Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[C:14]([O:29][CH2:30][CH2:31]Br)=[C:15]([C:20]2([CH3:28])[O:25]CC(C)(C)CO2)[CH:16]=[C:17]([Cl:19])[CH:18]=1>O1CCCC1.O>[C:20]([C:15]1[C:14]2[O:29][CH2:30][CH2:31][C:13]=2[CH:18]=[C:17]([Cl:19])[CH:16]=1)(=[O:25])[CH3:28]
Reactant: CC1(C)COC(C)(c2cc(Cl)cc(Br)c2OCCBr)OC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)cc2c1OCC2
Reaction time: 1.5 h
Yield: 25 %

Procedure:
1.6 M n-Butyllithium in hexane solution (4.7 mL, 7.6 mmol) was added dropwise to a solution of 2-[3-bromo-2-(2-bromoethoxy)-5-chlorophenyl]-2,5,5-trimethyl-1,3-dioxane (Reference compound No. 5-1, 2.8 g, 6.3 mmol) in anhydrous tetrahydrofuran (30 mL) over 5 minutes at −70° C. and the whole was stirred for 1.5 hours. The whole was stirred under ice cooling for 1 hour and at room temperature overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL), and brine (50 mL), and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and tetrahydrofuran (30 mL), methanol (5 mL) and 1N aqueous hydrogen chloride solution (30 mL) were added to the residue, and the whole was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and brine (50 mL), and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the obtained solid was filtered off with hexane (10 mL) to give the title reference compound (0.31 g) as a pale yellow solid (Yield 25%).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:7].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[Cl:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(Cl)c1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium ethoxide (117.8 g, 1.73 mol) was added in portions to a solution of 3-chloroacetophenone (178.5 g, 1.15 mol) and diethyl oxalate (188 mL, 1.39 mol) in ethanol (3 L) at 0° C. The mixture was stirred at room temperature for 1 h and was then heated at 70° C. for 2 h. After cooling, the mixture was acidified with 3M hydrochloric acid (pH˜3). The solvent was distilled off and to the mixture was added EtOAc. The organic layer was washed with water and saturated brine. The solvent was distilled off to give crude title product, which was used directly in the next step. MS (M+−1)=253.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.CN[C@H]1CCCC[C@@H]1NC>[Cu]I.CS(C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:17][CH:16]=1
Reactant: c1nc[nH]n1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Brc1ccc(-n2cncn2)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
A mixture of 1H-1,2,4-triazole (122 mg, 1.78 mmol, Aldrich), K3PO4 (751 mg, 3.53 mmol, Aldrich), Copper(I) iodide (33.7 mg, 0.177 mmol, Alfa-Aesar), 1-bromo-4-iodobenzene (500 mg, 1.78 mmol, Aldrich), (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (25 mg, 0.18 mmol, Strem) and DMSO (2 mL) was purged with Argon and then heated under microwave condition at 140° C. for 30 min and then at 160° C. for 30 min. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The organic layers were combined and concentrated in vacuo to a brown oil. The solid was purified by flash chromatography (SiO2, 0-100% EtOAc in hexanes) to yield 195 mg of desired product as a white solid. MS (ESI) 224 (M+H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([CH2:20][C:21]([O:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:26][CH:25]=1)=[O:22])=[O:19]>ClCCl>[Cl:4][CH:20]([C:18](=[O:19])[NH:17][C:8]1[CH:9]=[C:10]([C:13]([F:15])([F:16])[F:14])[CH:11]=[CH:12][C:7]=1[Cl:6])[C:21]([O:23][C:24]1[CH:45]=[CH:44][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:26][CH:25]=1)=[O:22]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)C(Cl)C(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.5 %

Procedure:
Sulphuryl chloride (9.5 g, 70.2 m mol) in dichloromethane (15 ml) was slowly added to a solution of the 4-equivalent coupler from (d) (40 g, 70.2 m mol) in dichloromethane (250 ml). After stirring at room temperature for 20 h, the volatiles were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (elutant 10% ethyl acetate in petrol (b.p. 60°-80° C.)) followed by recrystallization from methanol to give a white solid (25.2 g, 60%).
Reaction SMILES: [C:1]1([C:7]([NH:9][NH2:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14].O.C(=O)(O)[O-].[Na+]>C1COCC1.ClCCl.CO.C(OCC)(=O)C>[Cl:11][CH2:12][C:13]([NH:10][NH:9][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:8])=[O:14]
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NNC(=O)c1ccccc1

Procedure:
A suspension of 500 g (3.67 mol) of benzenecarbohydrazide in 3.75 liters of THF was heated to reflux, whereupon the benzenecarbohydrazide dissolved. 497.7 g (4.41 mol) of chloroacetyl chloride, dissolved in 125 ml of THF, were added dropwise to this solution, and the solution was stirred under reflux for another 30 min. After the reaction had gone to completion, (monitored by TLC, mobile phase dichloromethane/methanol 9:1), 22.5 liters of water and 10 liters of ethyl acetate were added and the mixture was adjusted to pH 7 with solid sodium bicarbonate. The aqueous phase was extracted once with 2.5 liters of ethyl acetate. The combined organic phases were dried and the solution was then concentrated to dryness under reduced pressure. The white solid obtained was dissolved in a 1:1 mixture of dichloromethane and methanol and applied to 3 kg of silica gel. Using two portions of silica gel (8 kg each), the product was chromatographed using initially 50 liters of dichloromethane/ethyl acetate 7:3 and then 125 liters of dichloromethane/ethyl acetate 1:1 as mobile phase. Concentration of the product fractions gave 424 g (1.99 mol, 54% of theory) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:5]=1[OH:18])[CH:2]=[CH2:3].S(OC)(O[CH3:23])(=O)=O.[OH-].[K+]>O>[CH3:23][O:18][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:9][CH:8]=[CH:7][C:6]=1[O:10][C:11]1[C:12]([CH3:17])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COS(=O)(=O)OC
Reactant: C=CCc1cccc(Oc2ccccc2C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=CCc1cccc(Oc2ccccc2C)c1OC

Procedure:
2-Allyl-6-(o-tolyloxy)phenol (80 g), dimethyl sulfate (63 ml), potassium hydroxide (56 g) and water (200 ml) were treated in a similar manner to that of Example 4-(1) to give oily o-tolyl 2-methoxy-3-allylphenyl ether (78.6 g). bp 120°-135° C./0.7 mmHg.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>O1CCOCC1>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:31][CH:30]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)cc1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCOCC3)cc2)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
A dry 50 mL flask was charged with N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (prepared below, 70 mg, 0.217 mmol) and Dioxane (10 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (200 mg, 1.122 mmol), and the mixture was stirred for 24 h at 100° C. Subsequently, the reaction mixture was cooled to room temperature. The resulting suspension was concentrated in vacuo and the resulting solid residue was recrystallized from iPrOH (˜5 mL). The solid recovered through filtration then was subjected to flash silica gel chromatography using a 5% MeOH/CHCl3 eluant mixture to afford the title compound in 33% yield (35 mg, 0.072 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:3]=1[CH:4]=O.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.CC(O)=O.ClCCCl>[Br:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:3]=1[CH2:4][NH:29][C:26]1[CH:25]=[CH:24][C:23]([C:17]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])=[CH:28][CH:27]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Cl)c(CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A DCE solution (33 mL) of 2-bromo-6-chloro-4-(trifluoromethyl)benzaldehyde (3.7 g, 12.9 mmol), 2′,4′-dichloro-[1,1′-biphenyl]-4-amine (3.4 g, 14.4 mmol), and HOAc (3.0 mL) was heated to 70° C. After 10 min the homogeneous solution was cooled to room temperature and solid NaBH(OAc)3 (5.46 g, 25.8 mmol) was added and the resulting mixture was warmed to 40° C. After 30 min, EtOAc and 2 M K2CO3 were added and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with 4 M NaCl, dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=1>CN(C)C=O>[C:10]1([C:8]2[N:9]=[CH:4][N:5]=[C:6]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2ncnc(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
25 g (62.5 mmol) of product b) are dissolved in 200 ml of dimethylformamide under a protective-gas atmosphere, and 7.7 g of 60% NaH in mineral oil (194 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-4,6-diphenyl-1,3,5-triazine (25 g, 68 mmol) in 300 ml of dimethylformamide is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is extracted with hot toluene, recrystallised from dichloromethane/isopropanol and finally sublimed in a high vacuum, the purity is 99.9%. The yield is 17 g (27 mmol, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH2:15].C(N(CC)CC)C.[OH-].[K+].[C:25](Cl)(=[O:28])[CH2:26][CH3:27].[Cl-]>ClCCl.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH2:13][CH2:14][NH:15][C:25](=[O:28])[CH2:26][CH3:27]
Reactant: CCC(=O)Cl
Reactant: COc1ccc2ccccc2c1CCN
Agent: [Cl-]
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(=O)NCCc1c(OC)ccc2ccccc12
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
1.40 g (6.96 mmol) of 2-(2-methoxynaphthyl)ethylamine, which is solubilized in 20 cm3 of anhydrous dichloromethane, are introduced into a 100-cm3 two-necked flask under an inert atmosphere. The mixture is cooled with an ice bath and stirred, and 1.5 cm3 (10.4 mmol) of triethylamine dried over potassium hydroxide and 0.7 cm3 (8.056 mmol) of propanoyl chloride are introduced. After the introduction of the reactants, the ice bath is removed and reaction is allowed to proceed at room temperature for 30 min. Hydrolysis of the excess chloride is carried out by pouring the reaction mixture into water. After extraction three times with dichloromethane, the organic phase is dried over magnesium sulfate. After evaporation of the solvent and recrystallization of the solid obtained, in the heated state, in a pentane/ethyl acetate mixture, 0.70 g (2.72 mmol) of N-[2-(2-methoxy-1-naphthly)ethyl]propionamide (white solid) is obtained, equivalent to a yield after purification of 39%. ##STR19##
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[NH:8][C:9]([CH3:29])=[C:10](C(O)=O)[CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])[C:12]=1[N+:13]([O-:15])=[O:14]>C(O)C>[CH3:6][C:7]1[NH:8][C:9]([CH3:29])=[CH:10][CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])[C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)C([N+](=O)[O-])=C(C)N1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CC1=CC(c2ccccc2C(F)(F)F)C([N+](=O)[O-])=C(C)N1

Procedure:
On heating in ethanol with the addition of a trace of sulphuric acid, 1,4-dihydro-2,6-dimethyl-3-nitro-4-(trifluoromethylphenyl)-pyridine-5-carboxylic acid (obtained as described in Example 30) was decarboxylated to give 1,4-dihydro-2,6-dimethyl-3-nitro-4-(trifluoromethylphenyl)pyridine in quantitative yield. Melting point 201° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[OH:9][C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=2[OH:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Oc1c(-c2ccnc(Cl)n2)cccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A vial was charged with 2,4-dichloropyrimidine (362 mg, 2.43 mmol), 2-hydroxy-3-trifluoromethylphenylboronic acid (250 mg, 1.21 mmol) and trans-dichlorobis(triphenylphosphine)palladium (II) (42.6 mg, 0.061 mmol). Acetonitrile (6 mL) and sodium carbonate (3.0 mL, 1.0 M aqueous, 3.0 mmol) were added, and the resulting mixture was degassed via nitrogen sparge. The reaction mixture was stirred at 70° C. for 6 h, then was allowed to cool to ambient temperature and was poured into water. The mixture was extracted with EtOAc, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 25% EtOAc in hexanes, then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 275.0 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 13.43 (s, 1H), 8.74 (d, J=5.5 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.76 (app d, J=5.5 Hz, 2H), 7.06 (t, J=8.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[CH:8]=1.[Br:14]Br>C(O)(=O)C>[Br:14][C:9]1[N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1
Reactant: BrBr
Reactant: FC(F)(F)c1ccc2nccn2c1
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc2ncc(Br)n2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 6-trifluoromethyl-imidazo[1,2-a]pyridine (1 eq, 6.2 mmol, 1.1 g) in acetic acid (15 ml) under an inert atmosphere of argon is added dropwise bromine (1 eq, 6.2 mmol, 0.313 ml). After stirring at room temperature for 1 hour, the reaction mixture is filtered to afford the title compound as a beige solid; [M+H]+=266(268)
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH:11]1([C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17])[CH2:13][CH2:12]1.C(N(CC)CC)C>ClCCl.O>[CH:11]1([C:14]([CH3:19])([CH3:18])[CH2:15][CH:16]=[O:17])[CH2:13][CH2:12]1
Reactant: CC(C)(CCO)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(CC=O)C1CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
Step D To a solution of oxalyl chloride (0.75 g, 5.9 mmol) (Aldrich) in dichloromethane (30 mL) at −78° C. was added the solution of dimethyl sulfoxide (0.84 mL, 11.8 mmol) in dichloromethane (5 mL) dropwise. After 5 mins, the solution of 3-cyclopropyl-3-methyl-butan-1-ol (0.69 g, 5.4 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (2.7 mL, 19.4 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-cyclopropyl-3-methyl-butyraldehyde as a light yellow oil (Yield: 0.68 g, 98%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]=[N:42][CH:43]=[C:44]([CH3:46])[N:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]=[N:42][CH:43]=[C:44]([CH3:46])[N:45]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncc(C)n4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncc(C)n4)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 72.8 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5-methyl-1,2,4-triazin-3-yl)methylthio]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.67 g) was suspended in dichloromethane (100 ml). The suspension was cooled to −78° C. A solution of 3-chloroperbenzoic acid (0.38 g) in dichloromethane (7 ml) was added dropwise to the suspension. The mixture was stirred for 1.5 hours at −78° C. To the mixure was added sodium thiosulfate solution, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(5-methyl-1,2,4-triazin-3-yl)methylsulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 39) (0.50 g) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:15]1[CH2:16][CH2:17][CH2:18][N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1noc(C)c1Cn1cc(N2CCCNC2=O)cn1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2CCCN(Cc3ccccc3)C2=O)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.4 %

Procedure:
1-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)tetrahydropyrimidin-2(1H)-one (example 9-5a) (50 mg, 0.18 mmol) and 60% sodium hydride (8 mg, 0.20 mmol) in DMF (3 mL) were stirred at room temperature for 15 minutes then cooled to 0° C. Benzyl bromide (31 mg, 0.18 mmol) was added to the mixture and allowed to warm up at room temperature then stirred for 2 hours. The reaction was quenched with methanol and concentrated. The reaction was diluted with brine (50 mL) and extracted with dichloromethane (2×, 50 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated on the rotovap. The residue was taken up in dichloromethane (5 mL) and purified by silica column chromotography (100% to 90% dichloromethane in methanol:30 minute gradient) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)tetrahydropyrimidin-2(1H)-one (20 mg, 30%) as a white solid. 1H NMR (DMSO-d6, 400 MHz)): δ1.85-1.91 (m, 2H), 2.10 (s, 3H), 2.37 (s, 3H), 3.12 (m, 2H), 3.55 (t, J=5.8 Hz, 2H), 4.48 (s, 2H), 5.05 (s, 2H), 7.22-7.31 (m, 5H), 7.49 (s, 1H), 7.84 (s, 1H). LC/MS; [M+H] calculated for C20H23N5O2; expected 366.19. found 366.15. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.65 μM.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]([C:15]([OH:17])=[O:16])=[C:4]([CH3:18])[CH:3]=1.C(=O)(O)[O-].[Na+].[NH3:24]>O1CCCC1>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([S:11]([NH2:24])(=[O:13])=[O:12])[C:5]([C:15]([OH:17])=[O:16])=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(C)c(C(=O)O)c(S(=O)(=O)Cl)c1C(=O)O
Reactant: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)O)c(S(N)(=O)=O)c1C(=O)O
Reaction time: 2 h

Procedure:
To a mixture of 5 g dimethyl 2-(chlorosulfonyl)-1,3-benzenedicarboxylic acid and 1.4 g sodium bicarbonate in 25 ml tetrahydrofuran (dried over alumina) at 0°-5° was added, dropwise, a solution of 0.4 ml ammonia in 5 ml dry tetrahydrofuran. After stirring for 2 hours, the solution was evaporated, the resulting solid was washed with methylene chloride, then with water to give 2.4 g, m.p. 169° of dimethyl 2-(aminosulfonyl)-1,3-benzenedicarboxylic acid.
Reaction SMILES: [K].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=1)([O-:4])=[O:3].Cl[CH2:17][CH:18]([OH:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[OH:20][CH:18]([CH3:19])[CH2:17][O:11][C:8]1[CH:9]=[CH:10][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][C:7]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: CC(O)CCl
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCC(C)O

Procedure:
0.5 mol (117 g) of the potassium salt of 4-nitro-2-acetylaminophenol is introduced into 300 ml of dimethylformamide in a boiling water-bath, with stirring. The mixture is treated with 0.5 mol (47.25 g) of 1-chloropropan-2-ol. With the heating maintained, 0.5 mol (47.25 g) of 1-chloropropan-2-ol and 0.25 mol (34.5 g) of potassium carbonate are added four times at 2-hour intervals. After heating for 10 hours, the reaction mixture is poured into 1,500 ml of iced water. The expected product, which has precipitated, is filtered off. It is washed with a 0.5N solution of sodium hydroxide and then with water. After drying in vacuo at 60° C., it melts at 123° C.