Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[CH3:8][C:9]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C:13](=[O:14])[CH:12]=[C:11]([CH3:15])[O:10]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:9]2([CH3:8])[C:13](=[O:14])[CH:12]=[C:11]([CH:15]=[CH:6][C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[O:10]2)=[CH:17][CH:18]=1
Reactant: O=Cc1ccsc1
Reactant: CC1=CC(=O)C(C)(c2ccc(F)cc2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccc(F)cc2)OC(C=Cc2ccsc2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.8 %

Procedure:
To a solution of 3-thiophenecarboxaldehyde (1.3 g, 1.2 mM) and 2,5-dimethyl-2-(4-fluorophenyl)-3(2H)-furanone (2.0 g, 9.8 mM) in ethanol (75 mL), was added 1N aqueous sodium hydroxide (2 mL, 2 mM). The reaction solution was stirred at room temperature for one day. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with dichloromethane (3×100 mL). The combined dichloromethane extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown oil. The crude product was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford a yellow solid (1.8 g, 62% yield), m.p. 97°-98° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:4]([Cl:23])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:34][C:35]([F:42])([F:41])[C:36](OCC)=[O:37]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13](=[O:15])[CH2:14][C:36](=[O:37])[C:35]([F:42])([F:41])[F:34])[N:10]=[C:9]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[C:4]([Cl:23])[CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)(F)F)c1cn(-c2ccc(Br)cc2Cl)c(-c2ccccc2Cl)n1
Temperature: -78 °C
Yield: 15.2 %

Procedure:
To a dry N2 purged 50 mL round bottom flask attached with addition funnel was added 1-(1-(4-bromo-2-chlorophenyl)-2-(2-chlorophenyl)-1H-imidazol-4-yl)ethanone (640 mg, 1.56 mmol) and anhydrous THF (12 mL). The reaction solution was cooled to −78° C. prior to dropwise addition of a 1.0 M LHMDS solution in THF (1.72 mL). The enolate solution was allowed to stir, warming to −200C over 1 h. The reaction solution was cooled to −600C, and ethyl trifluoroacetate (370 μL, 3.12 mmol) was added. The reaction solution was stirred at room temperature for 16 h. The reaction solution was quenched with H2O and diluted with EtOAc (100 mL). The EtOAc phase was partitioned, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was chromatographed through a 12 g SiO2 column using a 100% hexane to 60% EtOAc gradient to yield 120 mg (86% yield) of title compound. MS (ESI) 507.0, 509.0 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([NH:9][C:10]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:11]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NCc1ccccc1
Temperature: 80 °C
Reaction time: 9 h
Yield: 62.4 %

Procedure:
To N,N-dimethylformamide 0.5 mL solution of benzyl bromide 41 mg were added tert-butyl 2-amino-4-phenylbenzoate 54 mg and potassium carbonate 55 mg at room temperature, and it was stirred at 80° C. for 9 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Fuji SILYSIA Chemical Ltd., PSQ100B(spherical type), eluent; hexane:ethyl acetate=100:1] to give tert-butyl 2-benzylamino-4-phenylbenzoate 45 mg of a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][CH2:11][C:12]([OH:14])=[O:13]>[OH-].[Na+]>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[O:3]
Reactant: NCC(=O)O
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)OCC(Cl)(Cl)Cl
Temperature: 0 °C

Procedure:
2,2,2-Trichloroethyl chloroformate (23,30 g, 0.11 mole) and 4N NaOH (30 ml, 0.12 mole) are added alternately in about 5 equal portions over a period of 30 minutes to an ice-cold, vigorously stirring solution of glycine (7.51 g, 0.1 mole) in 4N NaOH (25 ml). Upon completion of the reaction, the solution is extracted with ether, and the aqueous portion is slurried with EtOAc and acidified in the cold to pH 2.5 with 6N HCl. The EtOAc solution is separated, washed with H2O, dried over MgSO4, filtered, and evaporated in vacuo to give N-(2,2,2-trichloroethyloxycarbonyl)-glycine.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[CH3:9][C:10]1[CH:15]=[C:14]([C:16](=[O:25])[CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])[CH:13]=[CH:12][N:11]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:1][C:2]([F:4])([F:3])[C:16]([C:14]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:9])[CH:15]=1)([OH:25])[CH:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:18]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C(=O)C(C)c2ccccc2)ccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccccc2)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
Trifluoromethyltrimethylsilane (2N in THF, 0.76 mL, 1.5 mmol) was added at 0° C. to a solution of 1-(2-methyl-pyridin-4-yl)-2-phenyl-propan-1-one (142 mg, 0.63 mmol) in THF (5 mL), followed by the addition of tetrabutylammonium fluoride trihydrate (40 mg, 0.13 mmol). After stirring overnight at r.t., an additional amount of trifluoromethyl-trimethylsilane (0.38 mL), followed by tetrabutylammonium fluoride trihydrate (20 mg) was added to drive the reaction towards completion. The solvent was evaporated, the residue was taken up in methanol, and the title compound (42 mg, 23%) was isolated by reversed-phase, preparative HPLC (Agilent Zorbax XdB-C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA[aq]). 1H NMR (300 MHz, DMSO-D6) □ 8.25 (1H, d), 7.17 (1H, s), 7.11 (2H, d), 7.09-7.00 (4H, m), 6.93 (1H, s), 3.62 (1H, q), 2.35 (3H, s), 1.42 (3H, d); MS (m/e)=296.4 [MH+].
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(3-fluorophenyl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (300 mg, 0.83 mol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (156 mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (239 mg, 1.25 mmol) and 1-hydroxybenzotriazole hydrate (127 mg, 0.83 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (283 mg, 64%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([Cl:19])=[O:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc2cc(C(=O)Cl)ccc2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Then, in a 200 ml-reaction vessel, 17.1 g (7.43×10-2M) of 6-acetoxy-2-naphthoic acid and 85 ml of dry benzene were placed. To the mixture, 15.9 g (6.91×10-2M) of phosphorus pentachloride was added in 30 minutes at room temperature, followed by stirring for 4 hours at 60° C. After cooling, the solvent of the reaction mixture was distilled off to provide oily 6-acetoxy-2-naphthoyl chloride.
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:23])[N:5]([CH3:22])[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)=[N:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:23])[N:5]([CH3:22])[C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccc(Oc3ccccc3)cc2)n(C)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(-c2ccc(Oc3ccccc3)cc2)ncc(O)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 133 g (4.30 mmol) 5-methoxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one in 25 ml CH2Cl2 was added 34.4 ml (34.4 mmol) of a 1 M solution of BBr3 in CH2Cl2. The reaction mixture was stirred for 1 h, cooled to 0° C., quenched with 100 ml MeOH, and concentrated in vacuo. Purification by HPLC gave 945 mg (70% yield) of 5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin -4(3H)-one. LCMS [M+H]+=295.1.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH:11]1([N:19]=[C:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.N1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH:11]1([N:19]2[C:1](=[O:9])[C:2]3[CH2:3][CH2:4][CH2:5][C:6]=3[O:7][C:20]2=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NC1CCCCCCC1
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: Cc1ccccc1C
Solvent: c1ccncc1
Product: O=c1oc2c(c(=O)n1C1CCCCCCC1)CCC2

Procedure:
With stirring and reflux cooling, 183 g (1 mole) of adipic acid chloride were added to a solution, kept at 120°C., of 168.6 g (1.1 moles) of cyclooctylisocyanate and 162 ml (2 moles) of pyridine in 500 ml of xylene. After 3 hours' reaction time, cooling was effected, followed by filtering off from the separated pyridine hydrochloride. The filtrate was first freed from solvent under reduced pressure and, finally, was distilled in a high vacuum. 158.2 g (60% of the theory) of 3-cyclooctyl-2,3,4,5,6,7-hexahydrocyclopenta[e]-1,3-oxazine-2,4-dione of the boiling point 172°-174°C/0.3 mm Hg were obtained when solidified to give a colorless crystal mass of the melting point 48°-51°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]2[NH:8][CH2:9][C:10]3([CH2:13][S:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:21]([N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:10]2([CH2:13][S:12][CH2:11]2)[CH2:9]1)(=[O:23])[CH3:22]
Reactant: Brc1ccc2c(c1)NCC21CSC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC2(CSC2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cooled solution of 6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] (0.25 g, 0.96 mmol), 4-dimethylaminopyridine (5.89 mg, 0.048 mmol), and triethylamine (0.269 mL, 1.928 mmol) in DCM (9.64 mL) was added acetyl chloride (0.137 mL, 1.928 mmol). The solution was stirred for 5 min at this temperature, the ice bath was removed and the solution was stirred at rt for 3 h. The reaction was poured into 2N HCl aqueous solution and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to give 1-acetyl-6-bromo-1,2-dihydrospiro[indole-3,3′-thietane] as a yellow solid. Mass Spectrum (ESI) m/e=297.9 [(M+1) (79Br)] and 300.0 [(M+1) (81Br)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:4](=[O:16])[C:3]=1[Br:17].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](Cl)=[O:29].[OH-].[Na+]>CN(C)C1C=CN=CC=1.C(#N)C>[Br:17][C:3]1[C:4](=[O:16])[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:28](=[O:29])[C:27]1[C:26]([F:25])=[CH:34][CH:33]=[CH:32][C:31]=1[F:35]
Reactant: Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1ccn(Cc2cccc(F)c2)c(=O)c1Br)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
4-amino-3-bromo-1-(3-fluorobenzyl)pyridin-2(1H)-one (from step 3) (0.30 g, 1.01 mmol) and 4-dimethylaminopyridine (0.002 g, 0.01 mmol) were suspended in acetonitrile (5 mL) followed by dropwise addition of triethylamine (0.2 mL, 1.41 mmol). This reaction mixture was stirred for 10 minutes at room temperature before being cooled to 0° C. 2,6-difluorobenzoyl chloride (0.37 g, 2.12 mmol) was added dropwise and the reaction was heated at reflux overnight. The reaction was cooled to room temperature and 1N NaOH (10 mL) was added. The reaction was then stirred for 45 minutes at room temperature. The reaction mixture was extracted with ethyl acetate (3×25 mL) and the organic layer washed with 1N NaOH (2×25 mL), H2O (until pH neutral), brine (50 mL), dried over MgSO4, concentrated, and subjected to chromatography (on C-18, acetonitrile/H2O with 0.1% trifluoracetic acid) to afford a white solid (0.19 g, 43%). 1H NMR (400 MHz, CDCl3) δ 8.42 (br s, 1H), 7.67 (d, J=7.65 Hz, 1H), 7.49 (app tt, J=6.31, 8.60 Hz, 1H), 7.33-28 (m, 2H), 7.10-6.97 (m, 5H), 5.17 (s, 2H). ES-HRMS m/z 437.0083 (M+H C19H12BrF3N2O2 requires 437.0107).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH:6]=[CH:5]1)=[N+:2]=[N-:3].[H-].[Na+].Br[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>O1CCCC1>[N:1]([C@@H:4]1[CH2:8][C@H:7]([O:9][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:6]=[CH:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: [N-]=[N+]=N[C@H]1C=C[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CO[C@@H]1C=C[C@H](N=[N+]=[N-])C1
Temperature: 25 °C

Procedure:
(1S-cis)-4-Azido-2-cyclopenten-1-ol (3.4 g) (prepared as described by D. R. Deardorff et al., J. Org. Chem, 1989, 54, 2759) in tetrahydrofuran (60 ml) was added dropwise to a suspension of sodium hydride (1.1 g. of a 60% suspension in oil) in tetrahydrofuran (60 ml) at 0° C. On completion of the addition the mixture was allowed to warm to ambient temperature the added dropwise to a solution of tert-butyl bromoacetate (10.1 ml) in tetrahydrofuran (60 ml) at 0° C. Water (200 ml) was added and the product extracted into ethyl acetate (200 ml) then dried and concentrated. Purification (SiO2, ethyl acetate:isohexane,10:90, as eluent) afforded the subtitle compound (3.6 g).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26]>N1C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:15][C:16]1[S:20][C:19]2[CH2:21][CH2:22][CH2:23][CH2:24][C:18]=2[C:17]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])(=[O:11])=[O:10]
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2C(F)(F)F)sc2c1CCCC2
Yield: 67.2 %

Procedure:
2-Trifluoromethylbenzenesulphonyl chloride (0.195 g) was added to a solution of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.150 g) in pyridine (1.7 ml) at room temperature and the resultant mixture was stirred for 64 hours. The solvent was removed and the residue was purified directly by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-(2-trifluoromethylbenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.194 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:29])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:12]2[N:11]=1)[CH3:2].[S:30]([Cl:34])(=O)(=[O:32])[OH:31].S(Cl)(Cl)(=O)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:30]([Cl:34])(=[O:32])=[O:31])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:29])[N:18]=[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3OCC)nn12
Solvent: O=S(=O)(Cl)Cl
Product: CCCCCCCCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12

Procedure:
The preparation is carried out analogously to the procedure of Example 27A using 400 mg (1 mmol) of 2-(2-ethoxyphenyl)-5-methyl-7-n-nonyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (Example 24A) and 1.18 g (10 mmol) of chlorosulphuric acid. This gives 402 mg (80.1%) of sulphonyl chloride which is directly reacted further.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[N:38]=[CH:37][CH:36]=[CH:35][N:34]=1)[NH2:32]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=3)[CH2:12][CH:11]([C:26]3[O:27][N:32]=[C:31]([C:33]4[N:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[N:30]=3)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=NO)c1ncccn1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ncccn3)no2)C1

Procedure:
150 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 77 mg (0.56 mmol) of N′-hydroxypyrimidine-2-carboximidamide were reacted according to the General Method 2. Yield: 100 mg (51% of theory).
Reaction SMILES: [CH3:1][CH:2](OC(=O)C)[C:3]#[CH:4].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1.C(OCC)C.[Cu]Cl>[N:9]1([CH:2]([C:3]#[CH:4])[CH3:1])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: C1CCNC1
Reactant: C#CC(C)OC(C)=O
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C#CC(C)N1CCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution acetic acid 1-methyl-prop-2-ynyl ester (prepared by the method of Clarke and Pinder, J. Chem. Soc. 1958, 1967).(7 g) and pyrrolidine (10.4 ml) in anhydrous tetrahydrofuran (125 ml) was treated with copper (I) chloride (0.3 g) and the mixture was heated to reflux temperatures for 1.5 hours. After then allowing the mixture to stir at room temperature for approximately 15 hours, the mixture was diluted with diethyl ether, and extracted thrice with 2N aqueous hydrochloric acid. These pooled acidic extracts were basified by addition of solid sodium hydroxide, and the solution was then extracted three times with ethyl acetate. These pooled organic extracts were then washed with water, brine, and dried over anhydrous magnesium sulfate. After removing the solvent in vacuo the resulting residue was distilled to obtain the desired product as a colorless oil. b.p. 35° C. (1.1 mm Hg). MS(+ES), m/z: 124 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[NH:11][N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3].[C:26]([N:34]=[C:35]=[S:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]([C:35]([NH:34][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[S:36])[N:10]=[C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-2,3-dihydro-1,3,4-thiadiazole (1.00 g, 2.79 mmol) in 20 mL of anhydrous THF was added benzoyl isothiocyanate (0.45 mL, 3.34 mmol). The reaction was allowed to stir overnight at reflux, then cooled and concentrated in vacuo. The residue was purified by flash column chromatography (5-35% ethyl acetate/hexanes) to afford the desired product as a yellow gum, 1.45 g, 54%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][C:10]([CH:20]([CH3:22])[CH3:21])=[N:9]2)=[CH:4][C:3]=1[N+:23]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[NH2:23][C:3]1[CH:4]=[C:5]([N:8]2[C:12]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])=[CH:11][C:10]([CH:20]([CH3:22])[CH3:21])=[N:9]2)[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: CC(C)c1cc(C(=O)OC(C)(C)C)n(-c2ccc(O)c([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1cc(C(=O)OC(C)(C)C)n(-c2ccc(O)c(N)c2)n1

Procedure:
To a solution of tert-butyl 1-(4-hydroxy-3-nitrophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.27 g, 0.78 mmol) in ethyl acetate/methanol (1:1, 10 mL) was added palladium on carbon (30 mg) and the mixture was hydrogenated (50 psi) overnight under Parr. The solution was filtered and washed with methanol. The combined filtrate was concentrated to afford tert-butyl 1-(3-amino-4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-5-carboxylate. The crude tert-butyl 1-(3-amino-4-hydroxyphenyl)-3-isopropyl-1H-pyrazole-5-carboxylate was treated with 25% TFA in CH2Cl2 (2 mL) and stirred overnight at RT. The solvent was evaporated to obtain 1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid. To a solution of 1-(benzo[d]oxazol-5-yl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid in xylenes (3 mL) was added triethyl orthoformate (0.16 mL, 0.96 mmol) and a catalytic amount of PPTS. The reaction mixture was heated at 140° C. for 4 hours. The solvent was evaporated and the residue was treated with methylene chloride with stirring for 1 hour. The resulting solid was filtered and washed with methylene chloride to obtain 1-(benzo[d]oxazol-5-yl)-3-isopropyl-1H-pyrazole-5-carboxylic acid (0.1 g, 45% yield: for three steps). MS (ESI) m/z: 272.0 (M+H+).