Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[N:8][N:9]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([O:20][C:19]([F:18])([F:30])[F:31])[CH:22]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1c(-c2ccncc2)n[nH]c1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(OC(F)(F)F)c2)c1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 53.8 %

Procedure:
A blue-green suspension of 5-methyl-3-pyridin-4-yl-1H-pyrazole-4-carboxylic acid ethyl ester (700 mg, 3.03 mmol), molecular sieves 4A, 3-(trifluoromethoxy)benzeneboronic acid (1.25 g, 6.05 mmol), copper (II) acetate (824 mg, 4.54 mmol) and pyridine (0.48 ml, 6.05 mmol) in 14 ml CH2Cl2 was stirred under argon atmosphere and at room temperature for 5 days. The reaction mixture was diluted with CH2Cl2 and washed with a saturated solution of NaHCO3 and brine. The aqueous phases were extracted twice with CH2Cl2, the combined organic layers dried over magnesium sulfate, and evaporated. The residue was treated with EtOAc:toluene, 1:9, filtered off. The filtrate was evaporated and chromatographed twice (amino-phase silica gel, toluene:EtOAc 9:1) to afford the title compound as a colorless oil (638 mg, 54%). MS: 392.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1F.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>CN1C(=O)CCC1>[CH2:13]([O:20][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: O=C(O)Cc1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 4-chloro-3-fluorophenylacetic acid (5 g, 26.5 mmol) and benzyl alcohol (5.5 mL, 53.0 mmol) in NMP (50 mL) at 0° C. was added sodium hydride (60% in mineral oil; 2.3 g, 58.3 mmol), and the reaction was then heated to 120° C. and stirred overnight. The mixture was acidified to pH 4 and extracted with EtOAc to give (3-benzyloxy-4-chloro-phenyl)-acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:24]=[CH:25][CH3:26])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:24]=[CH:25][CH3:26])=[C:20]([NH:23][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC=Cc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC=Cc1c(NC(=O)OCc2ccccc2)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of {(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzo-dioxin-2-yl}methyl 4-methylbenzenesulfonate (4.20 g, 11.2 mmole) in ethyl acetate (150 mL) was added benzyl chloroformate (8.00 mL, 56.0 mmole). The reaction mixture was stirred under nitrogen for 0.5 hour, then a solution of N,N-diisopropylethylamine (9.75 mL, 56 mmole) in ethyl acetate (75 mL) was added dropwise over a period of 0.5 hour. The mixture was stirred at room temperature under nitrogen overnight. The reaction was diluted in volume to 350 ml and was then washed with 2N HCl (2×100 mL), saturated sodium bicarbonate (150 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated to an oil. The crude oil was column chromatographed on silica gel with 10% ethyl acetate/hexane to remove impurities and the product eluted with 60% ethyl acetate/hexane to give the (R)-enantiomer of the title compound as a yellow oil (4.5 g, 79%). 1H (CDCl3) doublet 7.8 δ (2 ); multiplet 7.4 δ (7H); doublet 6.7 δ (2H); multiplet 6.0-6.2 δ (2H); singlet 5.2 δ (2H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); multiplet 4.0 δ (1H); singlet 2.4 δ (3H); doublet 1.9 δ (3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+](C1C=CC=CC=1)([O-])=O.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>>[Cl:1][C:2]1[C:7]2[N:8]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccnc(Cl)c1N
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Clc1nccc2[nH]c(-c3ccccc3)nc12
Temperature: 175 °C
Reaction time: 0.5 h

Procedure:
A mixture of 100 mg (0.696 mmol) of 2-chloropyridine-3,4-diamine [H. Dvorakova et al., Collect. Czech. Chem. Commun., 58, 629 (1993)], 0.086 mL (0.835 mmol) of benzaldehyde, and 2 mL of nitrobenzene was heated at 175° C. under microwave irradiation for 30 min. The cooled solution was treated with 500 mg of Montmorillonite K 10 clay, and microwave irradiation at 175° C. was continued for an additional 30 min. The cooled mixture was filtered through Celite, and the filter cake was washed with methanol. The combined filtrate and washings were concentrated to dryness. Flash chromatography of the residue on silica gel (0-5% methanol in dichloromethane) yielded the title compound as a foam. LC-MS 230 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11](Cl)=[O:12])=[CH:7][C:6]=1[O:16][CH3:17])(=[O:3])[CH3:2].N[CH2:19][C:20]12[CH2:27][CH2:26][C:23]([CH3:28])([CH2:24][CH2:25]1)[C:22](=[O:29])[O:21]2.Cl.[N:31]1C=CC=CC=1>>[CH3:19][C:20]12[CH2:27][CH2:26][C:23]([CH2:28][NH:31][C:11](=[O:12])[CH:10]=[CH:9][C:8]3[CH:14]=[CH:15][C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([O:16][CH3:17])[CH:7]=3)([CH2:24][CH2:25]1)[C:22](=[O:29])[O:21]2
Reactant: CC12CCC(CN)(CC1)OC2=O
Reactant: c1ccncc1
Reactant: COc1cc(C=CC(=O)Cl)ccc1OC(C)=O
Agent: Cl
Product: COc1cc(C=CC(=O)NCC23CCC(C)(CC2)OC3=O)ccc1OC(C)=O

Procedure:
0.65 g of 4-acetoxy-3-methoxycinnamoyl chloride was added to a solution of 0.44 g of 1-aminomethyl-4-methyl-2-oxabicyclo[2.2.2]-octan-3-one (Example 30) in 10 ml of pyridine. The resultant solution was stirred at room temperature for 16 hours. After reaction, 30 ml of 2N hydrochloric acid was added to the reaction solution. The resultant solution was extracted five times with 20 ml of ethyl acetate. The organic layer obtained was washed three times with 2N hydrochloric acid, twice with an aqueous sodium hydrogencarbonate solution and once with an aqueous sodium chloride solution, and then was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo, yielding 0.58 g of N-[1-(4-methyl-2-oxo-3-oxabicyclo[2.2.2]octanyl)methyl]-4-acetoxy-3-methoxycinnamamide (a compound of the present invention) as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]1([Mg]Br)[CH2:7][CH2:6]1.C1COCC1.[CH2:15]([C@H:17]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH3:16]>>[CH:5]1([C@:21]2([OH:22])[CH2:20][CH2:19][N:18]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[C@H:17]2[CH2:15][CH3:16])[CH2:7][CH2:6]1
Reactant: CC[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Reactant: Br[Mg]C1CC1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (8.64 g), 0.5 mol/L cyclopropylmagnesium bromide—THF solution (58.0 mL) and benzyl (2S)-2-ethyl-3-oxopyrrolidine-1-carboxylate (2.37 g), the title compound was obtained as colorless oil (yield: 2.01 g, yield: 73%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12](=[CH2:18])[C:13]([O:15]CC)=[O:14])=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[CH2:25]([SH:27])[CH3:26]>C(OCC)(=O)C>[CH2:25]([S:27][CH2:18][CH:12]([CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)[C:13]([OH:15])=[O:14])[CH3:26]
Reactant: CCS
Reactant: C=C(Cc1ccnc2ccccc12)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCSCC(Cc1ccnc2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
597 mg of ethyl 2-(4-quinolylmethyl)acrylate was dissolved in 3 ml of ethylmercaptan. Then, 50 mg of potassium tert-butoxide was added thereto, and the mixture was stirred at room temperature for two hours. Then, the reaction solution was diluted with 60 ml of ethyl acetate and washed with 40 ml of water and then with 40 ml of a saturated sodium chloride aqueous solution. The organic layer was separated, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residual syrup was purified by silica gel column chromatography (n-hexane/ethyl acetate=5/2) and dried to obtain 640 mg (yield: 85%) of the desired product as syrup.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15](=[O:29])/[CH:16]=[CH:17]/[C:18]2[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[N:22][CH:23]=2)[CH2:5][CH2:4]1.C1C=CC2[N:38]([OH:39])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C>[OH:39][NH:38][C:26](=[O:28])/[CH:25]=[CH:24]/[C:21]1[CH:20]=[CH:19][C:18](/[CH:17]=[CH:16]/[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:6]2[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]2)=[O:29])=[CH:23][N:22]=1
Reactant: On1nnc2ccccc21
Reactant: CN1CCN(c2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)nc2)CC1
Agent: Cl
Agent: NOC1CCCCO1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(c2ccccc2C(=O)/C=C/c2ccc(/C=C/C(=O)NO)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.2 %

Procedure:
(E)-3-(5-{(E)-3-[2-(4-Methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylic acid hydrochloride (crude mixture from Step A, 400 mg) was suspended in DMF (10 ml). HOBT (240 mg, 1.78 mmol), EDC (340 mg, 1.78 mmol), TEA (0.371 ml, 2.67 mmol) and NH2OTHP (125 mg, 1.06 mmol) were added to the resulting slurry. The mixture was stirred overnight at room temperature and then partitioned between water and AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (DCM/MeOH/NH4OH 95:5:0.2). The collected fractions were evaporated and the resulting product was dissolved in DCM and treated with HCl/Et2O for 1 h. The precipitate was filtered off and purified by preparative LC-MS to give 23.7 mg of (E)-N-hydroxy-3-(5-{(E)-3-[2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-pyridin-2-yl)-acrylamide as its trifluoroacetate salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([OH:15])=[O:14].CO.Cl[CH2:19]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][C:13]([O:15][CH3:19])=[O:14]
Reactant: ClCCl
Reactant: COc1cc([N+](=O)[O-])ccc1CC(=O)O
Solvent: CO
Product: COC(=O)Cc1ccc([N+](=O)[O-])cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(2-methoxy-4-nitrophenyl)acetic acid (step 2, 1.2 g, 5.5 mmol) in methanol/dichloromethane (11 ml, 1/1) was added trimethylsillyldiazomethane (2 M, 5.6 ml, 11.8 mmol) and stirred for 10 min at room temperature. The mixture was quenched with saturated citric acid aqueous solution and the extracted with ethyl acetate (3×20 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 1.2 g of title compound as orange solid.
Reaction SMILES: O.NN.[N+:4]([C:7]1[CH:20]=[CH:19][C:10]2[S:11][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:13][C:9]=2[CH:8]=1)([O-])=O>[Ni].C(O)C>[NH2:4][C:7]1[CH:20]=[CH:19][C:10]2[S:11][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:13][C:9]=2[CH:8]=1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2cc(N)ccc2s1
Yield: 81.8 %

Procedure:
Raney Nickel (1 g) and hydrazine hydrate (3 ml) was added to ethyl 5-nitrobenzo[b]thiophene-2-carboxylate (25 g) (obtained as described in Syn. Comm., (1991), 21, 959-964) in ethanol (500 ml) at 60° C. A vigorous reaction ensued and the mixture refluxed. Further portions of Raney Nickel (1 g) and hydrazine hydrate (3 ml) were added at 10 minute intervals until a total of 15 ml had been added and the mixture was then refluxed for 90 minutes. The hot mixture was filtered and the filtrate evaporated. The residue was dissolved in hot ethanol (300 ml) and activated charcoal was added. The mixture was filtered and the filtrate evaporated to dryness to give ethyl 5-aminobenzo[b]thiophene-2-carboxylate (18 g) as a pale yellow solid. The solid was added to a stirred mixture of concentrated hydrochloric acid (50 ml) and water (130 ml) at -0C. A solution of sodium nitrite (5.6 g) in water (20 ml) was added slowly and then the mixture was allowed to stir at 0° C. for a further 30 minutes. A solution of potassium iodide (130 g) in water (200 ml) was then added. The mixture was allowed to warm to ambient temperature and then heated at 50° C. for 30 minutes. The mixture was allowed to cool, extracted with chloroform (150 ml) and the organic layer washed with sodium metabisulphite solution. The organic phase was dried (MgSO4) and evaporated to give a brown oil. The oil was purified by chromatography on silica using a gradient of hexane increasing to 10% ethyl acetate/hexane. The appropriate fractions were combined and evaporated to give ethyl 5-iodobenzo[b]thiophene-2-carboxylate (14 g) as an oil; NMR (d6 -DMSO): 1.35 (t, 3H), 4.4 (q, 2H), 7.8 (dd, 1H), 7.9 (d, 1H), 8.15 (s, 1H), 8.45 (d, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([NH:31][C@H:32]3[CH2:37][CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33]3)=[O:30])[CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.ClCCl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([C@:15]([C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([NH:31][CH:32]3[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]3)=[O:30])[CH2:24]2)([OH:22])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:5]=[CH:4][CH:3]=1
Reactant: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)N[C@H]2CCCN(C(=O)OC(C)(C)C)C2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCCC[C@@](O)(c1cccc(F)c1-c1cccc(C)c1)[C@@H]1CCCN(C(=O)NC2CCCNC2)C1
Reaction time: 0.33 h
Yield: 55.6 %

Procedure:
(S)-tert-Butyl 3-((R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)piperidine-1-carboxylate (20 mg, 0.033 mmol) was dissolved in TFA/dichloromethane (1 mL, 1:3, v/v), stirred 20 min, evaporated, and purified by preparative HPLC to give the (3R)-3-((S)-1-(6-fluoro-3′-methylbiphenyl-2-yl)-1-hydroxy-5-methoxypentyl)-N-(piperidin-3-yl)piperidine-1-carboxamide (9.39 mg) as its TFA salt. 1H NMR (400 MHz, CD3OD): 6 ppm 7.57 (d, J=8.4 Hz, 1H), 7.36-7.20 (m, 3H), 7.04-7.02 (m, 2H), 6.92 (m, 1H), 4.03 (m, 1H), 3.85-3.75 (m, 2H), 3.39-3.32 (m, 3H), 3.29 (s, 3H), 2.86 (m, 1H), 2.71-2.56 (m, 3H), 2.37, 2.35 (two s, 3H, rotamer), 1.99 (m, 2H), 1.88-1.26 (m, 13H), 0.92 (m, 1H). MS m/z 512 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([OH:22])=[O:21])[CH2:10][NH:9]4)=[CH:5]1)([CH3:3])[CH3:2].[CH:23]1(O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:21])[CH2:10][NH:9]4)=[CH:5]1)([CH3:3])[CH3:2]
Reactant: OC1CCCCC1
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)O)CN[C@@H]1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)OC3CCCCC3)CN[C@@H]1C2

Procedure:
Following the procedure of Example 1, 1.5 g of 1-isopropylergoline-8β-carboxylic acid were esterified with 15 g of cyclohexanol in the presence of 1.5 g of p-toluenesulfonic acid to yield 1-isopropyl-8β-(cyclohexyloxycarbonyl)ergoline. The product, 1.91 g of an oil, was converted to the maleate salt in a 6:1 ether/ethyl acetate solvent mixture. The salt was isolated by evaporation and then recrystallized from ether/methanol; yield=0.93 g of cyclohexyl 1-isopropyl-8β-(cyclohexyloxycarbonyl)ergoline maleate (96.77% pure by HPLC); molecular ion at 380; [α]25D =-40.64°.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][S:10]([C:3]2[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])(=[O:12])=[O:11])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(N)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1F
Product: COc1ccc(NS(=O)(=O)c2ccc(F)c(F)c2F)cc1Cl

Procedure:
The title compound was prepared in a manner similar to that described in Example 1 by replacing 4-fluoro-3-nitrophenylsulfonyl chloride with 2,3,4-trifluorophenylsulfonyl chloride and replacing p-anisidine with 3-chloro-4-methoxyaniline. 1H-NMR (CDCl3): δ 7.56 (1H, m), 7.17 (1H, d, J=2.0 Hz), 7.02 (1H, m), 6.98 (1H, dd, J=9.0 and 2.0 Hz), 6.78 (1H, d J=9.0 Hz), 6.72 (1H, br s), 3.83 (3H, s). MS(EI): 352 (7, M+), 351 (20), 156 (100). Anal. Calcd. for C13H9ClF3NO3S: C, 44.39; H, 2.58; N, 3.98; S, 9.11. Found: C, 44.31; H, 2.58; N, 3.96; S, 9.08.
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=O)[CH2:2][CH3:3].C[O:12][C:13](=[O:23])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19](N)=[CH:18][CH:17]=1>>[CH2:8]([CH:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:13]([OH:23])=[O:12])=[CH:17][CH:18]=1)=[O:7])[CH2:9][CH3:10]
Reactant: COC(=O)C=Cc1ccc(N)cc1
Reactant: CCCC(CCC)C(=O)O
Product: CCCC(CCC)C(=O)c1ccc(C=CC(=O)O)cc1

Procedure:
This compound, a precursor to compounds 9 and 10, was synthesized from 2-propyl-pentanoic acid (0.78 mL, 4.9 mmol) and 3-(4-amino-phenyl)-acrylic acid methyl ester (0.86 g, 4.9 mmol) according to Methods a and b aforementioned. Total yield, 1.05 g (70% for 2 steps); 1 H NMR (CDCl3, 10% DMSO-d6) δ 9.49 (s, 1 H), 7.71 (d, J=8.5 Hz, 2 H), 7.55 (d, J=15.9 Hz, 1 H), 7.45 (d, J=8.4 Hz, 2 H), 6.31 (d, J=15.9 Hz, 1 H), 2.40 (m, 1 H), 1.7-1.1 (m, 8 H), 0.87 (t, 6 H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([NH2:13])=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].N1C=CC=CC=1>C(#N)C.ClCCl>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([NH:13][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[C:17]([O:16][CH3:15])[CH:18]=3)=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1nnc(N)n1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CC#N
Product: COc1cccc(C(=O)Nc2nnn(Cc3c(C)noc3C)n2)c1
Yield: 34.6 %

Procedure:
2-((3,5-dimethylisoxazol-4-yl)methyl)-2H-tetrazol-5-amine (Example 10-39a) (102 mg, 0.528 mmol), 3-methoxybenzoyl chloride (0.065 mL, 0.528 mmol) and pyridine (0.043 mL, 0.528 mmol) in acetonitrile (3 mL) were stirred at 100° C. for one hour. The reaction was diluted with dichloromethane (30 mL) and washed with brine (30 mL). The organics were dried over sodium sulfate, concentrated and purified by reverse phase HPLC (Solvent system: acetonitrile/water 10% to 100% gradient), 25 minute run) affording N-(2-((3,5-dimethylisoxazol-4-yl)methyl)-2H-tetrazol-5-yl)-3-methoxybenzamide as a white crystalline solid (60 mg, 35% yield) MS M+H calculated 329.1. Found 329. 1H NMR (400 MHz, DMSO-d6): δ 2.02 (s, 3H), 2.46 (s, 3H), 3.81 (s, 3H), 5.78 (s, 2H), 7.16 (m, 1H), 7.42 (t, J=8 Hz, 2H), 7.54 (m, 1H), 11.3 (s, 1H). The compound had an IC50 on hT2R8 bitter receptor of 1.87 μM.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.C([Li])CCC.[O:22]1[C:26]2([CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[O:25]C[CH2:23]1>O1CCCC1.CCCCCC.O>[C:4]1([CH:3]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:1]3([CH2:23][O:22][C:26]4([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[O:25]3)[O:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(c1ccccc1)c1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: c1ccc(C2OC3(COC4(CCCCC4)O3)c3ccccc32)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a cooled (-50° C.) stirred solution of 27.7 g of 2-bromobenzhydryl methyl ether in 80 ml of dry tetrahydrofuran is added dropwise under nitrogen 60 ml of 2.4 M n-butyllithium in hexane. The mixture is stirred for 2 hours and a solution of 15.9 g of 1,4-dioxaspiro[4.5]decan-8-one in 50 ml of dry tetrahydrofuran is added dropwise, maintaining the temperature at -40° to -30° C. The mixture is stirred overnight at -70° to +10° C., diluted with 100 ml of water and extracted with 100 ml of dichloromethane. The organic phase is washed with water (2×50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. A solution of the residue in 400 ml of ethanol is stirred with 50 ml of hydrogen bromide/ether at room temperature for 3 hours. The solvent is removed under reduced pressure and the remaining oil crystallizes from 100 ml of methanol to give 39.6% of product, mp: 130°-132° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[F:17][C:18]1([F:26])[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1.CS(C)=O.C(CN)O>O>[F:17][C:18]1([F:26])[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH3:13])(=[O:11])=[O:10])=[CH:4][C:3]=2[N+:14]([O-:16])=[O:15])[CH2:20][CH2:19]1
Reactant: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCC(F)(F)CC1
Solvent: NCCO
Solvent: O
Solvent: CS(C)=O
Product: CCS(=O)(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1
Temperature: 65 °C
Yield: 63.8 %

Procedure:
N-(4-Fluoro-3-nitrophenyl)ethanesulfonamide (26 g, 0.107 mol), [(4,4-difluorocyclohexyl)methyl]amine (approx. 15 g), DIPFA (20 mL) and DMSO (100 mL) were mixed together and heated to 65° C. overnight. Ethanolamine (5 g) was added and the reaction mixture was stirred until complete disappearance of N-(4-fluoro-3-nitrophenyl)ethanesulfonamide (approx. 4-5 hrs.). The room temperature cooled down reaction mixture was poured in cold water (900 mL). The product was extracted with DCM (5×200 mL). The combined organic phases were washed with HCl 2N (3×200 mL) and dried over anhydrous Na2SO4. The solvent was removed and the crude product was purified on silica gel by flash chromatography (this material can be re-crystallized using a mixture of EtOAc and hexane) to provide the title product (24.2 g) as orange solid.