Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14]Cl.O>CN(C=O)C>[CH3:11][N:12]([CH3:16])[CH2:13][CH2:14][O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: OCc1ccco1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOCc1ccco1
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
Furfuryl alcohol (10.0 g, 102 mmol) was dissolved in DMF (200 ml) and sodium hydride (60% dispersion in oil, 9.00 g, 225 mmol) was added under ice-cooling. The mixture was stirred for 15 min at the same temperature. Then, 2-dimethylaminoethyl chloride hydrochloride (15.4 g, 107 mmol) was added under ice-cooling and the mixture was stirred at the same temperature for 30 min and at room temperature for 3.5 hr. Water (200 ml) was added to the reaction mixture under ice-cooling and the mixture was extracted with diethyl ether (2×500 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by silica gel column chromatography (20:1 chloroform-methanol) to give the title compound (4.19 g, 24%) as a red-brown liquid.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][O:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]>CO.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])([CH2:18][CH2:19]3)[CH2:16][O:15]4)[NH:6][C:5]=2[C:4](=[O:27])[N:3]1[CH2:28][CH2:29][CH3:30]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C=CC(=O)O)(CC3)CO4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)O)(CC3)CO4)nc2n(CCC)c1=O
Reaction time: 0.5 h

Procedure:
3-[1-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-2-oxa-bicyclo[2.2.2]oct-4-yl]-acrylic acid was dissolved in 50 ml of MeOH. 10% Pd on C (10 mg) was added and the reaction mixture was hydrogenated at RT under 55 psi of H2 for 30 min. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford the title compound. MS (ES+) 419.
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH3:11])[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[N:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[CH3:11][N:10]1[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:1]=[O:13]
Reactant: O=[Se]=O
Reactant: Cc1nc2ccncc2n1C
Solvent: C1COCCO1
Product: Cn1c(C=O)nc2ccncc21
Yield: 52.2 %

Procedure:
Employing the procedure of Example 10B and starting with 774 mg of 2,3-dimethyl-3H-imidazo[4,5-c]pyridine (Preparation J2) and 584 mg of selenium dioxide in 30 ml of dioxane, there was obtained 442 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:25]([F:26])=[C:24]([Cl:27])[CH:23]=[C:22](F)[C:3]=1[C:4]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:25]([F:26])=[C:24]([Cl:27])[CH:23]=[C:22]2[C:3]=1[C:4](=[O:5])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][N:13]2[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)c1c(F)cc(Cl)c(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2cc(Cl)c(F)c(Cl)c2c1=O
Temperature: 0 °C
Yield: 92.8 %

Procedure:
43.6 g of ethyl 2-(2,4-dichloro-3,6-difluorobenzoyl)-3-(2,4-difluorophenylamino)-acrylate are heated in 260 ml of dimethylformamide at 150° C. with 15.2 g of potassium carbonate for 2.5 hours. The mixture is poured into 1 liter of ice-water and the precipitate is filtered off with suction, washed with water and dried. 38.6 g of ethyl 5,7-dichloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate are obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-])=O)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5]>C(O)(=O)C.[Fe]>[Br:18][C:16]1[CH:17]=[C:12]2[C:13](=[CH:14][CH:15]=1)[NH:19][C:3](=[O:2])[C:4]2([CH3:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)C(C)(c1ccccc1)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1(c2ccccc2)C(=O)Nc2ccc(Br)cc21
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(5-Bromo-2-nitro-phenyl)-2-phenyl-propionic acid methyl ester (5.9 g, 16.25 mmol) and iron powder (3.64 g, 65 mmol) in acetic acid (100 mL) is heated to 70° C. and stirred for 3 hours. The acetic acid is removed in vacuo. The residue is diluted with satu. aq. NH4Cl solution and extracted with ethyl acetate (3×100 mL). The combined organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue is recrystallized by ethyl acetate to give the desired product. Yield: 3.5 g (71%)
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[CH3:9])/[CH:4]=[CH:5]/[CH2:6][OH:7])[CH3:2].[O-:10][C:11]#[N:12].[Na+].FC(F)(F)C(O)=O>C1C=CC=CC=1>[C:11](=[O:10])([O:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])[NH2:12]
Reactant: C/C=C(/C=C/CO)CC
Reactant: N#C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC=C(C=CCOC(N)=O)CC
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a mixture of (E,E)-4-ethyl-2,4-hexadien-1-ol (3.0 g), sodium cyanate (3.1 g), and benzene (15 ml) at room temperature was added dropwise trifluoroacetic acid (5.42 g) during 1 hour. After being stirred for 2 hours at the same temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer separated was washed with aqueous sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (1% methanol-dichloromethane) to give 2.0 g of 4-ethyl-2,4-hexadien-1-yl carbamate.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([NH:13][CH:14]([CH3:16])[CH3:15])[N:7]=1)=O)C.[NH3:17]>CO>[CH:14]([NH:13][C:8]1[N:7]=[C:6]([C:4]([NH2:17])=[O:3])[CH:11]=[C:10]([CH3:12])[N:9]=1)([CH3:16])[CH3:15]
Reactant: N
Reactant: CCOC(=O)c1cc(C)nc(NC(C)C)n1
Solvent: CO
Product: Cc1cc(C(N)=O)nc(NC(C)C)n1

Procedure:
A solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid ethyl ester (1.46 g, 6.54 mmol) in 3M NH3 in MeOH (50 mL) is stirred at 60° C. for 1 day. Volatiles are evaporated to give the crude 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid amide as a pale yellow solid (1.24 g); LC-MS: tR=0.59; [M+H]+=195.0.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]([CH2:21][CH3:22])=[N:19][N:20]=2)=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.Cl>CO>[CH2:21]([C:18]1[O:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[CH:11][CH:12]=2)=[N:20][N:19]=1)[CH3:22]
Reactant: CCc1nnc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2)o1
Agent: Cl
Solvent: CO
Product: CCc1nnc(-c2ccc(CO)cc2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To an ice-cold solution of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-ethyl-1,3,4-oxadiazole (3.0 g, 9.4 mmol) in MeOH (30 mL) was added 1 M HCl (20 mL, 20 mmol) dropwise. The reaction was stirred over ice for 1 hr then concentrated. The residue was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to give (4-(5-ethyl-1,3,4-oxadiazol-2-yl)phenyl)methanol as an off-white solid (1.92 g, 93% yield).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[CH:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>>[F:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:13][CH:12]=1)[O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:39]2[CH:40]=[CH:41][C:36]([CH:33]([CH3:35])[CH3:34])=[CH:37][CH:38]=2)=[C:24]([CH3:30])[CH:23]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: Cc1cc(OC(CCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)C)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 128 starting from enantiomers of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-4,4,4-trifluoro-butyl]-benzoylamino}-propionic acid methyl ester and 4-isopropyl phenyl boronic acid. Isomer 1 MS: 540.2 [M−H]−, Isomer 2 MS: 540.2 [M−H]−.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[C:7](Cl)=[O:8]>C1(C)C=CC=CC=1>[CH3:5][CH:6]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:7]1=[O:8]
Reactant: Cc1ccccc1CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1cccc2c1CC(C)C2=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
36 g (270 mmol) of AlCl3 were added to 17.7 g (90 mmol) of acid chloride f4 in 50 ml of toluene in the course of 20 minutes, and the mixture was stirred at 80° C. for 4 hours. It was poured onto ice/HCl, extracted with toluene, washed with H2O, NaHCO3 solution and NaCl solution, dried and distilled (109° C./1 mmHg) or chromatographed (n-hexane/ethyl acetate 6:1, rF =0.44).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:23]1(=[O:28])[CH2:27][CH2:26][CH:25]=[CH:24]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:24]2[C:23](=[O:28])[CH2:27][CH2:26][CH:25]=2)=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: O=C1C=CCC1
Reactant: COc1ccc(-c2cnc(Cl)c(C=O)c2)cc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cnc(Cl)c(C(O)C3=CCCC3=O)c2)cc1
Yield: 90 %

Procedure:
The clear solution of 2-Chloro-5-(4-methoxyphenyl)-nicotinaldehyde (10 mmol, 2.45 g) and imidazole (10 mmol) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol. 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 90% yield (2.97 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Yield: 47 %

Procedure:
To a 3 ml of methylene chloride solution of 772 mg of N-tert-butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol synthesized in Step A, a 3 ml of trifluoroacetic acid was dropwise added under ice cooling. The resultant mixture was stirred at room temperature for 2-hours, then adjusted by 10% aqueous sodium hydroxide solution to pH=9 to 10 and extracted with ether. The extract was dried, filtered, then concentrated under reduced pressure to give a residue, which was then recrystallized from ether/methylene chloride to give 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine in an amount of 250 mg (yield 47%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH3:17])[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O>[CH3:17][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ccccc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1
Yield: 77.1 %

Procedure:
A solution of 2-methyl-biphenyl-4-carboxylic acid methyl ester (0.10 g, 0.44 mmol) in CH3OH (5 mL) and H2O (0.5 mL) is reacted with NaOH (88 mg, 2.2 mmol) at reflux for 2 h. Organic solvent is removed in vacuo, the residue is diluted with H2O, and extracted with Et2O. The aqueous layer is acidified with 5 M HCl, extracted with Et2O, dried with MgSO4, filtered and concentrated to give the title compound as a white solid (72 mg, 77%).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:23]=[CH:22][C:21]2[N:20]3[C:16](=[N:17][N:18]=[C:19]3[CH:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:26][CH2:25]3)[CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[CH:10]=1.C(N(CC)CC)C>ClCCl>[Cl:8][C:9]1[CH:23]=[CH:22][C:21]2[N:20]3[C:16](=[N:17][N:18]=[C:19]3[CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH2:28][CH2:29]3)[CH2:15][N:14]([C:5](=[O:7])[CH3:6])[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)CCNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Acetic anhydride (35 □l, 0.37 mmol) was added to a solution of the amine of example 22 (120 mg, 0.30 mmol) and triethylamine in dichloromethane (5 ml) and stirred at room temperature for 2 hours. The dichloromethane was evaporated off under reduced pressure and the residue was purified by chromatography on silica gel using methanol and ammonium hydroxide in dichloromethane (5:0.5:95) as eluant, to afford the title compound as a white solid (120 mg).
Reaction SMILES: Br[CH:2]([CH:13]([CH3:16])[CH2:14]Br)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[NH2:17][CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:6]([O:5][C:3]([C@H:2]1[C@@H:13]([CH3:16])[CH2:14][N:17]1[CH:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(CBr)C(Br)C(=O)OCc1ccccc1
Solvent: CC#N
Product: C[C@H]1CN(C(c2ccccc2)c2ccccc2)[C@H]1C(=O)OCc1ccccc1

Procedure:
A stirred mixture of 23.94 g of 3D, 37.6 g of aminodiphenylmethane and 170 ml of acetonitrile was refluxed for 40 hours. The mixture was cooled, filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in the minimum amount of methylene chloride, the solution was filtered through a short column of silica gel, using a 2:1 v:v mixture of hexane and ether as eluent. The solvents were evaporated. The residue was subjected to high pressure liquid chromatography (HPLC) twice, using an 8:1 v:v mixture of hexane and ether as eluent. The less polar portions thus obtained were combined, the solvents were evaporated and the residue crystallized from methylene chloride/hexane to give N-diphenylmethyl-cis-3-methyl-2-azetidinecarboxylic acid benzyl ester (3E), as a colorless solid, 112°-113.5° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[O:15][C:14](=O)[C:13]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:12]=2[C:11]=1[C:24]1[C:25]([CH3:34])=[C:26]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][CH2:28][CH2:27]2)(C(C)(C)C)(C)C.[CH3:35][NH2:36]>CCO>[OH:8][CH2:9][C:10]1[N:36]([CH3:35])[C:14](=[O:15])[C:13]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:12]=2[C:11]=1[C:24]1[C:25]([CH3:34])=[C:26]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][CH2:28][CH2:27]2
Reactant: Cc1c(-c2c(CO[Si](C)(C)C(C)(C)C)oc(=O)c3sc4c(c23)CCCC4)ccc2c1CCCO2
Reactant: CN
Solvent: CCO
Product: Cc1c(-c2c(CO)n(C)c(=O)c3sc4c(c23)CCCC4)ccc2c1CCCO2
Temperature: 65 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5-methylchroman-6-yl)-5,6,7,8-tetrahydro-1H-benzo[4,5]thieno[2,3-c]pyran-1-one (100 mg, 0.2 mmol) was dissolved in 4N MeNH2 (g)/EtOH (20 mL) and stirred at 65° C. for 3 hrs. After cooling to room temperature, the mixture was concentrated, and 4N HCl/ethyl acetate (20 ml) was added. The mixture was stirred at room temperature for 15 min and concentrated in vacuo. The residue was partitioned between ethyl acetate and sat. aq. NaHCO3 and the organic layer washed with water, dried over Na2SO4 and evaporated to afford the crude title product (60 mg, 75% yield) which was used for the next step directly. LCMS (m/z) ES+=396 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[NH:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24].[C:29]([C:33]1[CH:41]=[CH:40][C:36]([CH:37]=[N:38][OH:39])=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[CH:41]=[CH:40][C:36](/[CH:37]=[N:38]/[O:39][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:28])=[C:5]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([F:24])([F:26])[F:25])[CH:6]=2)=[CH:35][CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Reactant: COC(=O)c1ccc(OCCCBr)cc1NC(=O)c1ccccc1C(F)(F)F
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)c3ccccc3C(F)(F)F)c2)cc1
Yield: 64 %

Procedure:
The title compound (0.117 g, 64%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-(2-trifluoromethyl-benzoylamino)-benzoic acid methyl ester and 4-tert-butyl-benzaldehyde oxime using a procedure similar to step 1 of example 6. mp=121.1-122.0° C.; mass spectrum API-ES, (M−H) m/z 541. 1H NMR (400 MHz, DMSO-d6); δ 13.40 (bs, 1H), 11.90 (bs, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 7.96 (d, 1H), 7.88 (d, 1H), 7.80 (m, 3H), 7.50 (d, 2H), 7.39 (d, 2H), 6.82 (dd, 1H), 4.28 (t, 2H), 4.18 (t, 2H), 2.15 (m, 2H), 1.25 (s, 9H). Elemental analysis: Calcd. for C29H29F3N2O5: C, 62.2; H, 5.39; N, 5.16, Found: C, 63.8; H, 5.26; N, 5.04.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1.P(Br)(Br)[Br:16].N>O>[Br:16][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Clc1ccc(-c2cncc(Cl)n2)cc1
Reactant: BrP(Br)Br
Agent: N
Solvent: O
Product: Clc1ccc(-c2cncc(Br)n2)cc1
Temperature: 25 °C

Procedure:
To a flask containing 2-chloro-6-(4-chlorophenyl)pyrazine (2.35 g, 10.4 mmol), was added phosphorus tribromide (17 mL) and the mixture heated at reflux for 6 h under nitrogen. The reaction mixture was cooled to room temperature prior to pouring carefully into iced water (600 mL) the resulting mixture was adjusted to pH 6–7 using aqueous ammonia and extracted with diethyl ether (2×250 mL). The organic solution was dried (MgSO4) and the solvent removed in vacuo. The reaction had not gone to completion so the residue was treated with added phosphorus tribromide (17 mL) and heated at reflux for a further 5 h under nitrogen. Work up as before afforded the title compound as a pale yellow solid (0.97 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:19][CH2:18]1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:12])[C:9]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:26]=[CH:27][C:28]=3[CH3:29])[CH2:19][CH2:18]2)=[O:11])=[CH:6][CH:7]=1
Reactant: C[C@@H](C(=O)O)c1ccc(F)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Solvent: CO
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)[C@H](C)c2ccc(F)cc2)CC1

Procedure:
Example 169 was prepared from (2R)-2-(4-fluorophenyl)propanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12; [α]D=−9.1° (C=1.65, MeOH): 1H NMR (400 MHz, CDCl3) δ 7.51 (d, 1 H, J=2.0 Hz), 7.37–7.28 (m, 2 H), 7.23–7.14 (m, 2 H), 7.08 (d, 1 H, J=8.0 Hz), 7.05–6.96 (m, 2 H), 6.90–6.82 (m, 1 H), 3.54 (q, 1 H, J=7.2 Hz), 3.43–3.23 (m, 2 H), 2.95 (ABq, 2 H), 2.73–2.59 (m, 1 H), 2.57–2.42 (m, 1 H), 2.42–2.32 (m, 2 H), 2.28 (s, 3 H), 2.07–1.91 (m, 2 H), 1.83–1.57 (m, 6 H), 1.51 (d, 3 H, J=7.2 Hz), 1.23 (d, 6 H, J=6.8 Hz); ESMS m/e: 468.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[Cl:11][CH2:12][C:13](OCC)(OCC)OCC>C(O)C>[Cl:11][CH2:12][C:13]1[S:10][C:3]2[C:2]([N:1]=1)=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2
Reactant: CCOC(CCl)(OCC)OCC
Reactant: COc1ccc(N)c(S)n1
Solvent: CCO
Product: COc1ccc2nc(CCl)sc2n1
Temperature: 90 °C

Procedure:
3-Amino-6-methoxy-2-pyridinethiol (0.8 g, Maybridge Co.) and 2-chloro-1,1,1-triethoxyethane (1.26 g) were combined in ethanol (5 mL) and heated at 90° C. in a sealed tube for 2 hours. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (2:1, dichloromethane:hexanes) to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 4.00 (3H, s), 4.88 (2H, s), 6.88 (1H, d, J=8.7 Hz), 8.10 (1H, d, J=8.7 Hz); MS (DCI/NH3) m/z 215.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOCC>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH2:34][CH2:33][CH2:32][CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: BrCCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CCOC(=O)C(CCCCc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Yield: 73.4 %

Procedure:
To a solution of 2.62 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 40 ml of dry 1,2-dimethoxyethane was added 0.46 g of a 50% sodium hydride (suspension in oil) while ice-cooling, and then 2.05 g of 4-phenylbutyl bromide was added dropwise to the mixture. The mixture was heated under reflux for 19 hours. After cooling, an aqueous ether was added to the reaction mixture and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 2.77 g of 2-(1-naphthylmethyl)-2-(4-phenylbutyl)malonic acid diethyl ester as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH:42]=[CH:41][N:40]=[CH:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(-n3ccnc3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and imidazole according to conditions described in general procedure C. Mp: 175-176° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.60 (m, 6 H), 3.28-3.31 (m, 4 H), 6.96 (d, J=12.4, 1 H), 7.03-7.04 (m, 1 H), 7.10-7.12 (m, 1 H), 7.17 (d, J=8.8 Hz, 1 H), 7.47 (s, 1 H), 7.55-7.67 (m, 5 H), 7.88-7.90 (m, 1 H), 8.03 (d, J=8.4 Hz, 1 H), 8.18-8.19 (m, 1 H), 8.73-8.75 (m, 1 H), 10.49 (s, 1H).