Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C(N(CC)CC)C.C(O)CC.Br[C:20]1[CH:21]=[C:22]([O:44][CH3:45])[C:23]([NH:26][C:27](=[O:43])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)(=[O:36])=[O:35])[CH:29]=2)=[N:24][CH:25]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[CH3:45][O:44][C:22]1[C:23]([NH:26][C:27](=[O:43])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)(=[O:36])=[O:35])[CH:29]=2)=[N:24][CH:25]=[C:20]([CH:1]=[CH2:2])[CH:21]=1
Reactant: C=C[B-](F)(F)F
Reactant: COc1cc(Br)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=Cc1cnc(NC(=O)c2cccc(S(=O)(=O)N3CCCCC3)c2)c(OC)c1
Temperature: 80 °C
Reaction time: 10 h
Yield: 41.5 %

Procedure:
At room temperature, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.7 mg), potassium vinyltrifluoroborate (10.6 mg) and triethylamine (0.010 mL) were added in that order to an n-propanol (1.0 mL) solution of the compound (30.0 mg) obtained in Example 106, and stirred at 80° C. for 10 hours. After left cooled, ethyl acetate was added to the reaction liquid, then washed three times with water, and dried with sodium sulfate. The drying agent was removed through filtration, and the solvent was evaporated off under reduced pressure. The residue was purified through silica gel column chromatography (NH Biotage Column, ethyl acetate/hexane=from 0% to 80%, gradient) to give the entitled compound (11.0 mg, 42%) as a colorless oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12](O)[C:13]#[C:14][CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)[C:13]#[C:14][CH3:15]
Reactant: CC#CCO
Reactant: COC(=O)c1ccc(O)cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC#CCOc1ccc(C(=O)OC)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 5-hydroxypyridine-2-carboxylate (1.5 g, 9.8 mmol, Molbridge) in THF (39 ml) under argon was cooled to 0° C. and 2-butyn-1-ol (1.5 ml, 20 mmol, Aldrich), triphenyl phosphine (2.95 g, 11.2 mmol, Aldrich) and diisopropyl azodicarboxylate (2.2 ml, 11.2 mmol, Aldrich) were added consecutively. The reaction mixture was stirred at room temperature for 2 h. Additional diisopropyl azodicarboxylate (1 ml) was added and the reaction mixture was stirred at room temperature for another 1 h. The reaction mixture was diluted with CH2Cl2 and washed with saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (0% to 50% EtOAc/Hexanes) afforded the title compound as a light tan solid. MS m/z=206.0 [M+H]+.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.Cl.[CH3:9][N:10]([CH3:16])[C:11](=[O:15])[CH2:12][CH2:13][NH2:14]>C(O)C>[CH3:9][N:10]([CH3:16])[C:11](=[O:15])[CH2:12][CH2:13][NH:14][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: CN(C)C(=O)CCN
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Product: CN(C)C(=O)CCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N,N-dimethyl-R-alaninamide (2.12 g) in ethanol (25 mL) was added 4-thioxo-1,3-thiazolidin-2-one (2.43 g), which N,N-dimethyl-β-alaninamide hydrochloride was treated with AMBERLYST (registered trademark) A21, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol) to give the title compound (0.33 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([Cl:20])[N:3]=1.[CH:21]([Mg]Cl)([CH3:23])[CH3:22]>C1COCC1>[Cl:20][C:4]1[N:3]=[C:2]([CH:21]([CH3:23])[CH3:22])[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=1
Reactant: CC(C)[Mg]Cl
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(C(C)C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
A solution of 6.0 g (18.3 mmol) 2,6-dichloro-N-(4-chlorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide (synthesized according to the method described in section a) of example 2) in THF (180 ml) and NMP (60 ml) was degassed for 30 min followed by the addition of 1.3 g (3.7 mmol) Fe(acac)3. This mixture was degassed again for 20 min. At −40° C. 137 ml (2M in THF, 274 mmol) isopropylmagnesiumchloride was added dropwise over 1 h. The reaction mixture was allowed to reach 0° C. and was quenched at this temperature with a sat. aq. NH4Cl sol. followed by stirring at 10° C. for 30 min. Then the mixture was diluted with EtOAc and the organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 2.45 g (7.3 mmol, 40%) 6-chloro-N-(4-chlorobenzyl)-2-isopropyl-4-methyl-pyridine-3-carboxylic amide.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3([C:15]([O:17]CC)=O)[CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl.Cl.[NH:24]1[CH2:28][CH2:27][C:26]2([C:36]3[CH:35]=[CH:34][N:33]=[CH:32][C:31]=3[C:30](=[O:37])[O:29]2)[CH2:25]1>CO>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12]3([C:15]([N:24]4[CH2:28][CH2:27][C@@:26]5([C:36]6[CH:35]=[CH:34][N:33]=[CH:32][C:31]=6[C:30](=[O:37])[O:29]5)[CH2:25]4)=[O:17])[CH2:13][CH2:14]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C1(c2ccc(N3CCCC3)nc2)CC1
Reactant: O=C1OC2(CCNC2)c2ccncc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCCC5)nc4)CC3)C2)c2ccncc21

Procedure:
The above material of ethyl 1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropanecarboxylate was treated with LiOH in methanol to afford the corresponding acid, which was then coupled with 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride using procedures analogous to those for example 96 to afford (1R)-1′-{[1-(6-pyrrolidin-1-ylpyridin-3-yl)cyclopropyl]carbonyl}-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one. MS (ESI): (M+H)+=405.1
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8]S(C(F)(F)F)(=O)=O)[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.C[S-].[Na+]>COCCOC>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([CH3:16])=[C:4]([C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)nc(N)nc1-c1ccco1
Agent: C[S-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1c(-c2ccco2)nc(N)[nH]c1=O
Yield: 24.5 %

Procedure:
A stirred solution of 250 mg (0.77 mmol) trifluoromethanesulfonic acid 2-amino-6-furan-2-yl-5-methyl-pyrimidin-4-yl ester and 217 mg (3.09 mmol) sodium methanethiolate in 10 ml dry DME under argon was heated at 80° C. for 2 hours. The reaction mixture was then partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was triturated in ethyl acetate/ether and the crystals collected by filtration to afford 36 mg (24%) 2-amino-6-furan-2-yl-5-methyl-3H-pyrimidin-4-one as a yellow crystalline solid. The mother liquor was concentrated in vacuo and the residue triturated in ether/hexane and the crystals collected by filtration to afford 13 mg (8%) 4-furan-2-yl-5-methyl-6-methylsulfanyl-pyrimidin-2-ylamine as a yellow crystalline solid. EI-MS m/e (%): 221 (M+, 76), 188 ([M—SH]+, 100).
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[OH:27])[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][CH2:23][O:24]4)=[CH:19][C:18]=3[OH:27])[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCCO2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1C(c2cc3c(cc2O)CCCO3)c2ccccc2N1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90 %

Procedure:
A 500 mL round-bottom flask was charged with chroman-6-ol (9.2 g, 61 mmol) and tetrahydrofuran (120 mL). A 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (32.5 mL, 65.0 mmol) was added at 5° C. and the reaction mixture was stirred for 15 min and concentrated in vacuo. To the residue was added dichloromethane (180 mL), followed by a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (18.8 g, 60.0 mmol) in dichloromethane (180 mL) at 5° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 24 h. Saturated aqueous ammonium chloride (7 mL) was added and the reaction mixture was concentrated in vacuo. Trituration of the residue in methanol/water (1/100, 200 mL) afforded 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one. A mixture of the 1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one, triethylsilane (23.2 g, 200 mmol), trifluoroacetic acid (50.0 g, 438 mmol) and dichloromethane (200 mL) was stirred at ambient temperature for 20 h and concentrated in vacuo. Trituration of the residue in diethyl ether (150 mL) afforded 1-(diphenylmethyl)-3-(6-hydroxy-3,4-dihydro-2H-chromen-7-yl)-1,3-dihydro-2H-indol-2-one (24.3 g, 90%) as an off-white solid: MS (ES+) m/z 448.0 (M+1).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][C:22](=[O:26])[CH:23]=CC)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:11]=[CH:23][C:22](=[O:26])[CH2:21][N:13]1[C:14]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:20])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C=CC)C(=O)OC(C)(C)C
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(=O)C=C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 65 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
(S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-oxopent-3-enyl)carbamate (Intermediate 49, 27.0 g, 70.39 mmol) was dissolved in toluene (650 ml). The solution was purged with nitrogen for 15 minutes before the addition of Hoveyda-Grubbs Catalyst 2nd Generation (0.885 g, 1.41 mmol). The reaction mixture was heated under nitrogen at 65° C. After 2 hours LCMS showed complete formation of the product. The reaction mixture was concentrated under reduced pressure. Silica gel chromatography (10%-35% ethyl acetate/hexanes) afforded the desired product as a solid (17.0 g, 70%).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:11][CH2:10][C@@H:9]2[N:5]1[C:6](=[O:20])[C@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:8]2)(=O)[NH2:2].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O>[C:1]([C@@H:4]1[CH2:11][CH2:10][C@@H:9]2[N:5]1[C:6](=[O:20])[C@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:8]2)#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2CC[C@@H](C(N)=O)N2C1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H]2CC[C@@H](C#N)N2C1=O
Reaction time: 3 h

Procedure:
100 mg of tert-butyl ((2R,5S,7aS)-5-carbamoyl-3-oxohexahydropyrrolizin-2-yl)carbamate were dissolved in 2 ml of dimethylformamide, and 65 mg of cyanuric chloride were added. The mixture was stirred for 3 h, and the dimethylformamide was removed in vacuo. The residue was chromatographed on silica gel.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[CH2:8][CH2:9][CH:10]([OH:17])[CH2:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[C:18](O)(=[O:20])[CH3:19]>N1C=CC=CC=1>[C:18]([O:17][CH:10]1[CH2:9][CH2:8][C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=3)[C:13](=[O:16])[C:12]=2[CH2:11]1)(=[O:20])[CH3:19]
Reactant: O=c1c2c(oc3ccc(Br)cc13)CCC(O)C2
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CC(=O)OC1CCc2oc3ccc(Br)cc3c(=O)c2C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To 8.9 g of 7-bromo-2-hydroxy-1,2,3,4-tetrahydro-9-xanthone obtained in Example 67 were added 6.2 g of anhydrous acetic acid and 40 ml of pyridine. The mixture was stirred for 4 hours at 60° C., and after completion of the reaction, the solvent was removed by distillation. The resulting crystals were recrystallized from ethanol to obtain 9.9 g (yield: 97.9%) of 2-acetoxy-7-bromo-1,2,3,4-tetrahydro-9-xanthone as colorless needle-like crystals having a melting point of 177.5° to 178° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[Cl:8][C:3]1[C:2]([NH:1][C:42](=[O:43])[C:41]2[CH:45]=[C:37]([CH2:36][C:30]3[C:31](=[O:35])[C:32]([O:33][CH3:34])=[C:27]([O:26][CH3:25])[C:28](=[O:51])[C:29]=3[CH3:50])[CH:38]=[CH:39][C:40]=2[O:46][C:47](=[O:49])[CH3:48])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Cl
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccnc3Cl)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 54 %

Procedure:
3-Amino-2-chloropyridine (0.206 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:1) to obtain the titled compound (0.140 g, 0.289 mmol, 54%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:25]3[CH2:30][CH2:29]S[CH2:27][CH2:26]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O[O:32][S:33]([O-:35])=O.[K+]>C1COCC1.CO.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:25]3[CH2:26][CH2:27][S:33](=[O:35])(=[O:32])[CH2:29][CH2:30]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCSCC3)cs2)c1-c1ccc(F)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCS(=O)(=O)CC3)cs2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
To a mixed solution of 4-({2-[1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}acetyl)thiomorpholine (100 mg, 0.22 mmol) in THF (2 mL), MeOH (2 mL) and water (2 mL) was added Oxone (290 mg, 0.47 mmol) at 0° C., and the mixture was stirred at 0° C. for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure to give the title compound (82 mg, 0.172 mmol, 76%) as a white powder.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].Br[CH2:6][C:7]1[C:8]([CH3:19])=[N:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1>C1COCC1.[Cu]I>[CH2:6]([C:7]1[C:8]([CH3:19])=[N:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[CH:1]=[CH2:2]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CBr
Reactant: C=C[Mg]Br
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCc1c(C)noc1-c1ccc(Br)cc1
Temperature: -40 °C
Reaction time: 0.3 h

Procedure:
Copper(I) iodide (0.187 g, 0.98 mmol) was suspended in THF (43 mL) then cooled to −40° C. under N2 atmosphere. Vinylmagnesium bromide (1 M in THF, 9.74 mL, 9.74 mmol) was added over the course of 4 minutes and the reaction continued stirring for 18 minutes. Next, 4-bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole (2.15 g, 6.5 mmol) in THF (11 mL) was added over the course of 15 minutes. The reaction was placed in a −20° C. overnight. After warming the reaction was submitted to standard aqueous workup to afford the title compound.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:20][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH2:22])[C:8]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2C=C)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:22][C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:8]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1CC(=C)C(=O)OC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: COC(=O)C1=Cn2c(c(C3CCCCC3)c3ccc(C(=O)OC)cc32)-c2ccccc2C1
Temperature: 45 °C
Yield: 46.8 %

Procedure:
A mixture of methyl 3-cyclohexyl-1-(2-(methoxycarbonyl)allyl)-2-(2-vinylphenyl)-1H-indole-6-carboxylate (13, R=methyl), (3.1 g, 6.77 mmol) and Grubbs' 2nd generation catalyst (1.7 g, 1.35 mmol) in methylene chloride (350 mL) were heated at 45° C. for 96 hr. Solvent was removed in vacuo and the residue was chromatographed on silica gel using hexane/ethyl acetate (0-15%) to afford pure title compound as a bright yellow solid (1.36 g). The mixed fractions were combined and concentrated in vacuo and the residue was recrystallized using methanol to afford the title compound (175 mg). Total title compound obtained: 1.805 g, 53%. ESI-MS m/z 430 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16].[OH-].[Na+]>ClCCl>[OH:9][C:8]([C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[C:14]([C:13]#[N:17])[C:15]#[N:16]
Reactant: N#CCC#N
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: N#CC(C#N)=C(O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.2 %

Procedure:
A 0° C. solution of 4-nitrobenzoyl chloride (24.12 g, 130 mmol) and malononitrile (8.60 g, 130 mmol) in dichloromethane (200 mL) was treated with PhCH2N(CH2CH3)3Cl (3.0 g), treated dropwise with 10N NaOH (30 mL), stirred at 0° C. for 1 hour, and filtered. The filter cake was washed with dichloromethane and diethyl ether, dissolved in 5% HCl, and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethyl acetate/hexanes to provide 23 g of the desired product. MS(ESI(−)) m/e 214 (M−H)−.
Reaction SMILES: C([N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[C:13]([C:22]3[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:29])[N:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]=2[CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[H][H].C(=O)(O)[O-].[Na+]>C1COCC1.ClCCl.[OH-].[OH-].[Pd+2].O>[CH3:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:29])[C:22]=1[C:13]1[N:14]=[C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:10]2[CH2:9][NH:8][CH2:31][CH2:30][C:11]=2[N:12]=1
Reactant: [H][H]
Reactant: COCCCOc1nc(-c2c(C)cccc2C)nc2c1CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCCOc1nc(-c2c(C)cccc2C)nc2c1CNCC2
Reaction time: 5 h

Procedure:
To a solution of 6-benzyl-2-(2,6-dimethylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (170 mg, 0.41 mmol) in THF (3.5 mL) was added water (0.5 mL) and acetic acid (0.070 mL, 1.22 mmol). The reaction mixture was placed under argon and then charged with 20 mol % Pd(OH)2/C (50% wet, 114 mg, 0.081 mmol). The atmosphere was then replaced with hydrogen gas via a balloon and was permitted to stir for 5 hours. The mixture was then neutralized with saturated aqueous sodium bicarbonate, diluted with dichloromethane and filtered through a pad of Celite®. The eluent was further diluted with dichloromethane and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography [7-20% (2 M NH3 in MeOH)/DCM] to furnish 2-(2,6-dimethylphenyl)-4-(3-methoxypropoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. MS (ESI+) m/z 328.3 (M+H)+.
Reaction SMILES: [H-].[Na+:2].O1CCCC1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([S:16]([OH:19])(=[O:18])=[O:17])[CH:10]=1>C(O)C>[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([S:16]([O-:19])(=[O:17])=[O:18])[CH:10]=1.[Na+:2]
Reactant: Cc1cc(C)nc(S(=O)(=O)O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)nc(S(=O)(=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
In a 50 ml flask, sodium hydride (60% in oil) (200 mg, 5 mmol) and tetrahydrofuran (10 ml) were charged, and then 4,6-dimethylpyridine-2-sulfonic acid (935 mg) was gradually added at room temperature. Then, the mixture was stirred at room temperature for about 30 minutes. After the addition of a small amount of ethanol to the reaction mixture, the precipitated crystal was recovered by filtration. The crystal was washed with ethyl acetate and diethyl ether successively and dried to obtain sodium 4,6-dimethyl-2-pyridinesulfonate (1.05 g) at a quantitative yield. Melting point, 257°-258° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].Cl[CH2:19][C:20]1[O:24][C:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:21]=1.O>C(O)(C)(C)C>[CH2:28]([O:27][C:25]([C:23]1[O:24][C:20]([CH2:19][CH:8]([C:9](=[O:10])[CH3:11])[C:7]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:21][CH:22]=1)=[O:26])[CH3:29]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc(CC(C(C)=O)C(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
A solution of 1.78 g of potassium tert-butoxide in 60 ml of tert-butyl alcohol was stirred together with 3.00 g of tert-butyl acetoacetate at 60° C. for 30 minutes under heating and then cooled to room temperature. 3.40 g of ethyl 5-(chloromethyl)-2-furancarboxylate was added dropwise, and the solution was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=9/1→5/1] to give 2.26 g of the title compound as a colorless oily substance.