Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20]Cl)[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][SH:23].C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20][S:23][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CS
Reactant: CC(=O)c1cc(CCl)c(OCCCCCCC#N)cc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCc1cc(C(C)=O)c(O)cc1OCCCCCCC#N
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 600 mg of the compound from Example 127 was dissolved in 50 ml of methylene chloride and cooled to 0° C. Fifteen grams of methanethiol were added followed by the addition of 2 ml of triethylamine. The reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and an acidic sodium choride solution. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 40% ethyl acetate in hexane providing 200 mg of the desired title product, m.p.=78° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].P(OC)(OC)(OC)=O>O.CN(C)C=O>[CH:2](=[O:1])[C:3]1[CH:11]=[CH:10][C:8]([O:9][CH3:12])=[C:5]([O:6][CH3:7])[CH:4]=1
Reactant: COc1cc(C=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COP(=O)(OC)OC
Product: COc1ccc(C=O)cc1OC
Temperature: 100 °C
Yield: 96.6 %

Procedure:
In a three-neck flask (capacity 100 ml) equipped with a mechanical stirrer and reflux condenser, 20 ml of dimethylformamide (anhydrous), 5.00 g (0.033 mol) of vanillin and 5.00 g (0.036 mol) of anhydrous potassium carbonate were placed and the mixture was heated under a nitrogen atmosphere to 100° C. The mixture was a clear to amber solution of vanillin with carbonate in suspension. To this mixture was added 5.00 ml (0.043 mol) of trimethyl phosphate over about 5 minutes while maintaining the reaction temperature below 125° C. The mixture was maintained at about 80° C. for one hour and then cooled to 40° C. The mixture was poured into 200 ml water and extracted two times with 50 ml of methylene chloride. The methylene chloride extracts were washed twice with 100 ml of water. The combined extracts were dried over anhydrous potassium carbonate, filtered, and concentrated to give 5.3 g (95%) of veratraldehyde as a pale oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-:15])=[O:14])=[C:8]([NH:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:7]=1[N+:22]([O-:24])=[O:23])(=O)C.Cl.O>CO>[CH2:18]([CH:17]([NH:16][C:8]1[C:7]([N+:22]([O-:24])=[O:23])=[C:6]([C:11]([CH3:12])=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14])[CH2:5][OH:4])[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(COC(C)=O)c1[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(CO)c1[N+](=O)[O-]

Procedure:
A sample of 3-[(1-ethylpropyl)amino]-6-methyl-2,4-dinitrobenzyl acetate (23.1 g; 0.068 mol) is added to a mixture of concentrated hydrochloric acid (30 ml), water (40 ml) and methanol (320 ml). The reaction mixture is refluxed for 4 hours, cooled down and concentrated in vacuo. It is then diluted with water, extracted with ether, and the ether layer dried. The ether is removed in vacuo to leave a red oil, which readily solidifies to a yellow-orange solid (19.9 g; 98.5%). A similarly prepared and purified sample has a melting point of 51°-54° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[SH2:19].O>N1C=CC=CC=1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)(=[S:19])[NH2:2]
Reactant: S
Reactant: N#Cc1ccc(C(=O)O)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ccc(C(=O)O)cc1
Yield: 68 %

Procedure:
3 g of 4-cyanobenzoic acid 1 (20.4 mmol) were dissolved in 40 mL of pyridine and 2.1 mL of triethylamine (20.4 mmol) were added. Dry hydrogen sulphide was passed through the solution in a steady steam for 4 h. The mixture was then poured into water and the solid collected by filtration. Recrystallization from petroleum ether furnished 2.51 g of the pure compound 2 (68% yield).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[CH3:11][Al](C)C.[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1.C1(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)C=CC=CC=1>[CH3:11][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[Al](C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ncnc2nc[nH]c12
Temperature: 25 °C

Procedure:
A suspension of 6-chloropurine (0.2 mmol) and tetrakis(triphenylphosphino)-palladium (0.02 mmol) in dry THF (3 mL) was treated with trimethylaluminum (2M in toluene, 0.45 mmol) under nitrogen. The resulting solution was heated to reflux for 3 h, cooled to r.t., diluted with toluene (5 mL), and quenched with methanol (0.5 mL) followed by ammonium chloride (1 mmol). The mixture was heated to reflux for 2 h and filtered while hot through a Celite plug. Evaporation and purification by prep TLC afforded the 6-methylpurine. See J. Med. Chem. 1999, 42, 2064–2086.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([C:23]3[CH:24]=[C:25]([CH2:38][CH:39]4[CH2:44][CH2:43][N:42](C(OC(C)(C)C)=O)[CH2:41][CH2:40]4)[CH:26]=[N:27][C:28]=3[NH:29][C:30]3[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[N:17]=2)=[CH:12][CH:11]=1.C(Cl)Cl.[CH3:66][S:67](Cl)(=[O:69])=[O:68]>>[CH3:8][O:9][C:10]1[CH:62]=[CH:61][C:13]([CH2:14][N:15]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)[C:16]2[N:17]=[C:18]([C:23]3[C:28]([NH:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[N:27][CH:26]=[C:25]([CH2:38][CH:39]4[CH2:44][CH2:43][N:42]([S:67]([CH3:66])(=[O:69])=[O:68])[CH2:41][CH2:40]4)[CH:24]=3)[N:19]=[C:20]([CH3:22])[N:21]=2)=[CH:12][CH:11]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CC4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
TFA (4.00 mL, 51.9 mmol) was slowly added to a slightly cooled stirred solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)piperidine-1-carboxylate (0.2611 g, 0.350 mmol) in DCM (5.00 mL, 78 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was concentrated (under vacuum to remove as much TFA as possible). The sticky residue was taken up in DCM (10.00 mL) and TEA (0.487 mL, 3.50 mmol) followed by methanesulfonyl chloride (0.082 mL, 1.049 mmol) were slowly added at 0° C. The mixture was stirred for 1 h and then concentrated. The crude product was partitioned between 1 N NaOH(aq) and DCM (20 mL each). The separated aqueous layer was extracted with DCM (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography (ISCO Combiflash system, 10% to 50% ethyl acetate in hexanes) to give the desired product N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-((1-(methylsulfonyl)piperidin-4-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.1923 g, 0.265 mmol, 76% yield) as a yellow film. m/z (ESI, +ve ion) 725.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[N:19]2[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1.O>CN(C)C=O>[Cl:14][C:15]1[N:19]2[N:20]=[C:21]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1
Reactant: Clc1ccc2nnc(Cl)n2n1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1nnc2ccc(N3CCOCC3)nn12
Temperature: 20 °C
Reaction time: 19 h

Procedure:
0.9 cm3 of morpholine and 1.4 cm3 of triethylamine are added to a solution of 1.89 g of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine in 20 cm3 of N,N-dimethylformamide. The reaction is stirred at 20° C. for 19 h. 60 cm3 of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed with water and with brine and then dried over magnesium sulphate and concentrated to dryness, to give a beige solid. The latter is chromatographed by solid deposit on a Merck cartridge of 70 g of silica 15-40 μm, elution being carried out with a gradient of 100% dichloromethane to 95/5 dichloromethane/methanol. 1.97 g of 3-chloro-6-(morpholin-4-yl)[1,2,4]triazolo[4,3-b]pyridazine are obtained in the form of a very pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[H-].[Na+].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][C:14]1[N:15]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: c1ccc(-c2ccccc2Sc2nc3ccccc3[nH]2)nc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)n1c(Sc2ccccc2-c2ccccn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-[2-(2-Pyridyl)-phenyl thio]-benzimidazole (0.825 mmole) in anhydrous dimethylformamide (15 ml) was treated under nitrogen with sodium hydride (0.90 mmole). The mixture was stirred for 20 minutes at room temperature, cooled to 5° and benzyl chloroformate (0.90 mmole) was added. The mixture was allowed to attain room temperature, then stirred for 18 hours after which it was poured into ice/water and extracted with ethyl acetate (2×15 ml). The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to an oil. The oil was flash chromatographed on silica gel using 10% ethyl acetate in dichloromethane as eluant to give the sub-title compound as a brown oil, MW 437 Base Peak 91.
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:34]1(C)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>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.O1CCCC1>[C:19]1([C:2]2[C:15]3[C:16]4=[C:17]5[C:12](=[CH:13][CH:14]=3)[CH:11]=[CH:10][C:9]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:8]5[CH:7]=[CH:6][C:5]4=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: C1CCOC1
Product: c1ccc(-c2ccc3ccc4c(-c5ccccc5)ccc5ccc2c3c54)cc1

Procedure:
Under an argon atmosphere, 15.0 g of 1,6-dibromopyrene, 13.2 g of phenylboronic acid, 1.9 g of tetrakis(triphenylphosphine)palladium (0) [Pd(PPh3)4], 27.8 g of sodium carbonate (130 mL of clean water), toluene and tetrahydrofuran were placed into a flask, and the resulting mixture was allowed to react at 90° C. for 7 hours. After cooling, the reaction solution was filtered, and solids obtained were washed with methanol and clean water. Further, the solids were purified by silica gel chromatography (heated toluene). The resulting crude product which was obtained by a concentration was re-crystallized from toluene, followed by drying under a reduced pressure, whereby white solids of 1,6-diphenylpyrene (11.8 g) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:28][CH3:29])[CH:20]=1>>[ClH:1].[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH:23][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:17]=[N:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: COc1cc(Cl)c(OC)cc1N
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c(OC)cc1Cl
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-(2-pyrazinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.191 mmol) and 4-chloro-2,5-dimethoxyaniline (54 mg, 0.287 mmol) similar to Example 117 and isolated as a yellow solid (67 mg, 85%). 1H NMR (CDCl3): 9.77 (d, J=1.5 Hz, 1H), 8.79-8.78 (m, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.50 (bs, 1H), 7.70 (s, 1H), 7.05 (s, 1H), 7.04 (s, 1H), 4.06 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:7](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Reactant: Cc1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3cccc(C)c3)nc12

Procedure:
From meta-toluic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+17.7° (c=0.79, CHCl3), ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([CH3:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:15])[CH3:16])[C:11]([CH3:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[C:38]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)=[CH:37][N:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N(C)C
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N(C)C

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (265 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (420 mg, 71%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:13][OH:14])[CH2:8][CH2:7][CH2:6]2)=[CH2:2].C(N(C(C)C)CC)(C)C.[Si](Cl)(C)(C)C.[Li]N1C(C)(C)CCCC1(C)C.[C:40]1([C:46]2[C:50]([C:51]([F:54])([F:53])[F:52])=[C:49]([C:55](OC)=[O:56])[O:48][N:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[C:40]1([C:46]2[C:50]([C:51]([F:54])([F:52])[F:53])=[C:49]([C:55]3([OH:56])[O:14][N:13]=[C:9]4[C:10]5[C:5]([CH2:6][CH2:7][CH:8]34)=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=5)[O:48][N:47]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: C=Cc1ccc2c(c1)CCCC2=NO
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: C[Si](C)(C)Cl
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1ccc2c(c1)CCC1C2=NOC1(O)c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a stirred solution of 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (I-1, 4.03 g, 21.50 mmol) and diisopropylethylamine (6.83 mL, 39.1 mmol) in anhydrous THF (50 mL) was added TMS-Cl (2.75 mL, 21.50 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 30 min. The previously prepared LiTMP solution was added dropwise at −78° C. under nitrogen. After the mixture was stirred at the same temperature for 30 min, a solution of methyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (I-3, 5.3 g, 19.54 mmol) in anhydrous THF (10 mL) was added dropwise at −78° C. The solution was stirred at −78° C. for 30 min and then warmed to 0° C. over 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution (25 mL) and water (20 mL). The mixture was mixed with EtOAc (50 mL), stirred at room temperature for 30 min and filtered through a pad of celite. The filtrate was separated. The aqueous layer was extracted with EtOAc (2×25 mL). The combined organic solutions were washed with brine (50 mL), dried over sodium sulfate and concentrated to give a liquid. Flash chromatography purification (330 g silica gel column, 15-30% ethyl acetate in hexanes) afforded 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazol-3-ol (5 g, 11.73 mmol, 60.0% yield) as a yellow solid. The compound had an HPLC retention time=3.74 min (condition C); LC/MS M+1=426.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2.[C:18]([O-])(O)=O.[Na+].CI.O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH2:16][CH3:17])[C:13]([O:15][CH3:18])=[O:14])[CH2:7][CH2:6]2
Reactant: CC[C@H](C(=O)O)[C@@H]1CCc2cc(OC)ccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CC[C@H](C(=O)OC)[C@@H]1CCc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
A suspension of the acid prepared in Example 21 (220.0 g, 0.94 mol), NaHCO3 (237.0 g, 2.82 mol), CH3I (200 g, 1.41 mol) in DMF (2.0 L) was stirred under argon at rt for 18 h. Adding additional CH3I (100 g, 0.71 mol) and stirring for an additional 24 h at rt caused completion of the reaction. The reaction mixture was poured into 4.0 L water, and extracted with EtOAc (2×2 L). The combined organic layers were sequentially washed with water (2×1 L), NaOH (1 L, 1 N aqueous solution), water (2×1 L), and brine (0.5 L). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (233 g, 99%) as a light yellow. 1H NMR (300 MHz, DMSO-d6) δ 6.90 (d, 1H), 6.78 (d, 1H), 6.66 (dd, 1H), 3.70 (s, 3H), 3.60 (s, 3H), 3.20 (m, 1H), 2.80 (m, 2H), 2.40 (m, 1H), 2.08 (m, 1H), 1.80 (m, 1H), 1.58 (m, 1H), 1.40 (m, 1H), 0.80 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([OH:10])=[O:9])[CH:6]([NH:11]CC2C=CC=CC=2)[CH:5]([CH3:19])[C:4](=[O:20])[O:3]1.[H][H]>C(O)(=O)C.[Pd]>[CH3:1][CH:2]1[CH:7]([C:8]([OH:10])=[O:9])[CH:6]([NH2:11])[CH:5]([CH3:19])[C:4](=[O:20])[O:3]1
Reactant: [H][H]
Reactant: CC1OC(=O)C(C)C(NCc2ccccc2)C1C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1OC(=O)C(C)C(N)C1C(=O)O

Procedure:
(2SR,3SR,4RS,5RS)-Tetrahydro-2,5-dimethyl-6-oxo-4-benzylamino-2H-pyrane-3-carboxylic acid (100 mg) was dissolved in acetic acid (20 ml), and palladium hydroxidecarbon (prepared by the method as described in J.Am.Chem. Soc., 83, p.4798 (1961)) (20 mg) was added thereto. The resultant mixture was stirred at room temperature under hydrogen pressure of 3-4 kg/cm2 until the designed amount of hydrogen was consumed. The catalyst was collected by filtration and washed with water. The washing and the filtrate were combined together and concentrated at 40° C. under reduced pressure to give (2SR,3SR,4RS,5RS)-tetrahydro2,5-dimethyl-6-oxo-4-amino-2H-pyrane-3-carboxylic acid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]([CH2:19][O:20][CH3:21])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:47]1[CH2:52][CH2:51][CH:50]([C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:49][CH2:48]1.C(N(CC)CC)C>ClCCl>[CH:1]1([C:4]2[N:5]=[C:6]([CH2:19][O:20][CH3:21])[NH:7][C:8]=2[C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([N:47]2[CH2:52][CH2:51][CH:50]([C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=3)[CH2:49][CH2:48]2)=[O:13])[CH2:2][CH2:3]1
Reactant: COCc1nc(C2CC2)c(-c2cc(C(=O)O)ccc2C)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCc1nc(C2CC2)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2C)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
Into a round-bottom flask, was placed a solution of 3-(4-cyclopropyl-2-(methoxymethyl)-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 4.10, 30 mg, 0.10 mmol) in dichloromethane (5 mL). HBTU (76 mg, 0.20 mmol), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.2, 35 mg, 0.15 mmol, 1.50 equiv) and triethylamine (28 μL, 0.20 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was diluted with DCM (30 mL) and washed with water (3×15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (25.0% CH3CN up to 38.0% in 7 min, up to 100.0% in 3 min, down to 25.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (5.9 mg, 12%). m/z (ES+) 455 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.69 (d, J=8.0 Hz, 2H), 7.59-7.53 (m, 2H), 7.53-7.47 (m, 3H), ˜4.9-4.75 (m, 1H partially obscured by water peak), 4.72 (s, 2H), 3.99-3.85 (m, 1H), 3.52 (s, 3H), ˜3.3 (m, 1H overlapped with methanol solvent peak), 3.08-2.93 (m, 2H), 2.37 (s, 3H), 2.08-1.93 (m, 1H), 1.93-1.65 (m, 4H), 1.02-0.94 (m, 2H), 0.74-0.68 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([OH:13])=O)=[CH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:27][CH:28]1[CH:33]2[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]2)[CH2:29]1>>[N:30]12[CH2:35][CH2:34][CH:33]([CH2:32][CH2:31]1)[CH:28]([NH:27][C:11]([C:6]1[C:7]([O:9][CH3:10])=[N:8][C:3]([N:2]([CH3:1])[CH3:14])=[N:4][CH:5]=1)=[O:13])[CH2:29]2
Reactant: NC1CN2CCC1CC2
Reactant: COc1nc(N(C)C)ncc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1nc(N(C)C)ncc1C(=O)NC1CN2CCC1CC2

Procedure:
Following the procedure of Example 22, 2-(dimethylamino)-4-methoxy-5-pyrimidinecarboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.