Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1ccnc(Sc2cccc(CO)c2)c1
Product: CCc1c(OCc2cccc(Sc3cc(C#N)ccn3)c2)ccc(C(C)=O)c1O
Yield: 80 %

Procedure:
Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) isonicotinonitrile (1.35 g, 5.56 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (1.00 g, 5.56 mmol) affords the title compound (1.80 g, 80%). MS (APCI-neg) m/z (rel intensity): 403 (M−H, 100%).
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[CH:30]=[CH:29][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([C:23]3[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=3)[CH:16]=2)=[O:14])=[CH:9][CH:8]=1)([CH3:6])=[O:5])#[N:2].[Br:31]N1C(=O)CCC1=O>ClCCl.C(O)(=O)C>[C:1]([N:3]=[S:4]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][NH:12][C:13]([C:15]2[C:20](=[O:21])[C:19]([Br:31])=[C:18]([CH3:22])[N:17]([C:23]3[N:24]([CH3:28])[N:25]=[CH:26][CH:27]=3)[CH:16]=2)=[O:14])=[CH:29][CH:30]=1)([CH3:6])=[O:5])#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1-c1ccnn1C
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=NC#N)cc2)cn1-c1ccnn1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-methyl-1-(2-methyl-2H-pyrazol-3-yl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-(N-cyano-S-methylsulfonimidoyl)-benzylamide (preparation 4b, 150 mg, 0.118 mmol) in dichloromethane (2 mL) is added N-bromosuccinimide (21 mg, 0.35 mmol) and five drops of glacial acetic acid. After stirring for 18 h at room temperature the reaction mixture is concentrated under reduced pressure and purified by preparative reversed phase HPLC (Xbridge, gradient of acetonitrile in water, 0.1% TFA, 60° C.). Yield: 40 mg (23% of theory); ESI mass spectrum: [M+H]+=503 (bromine isotope pattern); r.t. HPLC: 0.82 min (Z012_S04).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:8]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=2[C:10](O)=O)[N:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:10]1[C:9]2[C:8](=[CH:16][CH:15]=[C:14]([C:17]([F:19])([F:18])[F:20])[CH:13]=2)[N:7]=[C:5]2[N:4]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:3]=[C:2]([CH3:1])[C:6]=12
Reactant: Cc1cc(Nc2ccc(C(F)(F)F)cc2C(=O)O)n(-c2ccccn2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(-c2ccccn2)c2nc3ccc(C(F)(F)F)cc3c(Cl)c12
Temperature: 25 °C
Yield: 50.5 %

Procedure:
A solution of 2-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-5-(trifluoromethyl)benzoic acid (14.0 g, 38.6 mmol) in phosphorous oxychloride (27.4 mL, 294 mmol) was heated under reflux for 1 hour. The solution was allowed to cool to room temperature, and the reaction solvent was evaporated under reduced pressure, and the residue was poured into iced water. The solution was neutralized by the addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:chloroform=1:1 to chloroform) to give the title compound (7.07 g, 50% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C@@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:11])[CH:6]=[CH:5][CH:4]=1.[C:17]([NH:24][CH2:25][C:26](O)=[O:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:20]([O:19][C:17]([NH:24][CH2:25][C:26]([NH:11][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1)=[O:27])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)[C@@H](N)Cc1cccc(OC)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl 3-(6-methoxy-2-pyridinyl)alaninate (1.045 g, 4.66 mmol), N-boc-glycine (0.898 g, 5.13 mmol, Aldrich, St. Louis, Mo.), HATU (2.126 g, 5.59 mmol, Aldrich, St. Louis, Mo.), and N,N-diisopropylethylamine (2.43 mL, 13.98 mmol, Aldrich, St. Louis, Mo.) in DMF (5 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 70% EtOAc/hexanes to give ethyl N-(tert-butoxycarbonyl)glycyl-3-(6-methoxy-2-pyridinyl)alaninate (1.29 g) as a colorless oil.
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:1][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13]
Reactant: C[Mg]Br
Reactant: C=CCCCCC(=O)N(C)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCCC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methyl magnesium bromide (3M in ether, 3 eq.) was added dropwise to a stirred mixture of N-methoxy-N-methylhept-6-enamide 58 in THF (0.1 M) cooled at 0° C. After sting for 1 h at 0° C., the mixture was poured into sat. aq. NH4Cl and diluted with EtOAc. The aqueous layer was further extracted with EtOAc, the combined organic layers were washed with brine and dried (Na2SO4). Evaporation of the solvent at 30 mbar afforded the title compound (96%) as a colorless oil. 1H NMR (400 MHz, CDCl3, 300 K) δ 5.81 (ddt, J 17.1, 10.3, 6.7, 1H), 5.02 (dd, J 17.1, 1.5, 1H), 4.97 (d, J 10.3, 1H), 2.46-2.43 (m, 2H), 2.15 (s, 3H), 2.10-2.05 (m, 2H), 1.65-1.57 (m, 2H), 1.45-1.37 (m, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([C:22](OC)=[O:23])=[N:19][N:18]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CO.[Li+].[BH4-]>C1COCC1.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH2:22][OH:23])=[N:19][N:18]=4)=[C:13]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1nnc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)o1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(CO)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazole-2-carboxylate (200 mg) in THF (10 mL):MeOH (10 mL) was cooled to 0° C. Added LiBH4 (3 equiv.) in portions to the reaction mixture, stirred for 30 min at 0° C. Gradually the reaction temperature was raised to room temperature and stirred for 30 min. The reaction was quenched using ice pieces. The reaction mass was concentrated under reduced pressure. The residue obtained was diluted with EtOAc. The organic layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by prep HPLC to afford the desired compound, (5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methanol. 1H NMR: 400 MHz, DMSO-d6: δ 657.15 (d, J=524681.20 Hz, 6H), 3.71-3.79 (m, 1H), 4.71 (d, J=6.40 Hz, 2H), 5.93 (t, J=6.40 Hz, 1H), 6.21 (s, 1H), 7.36-7.38 (m, 1H), 7.52 (d, J=7.20 Hz, 1H), 7.61 (dd, J=2.00, 8.80 Hz, 1H), 7.97 (d, J=8.80 Hz, 1H), 8.49 (s, 1H), 8.65 (d, J=2.00 Hz, 1H), 9.17 (s, 1H), 9.44 (s, 1H). LC/MS: XBridge Phe 8, 4.6×30 mm, 3.5 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.454 min; LCMS (ES-API), m/z 383.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.528 min; Purity: 85.66%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C.CCOC(C)=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCCBr
Reactant: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCNc1ccccn1
Temperature: 0 °C

Procedure:
2-Aminopyridine (3-1, 1.97 g, 20.9 mmol) in 10 mL DMF was added to a suspension of NaH (60% in oil, 1.00 g, 25 mmol) in 80 mL DMF cooled to 0° C. After warming to RT for 45 min, ethyl 5-bromopentanoate (4.2 mL, 25 mmol) was added dropwise. This mixture was heated at 75° C. overnight, then cooled to RT, diluted with EtOAc, washed with water (2×), sat. NaHCO3, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 50% then 70% EtOAc/hexane) provided 3-2 as a yellow oil.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[C:18]=1[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([Cl:1])[C:13]2[O:17][CH2:16][CH2:15][C:14]=2[C:18]=1[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24]
Reactant: CC(=O)NCCCc1c(Cl)ccc2c1CCO2
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)NCCCc1c(Cl)cc(Cl)c2c1CCO2
Reaction time: 64 h
Yield: 42.7 %

Procedure:
N-Chlorosuccinimide (173 mg) was added to a solution of N-[3-(5-chloro-2,3-dihydro-benzofuran-4-yl)-propyl]-acetamide (0.2 g) in glacial acetic acid (5 ml) at room temperature under nitrogen and the mixture stirred for 64 h. The solution was adusted to pH 9 with sodium carbonate (2N; 10 ml) and extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with brine (20 ml) and dried (MgSO4). The solvent was evaporated and the residue purified by HPLC, eluting with 50% acetonitrile/water+0.1% TFA gave the title compound as a colourless gum (97 mg)
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:20][C:21]#[N:22].[NH4+]>CO>[OH:19][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][C:11]([S:20][C:21]#[N:22])=[CH:10][C:9]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Temperature: -5 °C
Reaction time: 12 h

Procedure:
2,6,-Diphenylphenol (100.0 g, 0.406 mole) and ammonium thiocyanate (67.99 g, 0.893 mole) were suspended in methanol (150 ml) in a three-necked round bottom flask equipped with magnetic stirrer, thermometer and bubbler. The reaction mixture was cooled to -5° C. in an acetone/ice bath and chlorine gas bubbled through the solution for three hours. Maintaining the temperature below 10° C., ammonia gas was bubbled through the reaction for 2 hours. The contents of the flask were then poured into iced distilled water (250 ml) and allowed to stand for 12 hours in the refrigerator. After filtering, the solid was dried in vacuo at 45° C. for 12 hours. The title compound was purified by chromatography on silica and recrystallized from hexane, m.p. about 104°-106.5° C.
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH:4]([C:7]([N:17]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:18]([C@H:20]([NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8](=[O:10])[NH2:9])([CH3:6])[CH3:5].C(O)(=O)C>C(OCC)C.O1CCCC1>[CH3:3][O:24][C:23](=[O:25])[CH2:22][CH2:21][C@H:20]([C:18](=[O:19])[N:17]([C:7]([CH:4]([CH3:6])[CH3:5])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:8](=[O:10])[NH2:9])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH:26][C:27]([NH:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:28]
Reactant: CC(C)C(C(N)=O)(c1ccccc1)N(C(=O)[C@@H](CCC(=O)O)NC(=O)Nc1ccccc1)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CC[C@@H](NC(=O)Nc1ccccc1)C(=O)N(c1ccccc1)C(C(N)=O)(c1ccccc1)C(C)C

Procedure:
A solution of diazomethane in diethyl ether (generated from N-methyinitroso urea, 623 mg and 40% aqueous potassium hydroxide, 2 mL) was added dropwise to a solution of Example 4 (11.2 mg, 0.0217 mmol) in tetrahydrofuran (2 mL) until a yellow color persisted. Acetic acid was added until yellow color disappeard and the solvents were removed in vacuo. RP-HPLC (45% to 64%, 30 min) gave the titled product (10.3 mg) as a white iyophile. (45% to 64%, 30 min) Tr =13.07 min. 1H NMR (300 MHz, CDCl3) d 1.0 (2×d, J=7.0 Hz, 6H), 1.90 (m, 1H), 2.07 (m, 1H), 2.20 (m, 1H), 2.41 (m, 1H), 3.40 (d, J=16.6 Hz, 1H), 4.21 (s, 3H), 4.36 (d, J=16.6.0 Hz, 1H), 4.70 (m, 1H), 5.20 (sept, J=6.0 Hz, 1H), 6.57 (d, J=7.0 Hz, 1H), 6.88 (m, 4H), 7.10 (m, 4H), 7.21 (br, 2H), 7.38 (m, 4H), 7.59 (d, J=7.0 Hz, 2H), 8.30 (s, 1H). C31H36N4O6 requires m/z 560.6502; found 560.6541.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]O)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([O:18][CH2:31][CH2:30][N:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)=[O:17])=[C:9]([CH2:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: OCCN1CCOCC1
Reactant: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: Cc1ccccc1
Product: CCc1c(C)c2c(c(N)c1C/C=C(\C)CCC(=O)OCCN1CCOCC1)C(=O)OC2
Temperature: 117 °C
Reaction time: 2 h

Procedure:
7 g of (E)-6-(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and toluene (25 ml) are warmed gently to form a solution. A slight excess of 2-morpholinoethanol (3 g) and toluene (25 ml) are added. The reaction mixture is stirred for half an hour and then heated to reflux at an initial pot temperature of 117° C. (which increases a few degrees during reflux) under a Dean-Stark trap for 80 hours. The reaction mixture is cooled, washed with water (2×15 ml), 10% aqueous sodium bicarbonate (2×15 ml) and finally with water (15 ml). The toluene layer is stripped to a volume of about 20 ml in vacuo, n-hexane (30 ml) is added and the resulting slurry is aged at room temperature for 2 hours. The product is filtered, washed with n-hexane (ca. 10 ml) and dried in vacuo at 60° C. to yield 2-(morpholin-4-yl)ethyl (E)-6 -(4-amino-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[N:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C:9]=1[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])(=[O:3])[CH3:2].[BH4-].[Na+].O.C(Cl)(Cl)Cl>CO>[CH3:14][N:12]([CH3:13])[CH2:11][CH2:10][C:9]1[N:8]=[C:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:6]=[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:4]=1[CH:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1c(CCN(C)C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)c1c(CCN(C)C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 19.9 %

Procedure:
A mixture of 5-acetyl-6-(2-dimethylaminoethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine (1 g) and sodium borohydride (0.1 g) in methanol (40 ml) was stirred for 1 hour. The reaction mixture was poured into a mixture of water and chloroform and adjusted the pH to 9. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired product were combined and concentrated in vacuo. The residue was recrystallized from diethyl ether to afford 6-(2-dimethylaminoethyl)-5-(1-hydroxyethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine (0.2 g).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:12](C)C)CN)=[CH:5][CH:4]=1.C([O:19]C1C(OC)=CC(C(O)=O)=CC=1OC)CCC.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:9]([NH2:12])(=[O:19])[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(C(CN)N(C)C)cc1
Reactant: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-(4-methoxyphenyl)-N,N-dimethylethane-1,2-diamine represented by Formula 115 (134.6 mg, 0.69 mmol, purchased from Enamine Co.) was slowly added to 4-n-butoxy-3,5-dimethoxybenzoic acid represented by Formula 90 (193.8 mg, 0.76 mmol) prepared in Preparative Example 2 and diisopropylethylamine (0.48 mL, 2.77 mmol) in DMF (6 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 289.76 mg, 0.76 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (15 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 23 as a desired product (VVZ-024; 242.4 mg, 81% yield).
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:12][C:13]1[CH:14]=[C:15]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1>CC(N(C)C)=O>[CH3:12][C:13]1[CH:14]=[C:15]([C:22]2[CH:26]=[N:25][N:24]([CH2:4][C:3]([CH3:5])=[CH2:2])[CH:23]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: C=C(C)CBr
Reactant: Cc1cc(-c2cn[nH]c2)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C=C(C)Cn1cc(-c2cc(C)cc([N+](=O)[O-])c2)cn1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
3-Bromo-2-methylprop-1-ene (4.19 g, 31.0 mmol) and cesium carbonate (13.5 g, 41.3 mmol) were added to a solution of 4-(3-methyl-5-nitrophenyl)-1H-pyrazole (4.20 g, 20.7 mmol) in dimethylacetamide (41 mL) and stirred at 70° C. for 18 h. The mixture was allowed to cool to room temperature, passed through CELITE, washed with methanol, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/Hexane) to afford 4-(3-methyl-5-nitrophenyl)-1-(2-methylallyl)-1H-pyrazole. MS ESI calc'd. for C14H16N3O2 [M+H]+ 258. found 258.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:8][C:5]2([CH2:7][CH2:6]2)[CH2:4]1.CC1(C)N([O])C(C)(C)CCC1.CC(C(O)=O)CN>C(Cl)Cl>[CH:2]([CH:3]1[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:8][C:5]2([CH2:6][CH2:7]2)[CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C[C@H]1CO
Agent: CC(CN)C(=O)O
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C=O
Reaction time: 2 h

Procedure:
To (S)-tert-butyl 5-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (Intermediate 18, 20 g, 82.0 mmol) dissolved in 80 ml of DCM, TEMPO (2.6 g, 16 mmol) and BAIB (29.3 g, 90 mmol) were added. After 2 hours at 25° C., the reaction is diluted with DCM (150 ml), washed with an aqueous solution of Na2S2O3 then with water, dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether to petroleum ether/ethylacetate 95/5). (S) tert-butyl 5-formyl-6-azaspiro[2.5]octane-6-carboxylate was obtained as light yellow solid (7 g).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH2:28][CH3:29])=[N:17][N:18]3[C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=[O:5])C.O1CCCC1.[OH-].[Na+]>CO>[CH2:28]([C:16]1[C:15]2[C:19](=[CH:20][C:12]([C:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH:8]=3)=[CH:13][CH:14]=2)[N:18]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[N:17]=1)[CH3:29]
Reactant: CCOC(=O)C1CC=C(c2ccc3c(CC)nn(-c4ccc(F)cc4)c3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nn(-c2ccc(F)cc2)c2cc(C3=CCC(C(=O)O)CC3)ccc12
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a stirred solution of 1.13 g (2.87 mmol) of 4-(3-ethyl-1-(4-fluorophenyl)-1H-indazol-6-yl)-cyclohex-3-ene-carboxylic acid ethyl ester dissolved in 50 mL of methanol and 15 mL of tetrahydrofuran was added 8.62 mL (8.61 mmol) of 1 N sodium hydroxide and reaction mixture heated to reflux for 3 hr. After 3 hr, the reaction mixture was concentrated on a rotary evaporator, diluted with 200 mL of H2O, acidified to pH 1 with 1N HCl and extracted 2×200 mL ethyl acetate. The organic extracts were combined, washed with water, brine and dried over Na2SO4. Filtration, concentration and drying gave crude product. Recrystallization from ethyl acetate/hexane gave 0.31 grams of white crystalline product. mp=214-216° C.; MS, m/z 365 (M+H+, base).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C(OCC)(=O)C>[OH-].[Na+]>[C:14]1([S:20]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2nnn(O)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2nnn(OS(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Yield: 53.6 %

Procedure:
In 1 N aqueous sodium hydroxide (45 ml) is dissolved 1-hydroxy-6-nitro-1,2,3-benzotriazole (7.2 g). To the solution is added dropwise benzenesulfonyl chloride (7.0 g) with stirring at room temperature and further are added thereto water (50 ml) and ethyl acetate (100 ml) and the mixture is stirred for 1 hour. The ethyl acetate layer is separated, dried over magnesium sulfate-charcoal, filtered and concentrated until it becomes about 30 ml. n-Hexane (50 ml) is thereto added and the mixture is allowed to stand. The precipitated crystals are separated by filtration and dried to give faint yellow prisms of 1-benzenesulfonyloxy-6-nitro-1,2,3-benzotriazole (6.8 g), melting point: 122°-124° C. The product is recrystallized from ethyl acetate-n-hexane to give a pure product: melting point: 124° C.