 99.5% was obtained in a yield of 1.4 g (83.6%).