Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[F:11].CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:23]1[CH2:28][O:27][CH:26]=[CH:25][CH2:24]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:26]1[CH2:25][CH2:24][CH2:23][CH2:28][O:27]1)[N:6]=[C:5]2[F:11]
Reactant: C1=COCCC1
Reactant: Fc1n[nH]c2ccc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Fc1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
A mixture of 5-bromo-3-fluoro-1H-indazole (6.0 g, 27.9 mmol), PTSA (530.7 mg, 2.79 mmol) and DHP (3.05 g, 36.3 mmol) in dichloromethane (80 mL) was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane (370 mL) and washed with water (230 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:100 to 1:15) to afford the title compound as a yellow solid (6.2 g, yield 74.3%). 1H NMR (DMSO-d6, 400 MHz): δ 7.96 (s, 1H), 7.70 (d, 1H), 7.60 (d, 1H), 5.76 (dd, 1H), 3.84-3.80 (m, 1H), 3.71-3.64 (m, 1H), 2.20-2.15 (m, 1H), 1.97-1.87 (m, 2H), 1.69-1.64 (m, 1H), 1.53-1.47 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl-].[Ca+2].[Cl-].[CH3:18]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:18])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CO
Agent: [Ca+2]
Agent: [Cl-]
Product: COC(=O)CCCCCCCCCCBr
Yield: 84 %

Procedure:
11-Bromoundecanoic acid (commercial material, 25.0 g, 94 mmol), Duolite H+ resin (10 g), calcium chloride (26.2 g, 94 mmol) and methanol (700 ml) were stirred for 15 h. The methanol was removed and dichloromethane was added. The mixture was washed with water, dried (Na2SO4) and concentrated. Distillation gave pure 103 (22.0 g, 84%) with b.p. 103°-104° (2×10-2 torr). 1H-NMR (CDCl3, Me4Si) δ 3.67 (s, 3H, MeO), 3.41 (t, 2H, J=6.8 Hz, Br--CH2), 2.31 (t, 2H, J=7.3 Hz, CH2CO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[S:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:16]=1>CS(C)=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[S:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: Oc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(Oc2ccc(Cl)cc2)s1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chlorophenol (4.24 g, 33 mmol) in DMSO (100 mL) was added sodium hydride (857 mg of a 97% dry sample, 34.65 mmol) and the mixture was stirred for 20 mins. Ethyl 2-bromo-5-thiazolecarboxylate (7.79 g, 33 mmol) was then added as a solution in DMSO (10 mL) and the reaction was heated at 150° C. for 18 hrs. It was then cooled to r.t., diluted with brine (150 mL) and extracted with ethylacetate (3×150 mL). The organics were combined, dried with MgSO4 and concentrated to afford ethyl 2-(4-chlorophenoxy)-5-thiazolecarboxylate which was used as is.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C@H:18]([C:39]([O:41]C(C)(C)C)=[O:40])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:33][CH2:34][CH2:35][CH2:36][N:37]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>ClCCl>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][C@H:18]([C:39]([OH:41])=[O:40])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[NH:31][C:32]2[NH:33][CH2:34][CH2:35][CH2:36][N:37]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccccc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(CCCOc1ccc(C[C@H](Nc2nc3ccccc3s2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
2 ml of trifluoroacetic acid is added to 25 mg of ester 7-3 in 5 ml of dichloromethane, agitation is carried out for 2 hours at ambient temperature then 10 ml of toluene is added. After evaporating under reduced pressure, taking up in dichloromethane and crystallizing by adding an Et2O/pentane mixture. 20 mg of 7-4 is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[N:9]3[C:10](=[N:15][C:16]([CH3:17])=[C:8]3[C:7]1=[O:18])[CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>C(Cl)Cl>[CH3:17][C:16]1[N:15]=[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[N:9]2[C:8]=1[C:7](=[O:18])[N:6]3[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30]
Reactant: Cc1nc2cccc3n(CCCCN)c(=O)c1n23
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCCCn1c(=O)c2c(C)nc3cccc1n32
Yield: 74.9 %

Procedure:
To a solution of 1.22 g (5.0 mmol) of 1-[4-(amino) butan-1-yl]-1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one and 1.1 ml (7.9 mmol) of triethylamine in 40 ml of methylene chloride was added, while stirring under ice-cooling, 0.73 ml (6.5 mmol) of propan-1-ylsulfonyl chloride. The mixture was stirred for 0.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methylene chloride—methanol—ether to give 1.313 g of the desired compound (75.0%, pale brown crystals), m.p.150.0-151.0° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:39][CH2:40]OS(C1C=CC(C)=CC=1)(=O)=O>CCO>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=[CH:32][C:27]([C:25]2[O:26][C:22]([CH3:21])=[C:23]([CH2:39][CH2:40][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:7]=3)[N:24]=2)=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Reactant: CC(C)(Oc1ccc(O)cc1-c1ccccc1)C(=O)O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(-c2ccccc2)c1
Temperature: 67.5 °C

Procedure:
A mixture of 2-(5-hydroxy-biphenyl-2-yloxy)-2-methyl-propionic acid (80 mg, 0.26 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.22 mmol) (see Ex. 1, part F), and 1,5,7-triazobicyclo[4.4.0]dec-5-ene bound to polystyrene (200 mg, 2.6 mmol/g resin, Fluka) was diluted with absolute EtOH (2 mL) and was heated at 65-70° C. for 20 h. The warm mixture was filtered through a cotton plug, and the resin was washed with EtOH (2 mL). The combined filtrates were treated with aqueous 5N NaOH (0.3 mL), heated at 55° C. for 1.5 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (1 mL) and acidified with 5N aqueous HCl (0.5 mL). The mixture with CH2Cl2 (1 mL) was transferred to a ChemElute cartridge (3 g) and eluted with CH2Cl2. The eluent was concentrated to crude product which was purified by mass guided HPLC to afford a white foam. 1H NMR (400 MHz, CDCl3) δ 1.26 (s, 6H), 2.44 (s, 3H), 3.10 (t, 2H, J=5.9 Hz), 4.28 (t, 2H, J=6.1 Hz), 6.81 (dd, 1H, J=2.9, 8.8 Hz), 6.86 (d, 1H, J=2.9 Hz), 7.01 (d, 1H, J=8.8 Hz), 7.30-7.48 (m, 8H), 7.63 (d, 2H, J=7.3 Hz), 7.70 (d, 2H, J=8.3 Hz), 8.11 (d, 2H, J=8.3 Hz); MS (ES) m/e [M−1].
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[C:14](=O)[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][OH:30])[OH:19])[CH3:9].C([O-])(=O)C.[NH4+].C([BH3-])#[N:37].[Na+]>CO>[NH2:37][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][OH:30])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH:15]1[O:16][CH3:17]
Reactant: [BH3-]C#N
Reactant: COC1C(=O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC1C(N)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
2-(1,2-Epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-4oxocyclohexanol (1.07 g) and ammonium acetate (1.86 g) were dissolved in methanol (25 ml). To the solution was added sodium cyanoborohydride (304 mg), and the mixture was stirred for one hour. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate (100 ml). The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 40 g, developing solvent: chloroform-methanol-NH4OH=20:1:0.1) to obtain 4-amino-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxycyclohexanol (629 mg; yield 58%) as a colorless oily product.
Reaction SMILES: C(OC([N:8]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]3[N:28]=[CH:29][CH:30]=[C:31]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[C:26]3=[N:25][C:24]=2[C:38]#[C:39][C:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:41]=2)=[CH:19][N:18]=1)[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=O)(C)(C)C.[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51].C(Cl)Cl>CCOCC>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[O:35]1[CH2:36][CH2:37][N:32]([C:31]2[C:26]3[N:27]([C:23]([C:20]4[CH:21]=[CH:22][C:17]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[N:18][CH:19]=4)=[C:24]([C:38]#[C:39][C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=5)[N:41]=4)[N:25]=3)[N:28]=[CH:29][CH:30]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)CNc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Temperature: 0 °C

Procedure:
Compound 38b (0.40 g, 0.57 mmol) was treated with TFA:DCM (1:4 v/v, 15 mL) dropwise with stirring at 0° C. The resulting mixture was stirred for 30 min at rt and concentrated under reduced pressure. The residue obtained was treated with 10 mL of Et2O. The solids formed were collected by filtration and washed with Et2O (2×30 mL) to obtain the title compound 24 as an orange solid. 1H-NMR (300 MHz, DMSO-d6+D2O) δ (ppm): 8.64 (s, 1H), 8.42 (d, J=8.4 Hz, 1H), 8.35 (d, J=9.3 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 8.01-7.99 (m, 2H), 7.82 (t, J=15.3 Hz, 1H), 7.70-7.63 (m, 2H), 7.10 (d, J=9.3 Hz, 1H), 6.43 (d, J=5.7 Hz, 1H), 4.16 (s, 2H), 4.02-3.94 (m, 4H), 3.82-3.70 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N2O3: 506.2 (M+H). Found: 506.1.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=2[C:19](O)=[O:20])=O)=[CH:6][CH:5]=1.S(OC)(OC)(=O)=O.O>C1COCC1>[F:3][C:4]1[CH:23]=[CH:22][C:7]([CH:8]2[C:10]3[C:11](=[CH:12][C:13]([CH2:14][OH:15])=[CH:17][CH:18]=3)[CH2:19][O:20]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(C(=O)c2ccc(F)cc2)c(C(=O)O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: OCc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 55 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a suspension of sodium borohydride (15.0 g) dispersed in THF (130 ml) was added dropwise at 20-30° C. a solution of 4-(4′-fluorobenzoyl)isophthalic acid (26.0 g) synthesized in Example 4 in THF (260 ml) and the mixture was heated to 55° C. Dimethyl sulfate (51.0 g) was added dropwise at 55-65° C. After the dropwise addition, the mixture was refluxed for 5 hr, and hydrolyzed with water (130 ml) in an ice bath. THF was evaporated under reduced pressure. To the residue was added 85% phosphoric acid (52 g) and the mixture was stirred at 60° C. for 5 hr. Water (390 ml) was added and the mixture was cooled. The generated crystals were collected by filtration, washed with water and dried to give crude 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (20.4 g). This was recrystallized from a mixed solvent of ethyl acetate and heptane (2:3) to give nearly pure 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-ylmethanol (18.9 g, 86%). The various spectrum data of the crystals were the same as those obtained in Example 12.
Reaction SMILES: Cl[C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].O>CN(C)C=O.C1C=CC=CC=1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][O:19][C:16]1[CH:15]=[CH:14][C:3]2[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[F:11])=[N:12][O:13][C:2]=2[C:17]=1[Cl:18])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: ON=C(c1ccccc1F)c1ccc(O)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)COc1ccc2c(-c3ccccc3F)noc2c1Cl
Reaction time: 0.5 h

Procedure:
A solution of 18.4 g of 2,3-dichloro-4-hydroxy-2'-fluorobenzophenone oxime and 3.6 g of sodium hydride in 120 ml of dimethylformamide and 120 ml of benzene is maintained at a temperature of from 80°-85° C. for 3 hours. Thereafter, the mixture is permitted to reach ambient temperature after which a solution of 11.0 g of ethyl bromoacetate in 20 ml of dimethylformamide is added dropwise. After the addition is complete, the mixture is stirred for 30 minutes and then water is added to decompose any excess sodium hydride. The mixture is extracted with ethyl acetate and the combined extracts are dried and evaporated to dryness leaving a solid residue. The residue is recrystallized several times from 95% ethyl alcohol to yield the pure product ethyl{[7-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetat having a melting point of 102° to 104° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]2)=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[Si:14]([O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@@H]1CCN(c2ccc(Cl)nn2)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(Cl)nn2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To a solution of compound 27 (815 mg, 4.08 mmol) in DMF (15 mL) were added t-butyldimethylsilyl chloride (738 mg, 4.9 mmol) and imidazole (556 mg, 8.16 mmol). The thus obtained solution was stirred at room temperature for 6 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel eluting with 15% to 50% to give the compound 28 as a white solid (1.087 g, 85%). LCMS-ESI (POS), M/Z, M+1: Found 314.1, Calculated 314.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH3:11])[CH3:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.CC(C)([O-])C.[K+]>[CH2:1]([N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCn1c([N+](=O)[O-])cnc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1c([N+](=O)[O-])cnc1C=Cc1ccccc1

Procedure:
A slurry of β-(1-ethyl-5-nitro-2-imidazolyl)styrene (42.7 g. or 0.175 mole) in 350 ml. of methanol containing 14.6 ml. of water at 25° C. is treated with ozone until a nearly clear, pale-yellow solution is obtained. Subsequently, the mixture is treated with 42 g. of sodium iodide in 138 ml. of water and 20.3 ml. of glacial acetic acid at 25° C. The mixture is stirred for 40 minutes and 44.1 g. (0.288 mole) of sodium thiosulfate in 242 ml. of water added. The mixture is filtered, and the filtrate concentrated at 70°-75° C. under 15-20 mm. of pressure to give 450 ml. of solution. The solution is acidified with 50 ml. of 6N hydrochloric acid and the benzaldehyde removed at 70°-75° C. under 15-20 mm. of pressure. The residue is then neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate to give an 81.5% yield of solid aldehyde, melting point 61°-67° C. after stripping. A sublimed sample of the aldehyde melts at 68°-69° C. with softening at 65° C. When the aqueous ozonized solution, after benzaldehyde is removed, is treated with thiosemicarbazide and mineral acid or semicarbazide hydrochloride and heated, the 1-ethyl-5-nitro-2-imidazolecarboxaldehyde thiosemicarbazone, melting point 241° C., or semicarbazone, melting point 223°-226° C., is obtained. The compound β-(1-ethyl-5-nitro-2-imidazolyl)styrene is prepared by treating 1-ethyl-2-methyl-5-nitroimidazole with benzaldehyde in absolute ethanol and potassium tertiary butoxide in nitrogen atmosphere below 37° C. A sample purified from 95% ethanol melts at 136.5°-137.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[C:13]1([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:20][CH:21]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: Cc1ccc2ccc(N)cc2n1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccccc4)nc3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (100 mg, 0.63 mmol) and 6-phenylnicotinic acid (D48) (151 mg, 0.76 mmol) as a cream solid. 1H NMR (400 MHz, DMSO) δ (ppm): 10.75 (s, 1H), 9.25 (d, 1H), 8.50 (s, 1H), 8.45 (dd, 1H), 8.20 (m, 4H), 7.90 (m, 2H), 7.55 (m, 3H), 7.34 (d, 1H), 2.65 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[O:20]=[C:21]([CH2:27][C:28](=[O:30])[CH3:29])[C:22](OCC)=[O:23]>CC(O)=O>[C:28]([C:27]1[CH:16]([C:15]2[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=2)[N:1]([C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:22](=[O:23])[C:21]=1[OH:20])(=[O:30])[CH3:29]
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CC(=O)O
Product: CC(=O)C1=C(O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
A round-bottomed flask was charged 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) (3 g, 21.71 mmol), 4-chlorobenzaldehyde (2.348 g, 16.70 mmol) and ethyl 2,4-dioxovalerate (3.17 g, 20.04 mmol) in AcOH (50 mL) and the reaction mixture was heated up and stirred at 125° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, quenched with a saturated aq. NaHCO3 solution, extracted with EtOAc. The organic layer was discarded and the aq. phase was adjusted to pH 1-2, extracted EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title product (3.82 g, 8.71 mmol, 52% yield) as a black solid. tR: 3.54 min (HPLC 1); tR: 0.75 min (LC-MS 2); ESI-MS: 373 [M+H]+ (LC-MS 2).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[NH2:32]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:27][N:32]=[C:31]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[N:30]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(=NO)c1cccnc1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccnc3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 37.7 mg (0.275 mmol) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 26.0 mg (21% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13])#[N:2].C(N(CC)CC)C.[CH2:23]([OH:25])[CH3:24].[OH2:26].[CH2:27]([OH:29])[CH3:28]>[Pd].O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:23]([C:24]([O:29][CH2:27][CH3:28])=[O:26])=[O:25])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13])#[N:2]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Reactant: CCO
Reactant: O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 3 h
Yield: 82 %

Procedure:
A solution of 6.8 g (31.5 mmol) 2-cyano-5-nitrobenzotrifluoride in 200 ml ethanol was hydrogenated at atm. pressure by using 0.4 g 5% Pd-C as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The crude product was dissolved in 150 ml dry tetrahydrofuran and added 6.0 ml (43.6 mmol) dry triethylamine. A solution of 4.4 ml (39.4 mmol) ethyl oxalylchlorid in 30 ml dry tetrahydrofuran was added dropwise, and then stirring was continued at 25° C. for 3 h. The filtered and evaporated reaction product was stirred with ethanol-water to give 7.3 g (82%) of 2-cyano-5-ethoxalylaminobenzotrifluoride. M.p. 112-114° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.[OH2:25].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)(=[O:22])=[O:25]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)CCc1ccc2c(c1)OCO2
Temperature: 0 °C

Procedure:
3.5 g of 5-{2-(methylthio)ethyl}-1,3-benzodioxole was dissolved in 100 ml of chloroform. 8.8 g of m-chloroperbenzoic acid was added to the solution under cooling with ice/water to conduct the reaction for 2 h. 300 ml of chloroform and 300 ml of water were added thereto and then sodium carbonate was added to the mixture until the aqueous layer became alkaline. After separation of the layers, the chloroform layer was washed with water twice and dried over sodium sulfate. The solvent was distilled off under reduced pressure. After recrystallization from ethyl acetate/isopropyl ether, 3 g of the intended compound was obtained in the form of colorless needles.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:8]([NH2:11])[CH:9]=[CH2:10].[C:12]1(C)[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:8]([NH:11][CH:2]([CH3:1])[CH2:3][CH2:4][CH:5]=[CH2:6])[CH:9]=[CH2:10].[CH2:8]([N:11]=[C:16]([CH3:15])[CH2:17][CH2:12][CH:13]=[CH2:14])[CH:9]=[CH2:10]
Reactant: C=CCN
Reactant: C=CCCC(C)=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C=CCCC(C)=NCC=C
Product: C=CCCC(C)NCC=C
Reaction time: 8 h

Procedure:
Hex-5-en-2-one (9.8 g, 11.6 ml, 100 mmol) was added to a stirred solution of allylamine (8.55 mmol, 11.25 ml, 150 mmol), 4 Angstrom molecular sieves (52 g), and p-toluene sulfonic acid (10 mg) in CH2Cl2 (200 ml) and was stirred overnight. The reaction mixture was concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (13 g, 95%). Electrospray mass spec: M+H+=137.9