Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=2[C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:20][O:21][C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]=[C:29]=[S:30])=[O:27])=[CH:24][CH:23]=1>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:28][C:29](=[S:30])[NH:1][C:2]2[S:12][C:5]3[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][C:4]=3[C:3]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:27])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)N=C=S)cc1
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(C)(C)OC2
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC(=S)Nc2sc3c(c2C(=O)OC(C)(C)C)CC(C)(C)OC3)cc1
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A solution of tert-butyl 2-amino-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (1.0 mL, 0.083 M, 0.083 mmol) in THF was added to a solution of 4-methoxybenzoyl isothiocyanate (51 mg, 0.26 mmol) in THF (1 mL) and heated at 50° C. for 16 hours, then cooled to room temperature. The solvent was removed and EtOH (2 mL) was added. The product was filtered and rinsed with EtOH (3×5 mL). tert-Butyl 2-(3-(4-methoxybenzoyl)thioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylate (31 mg, 0.065 mmol, 78% yield) was isolated as a white solid. 1H NMR (400 MHz, CDCl3) δ 14.65 (s, 1H), 8.98 (s, 1H), 7.83 (apparent d, J=8.9 Hz, 2H), 6.91 (apparent d, J=8.9 Hz, 2H), 4.66 (s, 2H), 3.81 (s, 3H), 2.69 (s, 2H), 1.56 (s, 9H), 1.24 (s, 6H). 13C NMR (101 MHz, CDCl3) 173.90, 164.52, 164.49, 163.88, 147.40, 129.93, 129.13, 124.58, 123.65, 118.03, 114.34, 82.36, 70.79, 59.81, 55.62, 38.25, 28.49, 26.48.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:34]=[CH:35][C:36]([S:42](=[O:47])(=[O:46])[N:43]([CH3:45])[CH3:44])=[C:37]([CH:41]=1)[C:38]([OH:40])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:33]5[CH:34]=[CH:35][C:36]([S:42](=[O:46])(=[O:47])[N:43]([CH3:45])[CH3:44])=[C:37]([C:38]([OH:40])=[O:39])[CH:41]=5)[CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)S(=O)(=O)c1ccc(Br)cc1C(=O)O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)N(C)C)c(C(=O)O)c1
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (42 mg, 0.10 mmol), 5-bromo-2-(N,N-dimethylsulfamoyl)benzoic acid (31 mg, 0.10 mmol), 1 M K2CO3 (0.30 mL, 0.30 mmol), and Pd-FibreCat 1007 (8 mg, 0.004 mmol) were dissolved in DMF (1 mL) and heated at 80° C. for 3 hr in an oil bath. The mixture was filtered and purified by reverse phase HPLC to yield 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4-(N,N-dimethylsulfamoyl)-2′-methylbiphenyl-3-carboxylic acid. ESI-MS m/z calc. 522.6, found 523.5 (M+1)+; retention time 1.79 minutes.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH:13]=[CH2:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-:15].[Na+].OO.[Cl-].[Na+]>O1CCCC1.C(O)C>[Si:1]([O:8][CH2:9][CH:10]1[CH2:12][CH:11]1[CH2:13][CH2:14][OH:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=CC1CC1CO[Si](C)(C)C(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC1CC1CCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-vinylcyclopropylmethyl t-butyldimethylsilyl ether (17.1 g, 81 mmol) was dissolved in tetrahydrofuran (100 ml) and cooled to 0° C. A borane-dimethylsulfide complex (2.5 g, 33 mmol) was added thereto, and the mixture was stirred for one hour. Ethanol (38 ml), 3N sodium hydroxide (38 ml) and 30% hydrogen peroxide (18.2 ml) were added thereto, and the mixture was stirred for 30 minutes. The saturated sodium chloride aqueous solution was added thereto, and the product was extracted with ethyl acetate, then dried over anhydrous magnesium sulfate and concentrated. Then, it was purified by silica gel column chromatography to obtain 2-(2-hydroxyethyl)cyclopropylmethyl t-butyldimethylsilyl ether (15.0 g, yield: 81%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].Cl.N[C@@H:20]([C:24]1(C)CCCCC1)[C:21](O)=O>>[CH3:1][C:2]1([C@H:3]([NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6])[C:13]([OH:15])=[O:14])[CH2:17][CH2:24][CH2:20][CH2:21][CH2:16]1
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC1([C@H](N)C(=O)O)CCCCC1
Agent: Cl
Product: C=CCCCOC(=O)N[C@H](C(=O)O)C1(C)CCCCC1

Procedure:
(2S)-(1-methylcyclohexyl) {[(pent-4-en-1-yloxy)carbonyl]amino}acetic acid was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine by using (2S)-amino(1-methylcyclohexyl)acetic acid-HCl instead of t-butylglycine. LRMS (ESI) m/z 347.3 [(M+Na+CH3CN)+; calcd for C17H28N2NaO4: 347.2].
Reaction SMILES: [CH:1]1([C:7](=O)[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:44][O:45][CH3:46].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH:1]1(/[C:7](=[N:44]\[O:45][CH3:46])/[CH2:8][N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][C:32](=[O:34])[O:31][N:30]=4)=[CH:21][CH:22]=3)=[C:12]([CH2:35][CH2:36][CH3:37])[N:11]3[N:38]=[C:39]([CH3:41])[N:40]=[C:10]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C2CCCCC2)c2nc(C)nn12
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N/OC)C2CCCCC2)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
A mixture of 4-(2-cyclohexyl-2-oxoethyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.25 g), (aminooxy)methane hydrochloride (0.74 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.066 g, 26%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH2:34][CH:35]([CH3:37])[CH3:36])[NH:11][C:12](=[O:33])[C@H:13]([CH2:31][OH:32])[NH:14][C:15](=[O:30])[C@H:16]([CH2:18][CH2:19][C:20](=[O:29])[NH:21]C(OC(C)(C)C)=O)[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:39]>>[ClH:39].[CH2:1]([O:8][C:9](=[O:38])[C@H:10]([CH2:34][CH:35]([CH3:36])[CH3:37])[NH:11][C:12](=[O:33])[C@H:13]([CH2:31][OH:32])[NH:14][C:15](=[O:30])[C@H:16]([CH2:18][CH2:19][C:20](=[O:29])[NH2:21])[NH2:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCC(=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCC(N)=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
N-(N′-(Boc)-glutaminyl-serinyl)leucine benzyl ester (715 g, 1.33 M) (prepared as described in Step 2) was suspended in iPAc (3.5 L) at room temperature. To the slurry was added a 3.8 M solution of HCl in iPAc (3.5 L, 13.3 M) whereupon all the solids dissolved. After a short time, the product crystallized. The mixture was stirred at room temperature for 3.75 hours when HPLC showed complete reaction. The slurry was diluted with iPAc (4.0 L), stirred for 1 hour at room temperature and the solid collected by filtration under nitrogen. The product is very hygroscopic in the presence of excess HCl and must be collected under dry nitrogen.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:29])([CH3:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[CH3:28][C:19]([NH:29][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([CH3:18])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1
Reactant: CC(C)(N)CCc1ccncc1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(CCc1ccncc1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 1,1-dimethyl-3-pyridin-4-yl-propylamine (55 mg, 0.32 mmol) as starting materials and isolated (60.0 mg, 74%) as white solid; LC-MS (UV peak area, ESI) 94.93%, 380.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20](Br)[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[C:30]([Si:34]([CH3:46])([CH3:45])[O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:33])([CH3:32])[CH3:31].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.O.[Cl-].[NH4+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([C:39]4[CH:40]=[CH:41][C:36]([O:35][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:45])[CH3:46])=[CH:37][CH:38]=4)[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C(F)(F)F)c3Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c2ccc(C(F)(F)F)c3-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 110 °C
Yield: 35.1 %

Procedure:
(1S,2S)-2-[4-((R)-4-Bromo-5-trifluoromethyl-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (200 mg, 0.43 mmol), 4-(tertbutyldimethylsilyloxy)phenylboronic acid (118 mg, 0.47 mmol) potassium carbonate (176 mg, 1.28 mmol), 2,6-di-tert-butyl-4-methylphenol (47 mg, 0.21 mmol), tricyclohexylphosphine (10 mg, 0.03 mmol), and Pd2(dba)3 (16 mg, 0.02 mmol) are suspended in a mixture of dioxane (1.7 mL) and water (0.6 mL) in a sealed tube and heated at 110° C. for 4 hours. The mixture is diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried and concentrated under vacuum. The residue is purified by flash chromatography (eluent: 0-30% EtOAc in cyclohexane) to give the title compound (Yield 90 mg)
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[CH3:25][C:26]1[CH:31]=[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[N:29]=[CH:28][C:27]=1[NH2:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:37][C:27]3[CH:28]=[N:29][C:30]([N:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)=[CH:31][C:26]=3[CH3:25])[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Cc1cc(N2CCCC2)ncc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1c(Nc2cnc(N3CCCC3)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 36.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 1.50 g, 4.04 mmol), 4-methyl-6-pyrrolidin-1-ylpyridin-3-amine (1.44 g, 8.09 mmol) and p-toluenesulfonic acid monohydrate (695 mg, 4.04 mmol) in 1-methyl-2-pyrrolidinone (8 mL) was irradiated by microwave at 180° C. for 110 min. After cooling, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/isopropyl ether to give the title compound (745 mg, 1.46 mmol, 36%) as a colorless solid.
Reaction SMILES: [CH:1](O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([OH:19])(=[O:18])[CH2:16][SH:17]>>[CH:1]([S:17][CH2:16][C:15]([OH:19])=[O:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CS
Reactant: OC(c1ccccc1)c1ccccc1
Product: O=C(O)CSC(c1ccccc1)c1ccccc1
Yield: 99 %

Procedure:
This compound was prepared according to the procedure of Prisinzano. (Prisinzano, T.; Podobinski, J.; Tidgewell, K.; Luo, M.; Swenson, D. Tetrahedron: Asymmetry 2004, 15, 1053-1058). The synthesis employed benzhydrol (50.0 g, 271.4 mmol) and thioglycolic acid (25.0 g, 271.4 mmol) to give the title compound as a white solid: 69.2 g (99% yield); mp 126-129° C. Spectroscopic data was identical to lit. (Prisinzano, T.; Podobinski, J.; Tidgewell, K.; Luo, M.; Swenson, D. Tetrahedron: Asymmetry 2004, 15, 1053-1058).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.CC(C)([O-])C.[K+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH3:36])[C:21](=[O:35])[C:22]3[CH:32]=[C:31]([CH2:33]Cl)[CH:30]=[N:29][C:23]=3[N:24]([CH2:27][CH3:28])[C:25]=2[N:26]=1>CS(C)=O.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH3:36])[C:21](=[O:35])[C:22]3[CH:32]=[C:31]([CH2:33][C:1]4[CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=4)[CH:30]=[N:29][C:23]=3[N:24]([CH2:27][CH3:28])[C:25]=2[N:26]=1
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Reactant: Oc1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCN1c2ncc(Cc3cccc(O)c3)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 56.1 %

Procedure:
Resorcinol (0.082 g, 0.74 mmol) in dimethyl sulfoxide (1 mL) was treated with potassium tert-butoxide (1.0M in tetrahydrofuran, 0.15 mL, 0.15 mmol). The resulting stirred solution was treated with 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (0.050 g, 0.14 mmol) in dimethyl sulfoxide (1 mL) and the mixture was stirred an additional 16 hours. The mixture was diluted with ethyl acetate (50 mL) washed with brine, water, and brine (15 mL each). The organics were dried over sodium sulfate, concentrated and the residue was purified by flash chromatography (hexanes to 1:1 hexanes/ethyl acetate gradient) followed by crystallization from hexanes to give the title compound (0.031 g, 51%), m.p. 219°-220° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[CH:10]=2)=[CH:4][C:3]=1[CH3:17].I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].CCCCCCCCCCCCC>[CH3:16][C:11]1[CH:10]=[C:9]([N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH3:17])[CH:4]=2)[C:28]2[CH:29]=[CH:30][C:25]([C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)=[CH:26][CH:27]=2)[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: Ic1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(Nc2ccc(C)c(C)c2)cc1C
Agent: [Cu+2]
Agent: CCCCCCCCCCCCC
Agent: O=C([O-])[O-]
Solvent: O
Product: Cc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 25 °C
Yield: 71.2 %

Procedure:
In a 500-ml three-neck flask were placed 31 g of 3,3',4,4'-tetramethyldiphenylamine synthesized in Example 3 (1), 40 g of 4-iodobiphenyl, 19 g of anhydrous potassium carbonate, 2 g of copper sulfate pentahydrate and 20 ml of n-tridecane, and after carrying out the reaction for 28 hours at 200° C. under a nitrogen gas stream, the reaction mixture was cooled to room temperature. The reaction mixture was subjected to a column purification (solvent: n-hexane/toluene =10/1) with activated alumina and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to provide 37 g of N,N-bis(3,4-dimethylphenyl)biphenyl-4-amine. (Melting point 119° to 120.5° C. colorless crystals, IR spectrum shown in FIG. 4)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9]C=C(C3N(C(C)C)N=C(C)N=3)[N:12]=2)=[C:4]([F:22])[CH:3]=1.ClC1C=CC(C#N)=C(F)C=1.N[OH:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:9])[NH:12][OH:34])=[C:4]([F:22])[CH:3]=1
Reactant: NO
Reactant: Cc1nc(-c2c[nH]c(-c3ccc(Cl)cc3F)n2)n(C(C)C)n1
Agent: N#Cc1ccc(Cl)cc1F
Product: N=C(NO)c1ccc(Cl)cc1F

Procedure:
Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39. Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 42. Reaction of 42 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([CH:19]([OH:21])[CH3:20])[C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([CH:22]=C)[C:3]=1[C:24]#[N:25].[O:26]=[O+][O-].CSC>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[C:17]([CH:19]([OH:21])[CH3:20])[C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[C:4]([CH:22]=[O:26])[C:3]=1[C:24]#[N:25]
Reactant: C=Cc1c(C#N)c(Cl)cc(C(C)O)c1OCCNC(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: CC(O)c1cc(Cl)c(C#N)c(C=O)c1OCCNC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
Tert-butyl {2-[4-chloro-3-cyano-6-(1-hydroxyethyl)-2-vinylphenoxy]ethyl}carbamate (1.6 g, 4.4 mmol) was dissolved in methylene chloride (1.2 mL) cooled in a dry ice acetone bath and ozone/oxygen was bubbled through the solution until a persistent blue color remained. The reaction was purged with oxygen and nitrogen to remove excess ozone and dimethyl sulfide (0.80 mL, 11 mmol) was added to reduce the ozonide. After stirring for 1 h, the reaction was complete. This was concentrated in vacuo to give a residue give tert-butyl {2-[4-chloro-3-cyano-2-formyl-6-(1-hydroxyethyl)phenoxy]ethyl}carbamate. LCMS calculated for C17H21ClN2O5Na (M+Na)+: m/z=391.1; found: 391.1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19]>C(O)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]1[CH:8]([C:9]2=[O:14])[CH2:19][CH:18]=[CH:17][CH2:16]1)([O-:3])=[O:2]
Reactant: C=CC=C
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CCO
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)C2CC=CCC12

Procedure:
122 Grams of 5-nitro-1,4-naphthoquinone which contained 10% of the 6-nitro compound, 1,000 grams of ethanol and 48 grams of 1,3-butadiene were placed in an autoclave, followed by reaction at 80° C. for 2.5 hours. After the solution was allowed to cool for precipitating crystals, the crystals were separated by filtration, washed with water and dried to obtain 114 grams of 5-nitro-1,4,4a,9a-tetrahydroanthraquinone. The thus obtained nitro compound was introduced into 2,800 grams of methyl cellosolve, to which was added 1.2 grams of a 5% palladium on carbon catalyst and 120 grams of a 20% aqueous sodium hydroxide solution, followed by feeding hydrogen thereinto for hydrogenation while agitating at room temperature and under normal pressure to absorb hydrogen in an amount of 2 mols per mol of the crude 5-nitro compound. Thereafter, the catalyst was separated by filtration and air was injected to the resultant filtrate for oxidation at room temperature for 3 hours. Then, the methyl cellosolve was distilled off from the reaction solution until crystals were precipitated, followed by allowing to cool. The thus precipitated crystals were separated by filtration, washed with water and dried to obtain 92 grams of 1-aminoanthraquinone containing therein 1% of 2-aminoanthraquinone.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[N:12]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C1CCCC1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: N[C@@H]1CCC[C@@H]1c1ccccc1
Yield: 62 %

Procedure:
Scheme IA, step B: (+,−) 2-Phenyl-cyclopentanone oxime from preparation 6 above was dissolved in 35 mL of ethanol and hydrogenated using 90 mg of 5% Pd/C at 40° C. overnight at 413.69 kPa (60 psi). The solution was filtered and concentrated in vacuo to give 0.43 g (62%) of a colorless oil. Some dimeric material resulted by this procedure according to the mass spec. The cis:trans ratio was estimated to be 4:1. The amine was used directly without further purification. The NMR was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[CH:17]=O.Cl.[NH2:20][OH:21].Cl>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[C:4](=[O:16])[C:3]=1[CH:17]=[N:20][OH:21]
Reactant: O=Cc1c(Cl)ccn(-c2c(F)cccc2F)c1=O
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Product: O=c1c(C=NO)c(Cl)ccn1-c1c(F)cccc1F
Temperature: 100 °C
Yield: 70.8 %

Procedure:
A mixture of 4-chloro-1-(2,6-difluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step C (1.07 g), hydroxylamine hydrochloride (414 mg), conc. hydrochloric acid (0.0120 mL) and 2-propanol (10 mL) was heated at 100° C. for 2 hr, and cooled to room temperature. The resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (800 mg).