Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O.Cl.[NH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[SH:29].[Cl:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[C:33]([Cl:40])[C:32]=1[CH2:41][C:42](O)=O>>[Cl:28][C:26]1[CH:25]=[CH:24][C:23]2[S:29][C:42]([CH2:41][C:32]3[C:33]([Cl:40])=[CH:34][C:35]([N+:37]([O-:39])=[O:38])=[CH:36][C:31]=3[Cl:30])=[N:21][C:22]=2[CH:27]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=C(O)Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=[N+]([O-])c1cc(Cl)c(Cc2nc3cc(Cl)ccc3s2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
By a modification of the procedure of D. L. Boger (J. Org. Chem. 43, 2296–2297 (1978) a solution of P2O5/MeSO3H (Aldrich, 7.5 g, 1:10, w:w) was treated with 2-amino-4-chloro-benzenethiol hydrochloride (example 112, 1.96 g, 10.0 mmol) and (2,6-dichloro-4-nitro-phenyl)-acetic acid (example 110, 2.50 g, 10.0 mmol). The resulting mixture was stirred at room temperature for 1 hour, then heated at 90° C. overnight (15 hours). After cooled to room temperature, the reaction mixture was poured to ice and the resulting mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (CH2C12) to yield 3.7 g (99%) of compound 114 as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][CH3:35])=[CH:6]2.[OH-].[Na+]>C1COCC1.CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:7]([CH2:33][CH2:34][CH3:35])=[CH:6]2
Reactant: CCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)OCC)cc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCc1cc2cc(OC)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 89.7 %

Procedure:
Ethyl ester (99) (0.70 g, 1.50 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.59 g (90%) of the title compound (100) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.81 (t, J=7.3 Hz, 3H), 1.45-1.55 (m, 2H), 2.53 (t, J=7.7 Hz, 2H), 3.93 (s, 3H), 6.22 (d, J=16.0 Hz, 1H), 6.57 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.14 (m, 2H), 7.16 (d, J=2.4 Hz, 1H), 7.19-7.30 (m, 5H), 7.57 (s, 1H), 7.62 (d, J=15.9 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H). LCMS (APCI): m/z 439 (M+H)+, m/z 437 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:6][CH2:5][CH2:4][CH2:3]1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12>>[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([C:7]4[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=4)=[CH:16][CH:15]=3)=[O:14])[CH2:22][C:21]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CC1CCCC=C1c1ccc(C(=O)O)cc1
Product: CC1CCCC=C1c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 96.8 %

Procedure:
4-(6-Methyl-cyclohex-1-en-1-yl)-benzoic acid of Step B (0.070 g, 0.324 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.066 g, 0.356 mmol) were reacted in the manner of Example 15, Step D. The title compound was purified by recrystallization from a mixture of diethyl ether and petroleum ether to afford 0.120 g of white crystals, m.p. 108–109° C.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]1([CH2:29][CH2:28][N:5]2[CH2:6][CH2:7][N:2]([C:8]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=4)[N:9]=3)[CH2:3][CH2:4]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCCc1ccccc1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-n2nc(N3CCN(CCc4ccccc4)CC3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A stirred mixture of 4.0 g of 3-(1-piperazinyl)-1-[4-(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.4 g of (2-bromoethyl)benzene, 1.8 g of potassium carbonate and 60 ml of dimethylformamide was heated, under nitrogen, at 70°-75° for 8 hours, and then stirred at ambient temperature for 8 hours. The reaction mixture was poured into water, and the aqueous mixture extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was chromatographed on a Water's Model High Pressure Liquid Chromatograph utilizing silica columns and eluting with hexane/ethyl acetate (30%). Concentration of the appropriate fractions gave 4.3 g of 3-[4-(2-phenylethyl)-1-piperazinyl]-1-[4-(trifluoromethyl)phenyl]-1H-indazole. The free base was dissolved in diethyl ether and treated with hydrogen chloride to precipitate the corresponding hydrochloride salt. Recrystallization from ethanol/diethyl ether gave 3.1 g of 3-[4-(2-phenylethyl)-1-piperazinyl]-1-[ 4-(trifluoromethyl) phenyl]-1H-indazole hydrochloride, mp 255°-257°.
Reaction SMILES: Cl.[C:2]1([NH:8]N)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>CCO>[CH3:11][N:12]1[CH2:17][CH2:16][C:15]2[NH:8][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:14]=2[CH2:13]1
Reactant: NNc1ccccc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCc2[nH]c3ccccc3c2C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Phenyl hydrazine hydrochloride (1 equiv.) and 1-methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) is dissolved in EtOH and stirred at 80-90° C. overnight. The reaction is monitored by TLC. Upon completion, the reaction mixture is cooled to RT and the solvent is evaporated to dryness. The residue is dissolved in EtOAc and washed with a saturated sodium bicarbonate solution. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness to afford 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Yield: 98.4 %

Procedure:
To a 3-necked RBF (round bottomed flask) is added dichloromethane (2.4 L), (S)-4-benzyl-2-oxazolidinone (200 g, 1.13 moles) and N,N-Dimethyl-4-pyridinamine, (13.6 g; 111.32 mmoles). The flask is cooled in an ice water bath and triethylamine (472 mL; 3.39 moles) is added dropwise at 0° C. To the resulting solution is then added dropwise butanoyl chloride (152.2 mL; 1.46 moles) over 3 h, while keeping the temperature below 5° C. The reaction is then filtered and the filtrate is washed with 1M HCl (aq.) (500 ml×1) and saturated NaHCO3 (500 ml×1). The organic phase is dried over Na2SO4, filtered, and concentrated to afford the title compound (275 g, MS:[M+H]+=248.1 m/z).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].S(C1C=CC(C)=CC=1)(O[C@@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].Cl>CCC(C)=O>[CH3:19][C@@H:13]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCC[C@@H](C)Oc1ccccc1F
Reaction time: 14 h
Yield: 74.6 %

Procedure:
A reaction vessel was charged with 10 g of 2-fluorophenol, 25 g of (S)-1-methylhexyl tosylate, 20 g of potassium carbonate and 160 ml of MEK, and the mixture was refluxed with stirring for 14 hours (the disappearance of the starting materials was confirmed by TLC). The reaction liquid was poured into diluted hydrochloric acid and the mixture was extracted with benzene. The extract was washed with water and dried over Glauber's salt, and the solvents were distilled off. The residue was distilled under reduced pressure to obtain 14 g (74.5%) of (R)-2-(1-methylhexyl)oxyfluorobenzene.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:21][CH:22]([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][O:37][C:38](=[O:55])[C:39]1[CH:44]=[CH:43][C:42](B2OC(C)(C)C(C)(C)O2)=[CH:41][C:40]=1[F:54].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:36][O:37][C:38](=[O:55])[C:39]1[CH:44]=[CH:43][C:42]([C:20]([C:11]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)=[CH:21][CH:22]([CH3:24])[CH3:23])=[CH:41][C:40]=1[F:54]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Cc1ccc(S(=O)(=O)OC(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Yield: 83.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl ester (prepared as in Example 99, 3.09 g, 6 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (prepared as in Example 95, 5.88 g, 21 mmol) and dichlorobis(triphenylphosphine)palladium (II) (420 mg, 0.6 mmol) in dioxane (24 mL) was added an aqueous sodium carbonate solution (2 M, 7.5 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (200 mL), washed with a saturated aqueous sodium bicarbonate solution (3×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl]-2-fluoro-benzoic acid methyl ester (2.50 g, 83%) as a white solid: LC/MS m/e calcd for C26H22F2N2O4S [M+H]+ 497.54, observed 496.7.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH:35][C:5]([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4]
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Reactant: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCN(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 54 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-(dimethylamino)ethylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 54%. Melting point: 133-134° C. (hexane-ethyl acetate).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.CCOCC>[CH:21]1([C:4]([CH:6]2[CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH2:10][CH2:11]2)=[O:5])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(C1CCCCC1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of 25.1 g (0.085 mole) of 1-(phenylsulfonyl)-4-piperidinecarboxylic acid ethyl ester in 500 ml of dry tetrahydrofuran cooled to 0° C. and under an atmosphere of nitrogen, was added 95 ml of a 2 molar solution (0.19 mole) of cyclohexylmagnesium bromide in ether. The mixture was stirred for 2 hr at ambient temperature and then was quenched on an icy solution of ammonium chloride. The mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a semisolid material. This was recrystallized from ethanol to give 8.50 g (29.8% yield) of title compound as a white, crystalline solid, mp 141°-143° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].CC([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[CH:31][CH:30]=1)C(=O)[O-])(C)C>>[NH2:24][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[CH2:39][CH2:38][N:37]([C:2]3[N:11]=[C:10]4[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]4[CH:12]4[CH2:14][CH2:13]4)=[CH:4][C:3]=3[F:19])[CH2:36]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)N(Cc1ccc(C2CCNC2)cc1)C(=O)[O-]
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Product: NCc1ccc(C2CCN(c3nc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)cc1

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (0.94 g, 3.3 mmol) and 1,1-dimethylethyl[[4-(3-pyrrolidinyl)phenyl]methyl]carbamate, a procedure analogous to that given in Example 6 provided the title compound (1.30 g) as an off-white solid, mp 268°-272° C.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[CH:3]=1.[N:11]([O-])=[O:12].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=[O:12]
Reactant: O=N[O-]
Reactant: Cn1c(=O)cc(N)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(=O)[nH]c(N)c(N=O)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-amino-3-methylpyrimidine-2,4(1H,3H)-dione (6 g, 42.6 mmol) in acetic acid (50 mL) was added a solution of sodium nitrite (6.8 g, 98.6 mmol) in water (20 mL) dropwise, then the mixture was stirred at room temperature for 1 h. The mixture was filtered, the filter cake was washed with water and ethanol and dried under vacuum to give 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione as violet solid, which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[CH3:25])=[C:4]([CH:12]=[C:13]([F:16])[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[F:1][C:2]1[C:3]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[CH3:25])=[C:4]([C:5]([NH:7][O:8][CH2:9][CH2:10][O:11][C:33](=[O:35])[CH3:34])=[O:6])[CH:12]=[C:13]([F:16])[C:14]=1[F:15]
Reactant: CC(=O)Cl
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCCO)cc(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)OCCONC(=O)c1cc(F)c(F)c(F)c1Nc1ccc(I)cc1C
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 64.4 %

Procedure:
To a 0° C. solution of 3,4,5-trifluoro-N-(2-hydroxy-ethoxy)-2-(4-iodo-2-methyl-phenylamino)-benzamide (0.25 g, 0.536 mmol) in THF (10.72 mL) was added triethylamine (0.113 mL, 0.804 mmol). After 5 min, acetyl chloride (0.039 mL, 0.536 mmol) was added to the cold solution, which immediately produced a precipate. After stirring for 50 min between 0-5° C., the reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined and dried over anhydrous magnesium sulfate. The resultant mixture was filtered and the filter cake was thoroughly rinsed with ethyl acetate. The filtrate was concentrated in vacuo to obtain a yellow oil (0.1755 g). Chromatographed crude oil using a gradient of hexanes and ethyl acetate. Combined fractions and removed the solvent in vacuo to obtain a solid. The solid was recrystalized in a mixture of hexanes/acetone to afford 0.0221 g (8%) of a solid; 1H NMR (400 MHz, Acetone-d6): δ 10.15 (br s, 1H), 8.49 (br s, 1H), 7.88 (t, J=0.9 Hz, 1H),7.56 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 6.69 (dd, J=8.55, 5.86 Hz, 1H), 4.53 (br s, 2H), 4.19 (br s, 2H), 2.33 (s, 3H), 1.81 (br s, 3H). 19F NMR (375 MHz, Acetone-d6): δ −139.52 (br t, 1F), −146.62 (br q, 1F), −153.43 (br s, 1F). Anal. Calcd/Found for C18H16F3IN2O4: C, 42.54/40.87; H, 3.17/2.98; N, 5.51/5.17.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH2:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:28][CH2:29][NH:30][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(CCN)c1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCc3cccc(OC)c3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(3-methoxy-phenyl)-ethyl-amine to afford the title compound. MS: m/e=392 (M+H).
Reaction SMILES: [OH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([NH2:13])=[O:12].[C:14]1([CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:14]1([C:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][NH:13][C:11]([C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[OH:1])=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: NC(=O)c1c(O)sc2ccccc12
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NC=C(c1ccccc1)c1ccccc1)c1c(O)sc2ccccc12
Temperature: 150 °C

Procedure:
A stirred mixture of 2-hydroxybenzo(b)thiophene-3-carboxamide (0.485 g, 0.0025 m), diphenylacetaldehyde (0.51 g, 0.0026 m), p. toluenesulfonic acid hydrate (30 mg), and dried toluene (15 ml) is set in an oil-bath at 100° C., the bath temperature raised to 150° C., and the mixture heated under reflux until thin-layer chromatography of the mixture indicates completeness of reaction. The cooled reaction mixture is concentrated in vacuo and the residue chromatographed on silica gel (v/v 10-50% CH2Cl2 in hexane) to yield N-(2,2-Diphenylethenyl)-2-hydroxybenzo(b)thiophene-3-carboxamide.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([C:28]2[CH:32]=[C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:30][C:29]=2[C:39]([O:41][CH3:42])=[O:40])[C:19]([CH:21]2[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.C=O>CO.CC(O)=O.[Pd]>[CH3:42][O:41][C:39]([C:29]1[S:30][C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[CH:32][C:28]=1[N:18]([C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20])[CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH3:9])[CH2:12][CH2:13]1)=[O:40]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)C1CCC(C)CC1
Agent: [Pd]
Agent: C=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCN(C)CC1)C(=O)C1CCC(C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
4-{[(2-Methoxycarbonyl-5-phenyl-thiophen-3-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (190 mg, 0.32 mmol) was dissolved in MeOH (3.2 mL) and treated with formaldehyde (37% solution, 0.36 mL, 3.2 mmol), AcOH (1 drop) and 10% Pd/C (97 mg) under H2 (30 psi). The reaction was stirred at room temperature for 48 h and the mixture was filtered on celite. The solution was evaporated to a residue that was purified by silica gel column chromatography using CH2Cl2:MeOH as eluent to provide 3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-4-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester as an oil (46.5 mg, 31% yield). 1H NMR (CDCl3, 400 MHz): 7.62 (d, 2H), 7.43 (m, 3H), 7.10 (s, 1H), 3.97 (m, 1H), 3.85 (s, 3H), 3.20 (m, 3H), 2.48 (s, 3H), 2.42 (m, 1H), 2.10 (m, 1H), 1.85 (m, 3H), 1.70-1.40 (m, 8H), 1.30 (m, 2H), 0.78 (d, 3H), 0.68 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([OH:19])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:21][CH2:22][C:23]([CH2:33][CH3:34])([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)(=O)C>[CH2:22]([C:23]([S:29]([CH3:32])(=[O:30])=[O:31])([CH2:33][CH2:34][N:16]1[CH:17]=[CH:18][C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:14][C:15]1=[O:19])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: Oc1cc(-c2ccccc2)ccn1
Reactant: CCOC(=O)C(CC)(CCBr)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(CCn1ccc(-c2ccccc2)cc1=O)S(C)(=O)=O
Temperature: 55 °C
Reaction time: 72 h
Yield: 20 %

Procedure:
Cesium carbonate (0.71 g, 2.2 mmol, 4.0 equiv) was added to a solution of the 4-phenylpyridin-2-ol (0.10 g, 0.58 mmol, 1.05 equiv) and ethyl 4-bromo-2-ethyl-2-(methylsulfonyl)butanoate (0.17 g, 0.55 mmol, 1.0 equiv) in tetrahydrofuran (5 mL). The resulting mixture was heated to 55° C. and allowed to stir for 3 days. The reaction was diluted with ethyl acetate (20 mL), filtered through a pad of Celite, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (4:1-0:1 heptane/ethyl acetate) to provide a light yellow oil (43 mg, 20%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (t, J=7.42 Hz, 3H) 1.33 (t, J=7.13 Hz, 3H) 2.07-2.19 (m, 1H) 2.26-2.36 (m, 1H) 2.44 (ddd, J=14.89, 11.18, 4.98 Hz, 1H) 2.59-2.71 (m, 1H) 3.15 (s, 3H) 4.19-4.37 (m, 4H) 6.45 (dd, J=7.03, 1.56 Hz, 1H) 6.72-6.78 (m, 1H) 7.38-7.48 (m, 4H) 7.53-7.60 (m, 2H).
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2)C.C(=O)(O)[O-:16].[Na+]>Cl>[N:14]1[C:6]([C:5](=[O:16])[CH3:4])=[C:7]2[C:11]([N:10]=[CH:9][NH:8]2)=[N:12][CH:13]=1
Reactant: CCOC=Cc1ncnc2nc[nH]c12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: CC(=O)c1ncnc2nc[nH]c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.04 g of 6-(ethoxyvinyl)purine was dissolved in 80 ml of 1 N hydrochloric acid and stirred at room temperature for 15 hours. After neutralizing with a saturated aqueous solution of sodium bicarbonate, it was extracted with dichloromethane and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 0.70 g of crude title compound was obtained as a colorless oily substance.