Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([I:13])=[C:4]([CH2:8][C:9](OC)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>C(O)C>[F:1][C:2]1[C:3]([I:13])=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(F)c1I
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: OCCc1cccc(F)c1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl (3-fluoro-2-iodophenyl)acetate (1.2 g, 4 mmol) in 25 mL of ethanol was cooled to 0˜5° C., CaCl2 (900 mg, 8 mmol) was added and the mixture was stirred at 0˜5° C. for 10 min. NaBH4(600 mg, 15.7 mmol) was added slowly. The reaction was warmed to room temperature and stirred at room temperature for 2 hours. Recooled to 0˜5° C., quenched with aqueous citric acid solution, extracted with EtOAc. The organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to get 2-(3-fluoro-2-iodophenyl)ethanol. 1H-NMR (400 MHz, CDCl3) δ ppm 7.15˜7.20 (m, 1H), 6.99˜7.00 (m, 1H), 6.84˜6.88 (m, 1H), 3.81 (t, J=7.0 Hz, 2H), 3.02 (t, J=7.0 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[F:22]>>[N:3]1[C:4]2[N:5]([C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][C:21]([F:22])=[C:16]([CH:17]=1)[NH2:15]
Reactant: Nc1cc(B(O)O)ccc1F
Reactant: Brc1ccn2c(n1)nc1ccccc12
Product: Nc1cc(-c2ccn3c(n2)nc2ccccc23)ccc1F

Procedure:
The title compound was prepared using General Experimental Procedure A (Suzuki coupling reaction) from 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine and (3-amino-4-fluorophenyl)boronic acid. 5-(Benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)-2-fluoroaniline was obtained as a orange solid. 1H NMR (400 MHz, methanol-d4): δ 9.63 (d, J=7.2 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.17 (d, J=7.2 Hz, 1H), 7.92 (dd, J=8.8, 2.8 Hz, 1H), 7.88-7.80 (m, 2H), 7.73-7.68 (m, 2H), 7.19 (dd, J=10.8, 8.4 Hz, 1H); MS (ESI) m/z [M+H]+318.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][C:7](=[O:22])[C:8](=O)[CH2:9][C:10](=O)[CH2:11][C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH3:5]>CCO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[C:10]([CH2:11][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[NH:3][N:2]=1)=[O:22])[CH3:5]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)C[C@H](C)c1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(C[C@H](C)c2ccccc2)[nH]n1

Procedure:
Hydrazine hydrate (0.126 mL, 2.59 mmol) was added to a stirring room temperature solution of 78 0.0.6895 g, 2.63 mmol) in EtOH (2.6 mL, 1 M) under N2. The reaction was then heated to reflux until judged complete by HPLC (45 min): The reaction was concentrated and purified with 9:1 to 8:1 Hexanes:(3:1 CH2Cl2:2N NH3 in EtOH) to achieve 0.6153 g (90.6%) of 79. HPLC: 10.001 min.
Reaction SMILES: [Br-].[O:2]=[C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:4][N+:5]12CN3CN(CN(C3)C1)C2.[ClH:21]>C(O)C>[ClH:21].[NH2:5][CH2:4][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:2]
Reactant: O=C(C[N+]12CN3CN(CN(C3)C1)C2)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: CCO
Product: NCC(=O)c1ccccc1
Temperature: 0 °C
Yield: 129.3 %

Procedure:
1-(2-oxo-2-phenylethyl)-3,5,7-triaza-1-azoniatricyclo[3.3.1.13,7]decane bromide (3.3 g, 9.73 mmol) was suspended in a mixture of ethanol (50 mL) and hydrochloric acid (4.93 mL, 58.4 mmol) and heated at reflux in ethanol (50 mL) for 1.5 hours. The mixture was cooled to 0° C., filtered, and washed by ethanol (30 mL). The organic phase was evaporated to afford an HCl salt of the title compound (1.7 g) as a pale yellow solid. LC-MS (ES) m/z=136 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23].C(OC(C)C)(=O)C>C(#N)C>[O:23]=[C:22]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]1[CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccnc2N)CC1
Solvent: CC(=O)OC(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A 100 mL round bottom flask was charged with acetonitrile (20 mL, HPLC grade) and tert-butyl 4[(2-aminopyridin-3-yl)amino]piperidine-1-carboxylate (11, 1.89 g, 6.47 mmol) was added. Upon completion of addition, acetonitrile (5 mL) was added and the resulting suspension was stirred at room temperature for 30 minutes. Carbonyl diimidazole (1.57 g, 97.1 mmol) was then added over period of 10 minutes. The reaction mixture was heated to 50° C. and stirred overnight. The resulting solution was cooled to room temperature and concentrated under reduced pressure to give a brown solid. This solid was then mixed with 20 mL of isopropyl acetate and 20 mL of ice cold water. The resulting thick slurry was stirred overnight at room temperature. The brown solids were collected by vacuum filtration, washed with cold water (3×25 mL) and isopropyl acetate (3×25 mL) to give a light gray solid, which was dried to constant weight to give 1.73 g (84% yield) of tert-butyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate. This material was submitted to the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 11.56 (broad s, 1H), 7.89 (d, 1H), 7.54 (d, 1H), 6.98 (dd, 1H), 4.34 (m, 1H), 4.08 (broad m, 2H), 2.85 (broad m, 2H), 2.13 (m, 2H), 1.72 9 (d, 2H), 1.43 (s, 9H). MS (EI) for C16H22N4O3: 319 (MH+)
Reaction SMILES: Cl[CH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14])([OH:6])[CH2:4]Cl.C(=O)(O)[O-].[Na+].[CH2:20]([NH2:22])[CH3:21].O>C(#N)C.O1CCCC1.COC(C)(C)C>[F:14][C:8]1[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:3]1([OH:6])[CH2:4][N:22]([CH2:20][CH3:21])[CH2:2]1
Reactant: OC(CCl)(CCl)c1cccc(F)c1F
Reactant: CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: CCN1CC(O)(c2cccc(F)c2F)C1
Temperature: 120 °C
Yield: 48 %

Procedure:
1,3-dichloro-2-(2,3-difluorophenyl)propan-2-ol (6.0 g, 24.89 mmol) was dissolved in acetonitrile (90 ml) and transferred to 6 different microwave vials where each vial contained equal amounts (1.0 g, 2.49 mmol). In each tube sodium bicarbonate (1.04 g, 12.44 mmol (in total 6.27 g, 74.67 mmol)) was added and the tubes were sealed. Through the septum ethylamine in tetrahydrofurane (2.0 M, 2.07 ml, 4.15 mmol (in total 12.44 ml, 24.89 mmol) was added and the mixture was heated at 120° C. for 30 min under microwave irradiation. Additional ethylamine in tetrahydrofurane (2.0 M, 1.03 ml, 2.07 mmol (in total 6.22 ml, 12.44 mmol) was added and the mixture was heated at 120° C. for 30 min under microwave irradiation. The solutions where pooled, water (100 ml) and tert-butyl methyl ether (100 ml) was added and the organic phase was collected. The aqueous phase was extracted with tert-butyl methyl ether (100 ml), the pooled organic phase was dried (Na2SO4) and evaporated. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/methanol, 1:0 to 9:1) to give the title compound (2.53 g, 48%). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 148-150° C. MS m/z (relative intensity, 70 eV) 213 (M+, 1), 156 (39), 141 (75), 127 (56), 58 (bp).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:27]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)[CH:27]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)c1ccc(-c2cncc(CCl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cncc(-c3ccc(C(F)(F)F)cc3)c2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
A solution of 39 mg (0.17 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 2.0 ml N,N-dimethylformamide was treated at 0° C. with 7 mg (0.17 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 50 mg (0.17 mmol) 3-Chloromethyl-5-(4-trifluoromethyl-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 4 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 33 mg (41%) of the title compound as light brown powder.
Reaction SMILES: Cl[C:2]([F:9])([F:8])C(OCC)=O.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH:2]([F:9])[F:8])=[CH:22][CH:23]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)Oc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 26.7 %

Procedure:
Ethyl chlorodifluoroacetate (25 mL, 0.20 mol) was added to 4-(benzyloxy)phenol (20.10 g, 0.10 mol), and potassium carbonate (41.90 g, 0.30 mol) in dimethylformamide (200 mL) and the mixture was stirred at 80° C. for 18 h. Additional ethyl chlorodifluoroacetate (12.7 mL, 0.10 mol) and potassium carbonate (27.74 g, 0.20 mol) were added and the mixture was stirred at 80° C. for 6 h. Additional ethyl chlorodifluoroacetate (12.7 mL, 0.10 mol) and potassium carbonate (27.74 g, 0.20 mol) were added and the mixture was stirred at 120° C. for 15 h. The mixture was cooled, poured into water (1000 mL) and extracted with ethyl acetate (500 mL). The organic fraction was washed with aqueous sodium hydroxide (1M, 500 mL) and brine (500 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/CH2Cl2 (90:10) to give the title compound as a colorless solid (6.67 g, 27%). 1H NMR (360 MHz, CDCl3) δ 5.05 (2H, s), 6.42 (1H, t, J 74 Hz), 6.94 (2H, m) 7.06 (2H, m), and 7.31-7.44 (5H, m).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1C=O.BrC1C=C(F)C=CC=1C.C(O[CH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:28]([O:27][CH:23]([O:24][CH2:25][CH3:26])[C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[Br:1])[CH3:29]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(F)cc1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(OCC)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a solution of 6.5 g of 2-bromo4-fluoro-benzaldehyde (prepared by the oxidation of 2-bromo-4-fluoro-toluene by the method reported by V. J. Bauer, B. J. Duffy, D. Hoffman, S. S. Klioze, R. W. Kosley, Jr., A. R. McFadden, L. L. Martin, H. H. Ong and H. M. Geyer III, J. Med. Chem., 1976, 19, 1315) in 25 ml of ethanol was added triethylorthoformate followed by 0.05 g of p-toluene sulfonic acid. The solution was stirred at room temperature for 2.25 h then diluted with 100 ml of a 5% sodium carbonate solution and extracted with two 100 ml portions of ether. The combined organic layers were washed with 50 ml of brine and dried over sodium sulfate. Evaporation of the solvent yielded 8.8 g of 2-bromo4-fluoro-benzaldehyde diethyl acetal as an oil, 1H NMR (200 MHz; CDCl3) δH 5.60 (CHO3).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.[Br:25][CH:26](Br)[CH3:27].C(=O)([O-])[O-].[K+].[K+].[K+].[Br-]>CN(C)C=O>[Br:25][CH2:26][CH2:27][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:24])[CH:7]=[C:8]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)[O:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(=O)c3ccc(O)cc3o2)cc(OC)c1OC
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(=O)c3ccc(OCCBr)cc3o2)cc(OC)c1OC

Procedure:
This compound (58) was prepared from 7-hydroxy-3′,4′,5′-trimethoxy-flavone, 25 (2.3 g, 7 mmol), dibromo ethane (3 mL, 35 mmol) and potassium carbonate (2.9 g, 21 mmol) in dry dimethyl formamide (120 mL) using the identical procedure as described for 56. Yield 2.1 g (68%); mp 184-185° C.; MS (FAB) 435/437 (M++1); IR (KBr) 1631; 1H NMR (200 MHz, CDCl3) δ 8.15 (d, J=9.3 Hz, 1H), 7.10 (s, 2H), 7.01 (d, J=7.8 Hz, 1H), 6.99 (s, 1H), 6.71 (s, 1H), 4.43 (t, J=6.2 Hz, 2H), 3.96 (s, 6H), 3.93 (s, 3H), 3.70 (t, J=6.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH:15]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(F)cc1
Yield: 99.7 %

Procedure:
4-Fluorobenzaldehyde (27.2 ml, 0.23 Mol) and carboethoxymethylenetriphenylphosphorane (88.38 g, 0.23 Mol) were disolved in toluene (500 ml), and the mixture was heated overnight at reflux. The reaction was stripped then purified by flash chromatography in 25% EtOAc/Hexanes yielded 44.55g of a crystalline solid as product. NMR (300 MHz, CDCl3) δ 7.65 (d, 1H, J=16 Hz); 7.60-7.40 (m, 2H); 7.08 (t, 2H, J=7 Hz); 6.35 (d, 1H, J=16 Hz); 4.26 (q, 2H, J=7 Hz); 1.34 (t, 3H, J=7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(CNS(C)(=O)=O)c1ccc(-c2cccc(F)c2)cc1
Temperature: 100 °C
Yield: 9.6 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.1 g (7.7 mmol) of 3-fluorobenzeneboronic acid and 1.1 g (7.7 mmol) of potassium carbonate in 30 mL of toluene was added 0.2 g (0.3 mmol) of bis(triphenyl-phosphine)palladium(II) dichloride. The mixture was heated to 100° C. for 16 hours, cooled to ambient temperature and diluted with 20 mL of ethyl acetate. The mixture was washed once with 25 mL water and the organic portion was separated. The aqueous portion was extracted three times with ethyl acetate and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 75 g silica gel (20% ethyl acetate/toluene) followed by recrystallization from ethyl ether, filtration and drying in vacuo at 60° C. afforded 0.15 g (9%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br[CH2:31][C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34](=[O:35])[C:33]1[CH:38]=[CH:39][CH:40]=[CH:41][C:32]=1[CH2:31][N:19]1[C:18](=[O:23])/[C:17](=[CH:16]/[C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH2:6][C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=2[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]3)/[S:21][C:20]1=[O:22]
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC(=O)c1ccccc1CBr
Product: COC(=O)c1ccccc1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}benzoic acid methyl ester was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and methyl 2-bromomethylbenzoate following General Procedure S.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][NH:6][CH:7]1[CH2:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:11])[CH2:5][N:6]([C:16]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:18][N:19]=[C:14]([Cl:13])[N:15]=1)[CH:7]1[CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C(C)CNC1CCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCC1
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a mixture of 1.71 g (0.010 mole) of (rac)-3-cyclobutylamino-2-methyl-propanoic acid methyl ester, 1.94 g (0.010 mole) of 2,4-dichloro-5-nitro-pyrimidine, 50 mL of ethyl acetate and 25 mL of water was added 3.0 g (0.030 mole) of potassium bicarbonate. The mixture was stirred for 3 hours then diluted with 50 mL of ethyl acetate and 50 mL of water. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate (100:0-97:3) to give 2.54 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclobutyl-amino]-2-methyl-propanoic acid methyl ester (IV-52) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].[CH3:17][NH:18][O:19][CH3:20].Cl.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([N:18]([O:19][CH3:20])[CH3:17])=[O:6]
Reactant: CNOC
Reactant: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Amino-5-pentafluorosulfanylbenzoic acid (200 mg, Example 11a) was dissolved in methylene chloride (12 ml). The following were added successively with stirring: N,O-dimethylhydroxylamine×HCl (148 mg), 1-propanephosphoric anhydride (242 mg) and triethylamine (292 μl). The clear solution was stirred at RT for 4 h and allowed to stand over the weekend. For work-up, the reaction mixture was concentrated, and the residue was taken up in ethyl acetate and extracted twice with potassium hydrogensulfate solution. After the ethyl acetate phase had subsequently been extracted twice with sodium carbonate solution, it was dried over magnesium sulfate, filtered and concentrated. The crude product obtained was purified by means of preparative chromatography. The product-containing fractions were combined, freed from the acetonitrile, rendered basic with saturated sodium hydrogencarbonate solution and extracted with ethyl acetate three times. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 77 mg of the desired compound were obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.[OH-].[Na+]>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(-c2cc(Oc3ccc4[nH]ccc4c3)ncn2)cc1
Temperature: 25 °C

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example l(a)), (0.15 g, 0.61 mmol) and 5-hydroxyindole (0.24 g, 1.8 mmol, Aldrich) in 1,4-dioxane (12 mL), was added NaOH (8.0 mL, 8.0 mmol, 1.0 N). The mixture was heated at reflux for 4 h, and after cooling to room temperature, the solvent was removed in vacuum. EtOAc (15 mL) was added to the residue, and the organic layer was washed with 1 N NaOH (10 mL), water (10 mL), dried over Na2SO4, filtered, and concentrated in vacuum. After purifying the crude product by silica gel chromatography (4:1 hexanes/EtOAc), the resulting solid was dissolved in acetone (3 mL). Water (5 mL) was added dropwise to this mixture, and a white precipitate fell out of solution, which was collected by filtration, washed with water (0.5 mL), and dried under vacuum at 50° C. for 48 h to furnish the title compound. Mp: 143-145° C. MS (ESI, pos. ion) m/z: 344 (M+1). Anal. Calcd for C22H21N3O·(H2O)1/8: C, 76.44; H, 6.20; N, 12.16. Found: C, 76.63; H, 6.20; N, 12.12.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.[C:21](O)(=[O:23])[CH3:22]>C1COCC1.C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][N:15]=1
Reactant: CC(=O)O
Reactant: Cc1ccnc(Cl)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Cc1ccnc(Cl)c1
Reaction time: 1 h

Procedure:
To a stirred solution of diisopropylamine (14.22 ml, 101.43 mmol) cooled to −78° C. is added dropwise butyllithium (60 ml). The reaction mixture is stirred and allowed to warm to 0° C. over 15 minutes after which time 2-chloro-4-methylpyridine is added to the stirred solution. After 1 hour, ethyl acetate (18.88 ml) and THF (78 ml) are added over 45 minutes followed by acetic acid (11.4 ml, 193.2 mmol) and stirring continued for 20 minutes. The reaction mixture is concentrated in vacuo and the crude product dissolved in with water (200 ml). The aqueous is extracted with chloroform (3×300 ml) and the combined organic portions washed with water (200 ml), brine (200 ml), dried over MgSO4 and the solvent removed in vacuo to yield the crude product as a brown oil. Purification by chromatography on silica, eluting with ethyl acetate-hexane affords the titled compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Na+].[Cl-]>CN1CCCC1=O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH2:15][CH2:14]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 120 °C
Yield: 92.3 %

Procedure:
A homogeneous mixture of 4-fluoro-3-methylnitrobenzene 1 (20 g,129 mmol) and N-methylpiperazine 3 (25.82 g,258 mmol) in N-methylpyrrolidone (NMP) (10 mL) was refluxed (120° C.) under N2 for 24 hours. The reaction mixture upon cooling to room temperature was poured over a saturated NaCl solution (100 mL). The resulting solid was sonicated for approx. 30 seconds, filtered, washed with ice-cold water (2×10 mL) and dried under high vacuum to obtain 4-(4-methylpiperazin-1-yl)-3-methylnitrobenzene 5 (28 g, 92%). 1H NMR (CD3OD): δ8.02 (m, 2H), 7.13 (d, 1H, J=9.3 Hz), 3.08 (m, 4H), 2.66 (m, 4H), 2.38 (s, 6H); LCMS: purity: 99%, MS (m/e): 236 (MH+).