Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[O:3]=[C:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1.[BH4-].[Na+]>ClCCl>[OH:3][CH:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(O)CC1
Reaction time: 2 h

Procedure:
To a methanol (250 mL) solution of tert-butyl 4-oxoazepane-1-carboxylate (18.1 g, 85.0 mmol) at 0° C. was added sodium borohydride (8.01 g, 212 mmol). The reaction mixture was stirred for 2 hours before concentration in vacuo. The residue was dissolved in dichloromethane (250 mL) and washed with brine. The precipitate was removed by filtration, and the filtrate was dried (magnesium sulfate), filtered and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3) 3.87 (br s, 1H), 3.49-3.18 (m, 4H), 2.05-1.48 (m, 6H), 1.46 (s, 9H); LC-MS: m/z 238.2 (M+Na).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.OS(O)(=O)=O.[NH4+].[OH-].[CH3:19]O>>[OH:1][CH2:2][CH:3]1[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:19])=[O:10])[CH2:7][CH2:8]1
Reactant: CO
Reactant: O=C(O)C1CCC(CO)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)C1CCC(CO)CC1
Reaction time: 2 h
Yield: 83 %

Procedure:
To 4-hydroxymethylcyclohexanecarboxylic acid (TCI-JP, 0.50 g, 3.2 mmol) in 10 mL CH3OH was added 0.50 mL concentrated H2SO4. This mixture was warmed to reflux and allowed to stir for 2 h. The reaction mixture was then cooled and NH4OH was added until the solution tested basic using pH paper. The mixture was then extracted with 3×5 mL ethyl acetate. The combined organic extracts were washed with saturated, aqueous NaCl then were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 0.45 g of the title compound (0.26 mmol, 83% yield). MS (DCI/NH3) m/z 190 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([C:7]([O:9][C:10]2[C:15]([NH:16]C(=O)C3C=CC(OC)=C(C(F)(F)F)C=3)=[CH:14][C:13]([O:31][CH3:32])=[CH:12][C:11]=2[Br:33])=O)=[CH:5][C:4]=1[C:36]([F:39])([F:38])[F:37].O.C1(C)C(S(O)(=O)=O)=CC=CC=1>>[Br:33][C:11]1[C:10]2[O:9][C:7]([C:6]3[CH:34]=[CH:35][C:3]([O:2][CH3:1])=[C:4]([C:36]([F:37])([F:39])[F:38])[CH:5]=3)=[N:16][C:15]=2[CH:14]=[C:13]([O:31][CH3:32])[CH:12]=1
Reactant: COc1cc(Br)c(OC(=O)c2ccc(OC)c(C(F)(F)F)c2)c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Product: COc1cc(Br)c2oc(-c3ccc(OC)c(C(F)(F)F)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 20, Step d (Route a), from 2-bromo-4-methoxy-6-{[4-methoxy-3-(trifluoromethyl)benzoyl]amino}phenyl 4-methoxy-3-(trifluoromethyl)benzoate and p toluenesulfonic acid monohydrate. The product was obtained as an off-white solid, m.p. 183-185° C.; MS m/e 402 (M+H)4.
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2([C:29]([O:31]CCCC)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])CCC.O[Li].O>>[C:29]([C:24]1([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18](=[O:36])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:8]2([C:6]([OH:7])=[O:5])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:25][CH2:26][CH2:27][CH2:28]1)([OH:31])=[O:30]
Reactant: CCCCOC(=O)C1(CCCCCC(=O)CCCCCC2(C(=O)OCCCC)CCCC2)CCCC1
Agent: [Li]O
Solvent: O
Product: O=C(CCCCCC1(C(=O)O)CCCC1)CCCCCC1(C(=O)O)CCCC1

Procedure:
Compound 107m was prepared likewise Method D starting from 106m (21.03 g, 90% pure by 1H NMR, 37.3 mmol) and LiOH.H2O (7.83 g, 187 mmol) to give, after recrystallization from iPr2O/heptane, 107m (12.15 g, 83%) as white granules. mp=78-85° C. 1H NMR: δ 2.37 (t, J=7.4 Hz, 4H), 2.18-2.10 (m, 4H), 1.65-1.45 (m, 20H), 1.29-1.25 (m, 8H). 13C NMR: δ 211.5, 184.8 (2×), 54.0 (2×), 42.4 (2×), 38.9 (2×), 35.9 (4×), 29.2 (2×), 25.5 (2×), 24.9 (4×), 23.5 (2×). Anal. calcd for C23H38O5: C, 70.02; H, 9.71, found: C, 70.37; H, 9.72.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([O:8]C(OC(C)(C)C)=O)=O)([CH3:4])[CH3:3].[CH3:16][NH2:17]>C(Cl)Cl>[CH3:16][NH:17][C:6](=[O:8])[O:5][C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of Boc anhydride (7.5 g, 34.36 mmol) in DCM (40 mL) was added methylamine (173 mL, 2M solution in THF, 345 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent and excess methylamine were removed in vacuo and dilute 2M HCl (10 mL) was added. The aqueous layer was extracted with DCM (×2) and the combined organics were dried and concentrated to give the title compound as a yellow oil (3.791 g). δH (CDCl3, 400 MHz) 4.58 (1H, br.s), 2.73 (3H, d), 1.44 (9H, s).
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[NH:3]1.P(Cl)(Cl)([Cl:14])=O.P(Cl)(Cl)(Cl)(Cl)Cl>>[Cl:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1[nH]c(=O)ccc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 1 h
Yield: 182.2 %

Procedure:
A mixture of 2-oxo-5-nitro-6-methyl-1,2-dihydropyridine (38.95 g, 253 mmol), phosphorous oxychloride (12.3 mL, 130 mmol), and phosphorous pentachloride (27.9 g, 134 mmol) was heated at 110° C. for 2 hours, whereupon the reaction mixture was charged with an additional portion of phosphorous pentachloride and phosphorous oxychloride (9.9 g and 4.8 mL, respectively). The reaction was stirred 1 hour, then poured into ice-water (600 mL). The brown solid was filtered and washed with cold water, to give 40.88 g of the title compound (94%). MS(m/e): 173 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CO>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
To a stirring solution of 4-bromo-2-nitro-phenol (6 g, 27.52 mmol) in MeOH (150 mL) at room temperature was added a suspension of Na2S2O4 (29 g, 165.13 mmol). The mixture was stirred at room temperature for 3 hrs, filtered and concentrated down. The residue was partitioned between EtOAc and water. The organic layer was collected and dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-amino-4-bromo-phenol as a yellow solid (3.9 g, 75%): 1H NMR (200 MHz, DMSO-d6): δ 9.27 (s, 1 H), 6.70 (d, J=2.2 Hz, 1 H), 6.50 (m, 2 H), 4.79 (s, 2 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=20% ethyl acetate in hexanes; Rf=0.35.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[S-:10][C:11]#[N:12].[NH4+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][C:11]#[N:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.8 %

Procedure:
2,6-Dichlorophenol (100 g, 0.613 mole) and ammonium thiocyanate (102.73 g, 1.350 mole) were mixed in methanol and the solution cooled to 0° C. Chlorine gas was bubbled through the reaction, maintaining the temperature below 10° C. The solution turned a pale yellow color. The reaction was stirred for a total of 3 hours until acidic, at which time ammonia gas was bubbled through and the solution stirred for an additional three hours at 0° to 10° C. The reaction was poured into iced distilled water, and filtered, yielding approximately 20 g of a yellow solid which was dried overnight in vacuo. The filtrate was extracted with ethyl acetate, the extracts dried over magnesium sulfate and solvent removed in vacu to yield approximately 100 g of crude product. Following purification by silica chromatography, the material was taken up in 1 liter of toluene, charcoal added, filtered and recrystallized from hexane to yield 55.03 g of product as a yellow solid, m.p. about 94.5°-97° C. The structure was confirmed by NMR.
Reaction SMILES: [Al].[Li].[N:3]([CH2:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)=[N+]=[N-].O.[OH-].[Na+]>CCOCC>[NH2:3][CH2:6][C:7]1[N:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:9][CH:8]=1
Reactant: Cc1nc(CN=[N+]=[N-])ccc1OCc1ccccc1
Agent: [Al]
Agent: [Li]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1nc(CN)ccc1OCc1ccccc1
Reaction time: 0.75 h

Procedure:
Lithium aluminum hyride (1.27 g) is added to a solution of 6-azidomethyl-3-benzyloxy-2-methylpyridine (7.18 g) in 120 ml of dry ether at room temperature. After stirring for 45 minutes, 1.3 ml of water, 1.3 ml of 15% sodium hydroxide and 3.8 ml of water are added sequentially. The salts are filtered off and the filtrate is evaporated to yield 6-aminomethyl-3-benzyloxy-2-methylpyridine; NMR: (CDCl3) 1.67 (2H), 2.47 (3H), 3.8 (2H), 4.95 (2H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([OH:14])[CH:13]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:14][C:12]1[CH:13]=[C:8]([F:7])[CH:9]=[CH:10][C:11]=1[N+:15]([O-:17])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of K2CO3 (2.07 g, 15 mmol) in DMF (8 mL) is added 5-fluoro-2-nitrophenol (1.57 g, 10 mmol), followed by benzyl bromide (1.75 g, 10.2 mmol). The mixture is stirred at ambient temperature for 18 h, then poured into water and extracted into EtOAc. The organic phase is washed with water (3×), saturated NaCl (1×) and dried over sodium sulfate. The solvent is removed under reduced pressure and the residual oil filtered through a pad of silica gel using DCM to elute 2-benzyloxy-4-fluoro-1-nitrobenzene as a yellow oil, which slowly solidifies on standing: mp=52-54° C.; 1H NMR (CDCl3) δ 8.03-7.98 (m, 2H), 7.53-7.36 (m, 5H), 6.66 (dd, J=10.17, 2.64 Hz, 1H), 6.81-6.73 (m, 1H), 5.26 (s, 2H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](=[NH:9])[NH2:8])=[CH:5][CH:4]=1.CCN(CC)CC.[Cl:19][C:20]([SH:23])(Cl)Cl.[OH-].[Na+]>C(Cl)Cl.O>[Cl:19][C:20]1[S:23][N:8]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([CH3:2])=[CH:4][CH:5]=2)[N:9]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: Cc1ccc(C(=N)N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2nsc(Cl)n2)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A mixture of 4-methylbenzimidamide hydrochloride (1.55 g, 9.08 mmol) and Et3N (4.6 g, 6.33 ml, 45.4 mmol) in DCM (30 mL) was cooled with a NaCl/ice-bath to −10° C. Perchloromethyl mercaptan (1.86 g, 1.09 ml, 9.99 mmol) in DCM (10 mL) was added during 40 min. The resulting yellow suspension was stirred for 20 min at 0° C. and 2 h at RT. Water (40 mL) and aq. 2N NaOH (10 mL) was added. The organic layer was separated and extracted with brine (50 mL). The aqueous layers were extracted with DCM (2×40 mL). The combined organic layers were dried over Na2SO4, filtered off and concentrated in vacuo. The residue was purified by silica chromatography (Flash 50 g Si-cartridge using AcOEt: Heptane 1:19 to 1:9.) to yield 5-chloro-3-p-tolyl-1,2,4-thiadiazole (1.63 g, 7.74 mmol, 85% yield) as light yellow solid.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])[C:3]([OH:5])=[O:4].[CH3:15]O>S(=O)(=O)(O)O>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])[C:3]([O:5][CH3:15])=[O:4]
Reactant: CO
Reactant: O=C(O)C(O)c1ccccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccccc1[N+](=O)[O-]

Procedure:
Methyl 2-hydroxy-2-[2-nitrophenyl]acetate (FIG. 2; Compound 6) was prepared by dissolving crude acid 2-hydroxy-2-[2-nitrophenyl]acetic acid (entire amount) in methanol (100 ml). Sulfuric acid (5 drops) was added, and the mixture was refluxed for 2.5 hr. The solvent was then evaporated. The residue was taken up in ethyl acetate and extracted with saturated sodium bicarbonate, followed by water and brine. After drying over MgSO4, the solvent was evaporated to give 9.13 g (90%) of crude ester which was recrystallized from isopropyl ether to give 7.92 g (78%) of methyl 2-hydroxy-2-[2-nitrophenyl]acetate. mp. 69-71° C. 1H-NMR: 8.01 (d, J=8.19 Hz, 1H), 7.70-7.63 (m, 2H), 7.55-7.49 (m, 1H), 5.83 (d, J=4.88 Hz, 1H), 3.76 (s, 3H), 3.66 (d, J=4.89 Hz, 1H). HRMS(CI): calculated for C9H10NO5 [M+ +H] m/z=212.0559, observed 212.0555.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4]([CH2:14][CH2:15][CH3:16])=[CH:5][C:6](=[O:13])[O:7]2.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>>[CH2:14]([C:4]1[C:3]2[C:8](=[C:9]([C:17](=[O:20])[CH2:18][CH3:19])[C:10]([OH:12])=[CH:11][C:2]=2[OH:1])[O:7][C:6](=[O:13])[CH:5]=1)[CH2:15][CH3:16]
Reactant: CCCc1cc(=O)oc2cc(O)cc(O)c12
Reactant: CCC(=O)Cl
Product: CCCc1cc(=O)oc2c(C(=O)CC)c(O)cc(O)c12

Procedure:
acylating 5,7-dihydroxy-4-propylcoumarin with propionyl chloride in the presence of a Lewis acid to form 4-propyl-5,7-dihydroxy-8-propionylcoumarin;
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[C@H:3]([OH:6])[CH2:4][OH:5].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>N1C=CC=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:5][CH2:4][C@@H:3]([OH:6])[C:2]([CH3:8])([CH3:7])[CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)[C@H](O)CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To 6.65 g (56 mmol) of (2S)-3,3-dimethyl-1,2-butanediol in 13 mL of pyridine at 0° C. was added dropwise a solution of 10.68 g (56 mmol) of p-toluenesulfonyl chloride in 20 mL of pyridine. The solution was maintained at 0° C. for 5 h and then let warm to ambient temperature. After being stirred overnight, the mixture was concentrated, and the residue was taken up in 200 mL of diethyl ether. The ether solution was washed with 50 mL of 1N hydrochloric acid, 50 mL of saturated aqueous sodium bicarbonate, and 50 mL of water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (3.5:6.5) to give 13 g (85%) of (2S)-2-hydroxy-3,3-dimethylbutyl 4-methylbenzenesulfonate. 1H-NMR (300 MHz, DMSO-d6): δ 7.79 (d, J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H), 5.11 (br s, 1H), 4.08 (dd, J=10 Hz, J=3 Hz, 1H), 3.76 (dd, J=10 Hz, J=8 Hz, 1H), 3.23 (d, J=8 Hz, 1H), 2.41 (s, 3H), 0.76 (s, 9H). ES-LCMS m/z 273 (M+H), 295 (M+Na).
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[CH2:9](O)[CH2:10][OH:11].C(OCC)(OCC)OCC.C(OCC)(=O)C>O>[CH3:2][C:1]1([C:4]2[O:5][CH:6]=[CH:7][CH:8]=2)[O:11][CH2:10][CH2:9][O:3]1
Reactant: OCCO
Reactant: CC(=O)c1ccco1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: CC1(c2ccco2)OCCO1
Yield: 46.4 %

Procedure:
A mixture of 4 mL (139.6 mmol) 2-acetylfuran, 8.7 mL (156 mmol) of ethylene glycol, 198 mg (1 mmol) of ptoluenesulfonic acid monohydrate, and 22 mL (132.3 mmol) of triethyl orthoformate was reacted at room temperature under N2 for 3 days. The reaction mixture was poured into a mixture of ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined organic layer was washed with water (100 mL), sodium bicarbonate solution (150 mL), and brine (100 mL). The organic layer was dried over MgSO4, concentrated in vacuo, and the residue was distilled under reduced pressure (1.5 tort) to afford 9.98 g (50%) of 2-(2-methyl-1,3-dioxolan-2-yl)-furan, as a clear oil, b.p. 24° C./1.5 min.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.C(Cl)(=O)C([Cl:17])=O.CN(C)C=O>COCCOC>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:17])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 30.0 ml of 1,2-dimethoxyethane (DME), 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 6.97 g of oxalyl chloride at 5° C. to a mixture of 100 ml of DME and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 200 ml of ice water to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water, collected by filtration and then, stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.2 g (75.1%). Purity: 94.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)([O-])=O.Cl[Sn]Cl>C(O)C>[S:10]1[C:6]2[CH:5]=[C:4]([NH2:1])[CH:13]=[CH:12][C:7]=2[N:8]=[C:9]1[NH2:11]
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc2nc(N)sc2c1
Yield: 50 %

Procedure:
A mixture of 6-nitro-benzothiazol-2-ylamine (1.0 g, 5.12 mmol) and SnCl2 (4.86 g, 25.6 mmol) in 15 mL ethanol (denatured) was heated at reflux for 1 hour. The mixture was concentrated and partitioned between 100 mL CH2Cl2 and 50 mL 1.0 N NaOH. The organic layer was separated and the aqueous layer was extracted with 2×100 mL of CH2Cl2. The combined organic fractions were dried over MgSO4, filtered and evaporated to give a yellow solid. This was washed with a 1:1 mixture of Et2O and hexanes. Yield: 50%; 1H-NMR (acetone-d6): δ 7.14 (d, 1H, J=8.8 Hz); 6.92 (d, 1H, J=1.9 Hz); 6.62 (dd, 1H, J=1.9, 8.5 Hz).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.S([O-])([O-])(=O)=O.[Mg+2]>CCCCCC>[CH:6]1([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCCC1
Reactant: C1CCNC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCCCCC
Product: C1CCC(N2CCCC2)CC1

Procedure:
The structure-directing agent (SDA) is synthesized using the reaction sequence described in the scheme below. A three neck 3 000-ml flask is charged with 100 gm (1.4 mole) of pyrrolidine, 50 gm of cyclohexanone (0.51 mole) and 1000 ml anhydrous hexane. To the resulting solution, 122 gm (1.022 mole) of anhydrous magnesium sulfate is added and the mixture is mechanically stirred and heated at reflux (the reaction is monitored by NMR analysis) for 96 hrs. The reaction mixture is filtered through a fritted glass funnel. The filtrate is concentrated under reduced pressure on a rotary evaporator to give 75 gm of a clear (yellow-tinted) oily substance. 1H-NMR and 13C-NMR spectra are acceptable for the desired product 1-(1-pyrrolidino)cyclohexene. Saturation of 1-(1-pyrrolidino)cyclohexene, to give N-cyclohexylpyrrolidine, is accomplished in quantitative yield by hydrogenation in ethanol at a 55 psi pressure of hydrogen gas in the presence of 10% Pd on activated carbon.
Reaction SMILES: OS(O)(=O)=O.N([O-])=O.[Na+].C(O)(=O)C.N[C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[F:24].[BrH:25]>>[Br:25][C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[F:24]
Reactant: Br
Reactant: N#Cc1cc(F)c(N)c(F)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(Br)c(F)c1
Temperature: 40 °C

Procedure:
While stirring 420 cm3 of concentrated H2SO4 on an ice water bath, 54 g (0.78 mol) of pulverized NaNO2 was added at a rate that maintained a temperature under 40° C., and after the addition it was stirred in a hot water bath at 50° C. until the crystals dissolved completely. While stirring this solution on an ice water bath, 700 cm3 of glacial acetic acid was added dropwise, then 108 g (0.7 mol) of 4-amino-3,5-difluorobenzonitrile was added at a rate maintaining the temperature at 20°-25° C., and after the addition was completed it was stirred at this temperature until the crystals were completely dissolved to prepare a diazonium salt solution. A solution with 143 g (1.0 mol) of CuBr dissolved in 420 cm3 of 47% HBr was stirred in an ice water bath while the previously prepared diazonium salt solution was added dropwise for 2 hours, and after the dropping was completed, it was stirred on an ice water bath for 1 hour and at room temperature overnight. The crystals formed were filtered, and after washing the crystals in glacial acetic acid, they were recrystallized from a mixture of acetone and methanol to obtain 98 g (0.44 mol) of 4-bromo-3,5-difluorobenzonitrile.
Reaction SMILES: S(=O)(=O)(O)O.C(O)(=O)C.[C:10]([C:12]1[CH:18]=[C:17]([F:19])[C:15](N)=[C:14]([F:20])[CH:13]=1)#[N:11].O.[BrH:22]>[Cu]Br>[Br:22][C:15]1[C:17]([F:19])=[CH:18][C:12]([C:10]#[N:11])=[CH:13][C:14]=1[F:20]
Reactant: Br
Reactant: N#Cc1cc(F)c(N)c(F)c1
Agent: [Cu]Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(Br)c(F)c1
Temperature: 25 °C

Procedure:
4 g of sodium nitride was added to 30 ml of concentrated sulfuric acid and chilled to a temperature of 10° C. and 38 ml of acetic acid was added thereto. 8.9 ml of 4-cyano-2,6-difluoroaniline was added gradually to maintain the solution at a temperature of 20° to 25° C. The reaction mixture was added dropwise to a solution a 10 g of copper (I) bromide dissolved in 30 ml of concentrated hydrobromic acid. After the dropwise addition was completed, the reaction mixture was stirred for one and one half hours at room temperature. Water was added to the reaction mixture, the reaction mixture was extracted with chloroform and washed with water. The organic layer was removed by distillation, and the residue was recrystallized with a mixture of methanol and acetone to yield 6.6 g of 2-bromo-5-cyano-1,3-difluorobenzene.
Reaction SMILES: [C:1](=[C:4]1[CH2:9][CH2:8][C:7]([CH2:11][OH:12])([CH3:10])[CH:6]=[CH:5]1)([CH3:3])[CH3:2]>C(O)(C)C>[CH:1]([C:4]1[CH2:9][CH2:8][C:7]([CH2:11][OH:12])([CH3:10])[CH2:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)=C1C=CC(C)(CO)CC1
Solvent: CC(C)O
Product: CC(C)C1=CCC(C)(CO)CC1

Procedure:
A glass reaction vessel was charged with 1 g of 4-isopropylidene-1-methyl-2-cyclohexenylmethanol, the catalyst shown in Table 1 and 20 mL of isopropanol, and the contents of the reaction vessel were reacted with each other at a pressure of from 0.2 to 0.3 MPa and a temperature of 25° C. for the time period shown in Table 1. Thereafter, the reaction mixture was filtered to remove the catalyst therefrom, and then concentrated to obtain 4-isopropyl-1-methyl-3-cyclohexenylmethanol. The amount of hydrogen consumed and the yield of the 4-isopropyl-1-methyl-3-cyclohexenylmethanol are shown in Table 1.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH2:16]([NH:23][C:24]([NH:26][CH2:27][CH:28]([C:33]([OH:35])=O)[C:29]([F:32])([F:31])[F:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:23]1[C:33](=[O:35])[CH:28]([C:29]([F:32])([F:31])[F:30])[CH2:27][NH:26][C:24]1=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(NCc1ccccc1)NCC(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1Cc1ccccc1
Yield: 86 %

Procedure:
A solution of DCC (430 mg; 2.1 mmoles) in DMF (1 ml) was added dropwise to a solution of 1-benzyl-3-(2-hydroxycarbonyl-3,3,3-trifluoropropyl)urea (580 mg; 2.0 mmoles) obtained above in DMF (2 ml). One hour later, the precipitated solid was filtered off and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel (ethyl acetate:chloroform=1:1) to give 468 mg (yield: 86%) of 3-benzyl-5-trifluoromethyl-5,6-dihydrouracil.