Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH:22]=O)[N:6]=1)([CH3:4])[CH3:3].[S:24]1[CH2:30][C:28](=[O:29])[NH:27][C:25]1=[S:26].NCCC(O)=O>C(O)(=O)C.O>[CH3:3][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:18]([CH3:19])([CH3:21])[CH3:20])[N:8]=[C:7]([CH:22]=[C:30]2[S:24][C:25](=[S:26])[NH:27][C:28]2=[O:29])[N:6]=1)([CH3:4])[CH3:1]
Reactant: COCCOCOc1c(C(C)(C)C)nc(C=O)nc1C(C)(C)C
Reactant: O=C1CSC(=S)N1
Agent: NCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1nc(C=C2SC(=S)NC2=O)nc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
A mixture of 4,6-bis-(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-2-pyrimidine carboxaldehyde (0.5 g, 1.5 mmoles), rhodanine (0.25 g, 1.8 mmoles), and β-alanine (0.27 g, 3.1 mmoles) in acetic acid is heated at reflux for 1.5 hours. This solution is cooled to room temperature and diluted with 100 mL of water. The precipitate is collected by filtration and recrystallized from isopropyl ether/hexane. Yield of 5-[[4,6-bis (1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]methylene]-2-thioxo-4-thiazolidinone=0.26 g (48%). MP=257°-261° C. dec.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[I-].ClC1C=CC=C[N+]=1C.[CH2:31](O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Reactant: CCCCCCCCCCCCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccco1
Yield: 77.2 %

Procedure:
2.0 g of 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetic acid, 2.02 g of 2-chloro-1-methylpyridinium iodide, 1.47 g of laurylalcohol, 1.60 g of triethylamine and 60 ml of tetrahydrofuran are treated in the same manner as described in Example 27. 2.4 g of lauryl 2-[2-(4-chlorophenyl)-5-(2-furyl)-4-oxazolyl]acetate are obtained. Yield: 77.4%
Reaction SMILES: [OH:1][C@H:2]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:32])[CH3:4]>CN(C)C=O.[C].[Pd]>[OH:1][C@H:2]([C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[CH:11][C:10]=1[CH3:32])[CH3:4]
Reactant: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(O)cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.9 %

Procedure:
A mixture of benzyl 4′-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethylamino]ethoxy}-3′,5′-dimethylbiphenyl-4-carboxylate (0.108 g) and 10% palladium-carbon (50% wet, 0.05 g) in N,N-dimethylformamide (4 mL) was stirred at room temperature for 1.5 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. Methylene chloride was added to the residue. The resulting precipitate was collected by filtration, and purified by octadecyl silica gel column chromatography (eluent:acetonitrile/water=1/1) to afford the title compound (0.025 g) as a white amorphous. The structure and physical data were shown in table 1.
Reaction SMILES: C([O:8][N:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[C:10]1=[O:33])C1C=CC=CC=1>CS(O)(=O)=O>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([NH:15][C@@H:11]3[CH2:12][CH2:13][CH2:14][N:9]([OH:8])[C:10]3=[O:33])(=[O:17])=[O:18])=[CH:24][CH:23]=2)=[CH:31][CH:30]=1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCCN1OCc1ccccc1
Agent: CS(=O)(=O)O
Product: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCCN1O

Procedure:
A solution of (R)—N-(1-benzyloxy-2-oxo-piperidin-3-yl)-4-(4-chloro-phenoxy)-benzenesulfonamide (0.1 g) in step A in MeSO3H (1.5 mL) was stirred at room temperature under N2 for 16 h. The reaction was quenched with ice-water and the precipitate was filtered. The white solid was washed with water, Et2O/hexanes (1:5) to give the titled compound. MS (EI) 397 (M+H)+.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[OH-].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH2:7]([O:3][CH2:2][CH2:1][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: OCCOCc1ccccc1
Yield: 53 %

Procedure:
A mixture of 156.75 g of dry ethylene glycol and 64.37 g of 87.2% potassium hydroxide is warmed and stirred until a complete solution. The mixture is then stirred in a 90° C. oil bath and 130.51 g of benzyl chloride is added dropwise over 2 hours. This mixture is then stirred at 130° C. for 2 hours, cooled and 500 ml of water added. The oil is extracted twice with ether. The extracts are combined and evaporated. The residue is distilled, giving 83.2 g of ethylene glycol monobenzyl ether.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[Cl:14][CH2:15][CH:16]([OH:25])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC(C)=O.[Cr]>[Cl:14][CH2:15][C:16]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:25]
Reactant: OC(CCl)COc1ccccc1
Agent: O=[Cr](=O)=O
Agent: [Cr]
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCl)COc1ccccc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 49.7 %

Procedure:
8N Jones reagent (100 ml.) was added dropwise to a stirred solution of 1-chloro-2-hydroxy-3-phenoxypropane (28.3 g.) in acetone (100 ml.) during 1 hour while maintaining the reaction temperature at 20° C. The mixture was then stirred for 4 hours, and then sufficient water was added to dissolve the precipitated chromium salts. The mixture was extracted three times with diethyl ether and the combined ethereal extracts were dried over sodium sulphate, concentrated under reduced pressure, dried again over sodium sulphate, and concentrated further and distilled, to give 1-chloro-3-phenoxyacetone (13.9 g.), b.p. 150°-155° C./20 mm.Hg.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:13])[CH3:12])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:14].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:14][CH2:12][C:11]([C:8]1[S:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[CH:9]=1)=[O:13]
Reactant: [Br-]
Reactant: CC(=O)c1cc2c(Cl)cccc2s1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 124 %

Procedure:
A mixture of 1-(4-chlorobenzo[b]thiophen-2-yl]ethan-1-one (1.67 g), phenyltrimethylammonium tribromide (2.98 g) and tetrahydrofuran (40 ml) was stirred under nitrogen at ambient temperature for 22.5 hours then it was filtered and diluted with water (150 ml). The product was extracted into dichloromethane (3×30 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl]ethan-1-one (1.65 g) as an off-white solid, m.p. 116-118° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25]1>>[O:24]1[CH:28]=[CH:27][C:26]([C:29]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:30])=[CH:25]1
Reactant: O=C(Cl)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccoc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.062 mMol) 3-furoyl chloride, the title compound was prepared.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1)([CH3:5])([CH3:4])[CH3:3].[F:18][C:19]([F:31])([F:30])[C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C)C=O>[F:31][C:19]([F:18])([F:30])[C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:16][C@@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:7]([O:6][C:2]([CH3:3])([CH3:5])[CH3:4])=[O:17])=[CH:13][CH:12]=2)[CH3:15])(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a vial containing tert-butyl-4-[(1R)-1-aminoethyl]benzoate hydrochloride from Step 1 was added N,N-dimethylaminopyridine (3.91 mg, 0.032 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (0.059 g, 0.24 mmol), N,N-dimethylformamide (2 mL), and triethylamine (0.18 mL, 1.28 mmol). The mixture was stirred at rt for 16 h, after which the solvent was fully evaporated. To the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give (R)-tert-butyl 4-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)benzoate as a brown solid. LC-MS: (FA) ES+ 430.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[C:7](Br)[C:8]([NH2:15])=[C:9]([N+:12]([O-])=O)[CH:10]=2)[C:5](=[O:17])[NH:4][C:3]1=[O:18]>[Pd].CO>[CH3:1][C:2]1([CH3:19])[C:11]2[CH:10]=[C:9]3[NH:12][C:10]([C:11]4[CH:6]=[CH:5][N:4]=[CH:3][CH:2]=4)=[N:15][C:8]3=[CH:7][C:6]=2[C:5](=[O:17])[NH:4][C:3]1=[O:18]
Reactant: CC1(C)C(=O)NC(=O)c2c1cc([N+](=O)[O-])c(N)c2Br
Agent: [Pd]
Solvent: CO
Product: CC1(C)C(=O)NC(=O)c2cc3nc(-c4ccncc4)[nH]c3cc21
Reaction time: 4 h

Procedure:
27 g. (82 mmole) 4,4-dimethyl-6-nitro-7-amino-8-bromo-1,2,3,4-tetrahydroisoquinoline-1,3-dione were hydrogenated in 300 ml. methanol in the presence of 2 g. 10% palladium on charcoal. After separating off the catalyst, the filtrate was evaporated, the residue was mixed with 500 ml. methylene chloride and 50 ml. triethylamine and, while cooling, 24 g. isonicotinic acid chloride hydrochloride slowly introduced. After 4 hours, the methylene chloride was evaporated off, the residue was worked up with water, filtered off with suction and the moist residue heated under reflux for 20 hours in 500 ml. ethanol and 200 ml. concentrated hydrochloric acid. The evaporation residue was subsequently mixed with water, neutralized and purified by column chromatography (silica gel, elution agent: methylene chloride/ methanol saturated with ammonia; 10:1 v/v). After recrystallization from ethanol/water, there were obtained 12.2 g. (51% of theory) of the title compound; m.p. above 300° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([O:16]CC)=O)[N:11]=[CH:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][NH2:33])[CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:30][CH2:31][CH2:32][NH:33][C:14](=[O:16])[CH2:13][N:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[N:11]1)[CH3:26]
Reactant: CCN(CC)CCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccc(O)cc1
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccccc2)c1-c1ccc(O)cc1

Procedure:
A solution of 10 g (0.031 mol) of ethyl 5-(4-hydroxyphenyl)-4-phenyl-1H-pyrazole-1-acetate of example 5 in 48 mL of diethylaminopropylamine was stirred on a steam bath under nitrogen for 14 hours. The excess amine was removed in vacuo at 80° C., the residue dissolved in ethyl acetate, washed twice with water, once with brine and dried over sodium sulfate. They ethyl acetate was stripped to yield 12 g of a dark oil which was triturated in hot cyclohexane several times. The insoluble residue was combined with a small amount of a mixture of oil and crystals, which had separated from the cyclohexane on cooling, and recrystallized from ethyl acetate to yield 6.6 g of product, mp 110°-113° C.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C.[Ag]=O>[CH2:18]([O:8][C:7]([C:5]1[N:6]=[C:2]([Br:1])[N:3]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1)=[O:9])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1Br
Agent: O=[Ag]
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cc(C(=O)OCc2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Silver oxide (12.7 g, 54.8 mmol) was added to a solution of 2-bromo-1-((2-(trimethyl-silyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (11.7 g, 36.5 mmol) in ACN (200 ml) and stirred at RT for 10 min. Benzyl bromide (4.2 ml, 36.5 mmol) was added to the mixture and stirred at RT for 12 h. The reaction mixture was filtered through a celite bed and the filtrate was concentrated under reduced pressure. The product was purified by flash chromatography. Yield 10 g. 1H-NMR (400 MHz; CDCl3): δ −0.04 (s, 9H), 0.92 (t, 2H), 3.54 (t, 2H), 5.29 (s, 2H), 5.35 (s, 2H), 7.30-7.44 (m, 5H), 7.76 (s, 1H).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@@H:26]([CH3:37])[CH2:25]3)[CH:18]=2)[CH:14]=[CH:15][CH:16]=1>C1COCC1>[CH3:36][C:33]([O:32][C:30]([N:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:19]2[CH:18]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH:12]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:25][C@@H:26]1[CH3:37])=[O:31])([CH3:34])[CH3:35]
Reactant: C[C@H]1CN(Cc2cccc(-c3cccc(CN)c3)c2)CCN1C(=O)OC(C)(C)C
Reactant: O=C1CCCC(=O)O1
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2cccc(-c3cccc(CNC(=O)CCCC(=O)O)c3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
A mixture of glutaric anhydride (31 mg, 0.27 mmol) and 1,1-dimethylethyl (2S)-4-{[3′-(aminomethyl)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (100 mg, 0.24 mmol) in THF (5 mL) was stirred at room temperature for about 10 min. It was concentrated. Purification via a CombiFlash (MeOH/DCM) system then afforded the desired product (70 mg).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[CH3:3][CH:2]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[O:6][N:5]=1)[CH3:1]
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)c1noc(N2CCC(C=O)CC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
A solution of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Step 3, 1.50 g, 6.33 mmol) in CH2Cl2 (30 mL) was treated with pyridinium chlorochromate (2.09 g, 9.49 mmol). The reaction mixture was stirred at ambient temperature for 5 h. Et2O (50 mL) was added, and the mixture was stirred for 10 min, filtered through a plug of Celite® on top of a layer of silica gel and the filtrate was concentrated. The resulting brown residue was mixed with Et2O (100 mL) and filtered. The filtrate was dried over Na2SO4, filtered and concentrated to give 1.10 g (78%) of 1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinecarbaldehyde as a light brown oil which was used without further purification. 1H NMR (400 MHz, CDCl3): δ 9.69 (s, 1H), 4.15-4.00 (m, 2H), 3.30-3.20 (m, 2H), 2.88 (septet, 1H, J=7.0 Hz), 2.55-2.45 (m, 1H), 2.10-1.95 (m, 2H), 1.80-1.65 (m, 2H), 1.27 (d, 6H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH:14][CH3:15]>C(O)C>[CH3:13][N:14]([CH3:15])[C:6]1[C:5]([F:9])=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([F:1])[CH:7]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Solvent: CCO
Product: CN(C)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: 80 °C

Procedure:
To a solution of 2,4,5-trifluoronitrobenzene (8.9 g, 50 mmol) in 100 mL ethanol is bubbled dimethylamine gas (6.8 g, 150 mmol). The solution is heated at 80° C. in a Parr pressure reactor for 6 hours. After evaporation of the solvent the product is chromatographed on silica gel/methylene chloride to give Compound 18.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]4OCC[O:21]4)[O:18][CH:19]=3)[CH:5]=[CH:4][C:3]1=2.Cl>C1COCC1>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[O:21])[O:18][CH:19]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(Cc3coc(C4OCCO4)c3)ccc21
Agent: Cl
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(Cc3coc(C=O)c3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was mixed with 2-{4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- 2-naphthalenyl)methyl]-2-furyl}-1,3-dioxolane (246 mg, 0.72 mmol), 3.0 N HCl (10 mL) and THF (20 mL). The reaction mixture stirred for 16 hours at room temperature and was concentrated to one half volume. The resulting mixture was partitioned between saturated NaCl and ether. The ether layer was dried over MgSO4 and concentrated to dryness. The resulting oil showed an inseparable impurity by TLC and the product was used without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:37]([NH:41][C:42](=[O:44])[O-:43])([CH3:40])([CH3:39])[CH3:38].Cl[C:46]1[CH:57]=[CH:56][C:55]2[CH:51]3[CH2:52][NH:53][CH2:54][CH:50]3[CH2:49][C:48]=2[CH:47]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:37]([NH:41][C:42](=[O:43])[O-:44])([CH3:40])([CH3:39])[CH3:38].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:46]1[CH:57]=[CH:56][C:55]2[CH:51]3[CH2:52][NH:53][CH2:54][CH:50]3[CH2:49][C:48]=2[CH:47]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: Clc1ccc2c(c1)CC1CNCC21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)NC(=O)[O-]
Solvent: CC#N
Product: Fc1cccc(F)c1-c1ccc2c(c1)CC1CNCC21
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Triphenylphosphine (2 mg), palladium(II) acetate (1 mg), 2,6-difluorophenyl boronic acid (20 mg, 0.12 mmol), and aqueous sodium carbonate (0.15 mL, 0.3 mmol) were added to a solution of (N-tert-butylcarbamate-6-chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 11, Step F) (30 mg, 0.1 mmol) in acetonitrile (1 mL), and stirred for 24 h at 80° C. The reaction mixture was concentrated, diluted with EtOAc (5 mL) and washed with H2O (5 mL). The organic extract was dried over MgSO4 and concentrated to give the subtitle compound, which was used without further purification. MS calculated for C22H23F2NO2+H: 372, observed: 372.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH:11]([C:17]([CH3:19])=[O:18])[C:12](OCC)=[O:13])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.O>[OH:18][C:17]1[CH2:19][C:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:32][C:12](=[O:13])[C:11]=1[CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1CCc1ccccc1
Temperature: 0 °C

Procedure:
Alternatively, the title compound could be prepared as follows. A suspension of 0.25 g (6.2 mmol) of sodium hydride in 5 mL of dry THF was cooled to 0° C. under nitrogen and treated with a solution of 1.40 g (6.0 mmol) of ethyl 2-(2-phenylethyl)acetoacetate in THF (2 mL). The solution was stirred at 0° C. for ten minutes, treated with 4.3 mL of 1.4 M n-butyllithium, and stirred for another fifteen minutes. A solution of 0.55 g (3.0 mmol) of benzophenone in THF (3 mL) was added all at once, and the reaction mixture was stirred at room temperature for two hours. Water (75 mL) was added, and the mixture was stirred overnight at room temperature. The solution was washed with ether. The aqueous layer was acidified to pH 2 with 6 N HCl and extracted with ethyl acetate; the extract was washed with brine, dried over magnesium sulfate, and concentrated. The residue was triturated with ether:hexane 1:1, and the solids were filtered and dried to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:15][C@H:12]([CH2:13][O:14][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C@@H:10]([OH:11])[CH2:9]1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 42 h
Yield: 39.4 %

Procedure:
To an ice-cooled solution of 5-ethyl-2'-deoxyuridine (1.0 g, 3.9 mmole) in dry pyridine (10 ml), is added p-toluenesulfonyl chloride (0.83 g, 4.4 mmole) and the reaction is kept at 0° C. for 42 hours. Tlc indicates that the starting material remains. Additional p-toluenesulfonyl chloride (180 mg) is added, and the solution is stirred at ca. 0° C. for 5 hours. The mixture is then evacuated in vacuo to a syrup, which is chromatographed on a short vacuum silica gel column using chloroform-methanol (15:1) to yield a white amorphous powder (630 mg, 39%), m.p. 173°-175° C.