Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:18])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7](OCC)=[O:8].Cl.Cl[C:21]([NH2:23])=[NH:22].CS(C)(=O)=O.N>O>[NH2:23][C:21]1[NH:1][C:2]2[S:3][C:4]([CH3:18])=[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[C:7](=[O:8])[N:22]=1
Reactant: CCOC(=O)c1c(N)sc(C)c1-c1ccccc1
Reactant: N=C(N)Cl
Agent: CS(C)(=O)=O
Agent: Cl
Agent: N
Solvent: O
Product: Cc1sc2[nH]c(N)nc(=O)c2c1-c1ccccc1
Temperature: 135 °C
Yield: 94.1 %

Procedure:
A mixture of ethyl 2-amino-5-methyl-4-phenylthiophene-3-carboxylate (1 g, 3.8 mmol), chloroformamidine hydrochloride (1.1 g, 9.6 mmol) and dimethylsulfone (1.798 g, 19.1 mmol) was heated at 135° C. for 45 minutes. Water was added and the mixture was cooled down to room temperature. An aqueous ammonia solution was added to adjust the solution to pH 9. The precipitate was filtered off, yielding the title compound (920 mg) as a yellowish powder. 13C NMR δ (75 MHz, DMSO-d6) 166.50, 157.60, 153.02, 135.16, 133.40, 130.30 (2C), 127.35 (2C), 126.79, 124.22, 113.80, 13.33. MS (m/z) 258 [M+H]+.
Reaction SMILES: [OH2:1].[Na].[CH:3]1([C:6]2[CH:10]=[C:9]([NH2:11])[NH:8][N:7]=2)[CH2:5][CH2:4]1.[Na].[OH:13]OS([O-])=O.[K+]>O.CC(C)=O>[CH:3]1([C:6]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:1])[NH:8][N:7]=2)[CH2:5][CH2:4]1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(C2CC2)n[nH]1
Yield: 52 %

Procedure:
To a solution of 2.7 g of sodium hydrate in 454 ml of water 7.1 g (0.058 mol) of 3-cyclopropyl-5-amino-1H-pyrazole and 46.5 g of sodium hydrogenocarbonate were added at 0° C. After 10 minutes a solution of 337 ml of acetone in 221 ml of water and a solution of 130 g (0.21 mol) of oxone in 580 ml of water were contemporaneously dropped under vigorous stirring. After 4 hours at the same temperature the reaction is quenched with a saturated solution of sodium sulfite and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to give 4.6 g (52% yield) of the title compound.
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH:18]=[O:19])=[CH:13][CH:12]=1)([CH3:10])[CH3:9].CCCCCC.C(OCC)(=O)C>C(O)(=O)C>[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:18]=2[OH:19])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]
Reactant: CNN=CC(C)=O
Reactant: CC(C)c1ccc(C(=O)C=O)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC(=O)c1nn(C)c(-c2ccc(C(C)C)cc2)c1O
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 4.2 %

Procedure:
2-Oxopropanal methylhydrazone (10.44 mmol, 1.05 g) and (4-isopropylphenyl)(oxo)acetaldehyde (10.44 mmol, 1.84 g) synthesized in Reference Synthetic Example 12 were dissolved in acetic acid (37 mL) and stirred at 100° C. for 4.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) and then by silica gel thin layer chromatography (n-hexane/ethyl acetate=3/1) to give the desired product as an orange solid (113 mg, yield 4%).
Reaction SMILES: [BH4-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([O:27][CH3:28])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])[CH3:4].CO>O.O.O.O.O.O.[Ni](Cl)Cl.C1COCC1>[C:3]([N:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([O:27][CH3:28])[CH:19]=3)[CH2:14][CH2:13]2)[CH2:10][CH2:11]1)(=[O:5])[CH3:4]
Reactant: COc1cc(N2CCC(N3CCN(C(C)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(C(C)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
NaBH4 (0.190 g, 5.06 mmol) was added carefully in portions (exothermic) to a suspension of 1-acetyl-4-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (0.52 g, 1.45 mmol), nickel(II)chloride hexahydrate (0.170 g, 0.72 mmol), MeOH (8 mL) and THF (4 mL) at 0° C. The ice bath was removed and the reaction mixture was stirred at rt overnight (˜16 h). The solvent was evaporated and the residue was suspended in DCM and filtered through celite. Flash chromatography afforded the title compound of step B (0.36 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ 6.50-6.45 (m, 2H), 6.30-6.25 (m, 1H), 4.18 (bs, 2H), 3.71 (s, 3H), 3.45-3.36 (m, 6H), 2.45-2.38 (m, 3H), 2.31-2.23 (m, 1H), 1.96 (s, 3H), 1.82-1.74 (m, 2H), 1.58-1.44 (m, 2H).
Reaction SMILES: C(OC1C=CC([C@@H](O)CBr)=CC=1CO[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])C1C=CC=CC=1.[N:28]([CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:38]([NH:40][CH:41]=[O:42])[CH:39]=1)[OH:33])=[N+:29]=[N-:30]>>[N:28]([CH2:31][C@@H:32]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[C:38]([NH:40][CH:41]=[O:42])[CH:39]=1)[O:33][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[N+:29]=[N-:30]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c(NC=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 7, using Intermediate 11 in place of (R)-4-(2-bromo-1-hydroxyethyl)-2-(hydroxymethyl)phenol. ES/MS calcd. C22H31N4O3Si+ 427.2. Found m/z=427 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:21][S-:22].[Na+]>CN(C=O)C>[CH3:21][S:22][C:2]1[C:9]([CH2:10][CH2:11][CH3:12])=[C:8]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: CCCc1c(OCc2ccccc2)ccc(C=O)c1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCc2ccccc2)ccc(C=O)c1SC
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 2-chloro-3-propyl-4-benzyloxybenzaldehyde (Step C; 0.683 grams) in dry DMF (7 mL) was treated with sodium methanethiolate (0.166 grams). The solution was stirred at 50° C. for 3 hours. The reaction mixture was partitioned between isopropyl acetate and pH 7 buffer. The organic was washed 3 times with water, then dried over magnesium sulfate. Filtration and concentration afforded an oil which was chromatographed over silica gel to afford the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH2:25]([OH:27])[CH3:26]>[Pd]>[CH:1]([O:4][C:5]([C:7]1[N:8]([CH:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:25](=[O:27])[CH3:26])[CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:9]=[N:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1cncn1C1CCCc2ccc([N+](=O)[O-])cc21
Reactant: CCO
Agent: [Pd]
Product: CC(=O)Nc1ccc2c(c1)C(n1cncc1C(=O)OC(C)C)CCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(7-nitro-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester, which can be prepared as described in Example 5, (3.24 g, 9.84 mmol) in ethanol (125 mL) is added palladium on carbon (10% wt., 0.65 g, 0.61 mmol). The flask is flushed with hydrogen and stirred under balloon pressure at room temperature overnight. The catalyst is then filtered through Celite®. The Celite® cake is washed with methanol and the combined filtrate is concentrated to afford 3-(7-acetylamino-1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid isopropyl ester; 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (d, J=6.3 Hz, 3 H), 1.38 (d, J=6.3 Hz, 3 H), 1.62-1.83 (m, 2 H), 2.01-2.08 (m, 1 H), 2.13-2.21 (m, 1 H), 2.67-2.84 (m, 2 H), 5.22 (sept, J=6.3 Hz, 1 H), 6.17 (t, J=5.1 Hz, 1 H), 6.31 (d, J=2.5 Hz, 1 H), 6.62 (dd, J=8.2, 2.5 Hz, 1 H), 6.98 (d, J=8.2 Hz, 1 H), 7.21 (s, 1 H), 7.77 (s, 1 H).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH2:12][NH:13][C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)=[O:15])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[N:1]1([C:6]2[N:11]=[C:10]([CH2:12][NH:13][C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=3)=[O:15])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(CNC(=O)C2CCCN2)nc(-n2ccnc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)C2CCCN2Cc2ccc(C(F)(F)F)cc2)nc(-n2ccnc2)n1
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of pyrrolidine-2-carboxylic acid (2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amide (43 mg, 0.15 mmol) in dimethylformamide (1.5 mL) was added 4-(trifluoromethyl)benzaldehyde (22 μL, 0.16 mmol) and acetic acid (0.075 mL) at r.t. The solution was allowed to stir for 2 hrs. To the solution was added sodium triacetoxyborohydride (107 mg, 0.50 mmol) at r.t. The solution was stirred for 16 hrs then concentrated under vacuum. The residue was diluted with DCM, washed with NaOH (1N, 30 mL) and water (30 mL), dried over MgSO4, filtered and concentrated. The product was purified using mass-triggered LCMS to afford 5 mg of 1-(4-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid (2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amide as a white solid. [M+H]+ 444.96.
Reaction SMILES: C1([N:7]=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=O)=[CH:19][CH:18]=1.[N+](C1C=CC(O)=CC=1)([O-])=O>C(OCC)(=O)C>[OH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([NH2:7])=[O:27])=[CH:19][CH:18]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: NC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
N,N′-dicyclohexylcarbodiimide (2.48 g, 0.012 mol) was added to chilled (0° C.) 3-(4-hydroxyphenyl)propanoic acid solution (2 g, 0.012 mol) and 4-nitrophenol (1.95 g, 0.014 mol) in ethyl acetate (25 cm3) and mixed magnetically at 0° C. for 30 min. The reaction mixture was then stirred magnetically for 2 h at room temperature. Thereafter, the precipitated N,N′-dicyclohexylureaa was filtered out, washed using ethyl acetate (5 cm3) and the combined filtrates were evaporated until dry. Anhydrous methanol saturated with ammonia (10 cm3) was added and the reaction mixture was stirred magnetically for 2 hrs, thereafter the mixture was evaporated until dry, and the remainder was loaded onto a chromatography column packed with Merck 60H silica gel (5-40 μm). The column was eluted with chloroform-methanol (50:1, v/v). The chromatographically purified product was crystallized out of the methanol and then vacuum desiccated over phosphorus pentocide yielding 1.45 g 3-(4-hydroxyphenyl)propanoic acid amide (75% efficiency) (FIG. 1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][CH:16]([CH:30]([CH3:32])[CH3:31])[CH2:17][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]3[CH2:21][O:20]3)[CH:13]=2)[N:8]([CH3:33])[CH:7]=1>C(O)(C)C.C(N)(C)C>[OH:20][CH:19]([CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:17][CH:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:33])[CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:30]([CH3:31])[CH3:32])[CH2:21][NH:8][CH:9]([CH3:14])[CH3:10]
Reactant: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C3CO3)C(C)C)cc12
Solvent: CC(C)N
Solvent: CC(C)O
Product: COCCCc1cn(C)c2ccc(CC(CC(NC(=O)OC(C)(C)C)C(O)CNC(C)C)C(C)C)cc12

Procedure:
A solution of 0.032 g of tert-butyl {3-[3-(3-methoxypropyl)-1-methyl-1H-indol-5-ylmethyl]-4-methyl-1-oxiranylpentyl}carbamate in 1 ml of isopropanol and 0.044 ml of isopropylamine is stirred at 70° C. On completion of reaction (TLC monitoring), the reaction mixture is concentrated by evaporation, and the residue is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: C[C:2]1([C:8]([OH:10])=O)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[F:12][C:13]([F:37])([F:36])[C:14]1[CH:15]=[C:16]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:17][O:18][CH2:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][NH2:22].[CH2:38](N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[F:12][C:13]([F:36])([F:37])[C:14]1[CH:15]=[C:16]([CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=1)[CH2:17][O:18][CH2:19][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][NH:22][C:8]([CH:2]1[CH2:3][CH2:4][N:5]([CH3:38])[CH2:6][CH2:7]1)=[O:10]
Reactant: NCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reactant: CC1(C(=O)O)CCNCC1
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1CCC(C(=O)NCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
4-Methylpiperidine-4-carboxylic acid (0.41 g, 2.9 mmol), the compound produced in Example 17 (0.99 g, 2.9 mmol) and triethylamine (0.40 mL, 2.9 mmol) were dissolved in CH2Cl2 (10 mL) and WSC.HCl (0.56 g, 2.9 mmol) was added thereto at room temperature. After the mixture was stirred for 20 hours at room temperature, water was added to the residue obtained by evaporation of the solvent in vacuo and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water and a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was evaporated therefrom in vacuo to give Compound 1 (1.12 g, 93%) as an oily product.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:35])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:21]=[C:20]([CH2:22][NH:23]C(OC(C)(C)C)=O)[O:19][N:18]=3)[CH:15]=2)[N:10]([C:31](=[O:33])[CH3:32])[C@@H:9]([CH3:34])[CH2:8]1)[CH3:3].[ClH:36].CCOCC>O1CCOCC1>[ClH:36].[C:31]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]3[N:21]=[C:20]([CH2:22][NH2:23])[O:19][N:18]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:35])[O:4][CH:2]([CH3:1])[CH3:3])[CH2:8][C@@H:9]1[CH3:34])(=[O:33])[CH3:32]
Reactant: CC(=O)N1c2ccc(-c3noc(CNC(=O)OC(C)(C)C)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3noc(CN)n3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.9 %

Procedure:
To a solution of 1-methylethyl((2S,4R)-1-acetyl-6-{5-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-1,2,4-oxadiazol-3-yl}-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation, see Intermediate 60) (132 mg, 0.271 mmol) in 1,4-dioxane (2 mL) at room temperature was added HCl (4N in 1,4-dioxane, 2 mL, 8.00 mmol) and the resulting mixture was stirred at this temperature for 5 h then left standing at 4° C. for 16 h. The mixture was warmed to room temperature and most of the solvent was removed in vacuo. The residue was loaded on a 2 G SCX cartridge and eluted with MeOH then with a 2N NH3 solution in MeOH. The ammonia fractions were collected and concentrated in vacuo, The residue was dissolved in 1,4-dioxane (3 mL) and the solution was treated with 0.5 ml of HCl (4N in 1,4-dioxane) then concentrated in vacuo. Trituration of the residue with Et2O gave 1-methylethyl {(2S,4R)-1-acetyl-6-[5-(aminomethyl)-1,2,4-oxadiazol-3-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate hydrochloride (71 mg, 0.167 mmol, 61.9% yield) as a pale red solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:23][C:12]2=[N:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:24]OS([O-])=O.[K+].[OH2:30]>CO>[CH2:1]([S:8]([C:9]1[S:23][C:12]2=[N:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16](=[O:17])[N:11]2[N:10]=1)(=[O:24])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: O=S([O-])OO
Reactant: CCOC(=O)c1cnc2sc(SCc3ccccc3)nn2c1=O
Agent: [K+]
Solvent: CO
Product: CCOC(=O)c1cnc2sc(S(=O)(=O)Cc3ccccc3)nn2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
In 240 ml of methanol, 6.3 g of 2-benzylthio-6-ethoxycarbonyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. A suspension of 27.7 g of OXONE® dispersed in 110 ml of water was added to the methanol solution. The mixture was stirred at 60° C. for 2 hours, and was extracted with chloroform after cooling. The organic layer was washed with a sodium thiosulfate solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was recrystallized from an acetonitrile/isopropylether (2:1) mixture and 3.3 g of 2-benzylsulfonyl-6-ethoxycarbonyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 200°-203° C. Yield 49%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N:11]1[CH2:15][CH2:14][NH:13][C:12]1=[S:16].[I:17]I.[I-].[K+]>CO.O>[IH:17].[CH3:10][N:11]1[CH2:15][CH2:14][N:13]=[C:12]1[S:16][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: CN1CCNC1=S
Reactant: c1ccc2[nH]ccc2c1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CN1CCN=C1Sc1c[nH]c2ccccc12
Product: I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.85 g indole in 50 ml methanol and 5.8 g 1-methyl-2-imidazolidinethione in 100 ml methanol is treated with a solution of 12.7 g of iodine and 25 g potassium iodide in 100 ml water. The mixture is stirred for 2 hours at room temperature, the clear solution is concentrated in vacuo to one third of the original volume and cooled. The solid which separates is filtered off and recrystallized from a mixture of methanol and ethyl acetate to give 3-(1-methyl-2-imidazolin-2-ylthio)-indole hydriodide melting at 215°-216°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1.O[Li].O.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:7]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
Dimethyl 5-bromobenzene-1,3-dicarboxylate (5 g, 18.3 mmol, 1.0 eq) was dissolved in THF (50 mL) and LiOH.H2O (1.1 g, 27.5 mmol, 1.5 eq) and H2O (10 mL) were added. The mixture was stirred at room temperature overnight. The THF was removed in vacuo and the aqueous phase acidified with diluted HCl. The aqueous phase was extracted with EtOAc, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (CH2Cl2:MeOH, 50:1) to give the title compound as a white solid (3 g, 63%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18]>>[CH3:8][C:6]1[CH:7]=[C:2]([C:13]2[CH:12]=[C:11]([O:10][CH3:9])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Product: COc1cc(-c2cc(C)ncn2)cc(OC)c1OC

Procedure:
4-Chloro-6-methylpyrimidine (913 mg) and 3,4,5-Trimethoxyphenylboronic acid (2.73 g) were reacted in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][CH2:15][C@:16]1([CH3:29])[C@H:20]([CH:21]=[CH2:22])[O:19][C@H:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17]1)[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH3:49][O:50][C:51]1[CH:68]=[CH:67][C:54]([CH2:55][O:56][CH2:57]/[CH:58]=[C:59](\[CH3:66])/[C@@H:60](O)[C@@H:61]([CH3:64])[CH:62]=[CH2:63])=[CH:53][CH:52]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C1COCC1>[Si:1]([O:8][CH:9]([CH2:14][CH2:15][C@:16]1([CH3:29])[C@H:20]([CH:21]=[CH2:22])[O:19][C@H:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:17]1)[CH2:10][C:11]([O:13][C@@H:60]([C@@H:61]([CH3:64])[CH:62]=[CH2:63])/[C:59](/[CH3:66])=[CH:58]/[CH2:57][O:56][CH2:55][C:54]1[CH:67]=[CH:68][C:51]([O:50][CH3:49])=[CH:52][CH:53]=1)=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C[C@H](C)[C@H](O)/C(C)=C/COCc1ccc(OC)cc1
Reactant: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CC[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=C[C@@H]1O[C@H](c2ccccc2)O[C@]1(C)CCC(CC(=O)O[C@H](/C(C)=C/COCc1ccc(OC)cc1)[C@@H](C)C=C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.2 %

Procedure:
To an anhydrous THF (130 ml) solution of (3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(2S,4R,5S)-4-methyl-2-phenyl-5-vinyl-1,3-dioxolan-4-yl] pentanoic acid (6.50 g, 15.5 mmol) was added triethylamine (2.80 ml, 20.2 mmol) under nitrogen atmosphere and cooled to 0° C. 2,4,6-Trichlorobenzoyl chloride (2.65 ml, 17.0 mmol) was added to the reaction solution. After the reaction solution was stirred at 0° C. for 10 minutes, it was stirred at room temperature for two hours. After the reaction solution was filtered with celite, the organic layer was concentrated under reduced pressure. To the obtained residue, an anhydrous toluene (130 ml) solution of (3S,4S,5E)-7-[(4-methoxybenzyl)oxy]-3,5-dimethylhepta-1,5-dien-4-ol (4.71 g, 17.0 mmol) and 4-dimethylaminopyridine (2.46 g, 20.2 mmol) were added under nitrogen atmosphere. After the reaction solution was stirred at room temperature for two hours, it was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution, water and brine sequentially, it was dried over magnesium sulfate anhydrous. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=10:1→5:1) to obtain the title compound (9.81 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][CH:23]=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: Nc1cc[nH]n1
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)(F)F)n3nccc3n2)ccc1Cl
Yield: 98.4 %

Procedure:
A mixture of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (3.95 g, 14.9 mmol) and commercially available 3-aminopyrazole (1.24 g, 14.9 mmol) in acetic acid (40 mL) was refluxed for 5.5 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (4.57 g, 98%) as a yellow solid. MS (EI) 311.2 [(M)+]; mp 114° C.