Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH2:8][C:9]1[CH:22]=[CH:21][C:12]([C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[CH:11][CH:10]=1)[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34](Cl)(=[O:36])=[O:35])[CH:28]=[CH:27]2>C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:18]1[CH2:19][CH2:20][N:15]([C:13](=[O:14])[C:12]3[CH:21]=[CH:22][C:9]([CH2:8][N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:2])[CH3:3])=[CH:10][CH:11]=3)[CH2:16][CH2:17]1)(=[O:36])=[O:35])[CH:28]=[CH:27]2
Reactant: O=S(=O)(Cl)c1ccc2cc(Br)ccc2c1
Reactant: CC(C)N(Cc1ccc(C(=O)N2CCNCC2)cc1)C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)N(Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Br)ccc4c3)CC2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a mixture of 1-(4-diisopropylaminomethylbenzoyl)piperazine (200 mg) in 10% sodium hydrogen carbonate solution (10 ml) and ethyl acetate (15 ml), was added 6-bromonaphthalene-2-sulfonylchloride (179 mg), and the solution was stirred at room temperature for 30 minutes. The organic layer was separated, washed with water and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated. The residue was crystallized with ether to give the title compound (201 mg), as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([C:12]1[S:13][C:14](C2C=C(C(F)(F)F)C=CC=2Cl)=[CH:15][CH:16]=1)=[O:11].[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](I)[CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([C:14]2[S:13][C:12]([C:10](=[O:11])[NH:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[CH:16][CH:15]=2)[CH:32]=1
Reactant: COC(=O)c1ccc(C)c(I)c1
Reactant: O=C(Nc1c(F)cccc1F)c1ccc(-c2cc(C(F)(F)F)ccc2Cl)s1
Product: COC(=O)c1ccc(C)c(-c2ccc(C(=O)Nc3c(F)cccc3F)s2)c1

Procedure:
Compound 3 was synthesized in an analogous fashion as described for Compound 1 except that 3-iodo-4-methyl-benzoic acid methyl ester was used instead of 1-chloro-2-iodo-4-trifluoromethyl-benzene in step 1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=O)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)=[N:6][CH:7]=1.C1C=C[C:30]2[N:35]([OH:36])N=NC=2C=1.C(Cl)CCl.CNO.CCN(C(C)C)C(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([N:35]([OH:36])[CH3:30])=[O:22])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH3:15])[N:12]=[C:11]([CH3:16])[CH:10]=2)=[N:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)O)c(Cl)cn1
Agent: CNO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCn1nc(C)cc1Nc1cc(Nc2ccccc2C(=O)N(C)O)c(Cl)cn1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
A solution of 2-({5-chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)benzoic acid (55 mg, 0.148 mmol), HOBT (22.65 mg, 0.148 mmol) and EDC (28.4 mg, 0.148 mmol) in N,N-dimethylformamide (DMF) (5 mL) was stirred under nitrogen at room temp for 30 minutes. To this solution was added N-methylhydroxylamine (12.35 mg, 0.148 mmol) and the solution was stirred for another 15 minutes. The reaction mixture was cooled to 5° C. and DIEA (0.052 mL, 0.296 mmol) was added dropwise. After addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified using preparative HPLC (0.1% formic acid, 5 to 95% water: acetonitrile). Fractions were combined and evaporated. 2-({5-Chloro-2-[(1-ethyl-3-methyl-1H-pyrazol-5-yl)amino]-4-pyridinyl}amino)-N-hydroxy-N-methylbenzamide (16 mg, 0.034 mmol, 23.05% yield) isolated as a white solid. LCMS (M+H)+=401.0 (M+H); 1H NMR (400 MHz, MeOD) ppm 1.30 (t, J=7.20 Hz, 3 H) 2.19 (s, 3 H) 3.37 (d, J=1.52 Hz, 3 H) 3.96 (q, J=7.07 Hz, 2 H) 5.95 (s, 1 H) 6.32 (s, 1 H) 7.21-7.33 (m, 1 H) 7.42-7.53 (m, 2 H) 7.56 (d, J=7.33 Hz, 1 H) 7.86 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4](C)[CH:3]=1.BrC1C=CC(C=C)=C([Cl:21])C=1.B1C2CCCC1CCC2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[C:4]([Cl:21])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CCO
Reactant: C=Cc1ccc(Br)cc1Cl
Agent: B1C2CCCC1CCC2
Product: OCCc1ccc(Br)cc1Cl
Yield: 54 %

Procedure:
Using a procedure analogous to that used to prepare 30B, 61A (5 g, 23 mmol) was heated in a pressure vessel with 9-BBN at 100° C. for 10 h and worked up as in 30B to yield 61B (2.9 g, 54%) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.95 (t, J=6.59 Hz, 2 H) 3.85 (t, J=6.59 Hz, 2 H) 7.14 (d, J=7.91 Hz, 1 H) 7.33 (dd, J=8.13, 1.98 Hz, 1 H) 7.52 (d, J=2.20 Hz, 1 H).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:12]([O:19][C:20]1[C:21](=[O:29])[CH:22]=[C:23](C(O)=O)O[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(O)=O>O>[CH2:12]([O:19][C:20]1[C:21](=[O:29])[CH:22]=[CH:23][N:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reactant: CCCCc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1ccc(-n2ccc(=O)c(OCc3ccccc3)c2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-butylaniline (0.6 g, 4.1 mmol) and 5-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (1.0 g, 4.1 mmol) in a 1:1 mixture of AcOH:water (4 mL) was heated in a sealed reaction vessel at 120° C. for 72 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, diluted with 10 mL 10% aq. NaOH, and extracted with EtOAc (3×10 mL). The organic fractions were pooled, dried (Na2SO4), and concentrated under reduced pressure to provide 3-(benzyloxy)-1-(4-butylphenyl)pyridin-4(1H)-one, which was used in the subsequent step without further purification. LC/MS (M+H)+ 334.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.C([N:32]=[C:33]=[S:34])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>C(Cl)Cl>[NH2:32][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)=[S:34]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl piperidin-4-ylcarbamate (5.5 g) was dissolved in anhydrous DCM (75 ml). H-Fluoren-9-ylmethyl isothiocyanatidocarbonate (Fmoc isothiocyanate; 7.75 g) was added in small portions at room temperature after which time a white precipitate formed. The mixture was stirred at room temperature for 90 min. The solvent was removed in vacuo and the crude mixture was treated with 10% piperidine in MeOH (100 ml) for 12 h. The mixture was concentrated in vacuo and triturated with n-hexanes. The white crystalline material was filtered and washed well with n-hexanes and dried in vacuo to afford the title compound (6.55 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:20]3[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:41])C(=O)C1>ClCCl.C(#N)C>[Br:41][C:22]1[CH:23]=[CH:24][C:19]2[NH:18][C:17]3[N:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:16]=3[CH2:15][N:14]([S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[C:20]=2[C:21]=1[CH3:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Solvent: ClCCl
Solvent: CC#N
Product: Cc1c(Br)ccc2c1N(S(=O)(=O)c1ccc(C(C)(C)C)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 5 °C
Reaction time: 12 h

Procedure:
To a solution of the product of Step C (0.95 g, 2 mmol mol) in dichloromethane (5 ml) and acetonitrile (50 ml) was added NBS (0.35 g, 2 mmol mol) in portions at 0° C. After stirring at 5° C. for 12 h, the reaction mixture was concentrated, and the residue was partitioned between dichloromethane and water. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=7.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.13 (m, 5H), 6.52 (m, 2H), 5.20 (d, J=16.8 Hz, 1H), 4.34 (d, J=16.8 Hz, 1H), 2.65 (s, 3H), 1.24 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])C.O.C(=O)(O)[O-].[Na+]>C(O)=O>[CH2:15]([O:14][C:12]([C:11]1[CH:17]=[CH:18][C:8]([N:7]([CH2:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:21]=[O:23])=[CH:9][CH:10]=1)=[O:13])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)c1ccc(N(C=O)Cc2ccc(Cl)cc2)cc1
Temperature: 55 °C
Yield: 67 %

Procedure:
Ethyl 4-(4-chlorobenzylamino)-benzoate (7.2 g; 0.025 mole) was dissolved in formic acid (80%; 70 ml) and the solution was heated to 55° C. with stirring. Acetic anhydride (25 ml) was added dropwise at this temperature, allowed to cool to room temperature and stirred for 1 hour. The reaction mixture was added to iced water (100 ml) and the aqueous mixture was neutralised with solid sodium bicarbonate. The product was extracted into dichloromethane (2×100 ml), washed with water (1×100 ml), dried (anhydrous MgSO4) and evaporated. Pure N-(4-ethoxycarbonylphenyl)-N-(4-chlorobenzyl)-formamide (5.32 g; 67%) was obtained by chromatography on silica-gel in dichloromethane followed by crystallisation from ethanol. M.p. 72°-3° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccccc4OC)CC3)c(OC)nc2c1
Yield: 84 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): δ 3.13-3.16 (m, 4H), 3.66-3.78 (m, 4H), 3.88 (s, 3H), 3.90 (s, 3H), 4.12 (s, 3H), 6.87-7.14 (m, 7H), 7.76 (d, J=5.1 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[CH2:31]([O:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1)[CH3:32]>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([O:33][CH2:31][CH3:32])=[CH:35][CH:36]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(C(=O)N(C)Cc2cccc(-c3ccc(CC4SC(=O)NC4=O)cc3)c2)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 460 mg (2.5 mmol) of 4-ethoxybenzoyl chloride, and after purification, 960 mg (88%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4-ethoxy-N-methylbenzamide are obtained in the form of a white solid with a melting point of 182° C.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][OH:6].[O:7]1[CH2:12][CH2:11][O:10]CC1>O.Cl>[O:6]=[CH:5][C@H:12]([C@H:11]([C@H:12]([CH2:11][OH:10])[OH:7])[OH:10])[OH:7]
Reactant: CO
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 40 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
2,3-O-isopropylidene-L-ribofuranose (4.0 g) prepared in Example 2 was dissolved in a solvent mixture of dioxane (8 ml) and water (8 ml), and 1.0N hydrochloric acid solution (200 μl) was added thereto. The reaction proceeded for about 24 hours while maintaining the temperature in the reaction vessel of 40° C. After TLC revealed the completion of reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in water (15 ml) which was then washed with ethyl acetate to remove some impurities. Water was removed by distillation under reduced pressure to give a compound in the form of an oil. The compound thus obtained was purified by silica gel column chromatography (eluent: chloroform/methanol=4/1, v/v) to give the title compound (2.2 g, Yield 70%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C@@H:7]([NH:10][C:11](=[O:44])[C@@H:12]([NH:14][C:15]([C:17]2[N:21]3[C@@:22]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=4)([CH3:34])[C:23](=[O:33])[N:24]([C:25]4[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=4)[C:20]3=[N:19][CH:18]=2)=[O:16])[CH3:13])[CH2:6]1)=[O:4].Cl.O1CCOCC1>>[C:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@:22]2([CH3:34])[N:21]3[C:17]([C:15]([NH:14][C@@H:12]([CH3:13])[C:11]([NH:10][C@@H:7]4[CH2:8][CH2:9][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]4)=[O:44])=[O:16])=[CH:18][N:19]=[C:20]3[N:24]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:23]2=[O:33])=[CH:37][CH:38]=1)#[N:43]
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)[C@H](C)NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)C1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](NC(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N[C@@H]1CC[C@@H](C(=O)O)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
To (1R,3R)-3-((S)-2-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-propionylamino)-cyclopentanecarboxylic acid methyl ester (35.1 mg, 0.055 mmol) were added 1N HCl in 1,4-dioxane (1 mL, 1 mmol) and 1N HCl (0.5 mL, 0.5 mmol). The reaction tube was sealed and the reaction solution was stirred at 100° C. for 1 h. The reaction solution was then cooled to room temperature, filtered, and was purified by reverse phase HPLC to afford 21 mg of the title compound as a white solid, m/z 623.1 [M+1]+.
Reaction SMILES: [Na].[OH:2][N:3]=[C:4]([C:8]#[N:9])[C:5]([NH2:7])=[O:6].O.Cl[C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13]>CC(C)=O>[CH2:15]([O:14][C:12]([O:2][N:3]=[C:4]([C:8]#[N:9])[C:5]([NH2:7])=[O:6])=[O:13])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)COC(=O)Cl
Reactant: N#CC(=NO)C(N)=O
Agent: [Na]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)COC(=O)ON=C(C#N)C(N)=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A mixture of sodium salt of 2-hydroxyimino-2-cyanoacetic acid amide (13.5 g), water (80 ml) and acetone (10 ml) is cooled with ice-water, and isobutyl chloroformate (13.7 g) is dropwise added thereto. The resulting mixture is, after adjusted to pH 7, stirred at a temperature lower than 20°C for 1 hour. The precipitated crystals are collected by filtration and washed with water to give 2-isobutoxycarbonyloxyimino-2-cyanoacetic acid amide (12.3 g). A part of the product is recrystallized from ethyl acetate to obtain crystals melting at 156° to 158°C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[OH:10].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1.C(Cl)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+].CC([O-])(C)C.[K+].C(O[Na])(C)(C)C.S1(CCCC1)(=O)=O>C(C(C)=O)C.CC(C)=O.CN1C(=O)N(C)CCC1.CN(P(N(C)C)(N(C)C)=O)C.CS(C)=O.CCOCC>[CH2:17]([O:10][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1])[C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1ccc(F)c(F)c1F
Reactant: BrCc1ccccc1
Agent: CC(C)(C)O[Na]
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Solvent: ClCc1ccccc1
Solvent: CC(C)=O
Solvent: CCOCC
Product: Fc1ccc(OCc2ccccc2)c(F)c1F

Procedure:
2,3,4-Trifluorophenol was protected with hydroxy protection reagent (examples include BnBr, BnCl) at ambient temperature in the presence of base (include Na2CO3, K2CO3, NaHCO3, KHCO3, t-BuOK, t-BuONa) in appropriate inert solvent (include aliphatic and aromatic hydrocarbon (such as pentane, hexane, heptane, cyclohexane, petroleum ether, petrol, gasoline, benzene, toluene, xylene), aliphatic and aromatic halo-hydrocarbon (such as dichloromethane, 1,2-dichloroethane, chloroform, phenixin, chlorobenzene, o-dichlorobenzene), ether (such as diethyl ether, dibutyl ether, glycol dimethyl ether, 2-methoxyethyl ether, tetrahydrofuran, dioxane), ketone (such as acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone), ester (such as ethyl acetate, methyl acetate), nitrile (such as acetonitrile, propiononitrile), amide (such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidin-2-one), DMSO, sulfolane, HMPA, DMPU, prefer acetone and methyl ethyl ketone). The reaction proceeds for several hours (3-12 h, prefer 5-10 h). 1-(Benzyloxy)-2,3,4-trifluorobenzene is obtained after conventional workup.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCBr
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Yield: 85 %

Procedure:
This compound was prepared from 2,7-dibromofluorene and n-octyl bromide, using a similar procedure as described in Example III. The product was obtained in an 85% yield as colorless crystals.
Reaction SMILES: CC(C)[C@@H](N1CC2C(=CC(C3C=CC(NC(NC4C=CC=C(C(F)(F)F)C=4)=O)=CC=3)=CC=2)C1=O)C(O)=O.[CH3:38][C:39]([N:45]1[CH2:53][C:52]2[C:47](=[CH:48][C:49]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][C:61]([NH:63][C:64]4[CH:69]=[CH:68][CH:67]=[C:66]([C:70]([F:73])([F:72])[F:71])[CH:65]=4)=[O:62])=[CH:56][CH:55]=3)=[CH:50][CH:51]=2)[C:46]1=[O:74])([CH3:44])[C:40]([O:42]C)=[O:41]>>[CH3:44][C:39]([N:45]1[CH2:53][C:52]2[C:47](=[CH:48][C:49]([C:54]3[CH:59]=[CH:58][C:57]([NH:60][C:61]([NH:63][C:64]4[CH:69]=[CH:68][CH:67]=[C:66]([C:70]([F:72])([F:73])[F:71])[CH:65]=4)=[O:62])=[CH:56][CH:55]=3)=[CH:50][CH:51]=2)[C:46]1=[O:74])([CH3:38])[C:40]([OH:42])=[O:41]
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Agent: CC(C)[C@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Product: CC(C)(C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cc2C1=O
Yield: 87 %

Procedure:
The compound of example 340 was prepared analogous to compound of example 331 by hydrolysis of the compound of example 339.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[OH:19])([O-])=[O:2].[OH-].[Na+].C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.C(=O)C>O.CO>[OH:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N+:1]([O-:2])=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: CC=O
Agent: O=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
2-nitro-2'-hydroxy-5'-methylazobenzene 12.9 g was added to a mixture of methanol 60 ml, water 30 ml and 97% sodium hydroxide 12.4 g, and the resultant mixture was stirred while raising temperature to 65° C. 9-fluorenone 1.2 g and then 90% acetoaldehyde 3.2 g were added to the mixture for 1 hour. The resultant mixture was then heated to the boiling point (75° C.), and was stirred at the boiling point (75° C.) for 6 hours, thus almost all of the azobenzenes having disappeared to produce 2-(2-hydroxy-5-methylphenyl)benzotriazole-N-oxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2ccc(OCc3ccccc3)cc2)nc1
Temperature: 105 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethylpyridine (1.81 g, 10 mmol), 4-benzyloxyphenyl boronic acid (2.74 g, 12 mmol) and CsF (5.32 g, 35 mmol) in dioxane (40 mL) is degaseed and filled with nitrogen. PdCl2(dppf) (200 mg) is added under nitrogen, the reaction mixture is heated at 105° C. overnight. The mixture is cooled to room temperature, diluted with ethyl acetate (100 mL), filtered through a pad of Celite. The filtrate is concentrated and the residue is purified by column chromatography on silica gel giving the title compound (2.55 g, 77.4%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.Cl.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:29]([F:32])([F:31])[F:30])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH:23]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:29]([F:32])([F:30])[F:31])=[C:22]([C@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[CH:23]=1
Reactant: Fc1ccc(C(F)(F)F)c([C@H]2CCCN2)c1
Reactant: CCOC(=O)c1cnn2ccc(Cl)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Temperature: 120 °C
Yield: 96.4 %

Procedure:
Ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, 0.51 g, 2.26 mmol), (R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidine hydrochloride (0.610 g, 2.26 mmol) and diisopropylethylamine (1.12 mL, 6.78 mmol) were suspended in isopropanol (2.5 mL) and heated to 120° C. for 24 hours. The reaction mixture was purified by reverse phase chromatography eluting with 0-75% acetonitrile/water to yield the title compound (0.92 g, 96.4% yield). MS (apci) m/z=423.0.0 (M+H).