Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:20])[C:18]=2[OH:19])=[CH:15][C:14]([CH3:21])=[CH:13][CH:12]=3)[CH:5]=[CH:6][C:7]=1[OH:8].[C:22](OC(=O)C)(=[O:24])[CH3:23]>ClCCl>[OH:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:20])[C:18]=2[OH:19])=[CH:15][C:14]([CH3:21])=[CH:13][CH:12]=3)=[CH:3][C:2]=1[NH:1][C:22](=[O:24])[CH3:23]
Reactant: Cc1ccc2oc(-c3ccc(O)c(N)c3)c(O)c(=O)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2oc3ccc(C)cc3c(=O)c2O)ccc1O
Yield: 44 %

Procedure:
The compound prepared in Example 5 (10 mg, 35 μmol) was dissolved in dichloromethane (2 ml) and reacted with excess acetic anhydride for 1 hour at room temperature. The mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: 50% ethylacetate/hexane) to give 5 mg (Yield 44%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:22].[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:3]([CH3:22])[CH:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1Br
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 51.3 %

Procedure:
A mixture of 67 (380 mg, 1.06 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 220 mg (51%) of 68. 1H NMR (400 MHz, CDCl3): δ1.52 (s, 9H), 1.58 (m, 6H), 2.22 (m, 4H), 2.34 (s, 3H), 4.85 (s, 1H), 6.25 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.4 Hz, 2H), 6.90-6.97 (m, 4H), 7.44 (d, J=8.1 Hz, 1H), 7.84 (d, J=16.0 Hz, 1H).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:34]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:28]([O:27][C:25]([N:22]1[C:21]2[CH:32]=[CH:33][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:34])[C:20]=2[N:24]=[CH:23]1)=[O:26])([CH3:29])([CH3:30])[CH3:31]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1c(N)ccc2c1ncn2C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (DPT) (14.3 g) and 4-dimethylaminopyridine (0.1 g) in CH2Cl2 (500 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-4-methylbenzimidazole (7.82 g) in CH2Cl2 (250 mL). The mixture is stirred for 15 minutes at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:38]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:38][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=4)=[CH:16][CH:15]=3)[CH2:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(F)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(F)cn3)[nH]2)cc1)C1CC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 56.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-(5-fluoropyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (65 mg) in acetic acid (3 mL) was added ammonium acetate (170 mg), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (35 mg, yield 56%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 455 (MH+).
Reaction SMILES: [O:1]([C@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC([O-])=O.[Na+].C([BH3-])#N.[Na+]>C1COCC1.CO>[CH:15]1([NH:14][C@H:11]2[CH2:10][CH2:9][C@H:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: N[C@H]1CC[C@H](Oc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc(O[C@H]2CC[C@H](NC3CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of trans-4-phenoxycyclohexylamine (1 mmol) in 6 ml of THF and 6 ml of MeOH was added cyclohexanone (2 mmol), NaOAc (2 mmol) and 3 g of 3 Å molecular sieves. The mixture is stirred for 10 min after which 1N sodiumcyanoborohydride in tetrahydrofuran (2.4 mmol) is added. The reaction is stirred 1 day at room temperature then filtered through celite washing through with 30 mL of dichloromethane. The organic phase is washed with 10 ml of water, 10 mL of brine, dried (MgSO4), filtered and concentrated in vacuo to give crude cyclohexyl-(trans-4-phenoxy-cyclohexyl)amine which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.CN([Si](C)(C)C)C(=O)C(F)(F)F.[I:43][Si](C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][I:43])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1nsc(N)n1
Reactant: C[Si](C)(C)I
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CI)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7β-[(Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (319 mg) was suspended in methylene chloride (4 ml), followed by an addition of N-methyl-N-(trimethylsilyl)trifluoroacetamide (877 μl). The resulting mixture was stirred at room temperature for 1 hour. After ice-cooling, iodotrimethylsilane (268 μl) was added and the resulting mixture was stirred for 15 minutes. The reaction mixture was concentrated under reduced pressure to obtain the silylated derivative of 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH:9]=[N:8][C:5]2=[CH:6][CH:7]=1.C(OC(C)(C)C)=O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Nc3ccc(Br)cc32)CC1
Agent: CC(C)(C)OC=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1ccc(Br)cc12

Procedure:
Tert-butyl 5-bromospiro[indoline-3,4′-piperidine]-1′-carboxylate was prepared by the procedures described in Example 1, Step 2, substituting tert-butyl 5-chlorospiro[indole-3,4′-piperidine]-1′-carboxylate with tert-butyl 5-bromospiro[indole-3,4′-piperidine]-1′-carboxylate. LCMS (APCI+) m/z 267, 269 [M+H-Boc]+; Rt=3.89 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[Br:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[N:23][C:24]=1[Cl:25]>N1C=CC=CC=1.C(OCC)(=O)C.Cl>[Br:18][C:19]1[CH:20]=[C:21]([S:26]([NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:3]=2[Cl:2])(=[O:28])=[O:27])[CH:22]=[N:23][C:24]=1[Cl:25]
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1ccccc1Oc1ccc(Cl)cc1Cl)c1cnc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2,4-Dichlorophenoxy)aniline HCl (1.14 g, 3.94 mmol) and 5-bromo-6-chloropyridine-3-sulfonyl chloride (1.26 g, 4.33 mmol) were dissolved in pyridine (4 mL) and allowed to stir at ambient temperature for 1 hour. The reaction mixture was then diluted with 100 mL of ethyl acetate, 80 mL of 0.5 M HCl. The organic layer was washed successively with 100 mL of 0.5 M HCl, twice with 100 mL of water, 100 mL of half-saturated brine and finally 100 mL of brine. Drying of the organic layer over sodium sulfate was followed by filtration and solvent removal under reduced pressure. The resulting residue was purified by silica gel chromatography (linear gradient 60-100% DCM in hexanes) to yield 5-bromo-6-chloro-N-[2-(2,4-dichlorophenoxy)phenyl]pyridine-3-sulfonamide, giving proton NMR and mass spectral data consistent with theory.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[C:5]([O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.[O-:14][Mn](=O)(=O)=O.[K+].[OH-].[K+].Cl>O.CO>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:14])=[O:9])[C:5]([O:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCOc1ccc(C)nc1CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCOc1ccc(C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 500 ml round-bottom flask [6-methyl-3-(propyloxy)-2-pyridinyl]methanol D14 (3.50 g) was suspended in water (16 ml) and KMnO4 (6.10 g, 38.60 mmol) and KOH (1 M aqueous solution, 19 ml, 19 mmol) were added. The mixture was stirred at room temperature for 2 hours. The pH was adjusted to pH=4 by addition of a 1 M aqueous HCl solution and then MeOH (100 ml) was added. The solid was filtered off, volatiles were removed under reduced pressure and the aqueous phase was extracted twice with DCM. The collected organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford the title compound D16 (2 g). MS: (ES/+) m/z: 196 (M+1). C10H13NO2 requires 195. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 12.96 (bs, 1 H), 7.49 (d, 1 H), 7.31 (d, 1 H), 3.98 (t, 2H), 2.40 (s, 3 H), 1.60-1.80 (m, 2 H), 0.96 (t, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH3:11])[C:7]=2[CH:12]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+](C)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:20])=[C:8]([CH3:11])[C:7]=2[CH:12]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2occ(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: COc1ccc2oc(C(=O)c3ccccc3)c(C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a mixture of 5-methoxy-3-methyl-1-benzofuran (2.00 g) synthesized in Example A104(2), benzoyl chloride (1.68 mL) and nitromethane (20 mL) was added aluminum chloride (3.28 g), and the mixture was stirred at room temperature for 2 hr. Water was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) and further by silica gel column chromatography (20% ethyl acetate/hexane) to give the title object compound (2.03 g, 62%) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH:16][NH2:17])=[CH:14][C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH3:20])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=S.C(O)C>CN(C=O)C>[CH2:1]([N:8]1[C:15]2[NH:16][N:17]=[C:21]([NH:22][CH3:23])[C:14]=2[C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH3:20])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccccc2)c1=O
Reactant: CN=C=S
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 70 %

Procedure:
A solution of 1-benzyl-6-hydrazino-3-propyluracil (2.0 g, 7.3 mM) and methyl isothiocyanate (1.5 ml, 22 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. Ethanol (20 ml) was added to the solution, which was cooled to give crystals. Recrystallization from DMF/ethanol gave colorless needles (1.6 g, 70%), m.p. 307°-310° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[C:27]([O-:30])(O)=O.[Na+]>Br>[Cl:1][C:2]1[C:3]([NH:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][C:27]=2[OH:30])=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: O=C([O-])O
Agent: Br
Agent: [Na+]
Product: Oc1ccccc1Nc1c(Cl)cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c12
Temperature: 110 °C
Yield: 58 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (2:9 mg, 7.4 μmol) was dissolved in 48% aqueous HBr (1 ml) and heated at 110° C. for 3 h. whereupon the mixture was neutralized with saturated aqueous NaHCO3 and extracted with EtOAc (5 ml). The organic phase was washed with brine, dried (MgSO4) and evaporated to give a white powder (2.0 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][C:21]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].C[N:34](C)C=O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:20]=[C:21]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[N:34]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc2ccccc2c1
Product: Oc1ccccc1-c1cc(-c2ccc(F)c(F)c2)cc(-c2ccc3ccccc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (1.0 g), and ACOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-[4-(3,4-difluoro-phenyl)-6-naphthalen-2-yl-pyridin-2-yl]-phenol; mp 165-167° C.; 1H NMR (DMSO-d6) d 6.99 (m, 2 H), 7.38 (m, 1 H), 7.65 (m, 4 H), 8.06 (m, 4 H), 8.24 (d, J=6.8 Hz, 1 H), 8.42 (m, 2 H), 8.49 (d, J=1.2 Hz, 1 H), 8.74 (s, 1 H), 14.35 (s, 1 H); IR (KBr) 1602 cm−1; MS [M+H]+m/z =410. Anal. calcd for C27H17F2NO: C, 79.21; H, 4.19; N, 3.42; Found: C, 79.33; H, 4.19; N, 3.22.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1.C([O:26][CH2:27][CH3:28])(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:20])=[C:14]([N:19]4[C:9](=[O:10])[C:8]5[C:28](=[CH:2][CH:3]=[CH:4][CH:5]=5)[C:27]4=[O:26])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:22])[CH3:21])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(F)cc1)C(C)(C)O2
Product: Cc1c(C)c(N2C(=O)c3ccccc3C2=O)c(C)c2c1OC(C)(C)C2c1ccc(F)cc1
Yield: 72 %

Procedure:
By using 3-(4-fluorophenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine, the title compound was synthesized according to Reference Example 35a. Yield: 72%. Melting point: 209-211° C. (Ethyl acetate)
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH3:21])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:21][S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 36.2 %

Procedure:
A mixture of methyl thiosalicylate (0.93 g, 5.5 mmol), 2-cyano-6-methylthiopyridine (0.83 g, 5.5 mmol), triethylamine (1.17 ml, 8.3 mmol) and toluene (30 ml) was refluxed for 48 hrs as described in Example 1. The solvent was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the titled compound (0.57 g, 37%) as crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][C:5]=1[OH:22])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][C:5]=1[OH:22]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(O)c(N)c1
Temperature: 25 °C

Procedure:
A mixture of 61.4 g. (0.2 mole) of 2-nitro-4-dodecylphenol and 1 g. of 5% of palladium on carbon slurried in 100 ml of 95% ethanol was placed in a 250 ml hydrogenation bottle. The bottle was stoppered under an atmosphere of 45 psi of hydrogen and shaken at room temperature. The hydrogen was replenished during reaction. After 4 hours the hydrogen uptake was complete. The mixture then was filtered through a sintered glass funnel and the filtrate was stripped of solvent under reduced pressure. The yield of product, 2-amino-4-dodecylphenol, was quantitative. Infrared, nuclear magnetic resonance (nmr) and gas liquid chromatography (glc) analyses confirmed its structure and purity.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][C:3]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Cl.[CH3:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH2:39][NH2:40])=[N:37][CH:38]=1)(=[O:32])=[O:31].O>C(#N)C>[CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([NH:40][CH2:39][C:36]2[CH:35]=[CH:34][C:33]([S:30]([CH3:29])(=[O:32])=[O:31])=[CH:38][N:37]=2)=[O:21])=[CH:4][C:3]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)c1ccc(CN)nc1
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCc2ccc(S(C)(=O)=O)cn2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 96 %

Procedure:
6-Methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (52.0 kg, 1 mol eq, limiting reagent) and acetonitrile (208 L, 4 rel vol,) were charged. The reaction mixture was heated to 50° C. 1,1′-s carbonyldiimidazole as a solution in acetonitrile (208 L, 4 rel vol) is charged to the reaction until the reaction is complete as judged by HPLC. C-(5-(Methanesulfonyl)pyridine-2-yl)methylamine monohydrochloride (33.8 kg, 1.1 mol eq) was charged and the reaction maintained at 50° C. until the reaction was deemed complete as judged by HPLC. Water (780 L, 15 rel vol) was charged. The reaction mixture was stirred, cooled and further stirred. The solid was collected by filtration and washed twice with water (2×104 L, 2×2 rel vol) and dried to constant weight to yield the title compound (96.0 kg, 176.0 mol, 96%); 1H NMR (d6-DMSO): δ 1.83 (s, 3H); 3.29 (s, 3H); 3.72 (s, 3H); 4.73 (d, 2H, J 5.8 Hz); 6.33 (d, 1H, J=1.9 Hz); 7.53 (d, 1H, J=1.9 Hz); 7.57 (d, 1H, J 8.3 Hz); 7.81-7.88 (m, 2H); 7.92-7.94 (m, 1H); 8.03 (s, 1H); 8.21 (s, 1H); 8.27 (dd, 1H, J 2.3, 7.9 Hz); 8.99 (d, 1H, J=2.3 Hz); 10.06 (t, 1H, J 6.0 Hz); LCMS: m/z 546.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([CH:11]=O)[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:21]O.C(OC(=O)C)(=O)C>C(O)(=O)C>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[C:7]([C:11]#[N:21])[C:6]=2[C:5]([F:13])=[C:4]([F:14])[CH:3]=1
Reactant: NO
Reactant: O=Cc1coc2c(Br)cc(F)c(F)c12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: N#Cc1coc2c(Br)cc(F)c(F)c12
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
The compound (360 mg, 1.38 mmol) obtained in Step 3 was dissolved in acetic acid (5 mL), and sodium acetate (450 mg, 5.5 mmol) and hydroxylamine hydrochloride (140 mg, 2.1 mmol) were added thereto, and stirred at 60° C. for 2 hours. After that, acetic anhydride (0.26 mL, 2.75 mmol) was added thereto, and stirred at 100° C. for 2 hours. After cooling, the solvent was distilled away, and the resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.