Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([O:22][N:23]1[CH:31]=[N:30][C:29]2[C:24]1=[N:25][C:26]([NH:33][CH:34]=[O:35])=[N:27][C:28]=2[Cl:32])[CH2:11][O:12][CH2:13][P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:32][C:28]1[N:27]=[C:26]([NH:33][CH:34]=[O:35])[N:25]=[C:24]2[C:29]=1[N:30]=[CH:31][N:23]2[O:22][CH:10]([CH2:9][OH:8])[CH2:11][O:12][CH2:13][P:14]([O:16][CH2:17][CH3:18])([O:19][CH2:20][CH3:21])=[O:15]
Reactant: CCOP(=O)(COCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(Cl)nc(NC=O)nc21)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOP(=O)(COCC(CO)On1cnc2c(Cl)nc(NC=O)nc21)OCC
Yield: 38.1 %

Procedure:
A solution of 9-[1-(t-butyldimethylsilyloxy) -3-(diethoxyphosphorylmethoxy)prop-2-oxy]-6-chloro-2-formamidopurine (100mg, 0.18 mmol) in tetrahydrofuran (5 ml) was treated. with tetrabutylammonium fluoride (60mg, 0.18 mmol) and the solution stirred for 4 h at 20° C. The solvent was reduced in vacuo and the residue partitioned between saturated sodium hydrogen carbonate and dichloromethane. The dichloromethane was separated and dried (MgSO4) and the solvent evaporated in vacuo. The residue was chromatographed on silica, eluting with chloroform-methanol 20:1, affording 6-chloro-9-[1-(diethoxyphosphorylmethoxy) -3-hydroxyprop-2-oxy]2-formamidopurine (30mg, 37%) as a clear oil. νmax (film) 3400, 3250, 1700, 1610, 1570 and 1500 cm-1 ; δH (CDCl3) 1.37 (6H, t, J7.1 Hz, 2×CH2CH3), 3.84-3.96 (7H, m, CH2OH+CH2OCH2P), 4.21 (4H, m, 2×CH2CH3), 4.57 (1H, m, CHON), 8.37 (1H, s, H-8), 8.67 (1H, d, J10.1 Hz, D2O exchangeable, NH), 9.50 (1H, d, J10.1 Hz, CHO); m/z (FAB+ve Ion) 438 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[CH:5][C:6]([NH2:14])=[CH:7][C:8]=2[C:9]([CH3:13])([CH3:12])[CH2:10][CH:11]=1.Br[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:23]([O:22][C:20](=[O:21])[C:19]1[CH:25]=[CH:26][C:16]([NH:14][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:1])=[CH:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[CH:17][CH:18]=1)[CH3:24]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: CC1=CCC(C)(C)c2cc(N)ccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(Nc2ccc3c(c2)C(C)(C)CC=C3C)cc1
Temperature: 100 °C

Procedure:
General Procedure L To a solution of 5,8,8-trimethyl-7,8-dihydro-naphthalen-2-yl-amine (Compound 64, 0.33 g, 1.8 mmol) and ethyl 4-bromobenzoate (0.52 g, 2.3 mmol) in 10.0 mL of toluene while stirring under argon were added cesium carbonate (0.89 g, 2.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 33 mg, 0.04 mmol) and bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 47 mg, 0.08 mmol) consecutively. The reaction was then heated at 100° C. for 24 h. The reaction was then cooled to room temperature, diluted with water and extracted 2 times with ethyl ether. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed in vacuo. The crude product was purified by silica gel chromatography (10% ethyl acetate in hexanes) to give the title compound as a yellow solid.
Reaction SMILES: [Na].CC1C(C[S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=O)=NC=CC=1OCC1(C)OCC2(OCCO2)CO1.C[C:35]1(C)[O:40]CC(COC2C=CN=C(CO)C=2C)C[O:36]1>>[O:36]1[C:31]2[C:32](=[CH:33][C:27]3[NH:26][C:25]([SH:23])=[N:29][C:28]=3[CH:30]=2)[O:40][CH2:35]1
Reactant: Cc1c(OCC2COC(C)(C)OC2)ccnc1CO
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Agent: [Na]
Product: Sc1nc2cc3c(cc2[nH]1)OCO3

Procedure:
The same procedure as in the steps (5f) to (5h) of Example 5 was repeated using (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methanol obtained in the step (12b) above and 5H-[1,3]dioxolo[4,5-f]benzimidazole-6-thiol obtained in the step (78c) above to obtain the title compound (347 mg, total 51.9% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][SH:11])=[CH:7][C:6]=1[CH3:12])[CH3:3].C[O-].[Na+].CO.Cl[CH2:19][CH2:20][NH:21][C:22]([NH:27][CH2:28][CH:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:23][N+:24]([O-:26])=[O:25]>CO>[CH3:3][N:2]([CH2:4][C:5]1[S:9][C:8]([CH2:10][S:11][CH2:19][CH2:20][NH:21][C:22]([NH:27][CH2:28][CH:29]([OH:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:23][N+:24]([O-:26])=[O:25])=[CH:7][C:6]=1[CH3:12])[CH3:1]
Reactant: Cc1cc(CS)sc1CN(C)C
Reactant: O=[N+]([O-])C=C(NCCCl)NCC(O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CSCCNC(=C[N+](=O)[O-])NCC(O)c2ccccc2)sc1CN(C)C
Reaction time: 24 h
Yield: 10.5 %

Procedure:
In 5 ml of methanol was dissolved 0.14 g of 5-(dimethylamino)methyl-2-mercaptomethyl-4-methylthiophene, and 0.2 ml of a 3.57N sodium methoxide-methanol solution was added at room temperature in a nitrogen atomsphere, after which 0.2 g of N-(2-chloroethyl)-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine was added at one time, after which the reaction mixture was allowed to stand at room temperature for 24 hours, and the deposited substance was removed by filtration, after which the solvent was removed by distillation under reduced pressure. Chloroform was added to the resulting residue, and the insolubles were removed by filtration, after which the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography (basic alumina, eluent; chloroform:methanol=10:1 by volume) to obtain 0.033 g (yield 11%) of N-{2-[[5-(dimethylamino)methyl-4-methyl-2-thienyl]methylthio]ethyl}-N'-(β-hydroxyphenethyl)-2-nitro-1,1-ethenediamine having a melting point of 114°-115° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([C:14]([OH:16])=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C.C(OCC)(=O)C.O>[C:24]1([CH2:23][NH:30][C:14]([CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[O:16])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)C1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 86.9 %

Procedure:
A solution of 9-fluorene carboxylic acid (2.10 g, 10.0 mmol) in 50 mL of CH2Cl2 was treated with oxalyl chloride in dichloromethane (6.0 mL, 12.0 mmol) and two drops of DMF. After 0.75 h, the mixture was concentrated under reduced pressure to give a white solid. The solid was diluted with 50 mL of CH2Cl2, cooled to 0° C., treated with benzylamine (1.17 g, 11.0 mmol) and pyridine (0.87 g, 11 mmol). The transparent yellow solution was stirred for 3 h at room temperature and diluted with ethyl acetate and water. The organic fraction was dried over Na2SO4 and concentrated to a white solid. The solid purified by trituration with hexanes and recrystalization from hot methanol to give 2.60 g (86%) of title compound as white flakes. mp 195°-200° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][NH2:23])[N:17]=3)=[N:13][C:12]=2[CH3:24])=[O:10])[CH:2]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][NH:23][S:32]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)(=[O:34])=[O:33])[N:17]=3)=[N:13][C:12]=2[CH3:24])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn(CCN)n2)sc1C(=O)NCc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1nc(-c2ccn(CCNS(=O)(=O)c3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 2-[1-(2-amino-ethyl)-1H-pyrazol-3-yl]-4-methyl-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide) and 4-fluoro-benzenesulfonyl chloride as describe in Example 81 and isolated as a white solid (0.052 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.83-7.87 (m, 2H), 7.73 (d, J=8 Hz, 1H), 7.42 (d, J=2 Hz, 1H), 7.27-7.33 (m, 1H), 7.16 (t, J=8 Hz, 2H), 6.79 (d, J=2 Hz, 1H), 6.09-6.14 (bm, 1H), 5.36 (bs, 1H), 4.64 (d, J=8 Hz, 2H), 4.25-4.29 (m, 2H), 3.47 (bs, 2H), 2.74 (s, 3H); MS (M+H)+=500.8; Rt=1.08 min; HRMS (M+H)+=501.12.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH:6]=[C:5]([S:14][CH2:15][CH3:16])[C:4]=2[CH:3]=1.[CH:17]([C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)=[CH2:18].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:8]1([CH3:13])[CH2:7][CH:6]=[C:5]([S:14][CH2:15][CH3:16])[C:4]2[CH:3]=[C:2](/[CH:18]=[CH:17]/[C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: C=Cc1ccc(C(=O)OCC)cc1
Reactant: CCSC1=CCC(C)(C)c2ccc(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(/C=C/c2ccc3c(c2)C(SCC)=CCC3(C)C)cc1
Temperature: 90 °C

Procedure:
To a degassed solution of 0.50 g (1.7 mmol) of 2-bromo-5,6-dihydro-5,5-dimethyl-8-(ethylthio)-naphthalene (Compound A36) and 0.45 g (2.5 mmol) of ethyl 4-vinylbenzoate in 4.0 mL of triethylamine, was added 109 mg (0.36 mmol) of tri-o-tolylphosphine and then 35 mg (0.16 mmol) of palladium(II) acetate. The reaction was heated at 90 ° C. for 2.25 h. The reaction was concentrated in vacuo and purified by flash chromatography (silica, 2% ethyl acetate in hexane) to afford the title compound as a colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[BrH:14].CC(O)=O.BrBr>>[BrH:14].[Br:14][CH2:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: CC(=O)c1ccc2ncccc2c1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.3 %

Procedure:
A 250 mL RB flask was charged with 1-(quinolin-6-yl)ethanone (3.82 g, 22.3 mmol) and 30% HBr/AcOH (45.0 ml). Bromine (1.14 ml, 22.1 mmol) was added slowly. This was stirred at room temperature for 4 hours, at which point full conversion to product (with a small amount of dibrominated side product) was observed. The reaction mixture was filtered and the solid was washed with Et2O to give 2-bromo-1-(quinolin-6-yl)ethanone hydrobromide (5.6359 g, 76.3% yield). The compound was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=1)#[N:19].O>CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:18]#[N:19])=[CH:31][CH:30]=2)[CH:7]=[C:8]([CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1cc(C=CC(=O)OC)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1cc(C=CC(=O)OC)cn1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Methyl 3-[2-(n-butyl)pyrrol-4-yl]acrylate (AE) (6.2 g) (prepared, e.g., as described in Preparation 21), in DMF (200 ml) was treated with sodium hydride (1.8 g of 60% mineral oil dispersion) at 0° C., and the resulting mixture was stirred for 30 minutes at 0° C. 2'-(Cyano)biphenyl-4-ylmethyl bromide (9.8 g) was added, and the mixture allowed to come to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with water, brine, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluting with 25% ethyl acetate/hexane, affording methyl 3-[2-(n-butyl)-1-(2"-cyanobiphenyl-4'-ylmethyl)pyrrol-4-yl]acrylate (9.17 g), a compound of Formula AF, as an oil.
Reaction SMILES: [OH:1]O.[CH:3]([S:6][CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH3:14])([CH3:5])[CH3:4]>C(O)(=O)C>[CH:3]([S:6]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH3:14])=[O:1])([CH3:5])[CH3:4]
Reactant: CC1CCC(C)C(SC(C)C)C1
Reactant: OO
Solvent: CC(=O)O
Product: CC1CCC(C)C(S(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen peroxide (2.1 ml. of 30%, 18.3 mmoles) in glacial acetic acid (15 ml.) was added dropwise to a stirred solution of 2,5-dimethylcyclohexyl isopropyl sulphide, prepared as in Part A above (3.4 g., 18.3 mmoles) in glacial acetic acid (25 ml.). Heat was evolved initially and the resulting solution was stirred overnight at room temperature. The reaction mixture was poured into ferrous sulphate solution (800 ml.) and extracted with ether three times. The combined extracts were washed twice with N NaOH solution, water, and then dried (MgSO4). Removal of the solvent left a colourless oil (3.6 g.) which was purified by column chromatography, on silica gel eluting with CHCl3, (the product has a t.l.c. Rf 0.2 on silica gel, eluting with CHCl3) to yield 2,5-dimethylcyclohexyl isopropyl sulphoxide. (Found: C, 65.1; H, 10.8. C11H22OS requires C, 65.3; H, 10.9%) as a viscous oil which shows a strong S=O stretching frequency at 9.5-9.9 microns in the I.R.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]1[N:20]=[C:19]([C:21]2[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:24]([OH:33])=[CH:23][C:22]=2[OH:34])[N:18]=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:16]=1.[OH-].[K+].Br[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(OCCO)C>[CH2:27]([C:25]1[C:24]([O:33][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:23][C:22]([OH:34])=[C:21]([C:19]2[N:20]=[C:15]([C:3]3[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:7][C:2]=3[OH:1])[N:16]=[C:17]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:18]=2)[CH:26]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCBr
Reactant: CCCCCCc1cc(-c2nc(-c3ccccc3)nc(-c3cc(CCCCCC)c(O)cc3O)n2)c(O)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCCO
Product: CCCCCCOc1cc(O)c(-c2nc(-c3ccccc3)nc(-c3cc(CCCCCC)c(OCCCCCC)cc3O)n2)cc1CCCCCC
Temperature: 90 °C

Procedure:
To a 350 mL sulfonation flask equipped with a mechanical stirrer, condenser, dropping funnel and a nitrogen atmosphere are charged 16.2 g (30 mmol) of the product of Example 62, 3.7 g (66 mmol) of powdered potassium hydroxide and 100 mL of 2-ethoxyethanol. To the resulting red solution are then added 10.9 g (66 mmol) of 1-bromohexane are added dropwise over 30 minutes. The mixture is heated to 90° C. for 20 hours and filtered hot. The filtrate is warmed to 100° C. and 1 mL of acetic acid is added. The solution is cooled to 0° C. to give a precipitate. The crude yellow product is recrystallized from 70 mL of 2-ethoxyethanol to give the title compound in a yield of 13.1 g as a yellow solid melting at 118°-121° C.
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:30])(=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25]C(=O)C)=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[O:1]([C:8]1[C:16]([S:17](=[O:30])(=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH2:25])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1Oc1ccccc1
Temperature: 25 °C

Procedure:
The mixture of 2.5 g of 4-phenoxy-3-benzylamino-5-(2-acetamidophenylsulfamoyl)-benzoic acid and 25 ml of 2N aqueous sodium hydroxide is refluxed for four hours under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to pH = 2 and the precipitate recrystallized from ethanol, to yield the 4-phenoxy-3-benzylamino-5-(2-aminophenylsulfamoyl)-benzoic acid of the formula ##SPC14##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:21][N:22]([CH3:24])[CH:23]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-n2ncnc2-c2ccccc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc(-n2ncnc2-c2ccccc2)cc1

Procedure:
A 1.5 g. portion of 1-(p-aminophenyl)-5-phenyl-1H-1,2,4-triazole in 10.0 ml. of dimethylformamide dimethylacetal and 4.0 ml. of dimethylformamide is heated at 90°-95° C. for 1.5 hours. The solution is concentrated to 10 ml., cooled and then evaporated at 60° C. to an oil. This oil is triturated with 50 ml. of ether. The solid is collected by filtration and recrystallized from chloroform-hexane giving 670 mg. of the desired product as yellow plates, mp. 109°-111° C.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[C:16]([CH3:21])=[N:17][CH:18]=[CH:19][CH:20]=1.[C:22](=O)([O:26]CC)[O:23][CH2:24][CH3:25]>C1COCC1>[CH3:13][O:14][C:15]1[C:16]([CH2:21][C:22]([O:23][CH2:24][CH3:25])=[O:26])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)OCC
Reactant: COc1cccnc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)Cc1ncccc1OC
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A stirred solution of diisopropylamine (0.385 mL, 2.70 mmol) in THF (2 mL) at 0° C. was treated slowly with 1.6 M n-butyllithium in hexanes (1.69 mL, 2.70 mmol). The mixture was stirred for 15 min, then was added over 5 min to a stirred solution of 3-methoxy-2-picoline (0.133 g, 1.08 mmol) and diethyl carbonate (0.262 mL, 2.16 mmol) in THF (5 mL) at −78° C. After stirring for 45 min more, the cooling bath was removed and stirring was continued overnight at room temperature. The mixture was treated with saturated aqueous NH4Cl and diluted with EtOAc. The organic phase was separated, washed sequentially with saturated aqueous NaHCO3 and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (12 g), eluting with 50% EtOAc-hexanes, to provide ethyl 2-(3-methoxypyridin-2-yl)acetate as an oil (0.17 g, 81% yield). Mass spectrum m/z 196 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([NH:25][C:26]([CH3:33])([CH3:32])[CH2:27][O:28]C(=O)C)=[O:24])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:34]1[O:51][C@H:50]([CH2:52][O:53]C(=O)C)[C@@H:45]([O:46]C(=O)C)[C@H:40]([O:41]C(=O)C)[C@H:35]1[O:36]C(=O)C)(=O)C.C[O-].[Na+].C(=O)=O>CO>[OH:28][CH2:27][C:26]([NH:25][C:23]([NH:22][CH2:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:8]2[C:9]([CH3:11])=[CH:10][C:5]([OH:4])=[C:6]([C@@H:34]3[O:51][C@H:50]([CH2:52][OH:53])[C@@H:45]([OH:46])[C@H:40]([OH:41])[C@H:35]3[OH:36])[CH:7]=2)=[CH:14][CH:15]=1)=[O:24])([CH3:32])[CH3:33]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(CCCNC(=O)NC(C)(C)COC(C)=O)cc3)c(C)cc2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(O)c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(CCCNC(=O)NC(C)(C)CO)cc1
Temperature: 25 °C
Yield: 73.7 %

Procedure:
To a methanol solution (1 mL) of (1S)-1-[2-(acetoxy)-5-[4-[3-[[[[2-(acetoxy)-1,1-dimethylethyl)amino]carbonyl]amino]propyl]benzyl]-4-methylphenyl]-1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol (70 mg) was added sodium methoxide (a 1 M methanol solution, 0.5 mL, 0.5 mmol), and the mixture was stirred for an hour at room temperature. To this reaction solution was added dry ice, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (chloroform:methanol=5:1) to obtain the title compound (35 mg, 31%, 3 steps) as a colorless oily compound. NMR data and MS data of the compound are shown in Table 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15](O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:34]1[CH2:44][CH2:43][CH2:42][CH2:41][CH:35]1[C:36]([O:38][CH2:39][CH3:40])=[O:37].CCN(C(C)C)C(C)C>ClCCl.CN(C)C=O>[CH2:39]([O:38][C:36]([CH:35]1[CH2:41][CH2:42][CH2:43][CH2:44][N:34]1[C:15](=[O:16])[C:14]1[CH:18]=[C:19]([Cl:21])[CH:20]=[C:12]([O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:13]=1)=[O:37])[CH3:40]
Reactant: CCOC(=O)C1CCCCN1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CCCCN1C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Reaction time: 18 h
Yield: 101.5 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.12 g) in dichloromethane (4 ml) was added dimethylformamide (0.05 ml) followed by 2M oxalyl chloride solution in dichloromethane (0.183 ml). The resultant solution was stirred at room temperature for 1 h, and then ethyl pipecolinate (0.096 g) followed by DIPEA (0.160 ml) were added. After 18 h, the reaction mixture was concentrated under reduced pressure and the residue was subjected to preparative hplc. The title compound (0.165 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[F:29]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Fc1ccccc1CBr
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccccc3F)C2=O)cn1
Yield: 42 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 1-(bromomethyl)-2-fluorobenzene. Yield 42%. MS M+H calculated 384.1. found 384.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.08 uM.
Reaction SMILES: O[C:2]1([C:12]#[N:13])[CH2:11][CH2:10][C:5]2([CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3]1.N1C=CC=CC=1.S(Cl)(Cl)=O.Cl>O1CCCC1>[CH2:9]1[C:5]2([CH2:10][CH2:11][C:2]([C:12]#[N:13])=[CH:3][CH2:4]2)[CH2:6][CH2:7][CH2:8]1
Reactant: N#CC1(O)CCC2(CCCC2)CC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#CC1=CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
To a solution of 8-hydroxy-spiro[4.5]decane-8-carbonitrile (3.9 g) obtained in Step 1 in tetrahydrofuran (30 mL) were added successively pyridine (4.4 mL) and thionyl chloride (1.8 mL), followed by stirring the reaction mixture at room temperature for 15 hours. Then, after addition of 1N aqueous hydrochloric acid solution, the reaction mixture was extracted with diethyl ether. The organic layer was washed successively with 1N aqueous hydrochloric acid solution and saturated brine, dried and concentrated to give spiro[4.5]dec-7-ene-8-carbonitrile (2.8 g).