Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]4[C:28]([F:29])=[C:27]([F:30])[C:26]([F:31])=[C:25]([F:32])[C:24]=4[F:33])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:34])=[C:4]([O:35][CH3:36])[CH:3]=1.[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[C:42]([F:44])[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:37][C:38]1[CH:39]=[C:40]([C:2]2[CH:3]=[C:4]([O:35][CH3:36])[C:5]([N:9]3[C:18]4[C:13](=[CH:14][C:15]([S:19]([O:22][C:23]5[C:24]([F:33])=[C:25]([F:32])[C:26]([F:31])=[C:27]([F:30])[C:28]=5[F:29])(=[O:21])=[O:20])=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]3=[O:34])=[CH:6][C:7]=2[F:8])[CH:41]=[C:42]([F:44])[CH:43]=1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: OB(O)c1cc(F)cc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1cc(-c2cc(F)cc(Cl)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Temperature: 50 °C
Yield: 68 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate, (3-chloro-5-fluorophenyl)boronic acid (1.310 g, 7.52 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.307 g, 0.376 mmol), and potassium carbonate (2.60 g, 18.79 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (14.09 ml) and water (4.70 ml) were added. A reflux condenser was attached, and the flask was heated for 50° C. for 1.5 h. The mixture was cooled, diluted with water, and extracted with EtOAc (3×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (80-g Redi-Sep Gold column, 25-g silica gel loading column, 0-50% EtOAc/Heptane). Several mixed fractions were discarded, and the resulting fractions containing product were combined and concentrated to give a tan solid. The solid was concentrated from DCM, then taken up in DCM and filtered. The filtrate was concentrated to give perfluorophenyl 1-(3′-chloro-2,5′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (1.646 g, 2.56 mmol, 68.0% yield) as a tan solid. 1 H NMR (400 MHz, DMSO-d6) □=8.62 (d, J=2.3 Hz, 1 H), 8.28 (d, J=9.6 Hz, 1 H), 8.00 (dd, J=2.3, 9.1 Hz, 1 H), 7.72-7.57 (m, 4H), 7.52 (d, J=6.8 Hz, 1 H), 6.93 (dd, J=9.4, 10.4 Hz, 2 H), 3.78 (s, 3 H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[CH:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:8]=1)[CH3:3]>C(Cl)Cl.O=[Mn]=O>[C:2]([C:4]1[N:5]=[CH:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:8]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1cn(C(=O)OC(C)(C)C)cn1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1cn(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
4-(1-Hydroxyethyl)-1-(dimethylethoxycarbonyl)imidazole (8.7 g, 41 mmol) was dissolved in methylene chloride (100 mL) and MnO2 (10.7 g, 123 mmol) was added. The resulting reaction mixture was stirred overnight at ambient temperature. The reaction mixture was filtered, concentrated, and purified with silica column chromatography to afford 4 g of 4-acetyl-1-(dimethylethoxycarbonyl)imidazole and unreacted starting material.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[C:5]([CH3:32])[CH:4]=1)#[N:2].IC.[C:35](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH3:35])=[N:10]2)=[C:5]([CH3:32])[CH:4]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SC)=NC1c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyano-2-methylphenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 21; 100 mg, 0.22 mmol), 1-iodomethane (34.0 mg, 0.24 mmol) and potassium carbonate (34.1 mg, 0.25 mmol) are dissolved in 3 ml acetone and stirred at room temperature overnight. The solvent is removed in vacuo and the crude product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [C:1]([N:5]1[CH:17]=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.I[CH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1>C(OCC)(=O)C.CO.O1CCCC1>[C:1]([N:5]1[C:17]([CH2:33][CH2:34][CH:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:39][CH2:40]2)=[C:16]2[C:7]([C:8](=[O:18])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reactant: CC(C)(C)n1cc2c(n1)c(=O)[nH]c1ccccc12
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CCc2c3c(nn2C(C)(C)C)c(=O)[nH]c2ccccc23)CC1
Temperature: -78 °C
Yield: 6.1 %

Procedure:
To a round-bottomed flask containing 2-tert-butyl-2,5-dihydro-pyrazolo[3,4-c]quinolin-4-one (1.5 g, 6.2 mmol) was added tetrahydrofuran (20 mL) followed by N,N,N′,N′-tetramethylethylenediamine (3.6 g, 31.1 mmol). The reaction was stirred under nitrogen in an ice bath. To this suspension n-butyllithium (2.5 M in hexanes, 7.47 mL, 18.67 mmol) was added dropwise. The reaction mixture was cooled to −78° C. in an acetone-dry ice bath and tert-butyl 4-(2-iodoethyl)piperidine-1-carboxylate (2.3 g, 6.84 mmol) was added to the reaction. The reaction was warmed to ambient temperature over 30 minutes and stirred at that temperature for another 2 hours. Methanol was carefully added to quench the reaction and the solvent was evaporated to afford a dark oil. The oil was taken up in ethyl acetate and the organic layer was washed with aqueous saturated sodium bicarbonate. The organic layer was separated, dried (magnesium sulfate), filtered, and evaporated to afford a dark oil. The product was purified twice by automated flash chromatography (Combiflash Separation System, eluted with a gradient of 0-5% methanol in dichloromethane with 1% ammonium hydroxide) to provide tert-butyl 4-[2-(2-tert-butyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)-ethyl]-piperidine-1-carboxylate as a gray solid (0.17 g), mp 223-225° C.; MS (ESI) m/z 453 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([CH2:15][C:16]([OH:18])=[O:17])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.CO.[N+](=[CH2:23])=[N-]>CCOCC.C(O)(=O)C>[CH3:23][C:10]1[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[C:2]([OH:1])[CH:14]=3)[C:6]=2[CH:7]=[CH:8][C:9]=1[CH2:15][C:16]([OH:18])=[O:17]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc2c(c1)Cc1cc(O)ccc1-2
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: Cc1c(CC(=O)O)ccc2c1Cc1cc(O)ccc1-2
Reaction time: 0.33 h

Procedure:
A solution of 83mg. of 7-hydroxyfluorene-2-acetic acid in 2ml. of methanol and 5ml. of ether is treated with an excess of diazomethane in ether. After 20 min. at room temperature, the mixture is treated with several drops of acetic acid and evaporated. The residue is plate chromatographed on silica gel using chloroform as the developing solvent. The major band (UV) is eluted with ethyl acetate, evaporated, and the residue crystallized from acetone-isopropyl ether to give 36mg. of the title compound, mp 135.5°-136.5°. The analytical sample is prepared by recrystallization from acetone-isopropyl ether, mp 136-137°; λ KBr 5.85μ; τCDCl3 TMS 6.31 (S, 2-CH2CO2CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:11][C:10]1[CH:9]=[C:8]2[C:4]([CH:5]=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Fc1cc2[nH]ccc2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc3cc[nH]c3cc2F)cc1
Temperature: 80 °C
Yield: 21.8 %

Procedure:
A mixture of 5-bromo-6-fluoro-1H-indole (600.0 mg, 2.80 mmol), 4-methoxyphenyl boronic acid (426.0 mg, 2.80 mmol), 2N aqueous potassium carbonate (8.49 mL, 16.98 mmol) in EtOH (8 mL) and toluene (3 mL) were degassed with N2 for 5 minutes, treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (180.0 mg, 0.22 mmol), and degassed for an additional 5 minutes. The reaction mixture was sealed and heated to 80° C. for 16 hours. The reaction was cooled to room temperature and the layers were separated. The organic layer was concentrated in vacuo and the crude material was purified by flash chromatography (25-75% EtOAc/heaptane) to give the title compound (147 mg, 22% yield). MS (ES+) 242.3 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3[N:60]=[C:59]([NH:61][C:62]4[CH:67]=[CH:66][C:65]([NH2:68])=[CH:64][CH:63]=4)[N:58]4[N:69]=[CH:70][CH:71]=[C:57]4[CH:56]=3)=[CH:51][CH:50]=2)=[CH:45][CH:44]=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15](=[O:17])[NH:68][C:65]2[CH:66]=[CH:67][C:62]([NH:61][C:59]3[N:58]4[N:69]=[CH:70][CH:71]=[C:57]4[CH:56]=[C:55]([C:52]4[CH:53]=[CH:54][C:49]([C:46]5[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=5)=[CH:50][CH:51]=4)[N:60]=3)=[CH:63][CH:64]=2)=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Nc2nc(-c3ccc(-c4ccc(F)cc4)cc3)cc3ccnn23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCc1ccc(C(=O)Nc2ccc(Nc3nc(-c4ccc(-c5ccc(F)cc5)cc4)cc4ccnn34)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of 4-(tert-butoxycarbonylamino-ethyl)-benzoic acid (78 mg) and N-hydroxy-benzotriazole (HOBt)(45 mg) in DMF (5 ml) are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)(150 mg) and triethylamine (0.27 ml). The mixture is stirred for 0.5 h at ambient temperature. To this solution is added N-[5-(4′-Fluoro-biphenyl-4-yl)-pyrazolo[1,5-c]pyrimidin-7-yl]-benzene-1,4-diamine (compound B4)(0.1 g). After completion of the reaction the mixture is evaporated at high vacuum and the residue is treated with methanol. The resulting solid is filtered and dried. A yellow solid (0.097 g) is obtained.
Reaction SMILES: CC1C(CN2C=C(C(N=[N+]=[N-])=O)C=N2)=C(C)ON=1.[N:19]([C:22]1[CH:23]=[N:24][N:25]([CH2:27][C:28]2[C:29]([CH3:34])=[N:30][O:31][C:32]=2[CH3:33])[CH:26]=1)=[C:20]=[O:21].Cl.[NH2:36][C:37]([CH3:44])([CH3:43])[C:38](OCC)=[O:39]>C1(C)C=CC=CC=1>[CH3:34][C:29]1[C:28]([CH2:27][N:25]2[CH:26]=[C:22]([N:19]3[C:38](=[O:39])[C:37]([CH3:44])([CH3:43])[NH:36][C:20]3=[O:21])[CH:23]=[N:24]2)=[C:32]([CH3:33])[O:31][N:30]=1
Reactant: Cc1noc(C)c1Cn1cc(N=C=O)cn1
Reactant: CCOC(=O)C(C)(C)N
Agent: Cc1noc(C)c1Cn1cc(C(=O)N=[N+]=[N-])cn1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide (Example 10-1a) (10 g, 41.0 mmol) is stirred under nitrogen in dry toluene (150 mL) along with molecular sieves at reflux until no emission of nitrogen was observed, which indicates complete conversion of 1-((3, 5-dimethylisoxazol-4-yl)methyl)-1H-pyrazole-4-carbonyl azide into 4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole. The solution was cooled down to 50° C. and ethyl 2-amino-2-methylpropanoate hydrochloride (5.30 g, 41.0 mmol) was added in one portion. Stirring continued for 3 hours at 50° C. followed by reflux for 12 hours. The mixture was filtered over a pad of celite. The filtrate was concentrated on the rotovap and the residue was purified over silica gel using 25% ethyl acetate in hexanes. Yield 65% (8.00 g), white solid. 1H NMR (DMSO-d6, 400 MHz): . s, 6H), 2.15 (s, 3H), 2.41 (s, 3H), 5.18 (s, 2H), 7.78 (d, J=0.4 Hz, 1H), 8.16 (d, J=0.4 Hz, 1H), 8.59 (br s, 1H). MS 304 (MH+). This compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 2.27 μM.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:27][C@@H:28]1[CH2:33][C@@H:32]2[CH2:34][C@@H:30]([C:31]2([CH3:36])[CH3:35])[C@H:29]1[CH3:37].C(OCC)(=O)C>Cl.O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:27][C@@H:28]1[CH2:33][C@@H:32]2[CH2:34][C@@H:30]([C:31]2([CH3:36])[CH3:35])[C@H:29]1[CH3:37]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c1Br)C2(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCC3CCNCC3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl 4-[({[5-bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]piperidine-1-carboxylate (34.4 mg, 0.06 mmol) was dissolved in 4 M hydrogen chloride/1,4-dioxane (1 mL) and stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=50/1) to give the desired product.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:28][C:29]1[C:30]([F:43])=[C:31]([C:37](=O)[C:38]([F:41])([F:40])[F:39])[CH:32]=[C:33]([Cl:36])[C:34]=1[F:35]>O1CCCC1.CCCCC.O>[Cl:36][C:33]1[CH:32]=[C:31]([C:37]([C:38]([F:41])([F:40])[F:39])=[CH2:2])[C:30]([F:43])=[C:29]([Cl:28])[C:34]=1[F:35]
Reactant: O=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: C=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To the suspension of methyl triphenylphosphonium iodide (1.92 g) in tetrahydrofuran (12 ml) was added potassium tert-butoxide (0.53 g) slowly at argon atmosphere below 0° C. on ice/water bath. The reaction mixture turned to yellow and was stirred for 0.5 h. To the mixture was added a solution of 1-(3,5-dichloro-2,4-difluorophenyl)-2,2,2-trifluoroethanone (1.15 g) in tetrahydrofuran (3 ml) dropwise on ice/water bath. After addition, the reaction mixture was warmed to room temperature and stirred over night. The reaction mixture was diluted with pentane and water. The organic phase was separated and washed with water and dried over MgSO4. The crude residue was purified on silica-gel column chromatography (eluent: n-hexane) to give 1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.80 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[NH2:16]>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:9])[NH:16][C:15]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CN1CCN(C(=O)Cl)CC1
Solvent: ClCCl
Product: COc1cc(NC(=O)N2CCN(C)CC2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 10 g (0.061 mole) 1-methyl-4-chloroformyl-piperazine in 100 ml dry methylene chloride is added to a solution of 11.2 g (0.061 mole) 3,4,5-trimethoxy-aniline in a 100 ml methylenechloride. After stirring at ambient temperature for 24 hours, the solvent is evaporated off in vacuo; the residue is dissolved in the minimum of ethanol and then the crude hydrochloride precipated by the addition of diethyl ether, and dried.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)\[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[CH3:8][C:7]1[S:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)\[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:36][CH:37]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)sc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.4 %

Procedure:
A mixture of 4-(chloromethyl)-5-methyl-2-phenylthiazol (394 mg), methy E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N,N-dimethyformamide (10 ml) was stirred at room temperature for 72 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was subjected to silica gel chromatography to obtain methy E-4-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy) benzyloxyimino]-4-phenylbutyrate (570 mg, yield 71%) as a colorless oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.
Reaction SMILES: [F-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH2:19][CH2:20]OS(C)(=O)=O)[N:15]=[N:14]1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH3:12])=[CH:6][C:5]=1[N:13]1[C:17](=[O:18])[N:16]([CH:19]=[CH2:20])[N:15]=[N:14]1
Reactant: COc1cc(-n2nnn(CCOS(C)(=O)=O)c2=O)c(Cl)cc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=Cn1nnn(-c2cc(OC)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 39.6 %

Procedure:
A stirred mixture of 0.38 g (0.0066 mole) of potassium fluoride and 0.85 g (0.0022 mole) of 1-(2,4-dichloro-5-methoxyphenyl)-1,4-dihydro-4-[2(methylsulfonyloxy)ethyl]-5H-tetrazol-5-one in 35 mL of N,N-dimethylformamide was heated at 120°-130° C. for 2 hours, then stirred at room temperature for 3 days. The reaction mixture was poured into ice water then extracted with diethyl ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated under reduced pressure to leave a residue. The residue was purified by column chromatography on silica gel, eluting with methylene chloride, then recrystallized from ethyl acetate:heptane to yield 0.25 g of 1-(2,4-dichloro-5-methoxyphenyl)-4-ethenyl-1,4-dihydro-5H-tetrazol-5-one, mp 142°-143° C.
Reaction SMILES: O[C:2]1([CH:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>ClCCl>[C:2]1(=[C:8]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCC2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=C2CCCCC2)c2nc[nH]n2)cc1
Reaction time: 2 h
Yield: 21.4 %

Procedure:
7.24 g of crude 4-[1-hydroxycyclohex-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved at 0° in 50 ml of dichloromethane and stirred for 1 hour at 0° with 22.7 ml of thionyl chloride. Then the mixture is concentrated to dryness under vacuum, dissolved in 50 ml of dichloromethane, stirred with 30 ml of triethylamine for 2 hours, diluted with water, extracted four times with ethyl acetate, washed with sodium chloride solution, dried over sodium sulfate, concentrated to dryness under vacuum, and chromatographed on silica gel with hexane/ethyl acetate, yielding 1.45 g of 4-[1-cyclohexylidene-1-(1,2,4-triazolyl)methyl]benzonitrile as a free base, mp 92-93°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)[CH3:16].COC1C=CC(C(Cl)=O)=CC=1.FC1C=C(F)C=CC=1C1C=CC=CC=1C(N)C.C(N(CC)CC)C>CCCCCC.COC(C)(C)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3[C:10]([CH:15]([CH3:16])[N:17]([C:18]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)=[O:27])[C:2]=2[CH:7]=1)=[CH:11][CH:12]=[CH:13][CH:14]=3
Reactant: COc1ccc(C(=O)NC(C)c2ccccc2-c2ccc(F)cc2F)cc1
Agent: CC(N)c1ccccc1-c1ccc(F)cc1F
Agent: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: COC(C)(C)C
Product: CC1c2ccccc2-c2ccc(F)cc2N1C(=O)c1ccc(O)cc1

Procedure:
N-[1-(2′,4′-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzamide—The title compound was prepared from 4-methoxybenzoyl chloride (731 mg, 4.28 mmol), 1-(-2′,4′-difluoro-biphenyl-2-yl)-ethylamine (1 g, 4.28 mmol), and triethylamine (717 uL, 5.1 mmol) according to the procedure and in the same manner as described in Example 33, step c. The product was isolated from a Biotage® (40 Mi) column for flash column chromatography (5-30% methyl tert-butylether in hexane) resulting in the isolation of a white solid, 1.53 g (97%). mp 134.5-135° C.; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=5.43 Hz, 3 H) 3.80 (s, 3 H) 4.96 (m, J=5.95 Hz, 1 H) 6.97 (d, J=9.05 Hz, 2 H) 7.18 (m, 2 H) 7.36 (m, 3 H) 7.64 (d, J=4.14 Hz, 2 H) 7.83 (d, J=7.50 Hz, 2 H) 8.66 (s, 1 H); MS (ESI) m/z 368 ([M+H]+); Anal. calcd for C22H19F2NO2: C:71.92 H:5.21 N:3.81 Found: C:72.11 H:5.23 N:3.77
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][O:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:15]3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][N:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([CH2:21][O:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)[CH2:15]3)[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CCCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(OCC2CCCCN(CC3(c4ccc(Cl)cc4)CCC3)C2)cc1
Yield: 39.8 %

Procedure:
To a stirring 0° C. solution of [1-(4-Chloro-phenyl)-cyclobutyl]-[3-(4-trifluoromethyl-phenoxymethyl)-azepan-1-yl]-methanone (0.13 g, 0.28 mmol) under N2 in toluene (2.8 mL, 0.1M) was added sodium bis(2-methoxyethoxy)aluminum hydride (65+weight % in toluene) (0.30 mL, 0.98 mmol) dropwise with stirring. When the reaction was complete by HPLC, the reaction was quenched with H2O. 10% NaOH and ethyl acetate were added, and the organic was removed, dried with Na2SO4, and concentrated. The crude reaction mixture was purified by silica gel chromatography (90:8:2 Hexanes: methylene chloride: 2N NH3 in ethyl alcohol). A 40% yield (0.0504 g) of pure material was obtained as well as other impure fractions. 1H NMR (CDCl3, 300 MHz) 7.54 (2H, d, J=8.9 Hz), 7.22 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.3 Hz), 6.87 (2H, d, J=8.8 Hz), 3.62-3.45 (2H, m), 2.89 (1H, d, J=13.7 Hz), 2.80 (1H, d, J=13.7 Hz), 2.60 (1H, td, J=13.3, 3.7 Hz), 2.55-2.36 (3H, m), 2.30-2.10 (4H, m), 2.08-1.90 (2H, m), 1.90-1.25 (7H, m) ppm. 13C NMR (CDCl3, 75 MHz) 161.75, 148.53, 130.96, 128.00, 127.91, 127.03, 126.98, 122.98, 114.61, 71.38, 70.53, 60.37, 58.87, 48.07, 39.52, 31.84, 31.64, 30.23, 29.50, 24.97, 16.24 ppm. LRMS: 451.53.