Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl.[C:47]([O:51][C:52](=[O:74])[C@H:53]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[NH:54][C:55](=[O:64])[C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH2:63])=[CH:58][CH:57]=1)([CH3:50])([CH3:49])[CH3:48].C(OP(C#N)(=O)OCC)C.C(N(CC)CC)C>CN(C)C=O>[C:47]([O:51][C:52](=[O:74])[C@H:53]([CH2:65][CH2:66][C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])[NH:54][C:55](=[O:64])[C:56]1[CH:61]=[CH:60][C:59]([CH2:62][NH:63][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:58][CH:57]=1)([CH3:49])([CH3:50])[CH3:48]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (210 mg), 4-(aminomethyl)benzoyl-glutamic acid di-t-butyl ester hydrochloride (144 mg), diethylphosphorocyanidate (75 mg) and triethylamine (93 mg) in dimethylformamide (10 ml) was stirred at room temperature for 30 minutes. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:2) to yield the title compound (328 mg, yield 99%) as a colorless wax-like substance.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[C:14]([NH:21][CH3:22])[CH:13]=1.[OH-].[Na+]>O>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][C:14]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: CNc1cc(Cl)ccc1C(C)=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)c1ccc(Cl)cc1N(C)C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of acetic anhydride (12 ml) and formic acid (8 ml) was heated at 55° for 3 hours and then cooled to ambient temperature. 4'-Chloro-2'-(methylamino)acetophenone (9.7 g) was then added and the mixture stirred at ambient temperature overnight. Water (40 ml) was added and the mixture stirred in an ice/salt bath and neutralised by adding aqueous sodium hydroxide (specific gravity 1.5, 22 ml) whilst maintaining the temperature below 30°. The reaction mixture was extracted with dichloromethane (3×50 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-5'-chloro-N-methylformanilide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Cl)[CH:18]=4)[CH2:12][CH2:11]3)[S:9][C:5]=2[CH:4]=1.[C-:27]#[N:28].[Na+].O.C(OCC)(=O)C>CN(C)C=O>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][C:17]4[CH:18]=[C:19]([CH2:23][C:27]#[N:28])[CH:20]=[CH:21][CH:22]=4)[CH2:14][CH2:15]3)[S:9][C:5]=2[CH:4]=1
Reactant: [C-]#N
Reactant: ClCc1cccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1cccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
The mixture of 6-chloro[4-(3-chloromethylbenzyl)piperazine-1-yl]benzothiazole monohydrochloride (0.50 g; 1.27 mmol) and sodium cyanide (0.19 g; 3.82 mmol) in anhydrous N,N-dimethylformamide (5 ml) were stirred at 40° C. for 1.5 hours. After cooling, water and ethyl acetate were added to the reaction solution. The organic layer was separated and washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure and the percipitate was washed with diisopropyl ether to give {3-[[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl]phenyl}acetonitrile as pale blackish brown crystal (0.35 g; 72%).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8](Br)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.C([Sn](CCCC)(CCCC)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)CCC.C(N(CC)CC)C.CN(C)[CH:48]=[O:49]>>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:48]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:49])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: Brc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Reactant: CN(C)C=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 8.5 %

Procedure:
A mixture of 7-benzo[b]thiophen-2-yl-5-bromo-1H-indazole (Preparation #26, 0.25 g, 0.76 mol), tributylphenyltin (0.56 g, 1.52 mmol), triethylamine (0.23 g, 2.28 mmol) and trans-dichloro[bis(triphenylphosphine)]palladium (II) (0.08 g, 0.114 mmol) in N,N-dimethylformamide (4 mL) was purged with carbon monoxide then stirred under an atmosphere of carbon monoxide at about 90° C. in an oil bath for about 2 hours. The solvent was removed in vacuo and the residue was applied to a silica gel column then eluted with dichloromethane/methanol (95:5). The fractions that contained product were combined and triturated with heptane then the solids were collected by filtration and purified by preparative reverse phase HPLC to give (7-Benzo[b]thiophen-2-yl-1H-indazol-5-yl)-phenyl-methanone(23 mg, 8.5%); (DMSO-d6, 400 MHz) δ 13.85 (bs, 1H), 8.49 (bs, 1H), 8.27 (s, 1H), 8.18 (bs, 1H), 8.06 (m, 2H), 7.93 (m, 1H), 7.81 (m, 2H), 7.71 (m, 1H), 7.61 (m, 2H), 7.45 (m, 2H); RP-HPLC (Table 1, Method e) Rt 2.50 min; m/z: (M+H)+ 353.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[C-:12]#[N:13].[K+]>CN(C=O)C.O.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]#[N:13])=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: [C-]#N
Reactant: CCc1cc(Br)ccc1CBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCc1cc(Br)ccc1CC#N
Temperature: 45 °C
Yield: 81.9 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-ethyl-benzene (2.0 g, 7.25 mmol) in DMF/H2O (30 mL/6 mL) was added potassium cyanide (471 mg, 7.25 mmol). The reaction mixture was heated to 45° C. for 3 hours before it was cooled to room temperature. The mixture was diluted with Et2O and washed with H2O, brine and dried over MgSO4. The solvent was removed in vacuo to obtain the desired product (1.33 g, 80% yield). 1H NMR (300 MHz, CDCl3): δ 1.26 (t, J=7.5 Hz, 3 H), 2.60-2.67 (m, 2 H), 3.66 (s, 2H), 7.23-7.26 (m, 1H), 7.35-7.36 (m, 1 H), 7.38-7.40 (m, 1H).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]([S:20](=[O:30])(=[O:29])[NH:21]C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[S:20]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:7][C:6]([OH:31])=[O:5])(=[O:30])(=[O:29])[NH2:21]
Reactant: COC(=O)Cc1ccccc1N(CC(=O)OC(C)(C)C)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1N(CC(=O)O)S(N)(=O)=O
Reaction time: 0.5 h

Procedure:
The title D compound, N-(t-butoxycarbonyl-sulfamoyl)-N-[2-(methoxycarbonyl-methyl)-phenyl]-glycine t-butyl ester (1.87 g, 4.07 mmol) is dissolved in a mixture of TFA (35 mL) and CH2Cl2 (35 mL) and stirred for 30 min. The reaction is concentrated in vacuo, then triturated with diethyl ether to yield N-sulfamoyl-N-[2-(methoxycarbonylmethyl)-phenyl]glycine as a clear glass.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[CH:15]=3)=[CH:12][NH:11][N:10]=2)[C:5]([F:8])=[CH:6][CH:7]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[F:22][C:3]1[C:4]([C:9]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[CH:15]=3)=[CH:12][NH:11][N:10]=2)=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:31]([C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[F:23])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(N)c2F)ccn1
Solvent: c1ccncc1
Product: CNc1cc(-c2c[nH]nc2-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[3-(3-amino-2,6-difluoro-phenyl)-1H-pyrazol-4-yl]-pyridin-2-yl}-methyl-amine (144 mg, 0.48 mmol) in anhydrous pyridine (0.2 M), 2,5-difluoro-benzenesulfonyl chloride (64 μL, 0.48 mmol) was added and the reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried over anhydrous sodium sulfate and filtered. The product was isolated by silica gel column chromatography eluting with methanol 5% in methylene chloride (58%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[N:10]([C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O)[CH2:9][CH2:8]2.C(Cl)(Cl)Cl.CO.C(Cl)(Cl)Cl>C1COCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][N:10]1[CH:11]2[CH2:12][CH2:13][N:7]([CH2:15][CH2:14]2)[CH2:8][CH2:9]1
Reactant: O=C(c1ccccn1)N1CCN2CCC1CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: c1ccc(CN2CCN3CCC2CC3)nc1
Reaction time: 12 h

Procedure:
To a stirred solution of lithium aluminum hydride (0.33 mL of 1M THF solution) at ambient temperature was added dropwise a solution of (1,4-diazabicyclo[3.2.2]non-4-yl)(pyridin-2-yl)methanone (120 mg, 0.52 mmol) in dry THF (2 mL). The resulting yellowish solution was stirred for 12 hours, quenched with water and aqueous NaOH, and filtered through diatomaceous earth. The filtrate was concentrated to give the product which was subjected to chromatography on silica gel eluting with an ammoniated-chloroform to 15% MeOH/chloroform gradient to give the title compound as a free base syrup (28.0 mg). MS (ES+) 218 (MH+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH:21]([CH3:23])[CH3:22])[C:9]1=[O:24])C1C=CC=CC=1>C1COCC1>[CH:21]([CH:10]1[C:9](=[O:24])[NH:8][CH2:13][CH2:12][N:11]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])([CH3:23])[CH3:22]
Reactant: CC(C)[C@@H]1C(=O)N(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)C1C(=O)NCCN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a three-necked bottle containing THF (10 mL) was bubbled with NH3 (gas) at −78° C. for 5 mins. Na (300 mg, 13.0 mmol) was added to the mixture slowly at −78° C. After stirring for 30 min, (R)-tert-butyl 4-benzyl-2-isopropyl-3-oxopiperazine-1-carboxylate (700 mg, 2.11 mmol) was added dropwise at −78° C. The mixture was stirred at −78° C. for 30 min. The mixture was quenched with sat. aq NH4Cl (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by preparative TLC with PE/EtOAc 1/1 to afford tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (300 mg, 59% yield) as a white solid. The product was found to be a racemic mixture. The cause of racemization was not investigated. LC-MS m/z 187.1 [M-56+H]+, 265.1 [M+Na]+. 1H NMR (CDCl3 400 MHz): δ 6.29 (s, 1H), 4.55-3.99 (m, 2H), 3.51-3.36 (m, 1H), 3.32-3.12 (m, 2H), 2.34-2.29 (m, 1H), 1.46 (s, 9H), 1.09 (d, J=6.8 Hz, 3H), 0.99 (d, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)([N:15]1C=CN=C1)=O.N>O1CCCC1>[C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:15])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
Ex-92A: To a solution of 4-acetyl-benzoic acid (0.5 g, 3.05 mmol) in tetrahydrofuran (10 mL) was added carbonyldiimidazole (0.74 g, 4.75 mmol). The solution was allowed to stir at ambient temperature for one hour and cooled to 0° C. followed by addition of ammonia (28% in water, 3 mL, 21 mmol). The solution was continued to stir at 0° C. for another one hour. The solvent was removed under reduced pressure. The residue was treated with water, filtered, washed with water, dried in vacuo to give 4-acetyl-benzamide (0.25 g, 50%) as a white solid. 1H NMR (DMSO-d6) δ 8.11 (bs, 1H), 8.00 (d, J=9 Hz, 2H), 7.95 (d, J=9 Hz, 2H), 7.53 (bs, 1H), 2.59 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25].[C:26]([NH:33][C@@H:34]([C:42](O)=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[C:29]([O:28][C:26]([NH:33][CH:34]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:42]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH3:17])=[CH:11][C:10]=2[O:18][CH3:19])[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[N:4]([CH3:24])[C:3]1=[O:25])=[O:43])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: COc1cc(C)cc(OC)c1C1=NC(N)C(=O)N(C)c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C)cc(OC)c1C1=NC(NC(=O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N(C)c2ccccc21
Temperature: 5 °C
Reaction time: 8 h

Procedure:
1.73 g of 3-amino-1,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-1,4-benzodiazepin-2-one are dissolved in 30 ml of dimethylformamide in the presence of 1.42 g of BOC-D-phenylalanine, followed by cooling to 5° C. and addition of 1.07 ml of triethylamine and then 2.4 g of BOP. The reaction mixture is allowed to return to room temperature and is left stirring overnight. It is then poured into water and extracted with ethyl acetate. The organic phase is washed with water, separated out after settling of the phases, dried over Na2SO4, filtered and concentrated under vacuum. An oily residue of 2-tert-butoxycarbonylamino-N-[2,3-dihydro-5-(2,6-dimethoxy-4-methylphenyl)-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]-3-phenylpropionamide, obtained in quantitative yield, is used as it is for the following step (Compound 16).
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: COc1n[nH]c(=O)[nH]1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1n[nH]c(=O)n1Cc1cccc(Br)c1
Reaction time: 6 h
Yield: 29.9 %

Procedure:
To a solution of 2.30 g (20 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 20 ml acetonitrile was added 2.90 g (21 mmol) of potassium carbonate. A solution of 5.00 g (20 mmol) of 3-bromobenzylbromide in 20 ml of dry acetonitrile was added dropwise thereto at 55° C. After the mixture was stirred at the same temperature for additional 6 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (5.2 g) was added a mixture of equal amounts of tert-butyl methyl ether and n-hexane and the solid was washed, ice-cooled, collected by filtration and concentrated. Further, to the resultant solid residue was added tert-butyl methyl ether and the solid was washed, cooled, collected by filtration and dried to obtain 1.70 g (5.98 mmol) of 4-(3-bromobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([CH3:23])[CH:16]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.ClCCl>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[C:17]([CH3:23])[CH:16]=1
Reactant: Cc1cc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A 250 mL round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (2.80 g, 15.0 mmol, 1.00 equiv), 4-bromo-2-methylbenzaldehyde (3.28 g, 16.5 mmol, 1.10 equiv), dichloromethane (80 mL). Triethylamine (4.56 g, 45.1 mmol, 3.00 equiv) was added. The resulting solution was stirred for 30 mins at room temperature. Sodium triacetoxyborohydride (9.60 g, 45.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature and then diluted with water (100 mL). The resulting solution was extracted with dichloromethane (3×60 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 5.70 g (98% yield) of tert-butyl 4-[(4-bromo-2-methylphenyl)methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 369 [M+H]+.
Reaction SMILES: [CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[S:21][C:20]=2[CH2:30][CH3:31])[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([C:19]2[CH:23]=[C:22]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[S:21][C:20]=2[CH2:30][CH3:31])[O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)OC)cc1)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1sc(C2CCCCC2)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Yield: 35.8 %

Procedure:
To a mixture of methyl 4-[cyclohexyl(5-cyclohexyl-2-ethylthiophen-3-yl)methoxy]benzoate (560 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred with heating under reflux overnight. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a white solid. The obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (194 mg, 36%) as a colorless crystal.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][CH2:7][CH:8]1[O:13][C:12]2=[CH:14][S:15][CH:16]=[C:11]2[O:10][CH2:9]1)C.C(O)C.[OH-].[K+]>O>[O:13]1[CH:8]([CH2:7][O:6][CH2:5][C:4]([OH:17])=[O:3])[CH2:9][O:10][C:11]2=[CH:16][S:15][CH:14]=[C:12]12
Reactant: CCOC(=O)COCC1COc2cscc2O1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COCC1COc2cscc2O1
Temperature: 35 °C

Procedure:
(2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-acetic acid ethyl ester (10.2 g, 40 mmol) was dissolved into ethanol (100 mL) and water (50 mL), blanketed by nitrogen. Potassium hydroxide (2.9 g) was added and the mixture was heated at 35° C. for 30 min. The solvents were then removed by distillation, ethyl acetate (50 mL), ice-water (50 mL) and concentrated hydrochloric acid (5 mL) were added and the mixture was vigorously stirred. Subsequently, the organic phase was separated, washed with an aqueous, saturated sodium chloride solution, dried with anhydrous magnesium sulphate and concentrated. Finally the raw product was recrystallized from ethyl acetate/hexanes (1/1) resulting in pure (2,3-dihydro-thieno[3,4-b][1,4]dioxin-2-ylmethoxy)-acetic acid as demonstrated by NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]=[CH:10][CH3:11].[O-2].[O-2].[O-2].[Al+3].[Al+3]>>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:10]([CH3:11])[CH3:9]
Reactant: C=CC
Reactant: Cc1ccccc1N
Agent: [Al+3]
Agent: [O-2]
Product: Cc1ccccc1NC(C)C

Procedure:
The procedure of Example 3 was repeated using the fixed bed catalytic reactor, except that ortho toluidine or rather 2-methyl-aniline was alkylated with propylene in the presence of gamma-alumina. Table 3 below sets forth the reaction conditions and product selectivity.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[S:45][C:46]([C:49]([F:52])([F:51])[F:50])=[N:47][N:48]=1>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:43][C:44]1[S:45][C:46]([C:49]([F:52])([F:51])[F:50])=[N:47][N:48]=1)=[O:41]
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C(F)(F)F)s4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.2 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (5 ml) and triethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was then stirred at room temperature for 15 min. Next, 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (65 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 48 mg of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[CH2:16]([OH:19])[CH2:17][OH:18].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.C1(C)C=CC=CC=1>[CH3:20][S:21]([O:18][CH2:17][CH2:16][O:19][S:21]([CH3:20])(=[O:23])=[O:22])(=[O:23])=[O:22]
Reactant: OCCO
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCOS(C)(=O)=O
Reaction time: 3 h

Procedure:
Potassium carbonate (6.7 g, 48.5 mmol) and diisopropylethylamine (0.3 g, 2.3 mmol) were suspended in dichloromethane-toluene (1/1, 10 mL), and ethylene glycol (1.5 g, 23.3 mmol) and methanesulfonyl chloride (5.5 g, 48.0 mmol) were dropped at the same time in an ice bath. A reaction was effected at room temperature for 3 hours and, thereafter, the reaction was terminated by addition to ice water. An organic layer separated through liquid separation was concentrated, so as to obtain the desired product, 1,2-bis(methanesulfonyloxy)ethane, at a yield of 36% (1.8 g, 8.4 mmol). The measurement result of 1H NMR is as described below.