Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12](=[O:34])[NH:13][N:14]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:35])[N:7]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][OH:45]>CN(C=O)C>[C:1]([O:4][CH2:5][C:6]1[C:11]2[C:12]([O:34][CH2:43][CH2:44][OH:45])=[N:13][N:14]([C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]=2[CH:9]=[C:8]([Cl:35])[N:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc(Cl)cc2c1c(=O)[nH]n2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc(Cl)cc2c1c(OCCO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (6-chloro-3-oxo-1-trityl-2,3-dihydro-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate (504.6 mg, 1.043 mmol) and potassium carbonate (558.3 mg, 4.04 mmol) in DMF (10 ml) was charged with 2-bromoethanol (0.30 ml, 4.25 mmol) and stirred at RT for 6 hr. Quenched with water and extracted 3× with Et2O. Washed organics with brine, dried over MgSO4, filtered and concentrated in vacuo. Purified via flash chromatography (0-100% EtOAc/Hex) to provide (6-chloro-3-(2-hydroxyethoxy)-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl acetate. MS: [M+H]+ m/z 528.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[SH:11].[Hg](C#N)C#N.[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@@H:22]1Br)(=[O:19])[CH3:18]>>[C:17]([O:20][C@@H:21]1[C@@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:25]([O:31][C:32](=[O:34])[CH3:33])[CH2:24][S:23][C@H:22]1[S:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Sc1ccc2ccccc2c1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccc3ccccc3c2)SC[C@H]1OC(C)=O
Yield: 39.8 %

Procedure:
If the procedure described in Preparation I is followed starting from 6.8 g (42.4.10-3 mol) of naphthalene-2-thiol, 10.8 g (42.4.10-3 mol) of mercuric cyanide, Hg(CN)2, and 12 g (33.2.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 5.84 g (yield: 40%) of the expected product are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:19](=[O:34])[CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C)[CH:27]=2)(=[O:25])=[O:24])=[CH:5][C:4]=1[F:35])#[N:2].B(Br)(Br)Br>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:19](=[O:34])[CH2:20][CH2:21][NH:22][S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)(=[O:25])=[O:24])=[CH:5][C:4]=1[F:35])#[N:2]
Reactant: COc1cccc(S(=O)(=O)NCCC(=O)N2CCc3ncn(C)c3C2c2ccc(C#N)c(F)c2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cnc2c1C(c1ccc(C#N)c(F)c1)N(C(=O)CCNS(=O)(=O)c1cccc(O)c1)CC2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
N-{3-[4-(4-Cyano-3-fluoro-phenyl)-3-methyl-3,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl]-3-oxo-propyl}-3-methoxy-benzenesulfonamide (0.05 g, 0.100 mmol), prepared as described in Step H, was dissolved in CH2Cl2 (2 mL) and cooled to 0° C. A 1M solution of BBr3 in CH2Cl2 (2.0 mL, 2.00 mmol) was added dropwise via syringe and stirred for 4 h. The reaction mixture was diluted with CH2Cl2 and saturated NaHCO3 solution and separated. The aqueous layer was washed with CH2Cl2 (2×), the organic layers combined, dried (Na2SO4), filtered and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.Cl.[CH2:12]([O:14][NH2:15])[CH3:13].C(N(CC)CC)C>C(Cl)Cl.CCOCC>[CH2:12]([O:14][NH:15][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[S:10])[CH3:13]
Reactant: Fc1ccc(N=C=S)cc1
Reactant: CCON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCONC(=S)Nc1ccc(F)cc1

Procedure:
4-Fluorophenyl isothiocyanate (306 mg, 2.0 mmol), O-ethyl hydroxylamine hydrochloride (585 mg, 6.0 mmol), and triethylamine (1.5 mL, 11.0 mmol) are stirred in CH2Cl2 (50 mL) for 2 h. The reaction mixture is diluted with ether, washed with water and 1 M HCl, dried (MgSO4), and concentrated. The residue is purified by column chromatography with hexane-EtOAc yielding a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7]Br.[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15].Cl>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[O:5][CH2:6][CH2:7][NH:17][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: Clc1cc(Cl)cc(OCCBr)c1
Reactant: CC(C)CN
Agent: Cl
Product: CC(C)CNCCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared by the method of Preparation 34 from 2-(3,5-dichlorophenoxy)-1-bromoethane and isobutylamine (72 hr) and hydrogen chloride. The free base was obtained as an oil. The hydrochloride salt melted at 190°-191.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:31]=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1cnc2ccccc2c1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1cnc2ccccc2c1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-3-ylmethyl-amine
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.[H][H]>CO.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(O)cc(C(F)(F)F)c1
Yield: 98.2 %

Procedure:
A mixture of 3-nitro-5-(trifluoromethyl)phenol (50 g, 241.42 mmol, 1.00 equiv) and Raney-Ni (6 g) in methanol (500 mL) was stirred under 1 atmosphere of hydrogen at 25° C. for 8 h. The catalyst was removed by filtration. The filtrate was concentrated under vacuum to give 42 g (98%) of 3-amino-5-(trifluoromethyl)phenol as a light yellow solid. LCMS (method D, ESI): RT=0.84 min, m/z=178.0 [M+H]+.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][O:36][Si](C(C)(C)C)(C)C)[O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:21]([CH3:31])[CH2:22][CH2:23][CH2:24][C:25]([CH2:29][CH3:30])([OH:28])[CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[CH2:35][OH:36])[O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:21]([CH3:31])[CH2:22][CH2:23][CH2:24][C:25]([CH2:29][CH3:30])([OH:28])[CH2:26][CH3:27])[CH:18]=[CH:19][CH:20]=1
Reactant: CCC(O)(CC)CCCC(C)c1cccc(COc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCC(O)(CC)CCCC(C)c1cccc(COc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 3(i), by reacting 230 mg (0.36 mmol) of 7-{3-[3,4-bis-(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]phenyl}-3-ethyloctan-3-ol with 1.2 ml of tetrabutylammonium fluoride, a colourless oil (m=110 mg; Y=75%) is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=2[CH:18]=1.[Cl:19][C:20]1[CH:21]=[C:22]([SH:27])[CH:23]=[CH:24][C:25]=1[Cl:26]>>[Cl:19][C:20]1[CH:21]=[C:22]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=3[CH:18]=2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CC1OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC1OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4-methyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (50 mg, 0.133 mmol) was dissolved in 0.5 mL of DMF and cooled to 0° C. Lithium bis(trimethylsilyl)amide (0.146 ml, 0.146 mmol) was added dropwise and the reaction was allowed to stir for 10 minutes. (bromomethyl)benzene (0.024 ml, 0.200 mmol) was added to the reaction, and was allowed to stir overnight at room temperature. The reaction showed disappearance of the majority of the starting material. The reaction was quenched with water. It was then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution three times and dried over magnesium sulfate, filtered and concentrated. The crude material was purified through silica gel chromatography using 25% EtOAc:DCM. 1H-NMR (400 MHz, DMSO -d6) 7.64-7.55, 7.42-7.15, 7.13-7.06, 6.75-6.68, 5.56-5.47, 4.64, 4.57-3.91, 3.21-2.89, 2.78, 1.92-1.20
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]2[N:6]([N:10]=[CH:11][CH:12]=2)[CH:7]=[CH:8][CH:9]=1.S(C1C=CC(C)=CC=1)(O[CH2:17][CH:18]1[O:20][CH2:19]1)(=O)=O.[NH4+].[Cl-]>CCOCC.O.CN(C=O)C>[N:10]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:17][CH:18]3[O:20][CH2:19]3)[C:5]2=[CH:12][CH:11]=1
Reactant: Oc1cccn2nccc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CO2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: c1cc(OCC2CO2)c2ccnn2c1
Reaction time: 0.5 h

Procedure:
NaH (containing 60% of oil, 270 mg, 4.5 mmole) was washed with anhydrous petroleum ether, and was admixed, under atmosphere of argon gas, with distilled DMF (15 ml) and 4-hydroxypyrazolo[1,5-a]pyridine (5) (402 mg, 3.0 mmole), followed by stirring for 30 min to give a light pink suspension. Subsequently, glycidyl tosylate (821 mg, 3.6 mmole) was added to the suspension, followed by stirring overnight under atmosphere of argon gas to obtain a red-yellow suspension. The reaction mixture was neutralized by adding about 10 ml of saturated aqueous NH4Cl, followed by addition of water (20 ml) and extraction with ether. The extract was washed with water, dried and freed of the solvent by distillation, and the residue was purified on a column of silica gel (7734, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH2:22]([N:29]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:10](=[CH:11][CH:12]=[C:2]([Br:1])[CH:3]=2)[C:8]1=[O:9])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CO
Product: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid (1.00 g) in methanol (20 ml) was added benzylamine (3.16 ml) and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated under reduced pressure and 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid and saturated brine and magnesium sulfate was added to dry the mixture. The solvent was evaporated under reduced pressure, and 4N hydrogen chloride-ethyl acetate solution (17 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 18 hrs. The solvent was evaporated under reduced pressure, and addition of water allowed crystal precipitation. The obtained crystals were collected by filtration, washed successively with water and ether and dried under reduced pressure at 50° C. to give the title compound (921 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1.[O:20]=[C:21](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[N:1]([C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:10])([F:11])[F:12])[O:8][C:4]=2[CH:3]=1)=[C:21]=[O:20]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Solvent: C1COCCO1
Product: O=C=Nc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 110 °C
Reaction time: 6 h
Yield: 84.2 %

Procedure:
37 g of the product of Example 33 were dissolved in 50 ml of absolute 1,4-dioxane, and a solution of 13.5 g of diphosgene in 80 ml of absolute 1,4-dioxane was added. The mixture was then stirred for 6 hours at 110° C. (bath temperature), the solvent was then removed under vacuum and the remaining residue was subjected to fractional distillation under vacuum to give 18 g of product (=44% of theory) with a boiling point of 63° C. at 0.1 mbar. NMR: -59.3 and -85.0 ppm. 1H NMR: 3.0 ppm.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:24][F:25])([CH2:22][F:23])[CH:9]=1)=O)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1.C1C=CC=CC=1>C(Cl)Cl>[C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:13]2[CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH2:24][F:25])([CH2:22][F:23])[CH:9]=1)=[S:35])#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#CCCNC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Solvent: c1ccccc1
Solvent: ClCCl
Product: N#CCCNC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Temperature: 80 °C
Yield: 89.6 %

Procedure:
A mixture of 92 mg of N-(2-cyanoethyl)-2,2-bisfluoromethyl-6-trifluorometyl-2H-1-benzopyran-4-carbamide, 60 mg of Lawesson's reagent and 2 ml of benzene was stirred with heating at 80° C. for one hour. The reaction mixture was subjected to silica gel column chromatography (eluent:methylene chloride) to give 50 mg of N-(2-cyanoethyl)-2,2-bisfluoromethyl-6-trifluoromethyl-2H-1-benzopyran-4-carbothioamide; m.p. 105-106° C.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].OCC([C@H]([C@@H]([C@H](C)O)O)O)=O.OCC([C@H]([C@H]([C@@H](CO)O)O)O)=O>>[OH:1][CH2:2][C:3]([C@H:5]([C@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=O
Agent: C[C@H](O)[C@@H](O)[C@H](O)C(=O)CO
Agent: O=C(CO)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: C[C@H](O)[C@H](O)[C@H](O)C(=O)CO

Procedure:
Using L-rhamnose isomerase, L-rhamnose is isomerized to L-rhamnulose (6-deoxy L-fructose), which is then epimerized with D-tagatose 3-epimerase to produce 6-deoxy L-psicose.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]2[C:9]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[O:10][CH2:11][C:5]=2[CH:4]=1)=O.CO.CC([O-])=O.[Na+].[NH2:29][OH:30].Cl>O>[OH:30][N:29]=[CH:1][C:3]1[N:8]=[CH:7][C:6]2[C:9]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:12]3)[O:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=O)ncc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1cc(C=NO)ncc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
To a stirred solution of tert-butyl 6′-formyl-1′H-spiro[azetidine-3,3′-furo[3,4-c]pyridine]-1-carboxylate (0.15 g, 0.52 mmol, 1 eq.) in mixture of methanol (4.0 mL):water (4.0 mL) was added NaOAc (85 mg, 1.03 mmol, 2 eq.) followed by addition of NH2OH.HCl (72 mg, 1.03 mmol, 2 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption starting material, reaction mixture was concentrated under reduced pressure; resulting residue was diluted with water (5.0 mL) and extracted by ethyl acetate (3×20 mL). Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford title compound as brown solid (0.15 g, 95%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.16 (d, J=9.64 Hz, 2H), 4.34 (d, J=9.6 Hz, 2H), 5.10 (s, 2H), 7.67 (s, 1H), 8.27 (s, 1H), 8.72 (s, 1H). LC-MS (m/z): 306.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:11](=[N:12][CH:13]=[N:14][CH:15]=3)[N:10]=2)=[C:5]([O:18][CH2:19][CH2:20][S:21][CH3:22])[CH:4]=1.OO.C(=O)([O-])[O-:26].[K+].[K+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:11](=[N:12][CH:13]=[N:14][CH:15]=3)[N:10]=2)=[C:5]([O:18][CH2:19][CH2:20][S:21]([CH3:22])=[O:26])[CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCSC)c1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3ncncc3[nH]2)c(OCCS(C)=O)c1
Reaction time: 3.5 h

Procedure:
One gram of 8-[4-methoxy-2-(2-methylmercapto-ethoxy)phenyl]purine was dissolved in 10 ml of glacial acetic acid and mixed with 0.5 ml of 30% hydrogen peroxide. After standing for 3.5 hours at room temperature, the reaction mixture was diluted with water and made alkaline by means of potassium carbonate. The precipitate was recrystallized from isopropanol/ethanol in a volume ratio of 1:1.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([OH:9])[N:4]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1nccc(C(F)(F)F)n1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C(=O)Oc1nccc(C(F)(F)F)n1)c1ccccc1
Yield: 39.3 %

Procedure:
A solution of 4-(trifluoromethyl)-2-pyrimidol (0.49 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl -carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (30:70)) yielding the title compound (0.35 g, 39% yield) as a colourless oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([CH3:17])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)=[O:4].[CH3:18][C:19]([SH:22])([CH3:21])[CH3:20]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:8][N:7]=[C:6]([CH3:17])[C:5]=2[C:3](=[O:4])[CH2:2][S:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[CH:11][CH:12]=1
Reactant: CC(C)(C)S
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CBr
Product: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CSC(C)(C)C

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 2-bromo-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanone and 2-methyl-propane-2-thiol.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C([O:14][C:15]([CH:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O)=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[O:14]=[C:15]1[CH:17]2[CH2:21][CH2:20][CH2:19][C:18]2=[N:2][N:1]1[C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: NNc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C(O)c1ccc(N2N=C3CCCC3C2=O)cc1

Procedure:
A solution of 4-hydrazinobenzoic acid (0.3 g), ethyl-2-oxocyclopentanecarboxylate (0.31 g) and p-toluenesulfonic acid (340 mg) in ethanol (12 ml) was boiled under reflux for 12 hours. The concentrated reaction solution was purified by preparative HPLC. The isolated reaction product (as ethyl ester) was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 244.25 (C13H12N2O3); MS (ESI): 245 (M+H+).
Reaction SMILES: [C:1]([O:5]C)(=O)[CH:2]=[CH2:3].[NH2:7][C:8]1[NH:9][C:10]2[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:11]=2[N:12]=1>C(O)C>[CH3:17][C:15]1[C:14]([CH3:18])=[CH:13][C:11]2[N:12]=[C:8]3[NH:7][C:1](=[O:5])[CH2:2][CH2:3][N:9]3[C:10]=2[CH:16]=1
Reactant: Cc1cc2nc(N)[nH]c2cc1C
Reactant: C=CC(=O)OC
Solvent: CCO
Product: Cc1cc2nc3n(c2cc1C)CCC(=O)N3
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.4 %

Procedure:
Methyl acrylate (15 g.) was added to a solution of 2-amino-5,6-dimethylbenzimidazole (27.2 g.) in ethanol (100 ml.). After stirring for 2 days at room temperature, the crystalline precipitate which had formed in the reaction mixture was separated by filtration, washed with ethanol and then with ether, to give 7,8-dimethyl-3,4-dihydropyrimido[1,2-a]-benzimidazol-2(1H)-one (37.2 g.), m.p. 322°-323° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(-c2nc(Sc3ccc(C)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(C)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is dropped to a solution of 4.03 g of 4,5-bis(4-methoxyphenyl)-2-(4-methylphenylthio)imidazole in 100 ml of dichloromethane. The solution is agitated for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus obtaining 3.71 g of 4,5-bis(4-methoxyphenyl)-2-(4-methylphenylsulfinyl)imidazole as an amorphous foam.