Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C@H:4]1[C:6]([CH3:8])([CH3:7])[C@H:5]1[C:9]([OH:11])=[O:10].N(C(C)(C)C#N)=NC(C)(C)C#N.BrBr>C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]([CH3:12])=[CH:3][CH:4]1[C:6]([CH3:7])([CH3:8])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)O)C1(C)C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
500 mg of (-)-cis-chrysanthemic acid was dissolved in 10 ml of toluene, followed by adding 20 mg of azobisisobutyronitrile. Thereto was added dropwise a solution of bromine (19 mg) in carbon tetrachloride at 80° C. over a period of 10 minutes with stirring. After 15 minutes, the reaction mixture was subjected to a treatment similar to Example 1 to obtain 452 mg of chrysanthemic acid. The optical isomer ratio was as follows: (+)-cis, 3.3%; (-)-cis, 3.2%; (+)-trans, 47.0%; and (-)-trans, 46.5%.
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:9][C:10]1[C:11]([C:28](N(OC)C)=[O:29])=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:14][N:15]=1>C1COCC1>[NH2:9][C:10]1[C:11]([C:28]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:29])=[N:12][C:13]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH:25]([CH3:27])[CH3:26])(=[O:23])=[O:24])=[CH:20][CH:21]=2)=[CH:14][N:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
1M Bromo(phenyl)magnesium in THF (823.2 μL, 0.8232 mmol) was added dropwise to a stirred solution of 3-amino-6-(4-isopropylsulfonylphenyl)-N-methoxy-N-methyl-pyrazine-2-carboxamide (100 mg, 0.2744 mmol) in anhydrous THF (6 mL) at −78° C. under an atmosphere of nitrogen. The reaction was stirred at this temperature for 30 minutes then allowed to warm to ambient temperature over 16 hours. The reaction mixture was concentrated in vacuo and residue was partitioned between DCM and water. The layers were separated and the organic extract was dried (MgSO4) and concentrated in vacuo. The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound as a yellow solid (49 mg, 42% Yield). NMR (400.0 MHz, DMSO) δ 1.16 (d, 6H), 3.44 (sept, 1H), 7.55-7.59 (m, 2H), 7.66 (m, 1H), 7.90 (d, 2H), 7.95-7.97 (m, 2H), 8.07 (br s, 2H), 8.18 (d. 2H) and 9.10 (s, 1H) ppm; (ES+) 382.0.
Reaction SMILES: [Cl-].[CH2:2]([N+:20]([CH3:23])([CH3:22])C)[CH2:3]CCCCCC[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:24]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)(=[O:28])[C:25]([CH3:27])=[CH2:26].[CH:36](C1C=CC=CC=1C=C)=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].S([O-])(O)=O.[Na+]>O>[CH:18]([C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:11]=[CH2:10])=[CH2:19].[C:24]([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)(=[O:28])[C:25]([CH3:27])=[CH2:26].[C:24]([O:29][CH2:30][CH2:23][N:20]([CH2:2][CH3:3])[CH2:22][CH3:36])(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: CCCCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: C=C(C)C(=O)OC1CCCCC1
Agent: C=Cc1ccccc1C=C
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Solvent: O
Product: C=C(C)C(=O)OCCN(CC)CC
Temperature: 60 °C

Procedure:
216 g of distilled water was placed in a reaction vessel, deaerated with a nitrogen gas, and heated to 60° C. in the presence of the nitrogen gas. 15.8 g of stearyltrimethylammonium chloride, 0.07 g of polyvinyl alcohol, 33.7 g of cyclohexyl methacrylate, 37.1 g of N,N-diethylaminoethyl thacrylate, and 2.0 g of divinylbenzene were added thereto. Then, 0.44 g of potassium persulfate dissolved in 9.3 ml of distilled water deaerated with a nitrogen gas, and 0.14 g of sodium hydrogensulfite dissolved in 1.5 ml of distilled water deaerated with a nitrogen gas were simultaneously added thereto, and heated for about one hour. Subsequently, the above-described potassium persulfate aqueous solution and the sodium hydrogensulfite aqueous solution were again added thereto, followed by continuing heating for about 5 hours. Then, the system was cooled to room temperature, and filtered to obtain a polymer dispersion containing 22.8 wt% solids.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1C)=[O:10].ClC1C=CC2N=[C:24](C3C=CC=CC=3)[O:25]C(=O)C=2C=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:25][CH3:24])[CH:12]=1)=[O:10]
Reactant: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reactant: Cc1ccccc1C(=O)c1cc(Cl)ccc1N
Product: COc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Yield: 64 %

Procedure:
In a manner similar to that described above for compound 1m, 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to 1s (64% yield) MS m/z=262 (M+H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[CH:19][CH:18]=3)[N:14]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]2=[N:12][CH:13]=1)=O)#[N:2].[N-:37]=[N+:38]=[N-:39].[Na+].N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[C:27]([Si:24]([CH3:25])([CH3:26])[O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]3=[N:12][CH:13]=[C:8]([C:6]4[N:5]([CH2:4][CH2:3][C:1]#[N:2])[N:39]=[N:38][N:37]=4)[CH:9]=[C:10]3[N:16]=2)=[CH:22][CH:21]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C(=O)NCCC#N)cnc3n2C2CCCCC2)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(-c4nnnn4CCC#N)cnc3n2C2CCCCC2)cc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
A solution of intermediate 61 (250 mg, 0.5 mmol), sodium azide (33 mg, 0.5 mmol), and 2,6-lutidine (116 μL, 1.0 mmol) in dichloromethane (3 mL) was cooled to 0° C. and trifluoromethanesulfonic anhydride (84 μL, 0.5 mmol) from a freshly opened ampule was added under a nitrogen atmosphere. The reaction mixture was allowed to warm up slowly to rt over 2 h and stirring continued for 20 h at which point dichloromethane was added (25 mL). The resulting organic phase was washed with saturated NaHCO3 (1×20 mL), dried (Na2SO4), and concentrated on a rotary evaporator. The foamy residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.05% trifluoroacetic acid) to afford intermediate 62 as a white solid (48 mg, 18%). ESI-MS m/e 529.1 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:12]([C:13]([O:15]C)=[O:14])[C:11]([NH2:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:18][C:19](=[O:22])[CH2:20][CH3:21])=[C:12]([CH:17]=1)[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: COC(=O)c1cc(Cc2ccccc2)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1ccc(Cc2ccccc2)cc1C(=O)O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Methyl 5-benzylanthranilate (300 mg; 1.24 mmols) was dissolved in 7 mL of chloroform and propionyl chloride (344 mg; 3.72 mmols) was added and the reaction mixture was left at room temperature for 18 hours. Aqueous saturated sodium bicarbonate (5 mL) was added to the reaction mixture whereafter the organic phase was separated, dried over magnesium sulphate, filtered and evaporated to dryness. The resulting yellow oil was dissolved in 5 mL of methanol and aqueous sodium hydroxide (1M, 5 mL) was added. The reaction mixture was then heated to 60° C. for two hours. After cooling to room-temperature the reaction mixture was acidified with 20 mL of hydrochloric acid (1M). The white precipitate was filtered with suction, washed twice with water and dried under vacuum yielding the title compound quantitatively. 1H NMR (DMSO-d6) δ 1.09 (t, 3H, J=7.4, —CH3), 2.37 (q, 2H, J=7.5, —CH2—CH3), 3.92 (s, 2H, —CH2-Ph), 7.13–7.45 (m, 5H, -Ph), 7.44 (d, 1H, J=8.6, H4), 7.79 (s, 1H, H6), 8.39 (d, 1H, J=8.5, H3), 11.01 (s, 1H, >NH), 13.54 (bs, 1H, —COOH).
Reaction SMILES: Br[CH:2]([CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]([O:5]C)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18]>>[CH3:10][CH:7]([CH:2]1[C:3](=[O:5])[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]1)[CH2:8][CH3:9]
Reactant: CCC(C)C(Br)C(=O)OC
Reactant: Nc1ccccc1S
Product: CCC(C)C1Sc2ccccc2NC1=O
Yield: 72.6 %

Procedure:
In the same manner as in Reference Example 9, methyl 2-bromo-3-methylvalerate (1:1 diastereomer mixture) and 2-aminothiophenol were allowed to react followed by ring closure reaction, to give 2-(1-methylpropyl)-2H-1,4-benzothiazin-3(4H)-one (1:1 diastereomer mixture) as colorless prisms. mp 99°-100° C. (recrystallized from ethanol). Yield 72.6%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([Cl:25])=[N:20][N:19]=[C:18]3Cl)=[O:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].[O:29]1CCOCC1.Cl>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([Cl:25])=[N:20][NH:19][C:18]3=[O:29])=[O:14])[CH:9]=[CH:10][CH:11]=1
Reactant: C1COCCO1
Reactant: O=C(Nc1cccc(-c2ccco2)c1)c1ccc2c(Cl)nnc(Cl)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1cccc(-c2ccco2)c1)c1ccc2c(Cl)n[nH]c(=O)c2c1
Temperature: 50 °C

Procedure:
A mixture of 1,4-dichloro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide (400 mg, 1.041 mmol), 2N NaOH (5.2 mL, 10.41 mmol) and dioxane (5 mL) was heated to 50° C. for 5 h. The reaction was diluted with water, acidified with conc. HCl to pH 6. The reaction mixture was concentrated to low volume and filtered through celite. Chromatography (Hex/EtOAc) afforded 1-chloro-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide (43 mg) as a pale yellow solid, 1H NMR (400 MHz, d6-DMSO) δ: 6.76 (m, 1H), 7.08 (d, 1H), 7.58 (t, 1H), 7.64 (m, 1H), 7.90 (m, 2H), 8.30 (d, 1H), 8.34 (s, 1H), 8.70 (dd, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 13.19 (s, 1H) ppm; m/z (M+1) 365.90; and 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid (3-furan-2-yl-phenyl)-amide (40 mg) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ: 6.62 (m, 1H), 6.92 (d, 1H), 7.44 (t, 1H), 7.50 (m, 1H), 7.74 (m, 1H), 7.78 (s, 1H), 8.17 (m, 1H), 8.45 (m, 2H), 8.52 (s, 1H), 10.80 (s, 1H), 13.01 (s, 1H) ppm; m/z (M+1) 365.97.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)[CH:3]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(Nc3cccc(C4OCCO4)c3)CC2)cc1
Temperature: 80 °C
Yield: 91 %

Procedure:
To a dry flask containing 2-(3-bromophenyl)-1,3-dioxaolane (1.0 mL; 1.0 eq) and amine 6, (1.6 mL; 1.2 eq) in dry toluene (20 mL) was added BINAP (124 mg; 0.03 eq), palladium acetate (30 mg; 0.02 eq) and sodium tert-butoxide (0.89 g; 1.4 eq). The reaction was heated to 80° C. under nitrogen. After 2 hours the solution was cooled, diluted with ethyl acetate and washed with one portion water. The organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography, eluting with 5% methanol in dichloromethane. An orange oil was obtained (2.035 g; 91% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:10]=1[Cl:11])=[O:5])C.O1CCCC1.CO.[H-].[OH-].[Li+]>O>[Cl:11][C:10]1[O:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc(-c2ccccc2)oc1Cl
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1nc(-c2ccccc2)oc1Cl
Yield: 88.2 %

Procedure:
Solution of 5-chloro-2-phenyl-oxazole-4-carboxylic acid ethyl ester (92 mg, 0.37 mmol) in a mixture solution of tetrahydrofuran, methanol and water (3:1:1, 5 mL) was treated with lithium hydroxide monohydride (44 mg, 1.1 mmol) at room temperature for two hours. After the reaction was complete, solvent was evaporated. To the residue, water was added, and pH value of the aqueous layer was adjusted to ˜1-2 by addition of dilute hydrochloride acid (1N). The white precipitation was collected by centrifugation to give 5-chloro-2-phenyl-oxazole-4-carboxylic acid (73 mg, 88%). LCMS calcd for C10H6ClNO3 (m/e) 223, obsd 224 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([S:11][CH2:12][CH3:13])[CH:8]=[C:7]([NH2:14])[C:6]=1[NH2:15])[CH3:2].COC(C1C2N=C(N)[NH:26][C:25]=2C=CC=1)=O.BrC#N>CO>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:15]=[C:25]([NH2:26])[NH:14][C:7]=2[CH:8]=[C:9]([S:11][CH2:12][CH3:13])[CH:10]=1)=[O:16])[CH3:2]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: CCOC(=O)c1cc(SCC)cc(N)c1N
Agent: N#CBr
Solvent: CO
Product: CCOC(=O)c1cc(SCC)cc2[nH]c(N)nc12
Yield: 90 %

Procedure:
0.9 g (3.75 mmol) of 2,3-diamino-5-ethylsulfanyl-benzoic acid ethyl ester was subjected to a similar cyclization condition as illustrated in intermediate A by using 1.2 g (11.3 mmol) of BrCN in methanol to produce 0.9 g (3.4 mmol, 90%) of 2-amino-6-ethylsulfanyl-1H-benzoimidazole-4-carboxylic acid ethyl ester. LCMS: 266 (M+1)+.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[O:23]1[CH:25]([CH2:26][CH3:27])[CH2:24]1.[OH-].[Na+].C(=O)(OC(C)(C)C)OC(C)(C)C>C1COCC1.CO>[ClH:1].[OH:23][CH:25]([CH2:26][CH3:27])[CH2:24][NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: CCC1CO1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)CNCc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a mixed suspension of 4-aminomethylbenzenesulfonamide hydrochloride (4.45 g), methanol (20 ml) and THF (10 ml) was added N-ethyldiisopropylamine (5.2 ml) and then 1,2-epoxybutane (2.58 ml) was added, and the mixture was heated under reflux for 12 hrs. A 1N aqueous sodium hydroxide solution was added and the reaction mixture was basified and di-t-butyl carbonate (6.55 g) was added. The mixture was stirred at room temperature for 2 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3→1/1). To the obtained colorless amorphous form was added 4N hydrochloric acid ethyl acetate solution (10 ml), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, toluene was added and the solvent was again evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and the mixture was crystallized to give the title compound (2.58 g, 46%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[C:12]2=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N#N>CO.[Pd]>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[N:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][CH:7]=1)[C:12]2=[O:24]
Reactant: CC(C)(C)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC(C)(C)c1ccc(N2C(=O)c3cccc(N)c3C2=O)cc1
Reaction time: 2 h

Procedure:
In a 100 mL round bottomed flask, 2-(4-tert-butyl-phenyl)-4-nitro-isoindole-1,3-dione (980 mg, 3.02 mmol) was dissolved in MeOH (30 mL). To this was added 10% Pd/C (100 mg) under a stream of N2. The flask was purged of oxygen and subjected to a balloon of H2 for 2 h. The reaction was filtered through a bed of Celite®, and the resulting filter cake was washed with EtOH. The filtrate was concentrated to a yellowish residue which was subjected to flash chromatography over silica gel eluting with 20% EtOAc in hexanes to give a yellow foam. MS (ES+): 295.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:10]([C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:25]([OH:27])[CH3:26])=[O:24])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>C(Cl)Cl>[CH3:8][C:9]1[N:10]([C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([N:25]([O:27][C:28](=[O:30])[CH3:29])[CH3:26])=[O:24])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)n1-c1ccc(/C=C/C(=O)N(C)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ON(C)C(=O)/C=C/c1ccc(-n2c(C)ccc2C)cc1
Reaction time: 0.25 h

Procedure:
Triethylamine (2.06 g) is added to a mixture of 5.0 g of (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-hydroxy-N-methyl-2-propenamide in 100 ml of methylene chloride and the mixture is stirred for 15 minutes. Acetic anhydride (2.07 g) is added and the mixture is stirred at room temperature overnight. The reaction mixture is washed with water and sodium bicarbonate solution, the organic layer is separated, treated with charcoal, dried and evaporated to dryness. The residue is crystallized from ethanol, water (1:1) to yield (E)-3-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-N-acetoxy-N-methyl-2-propenamide, m.p. 120°-121°.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[NH:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)[N:19]=2)=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[NH:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)[N:19]=2)=[CH:10][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: COC(=O)COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(OCC(=O)O)c3)nc2-c2ccc3ncccc3c2)n1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a stirred solution of methyl 2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate (Example 93) (47.5 mg, 0.098 mmol) was added aqueous NaOH solution (6 mg, 0.148 mmol, H2O (0.3 mL)). The reaction mixture was stirred for 1 hour, then diluted H2O (3 mL), and neutralized by addition of acetic acid to pH 7. The precipitate was filtered, washed with water, and dried under vacuum for overnight to afford the title compound (42.6 mg, 93%). (300 MHz, CDCl3+CD3OD) δ 2.57 (3H, s), 4.04 (N—H, 1H, bs), 4.75 (N—H, 1H, bs), 6.86 (1H, bs), 7.11 (2H, d), 7.23 (1H, d), 7.46-7.53 (2H, m), 7.85 (1H, dd), 8.05 (1H, d), 8.20 (1H, bs), 8.25 (1H, d), 8.87 (1H, dd). MS (EST) m/z 469 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[F:36][C:37]([F:42])([F:41])[CH2:38][CH2:39][NH2:40]>CN(C=O)C.O.C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:40][CH2:39][CH2:38][C:37]([F:42])([F:41])[F:36])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NCCC(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(NCCC(F)(F)F)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1

Procedure:
At 100° C., 150 mg (0.21 mmol, purity about 74%) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 93 mg (0.82 mmol) of 3,3,3-trifluoropropan-1-amine were stirred in 2.0 ml of DMF for 2 h. The reaction mixture was then diluted with about 1 ml of water and about 3 ml of THF and purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 105 mg (83% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:7]=[C:8]([C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[NH:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.Cl[CH2:23][CH:24]=O.C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:16]([CH:17]([CH3:19])[CH3:18])[CH:23]=[CH:24][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: CC(C)NC(=N)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 80 °C
Yield: 96.1 %

Procedure:
To a solution of 8-bromo-N-isopropyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxamidine (878 mg, 2.4 mmol) in THF (15 mL) was added chloroacetaldehyde solution (˜50 wt. % in H2O, 7.53 mL, 47.9 mmol) and aqueous saturated sodium bicarbonate solution (6 mL) at RT. The mixture was heated to 80° C. with rapid stirring. After heating for 20 hours the mixture was allowed to cool to RT and was extracted with DCM (150 mL). The organic layer was washed with water followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (900 mg, 96%). LCMS RT=4.90 min, [M+H]+=390/392
Reaction SMILES: [BrH:1].[C:2]1([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH2:16][CH2:17][CH2:18][C:19](=[O:20])[C:12]=2[S:11]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr>Br>[BrH:1].[Br:1][CH:18]1[CH2:17][CH2:16][C:13]2[N:14]3[CH:15]=[C:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:9]=[C:10]3[S:11][C:12]=2[C:19]1=[O:20]
Reactant: O=C1CCCc2c1sc1nc(-c3ccccc3)cn21
Agent: Br
Agent: BrBr
Product: O=C1c2sc3nc(-c4ccccc4)cn3c2CCC1Br
Temperature: 75 °C
Reaction time: 2 h
Yield: 186.5 %

Procedure:
2-Phenyl-5,6-dihydroimidazo[2,1-b]benzothiazole-8(7H)-one hydrobromide (11.2 g) was placed into conc. hydrobromic acid (130 ml), and bromine (18.2 ml) was added dropwise to the reaction mixture while maintaining the temperature of 70-80° C. The reaction mixture was stirred at the same temperature for 2 hours, cooled, and washed with cold water to give yellow titled compound (12.8 g, 93%).