Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH:14]([CH3:51])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C>[OH:13][CH:14]([CH3:51])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (271 mg), sodium hydrogen carbonate (437 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C. for 30 min, 4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (138 mg) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→35/65 (volume ratio)] to give the title compound as a colorless amorphous compound (57 mg, 37%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C1C=CC=CC=1>[Cl:8][C:7]1[C:2]([NH:1][C:18](=[O:19])[CH2:17][Cl:16])=[C:3]([SH:9])[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1c(S)cccc1Cl
Reactant: O=C(Cl)CCl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(CCl)Nc1c(S)cccc1Cl
Temperature: 25 °C
Yield: 84.5 %

Procedure:
2-Amino-3-chlorothiophenol (1.6 g) and pyridine (0.8 g) were dissolved in benzene (20 ml), and chloroacetyl chloride (1.2 g) was gradually added dropwise thereto at room temperature (25° C.) with stirring. After the addition was finished, the reaction mixture was stirred at room temperature for 30 minutes, and the solvent was removed under reduced pressure. The residue obtained was washed with water, dried and recrystallized from chloroform to obtain 2.0 g of 3-chloro-2-chloroacetylaminothiophenol (m.p. 186°-187° C.).
Reaction SMILES: [Br-].O[CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].[ClH:15].[Cl-]>O>[ClH:15].[Cl-:15].[Cl:15][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][N+:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]
Reactant: CN(CCCO)CCC[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Agent: [Cl-]
Solvent: O
Product: CN(CCCCl)CCC[N+](C)(C)C
Reaction time: 1 h

Procedure:
A sample of 44.4 g. of product from Step 3, 3-[N'-(3-hydroxypropyl)-N'-methylamino]-N,N,N-trimethyl-1-propanaminium bromide, is dissolved in 500 ml. of water and acidified to pH 2 with concentrated hydrochloric acid. The solution is passed through a column of Dowex 1-X2 chloride form ion exchange resin and the eluant is evaporated under reduced pressure. The residual viscous oil is dried in vacuo and treated with thionyl chloride (25 ml.) added dropwise with stirring during one hour. The solution is heated at 50° for 1.5 hours and then evaporated under reduced pressure.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([N:11]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([CH3:21])=O.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH:19]([N:14]1[CH2:15][CH2:16][CH2:17][N:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1][CH2:2][CH2:3]2)[CH2:12][CH2:13]1)([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: c1ccc2c(c1)CCCC2N1CCCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)N1CCCN(C2CCCc3ccccc32)CC1
Yield: 96.6 %

Procedure:
R(−) N-(1,2,3,4-tetrahydronaphthalen4-yl)homopiperazine (2.00 g; 8.7 mmol) in THF (50 ml), methanol (25 ml) and acetone (15.5 ml; 174 mmol) was reacted with sodium cyanoborohydride (1.1 g; 17.6 mmol) and acetic acid (1.0 ml) as in Example 14. Kugelrohr distillation gave the title compound (2.29 g), bp (air bath temperature) 165-175° C. at 180 mtorr; [α]D22−74° (c=0.64, methanol).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[C:13](Cl)(=[O:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:13]([C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[NH:8]2)=[CH:4][C:3]=1[OH:2])(=[O:15])[CH3:14]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1O)CC(=O)N2
Reaction time: 8 h
Yield: 52.4 %

Procedure:
The procedure described in Example 33a was followed with 1,3-dihydro-5-methoxy-2H-indol-2-one (4.4 g, 26.96 mmol), acetyl chloride (4.8 mL, 67.41 mmol), and AlCl3 (14.4 g, 107.8 mmol) in 1,2-dichloroethane (210 mL) for 6 hours. After aqueous work-up and overnight stirring, a precipitate was obtained. This yellow solid was collected by filtration and dried to give the title compound (2.7 g, 52%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[O:22])[CH2:11]1)=[O:7])(C)(C)C.[ClH:33].O1[CH2:39][CH2:38][O:37][CH2:36]C1>>[NH2:25][C:26]1[C:27]([Cl:33])=[CH:28][C:39]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH3:32])[CH:24]=3)=[O:22])[CH2:11]2)=[O:7])=[C:38]([O:37][CH3:36])[CH:31]=1
Reactant: C1COCCO1
Reactant: Cl
Reactant: Cn1cc(C(=O)NCCCCCN2CC[C@H](CNC(=O)OC(C)(C)C)C2)c2ccccc21
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCCNC(=O)c2cn(C)c3ccccc23)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-(5-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)-pentyl)-1-methyl-1 H-indole-3-carboxamide (1.53 g) was dissolved in 4N hydrochloric acid-dioxane solution (10 ml) and the mixture was stood at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. Dimethylformamide (30 ml) was added to the residue and the mixture was neutralized with triethylamine (1.45 ml). 4-Amino-5-chloro-2-methoxybenzoic acid (0.70 g) and 1-hydroxybenzotriazole (0.51 g) were added thereto, and the mixture was stirred at 0° C. for 15 min. Then, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.73 g) was added, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure. Aqueous potassium carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give 0.89 g of N-(5-((3R)-3-(4-amino-5-chloro-2-methoxybenzoylaminomethyl)pyrrolidin-1-yl)pentyl)-1-methyl-1 H-indole-3-carboxamide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O.[S-2:15].[Na+].[Na+].[S].[CH2:19](O)[CH3:20]>>[CH3:11][O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[S:15][C:19]([CH3:20])=[N:12][C:3]=2[CH:4]=1
Reactant: [S-2]
Reactant: CCO
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1OC
Agent: [Na+]
Agent: [S]
Product: COc1cc2nc(C)sc2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1-Bromo-4,5-dimethoxy-2-nitro-benzene (10 g) was suspended into ethanol (50 ml). To the reaction mixture was added the suspension of sodium sulfide (5 g) and sulfur (0.65 g) in ethanol (12 ml). The reaction mixture was refluxed 1.5 hour and then the resultant solid was filtered and washed with hot water and ethanol. The dry solid was slurried with acetic acid (60 ml) and acetanhydridi (35 ml). To the suspension was gradually added zinc (16.6 g) and the suspension was stirred at room temperature for 15 min before filtering off. The residue was evaporated to dryness. The product was purified by column chromatography using toluene-ethyl acetate-acetic acid 8:1:1 as the eluent.
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([NH2:18])[CH:10]=2)[CH:2]([CH3:4])[CH3:3].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:36])[CH2:29][CH:30]([CH3:35])[CH2:31][C:32](O)=[O:33])=[CH:23][CH:22]=1)#[N:20].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:19]([C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:36])[CH2:29][CH:30]([CH3:35])[CH2:31][C:32]([NH:18][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3=2)=[O:33])=[CH:25][CH:26]=1)#[N:20]
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Reactant: CC(C)Cn1c2c(c3cc(N)ccc31)CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cn1c2c(c3cc(NC(=O)CC(C)CC(=O)Nc4ccc(C#N)cc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 53.1 %

Procedure:
To a solution of the compound obtained in Step 2 (235 mg, 0.97 mmol), 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (239 mg, 0.97 mmol) and DIEA (0.508 mL, 2.91 mmol) in DMF (6 mL) was added HATU (553 mg, 1.45 mmol), and the mixture was stirred at room temperature for 14 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the title compound (242 mg, 0.515 mmol, 53.1%) as a white powder.
Reaction SMILES: C(O[C:6](=[O:21])[NH:7][C@H:8]([CH2:19]O)[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.Cl.C([O-])([O-])=O.[K+].[K+].[N:29]#CBr>C(O)C>[C:13]1([S:10]([CH2:9][C@H:8]2[CH2:19][O:21][C:6]([NH2:29])=[N:7]2)(=[O:11])=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#CBr
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC1=N[C@@H](CS(=O)(=O)c2ccccc2)CO1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
((R)-2-Benzenesulfonyl-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester (0.29 g, 0.92 mmol) was dissolved in ethanol (2 ml), hydrochloric acid in ethanol (5M, 5 ml) was added and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated and the residue was taken up in tetrahydrofuran (5 ml). K2CO3 (0.326 g, 2.36 mmol) and cyanogen bromide (0.136 g, 1.29 mmol) were added. The mixture was stirred overnight and afterwards partitioned between ethyl acetate and water. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, EtOAc/MeOH=95:5 to yield a white solid, (0.062 g, 28%); MS (ISP): 241.1 ((M+H)+.).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C@H:23]4[CH2:27][CH2:26][NH:25][CH2:24]4)=[CH:18][C:17]=3[O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:11][C:10]=2[CH:33]=1)(=[NH:5])[NH2:4].S(Cl)([Cl:36])=O.[CH2:38](O)[CH3:39]>>[ClH:36].[ClH:1].[CH2:38]([O:31][C:30](=[O:32])[CH2:29][O:28][C:17]1[CH:18]=[C:19]([O:22][C@H:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)[CH:20]=[CH:21][C:16]=1[CH2:15][CH2:14][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([C:3](=[NH:4])[NH2:5])=[CH:33][C:10]=2[CH:11]=1)[CH3:39]
Reactant: O=S(Cl)Cl
Reactant: N=C(N)c1ccc2oc(CCc3ccc(O[C@H]4CCNC4)cc3OCC(=O)O)cc2c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)COc1cc(O[C@H]2CCNC2)ccc1CCc1cc2cc(C(=N)N)ccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.65 g of [2-[2-(5-amidino-2-benzofuranyl)ethyl]-5-[((3S)-3-pyrrolidinyl)oxy]phenyl]oxyacetic acid dihydrochloride was dissolved in 50 ml of ethanol. 0.2 ml of thionyl chloride was added to the above solution with ice cooling, and the resulting mixture was stirred at room temperature for 18 hours. Thereafter, the resulting reaction solution was concentrated to dryness, dissolved once in water, and then concentrated again to dryness. In this way, 0.65 g of the title compound was obtained in a solid form.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=[C:15]([O:22]C)C=C4)N(CC2)C1.[C:59]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])(=[O:65])CCCC=C.CCOC(C)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O.[CH2:87]([OH:91])[CH2:88][CH2:89][CH3:90]>>[OH:91][C@H:87]([CH2:15][OH:22])[CH2:88][CH2:89][CH2:90][C:59]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65]
Reactant: CCCCO
Reactant: C=CCCCC(=O)OC(C)(C)C
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCC[C@H](O)CO
Temperature: 0 °C
Reaction time: 70 h

Procedure:
To a suspension of AD-mix alpha (70 g) in water/butanol 1:1 (512 mL) cooled to 0° C., tert-butyl hex-5-enoate (8.5 g, 49.92 mmol) was added. The reaction mixture was stirred at 4° C. for 70 hrs. Then the reaction mixture was cooled to 0° C. and EtOAc (280 mL), followed by continuous portionwise addition of sodium metabisulfite (20.6 g). The mixture was stirred for 30 min at 0° C. and at rt for 1 hour. The organic layer was separated and the aqueous phase extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Chromatography over silica gel eluting with EtOAc 100% afforded the title compound as a pale yellow oil.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S@:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:8])=[CH:3][CH:2]=1.C([Mg]Br)(C)(C)C.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][C@H:31]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:32][CH:33]=[O:34].Cl>CCOCC.C1COCC1>[OH:34][CH:33]([CH2:32][CH:31]([O:30][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@H:9]([S@@:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=1)=[O:8])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CCCCCCCCCCC[C@H](CC=O)OC1CCCCO1
Reactant: Cc1ccc([S@@](=O)CC(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCC(CC(O)[C@H](C(=O)OC(C)(C)C)[S@](=O)c1ccc(C)cc1)OC1CCCCO1
Temperature: -78 °C
Yield: 61.3 %

Procedure:
(G)(a) 16.5 g of t-butyl [(S)-p-tolylsulfinyl]acetate were dissolved in a mixture of 600 ml of ether and 60 ml of THF and cooled to -78° C. 43 ml of t-butylmagnesium bromide were then added dropwise in such a manner that the temperature remained below -70° C. After stirring at -78° C. for 1 hour 13.4 g of (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]-tetradecanal in 100 ml of THF were added dropwise. After 2 hours at -78° C. the reaction mixture was hydrolyzed with 2N hydrochloric acid and the solvent was evaporated off. The reaction mixture remaining behind was extracted with ether and the ethereal phase was dried and evaporated. After chromatography on silica gel there were obtained 14.9 g of t-butyl 3-hydroxy-(R)-5-[(tetrahydro-2H-pyran-2-yl)oxy]-2-[(S)-p-tolylsulfinyl]-hexadecanoate (67% yield). m.p. 97°-98° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[CH:9]=[CH:10][O:11][C:4]=2[CH2:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:14]=1[CH3:20]>>[ClH:12].[Cl:12][C:13]1[C:14]([CH3:20])=[C:15]([O:8][CH:6]2[CH2:7][N:2]([CH3:1])[CH2:3][C:4]3[O:11][CH:10]=[CH:9][C:5]2=3)[CH:16]=[CH:17][CH:18]=1
Reactant: CN1Cc2occc2C(O)C1
Reactant: Cc1c(F)cccc1Cl
Product: Cc1c(Cl)cccc1OC1CN(C)Cc2occc21
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-6-fluorotoluene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: CN([CH2:4][C@H:5]1[CH:11]=[C:10](SC2C=CC=CC=2)[CH:9]=[CH:8][C@H:7]([CH3:19])[C@@H:6]1[OH:20])C.[CH:21]1[CH:26]=[C:25](Cl)[CH:24]=[C:23](C(OO)=O)[CH:22]=1.[OH:32][S:33]([O-:35])=O.[Na+]>C(Cl)Cl>[C:25]1([S:33]([C:10]2[CH:9]=[CH:8][C@H:7]([CH3:19])[C@H:6]([OH:20])[C:5](=[CH2:4])[CH:11]=2)(=[O:35])=[O:32])[CH:24]=[CH:23][CH:22]=[CH:21][CH:26]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@H]1C=CC(Sc2ccccc2)=C[C@H](CN(C)C)[C@H]1O
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C1C=C(S(=O)(=O)c2ccccc2)C=C[C@H](C)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of amine 34 (42 mg, 0.14 mmol) in CH2Cl2 (2 mL) was added 140 mg of m-CPBA (0.57 mmol based on 70% content). The mixture was stirred at room temperature for 30 min, then aqueous NaHSO3 was added, the resulting two layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×3 mL). The combined organic layers were washed with saturated aqueous Na2CO3, dried with Na2SO4, and concentrated. The residue was purified by flash column chromatography (EtOAc/hexanes; 1:2) to afford 36 mg (91%) of trienyl sulfone 35. 1H NMR (CDCl3, 300 MHz) δ 7.88-7.92 (m, 2H), 7.54-7.67 (m, 3H), 7.51 (s, 1H), 6.24 (dt, J=11.4 Hz, 1.2 Hz, 1H), 5.90 (dd, J=11.4 Hz, 5.4 Hz, 1H), 5.78 (s, 1H), 5.72(s, 1H), 4.36 (s, 1H), 2.64 (m, 1H), 1.81 (br s, 1H), 1.11 (d, J=7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 145.6, 140.2, 139.3, 137.0, 136.1, 133.6, 129.5, 128.1, 128.0, 120.2, 75.1, 39.3, 16.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:6](O)[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[O:3]1.[NH:13]1[CH:17]=[C:16]([C:18]([O:20][CH3:21])=[O:19])[N:15]=[CH:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:21][O:20][C:18]([C:16]1[N:15]([CH:6]2[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[O:3][C:2]2([CH3:12])[CH3:1])[CH:14]=[N:13][CH:17]=1)=[O:19]
Reactant: CC1(C)Oc2ccccc2C1O
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1cncn1C1c2ccccc2OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-dimethyl-2,3-dihydro-benzofuran-3-ol (375 mg, 2.28 mmol) in THF (20 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 432 mg, 3.42 mmol), followed by triphenylphosphine (896 mg, 3.42 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (787 mg, 3.42 mmol) is added. The reaction is permitted to warm to room temperature and stirred for 2 hours. The reaction mixture is then cooled to 0° C. and quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:5) to furnish 3-(2,2-dimethyl-2,3-dihydro-benzofuran-3-yl)-3H-imidazole-4-carboxylic acid methyl ester; HRMS: (ESI) m/z 245.0934 [(M+H)+: Calcd for C13H13N2O3: 245.0926]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05 (s, 3H), 1.57 (s, 3 H), 3.92 (s, 3 H), 6.32 (s, 1 H), 6.92 (d, J=8.1 Hz, 1 H), 6.95-7.02 (m, 2 H), 7.25 (s, 1 H), 7.32-7.40 (m, 1 H), 7.80 (s, 1 H).
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][O:17][CH3:18])[O:15][C:11]=2[C:10]([O:19]C)=[CH:9][CH:8]=1>CN(C)C=O>[Br:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:16][O:17][CH3:18])[O:15][C:11]=2[C:10]([OH:19])=[CH:9][CH:8]=1
Reactant: COCc1cc2c(Br)ccc(OC)c2o1
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: COCc1cc2c(Br)ccc(O)c2o1
Temperature: 160 °C
Yield: 62.5 %

Procedure:
To a stirred solution of sodium hydride (334 mg, 60% in mineral oil) in dry N, N-dimethylformamide (25 ml) under an atmosphere of dry nitrogen at room temperature was added dropwise ethane thiol (0.586 ml). After stirring for 20 minutes a solution of 4-bromo-7-methoxy-2-methoxymethylbenzofuran (2.04 g) in N,N-dimethyl-formamide (7 ml) was added dropwise and the reaction mixture was heated at 160° C. for 2 hours. The reaction was cooled and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (70 ml) and washed with ammonium chloride solution (70 ml). The organic extract was dried over magnesium sulphate, filtered and the solvent removed in vacuo. Purification by column chromatography on silica eluting with 50% ethyl acetate in hexane afforded the title compound as a white solid (1.21 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]=[C:15]=[O:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Cl:17][C:18]1[CH:19]=[C:20]([NH2:27])[C:21](=[CH:25][CH:26]=1)[C:22](O)=[O:23]>>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]2[C:22](=[O:23])[C:21]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:26][CH:25]=3)[NH:27][C:15]2=[O:16])(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: C=CCOc1ccc(S(=O)(=O)N=C=O)cc1
Product: C=CCOc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 54.3 %

Procedure:
1.50 g (7.03 mmol) of 4-allyloxybenzenesulfonyl isocyanate and 1.2 g (7.03 mmol) of 4-chloroanthranilic acid were treated in the same way as in Preparation Example 5 to obtain 1.5 g (yield 53%) of 3-(4-allyloxybenzenesulfonyl)-7-chloro-2,4 (1H,3H)-quinazolinedione. 500 mg (1.27 mmol) thereof was similarly treated to obtain 405 mg of the above-identified compound (yield 90%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δ ppm, DMSO-d6): 6.98 (2H, d), 7.11 (1H, s), 7.23 (1H, d), 7.85 (1H, d), 8.00 (2H, d), 11.25 (1H, br).
Reaction SMILES: C([N:3](CC)CC)C.C(OC(Cl)=O)C(C)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([OH:38])=O)[CH2:31]1.N>O1CCCC1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH3:29])[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([NH2:3])=[O:38])[CH2:31]1
Reactant: CCN(CC)CC
Reactant: COCOc1ccc(C2CCCC(C(=O)O)C2)c(OCOC)c1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: COCOc1ccc(C2CCCC(C(N)=O)C2)c(OCOC)c1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Triethylamine (16 μl) and isobutylchloroformate (14 μl) were added to a stirred solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanecarboxylic acid in anhydrous tetrahydrofuran (2 ml) at 0° C. under argon. After 30 min, aqueous ammonia solution (0.5 ml, 28% w/w) was added. The reaction mixture was partitioned between water (20 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (2×20 ml) and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to give the title compound (26 mg, 87%) as a mixture of diastereoisomers; m/z (ES+) 324 (M+H)+.