Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[C:6]([NH2:21])[CH:5]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+].Cl>C1COCC1.CO>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](/[CH:11]=[CH:10]/[C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:22])=[CH:5][C:6]=2[NH:21][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:13]1
Reactant: COC(=O)c1ccc(C=Cc2n[nH]c3ccccc23)c(N)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2ccccc2)c1
Reaction time: 4 h
Yield: 91.3 %

Procedure:
A solution of 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid methyl ester (0.30 g, 1.0 mmol) obtained in Step 1 of Example 217 and triethylamine (0.43 ml, 3.1 mmol) in THF (10 mL) was added with benzoyl chloride (0.13 mL, 1.1 mmol) followed by stirring for 4 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and concentrated under reduced pressure to obtain crude product. Further, the product was dissolved in methanol (20 mL) and the solution was added with 2 mol/L aqueous sodium hydroxide solution (5.0 mL), followed by stirring at 60° C. for 1 hour. The reaction mixture was acidified by hydrochloric acid (6 mol/L) and the precipitated crystal was collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl)vinyl]-3-(benzoylamino)benzoic acid (0.35 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1>COC(OC)N(C)C.CN(C)C=O>[N:11]12[CH2:12][CH2:13][CH:14]([CH2:15][CH2:16]1)[CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:17]=[C:18]([Cl:19])[C:2]([N:1]=[CH:10][N:11]([CH3:16])[CH3:12])=[CH:3][C:4]=1[O:20][CH3:21])[CH2:10]2
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: COc1cc(N=CN(C)C)c(Cl)cc1C(=O)NC1CN2CCC1CC2
Yield: 121.4 %

Procedure:
A solution of 4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-methoxybenzamide (4.03 g, 13 mmol) in dimethylformamide dimethyl acetal (15 mL) and anhydrous dimethylformamide (5 mL) was heated to 100° C. for 4 hours, then concentrated in vacuo. The residue was dissolved in 6:1 tetrahydrofuran/methanol and filtered through a short column of alumina (eluted with 6:1 tetrahydrofuran/methanol). The filtrate was concentrated in vacuo to a purple residue, which was triturated from cold ether and recrystallized (2 crops) from acetonitrile to afford 2.88 g (61%) of fine colorless needles; mp 178.5°-179.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(-c3ccsc3)n2Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3ccsc3)n2Cc2ccccc2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
1-Benzyl-5-chloro-2-(3-thienyl)-1H-pyrrolo[3,2-b]pyridine (44 mg, 0.14 mmol, from Step 1), di-tert-butyl hydrazine-1,2-dicarboxylate (47 mg, 0.20 mmol) and Cs2CO3 (66 mg, 0.20 mmol) were combined in toluene (4.7 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (11 mg, 0.014 mmol) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The reaction was stirred at 120° C. overnight. The mixture was then diluted with DCM, filtered, and concentrated. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded intermediate di-tert-butyl 1-[1-benzyl-2-(3-thienyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]hydrazine-1,2-dicarboxylate (30.4 mg). This intermediate was dissolved in AcOH (2.2 mL) and heated in the microwave at a temperature of 180° C. for 7 minutes. AcOH was removed in vacuo and the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (12.4 mg, 26%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].N1C=CC=CC=1.[P:11](Cl)([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12].Cl>ClCCl.C(OCC)C>[CH2:14]([O:13][P:11](=[O:12])([O:16][CH2:17][CH3:18])[O:4][CH2:3][CH2:2][Br:1])[CH3:15]
Reactant: OCCBr
Reactant: CCOP(=O)(Cl)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOP(=O)(OCC)OCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 93 %

Procedure:
A solution of 2-bromo ethanol (1.42 mL, 20 mmol) and dry pyridine (3.23 mL, 40 mmol) in dry dichloromethane (25 mL) was cooled to 0° C. Diethyl chlorophosphate (3.36 mL, 23 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 24 h. Diethyl ether (40 mL) and 1 N HCl (40 mL) were added and the organic layer was separated and washed consecutively with 1 N HCl and saturated NaHCO3 and dried over MgSO4. After evaporation of the solvents the residue was purified by column chromatography (silica gel, ethyl acetate/pentane 1:1) to give the product (4.85 g, 18.6 mmol, 93%) as light yellowish oil. 1H NMR (CDCl3, 400 MHz) δ=1.34 (dt, 6H, 2×CH3, 3J(H,H)=7.2 Hz, 4J(H,P)=1.2 Hz); 3.52 (t, 2H, CH2Br, 3J=6 Hz); 4.13 (dq, 4H, 2×CH2CH3, 3J(H,H)=7.2 Hz, 3J(H,P)=7.2 Hz); 4.28 (dt, 4H, 2×OCH2CH2Br, 3J(H,H)=6.4 Hz, 3J(H,P)=8.4 Hz). 13C NMR (CDCl3, 100.5 MHz) δ=16.0 (d, 2×CH3, 3J=6.8 Hz); 29.4 (d, CH2Br, 2J=7.6 Hz); 64.0 (d, OCH2, 2J=5.3 Hz); 66.5 (d, OCH2, 2J=5.3 Hz).
Reaction SMILES: [N+]([O-])(O)=O.N([O-])=O.[Na+].[OH:9][CH2:10][C:11]1[N:15]([CH2:16][CH3:17])[C:14](S)=[N:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:16]([N:15]1[CH:14]=[N:13][N:12]=[C:11]1[CH2:10][OH:9])[CH3:17]
Reactant: CCn1c(S)nnc1CO
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: CCn1cnnc1CO
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a mixture of 90% nitric acid (15 ml) and water (22 ml) was added sodium nitrite (0.06 g) and then 3-hydroxymethyl-5-mercapto-4-ethyl-4H-1,2,4-triazole (7.5 g) was slowly added for 0.5 hours at 45° C. After allowing the mixture to be cooled to room temperature, sodium carbonate was slowly added thereto to adjust pH to 7 at 0° C. The reaction mixture was concentrated under reduced pressure, methanol was added to the residue, and the precipitates were removed by filtration. The mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 2:1), to give 4-ethyl-3-hydroxymethyl-4H-1,2,4-triazole (4.60 g) as brown oil.
Reaction SMILES: Br.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[CH2:8][CH2:7]2.[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[C:20]([CH3:29])=[C:21]([S:25]([NH:14][C:12]2[S:13][C:9]3[CH2:8][CH2:7][C:6]4[C:15](=[CH:16][CH:17]=[C:4]([O:3][CH3:2])[CH:5]=4)[C:10]=3[N:11]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc2c(c1)CCc1sc(N)nc1-2
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Agent: Br
Product: COc1ccc2c(c1)CCc1sc(NS(=O)(=O)c3cccc(Cl)c3C)nc1-2

Procedure:
The title compound was prepared from 7-methoxy-4,5-dihydronaphto[1,2-D][1,3]thiazol-2-amine hydrobromide and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (30.7 mg) with purity >90%. MS (pos) m/z 421.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:7]([OH:9])=[O:8])([O-])=O.N#N>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH3:14])[C:7]([OH:9])=[O:8]
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CNc1ccc(C(=O)O)cc1N
Reaction time: 16 h
Yield: 61.9 %

Procedure:
((b) Ethyl alcohol (100 mL) was added to a flask containing 3-nitro-4-methylaminobenzoic acid (2.09 g, 10.7 mmol) and 10% Pd/C (30 mg) under a steady stream of N2. The mixture was stirred under hydrogen for 16 hours, filtered through a milipore 0.22 μm type GV filter disc and concentrated on a rotary evaporator. The residue was dried under vaccum to provide 3-amino-4-methylaminobenzoic acid (1.1 g, 61% yield).
Reaction SMILES: CS([Br:5])(=O)=O.[CH3:6][O:7][C:8](=[O:35])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33]O)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1.C(N(CC)CC)C>ClCCl>[CH3:6][O:7][C:8](=[O:35])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][Br:5])[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CO)ccc21
Reactant: CS(=O)(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylsulfonyl bromide (0.96 mL) is added to a solution of {(S)-6-[(R)-4-hydroxymethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (2.00 g) and triethylamine (1.98 mL) in dichloromethane (20 mL) chilled in an ice bath. The cooling bath is removed, and the solution is stirred at room temperature overnight. More dichloromethane is added, and the resulting solution is washed with aqueous NaHCO3 solution and brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate) to give the title compound. LC (method 2): tR=1.24 min.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=O)[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[N+:5]([C:8]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=c1c2ccccc2[nH]c2c([N+](=O)[O-])cccc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc2c1Nc1ccccc1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
1.361 g (10 mmol) of aluminum chloride was dissolved in 10 ml of dry tetrahydrofuran. To the solution thus obtained was slowly added 75 ml of a solution of 1.201 g (5 mmol) of 4-nitro-9(10H)-acridinone in dry tetrahydrofuran. After stirring at room temperature for 30 minutes, 759 mg (20 mmol) of lithium aluminum hydride was added thereto in portions. After stirring at room temperature for 30 minutes and then at 55° C. for additional 30 minutes, the reaction mixture was cooled to room temperature and 5 ml of 1N hydrochloric acid was added thereto. After concentrating, ethyl acetate and water were added to the residue and the formed insoluble matters were filtered off. The organic layer was separated from the filtrate and dried over magnesium sulfate. After concentrating, the residue was purified by silica gel column chromatography. Thus 148 mg of the title compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:21][C:22](=[O:51])[CH2:23][C:24]1([CH2:27][CH2:28][CH:29](/[CH:42]=[CH:43]/[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[OH:50])[CH2:30][CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:26][CH2:25]1)[CH3:20]>C(#N)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2/[CH:43]=[CH:42]/[CH:29]([CH2:28][CH2:27][C:24]2([CH2:23][C:22]([O:21][CH2:19][CH3:20])=[O:51])[CH2:25][CH2:26]2)[CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:40][CH:41]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1(CCC(/C=C/c2ccccc2O)CCc2ccc(C(=O)OC)cc2)CC1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC1(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C(=O)OC)cc2)CC1

Procedure:
134.6 mg (0.59 mmol) of 4-(tert-butyl)benzyl bromide and 163.8 mg (1.18 mmol) of anhydrous potassium carbonate are added to a solution of 178 mg (0.395 mmol) of methyl 4-[(4E)-3-{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}-5-(2-hydroxyphenyl)pent-4-en-1-yl]benzoate in 5 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The crude product obtained is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). This gives 130.6 mg (55% of theory) of a solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][NH:25][CH2:26][CH3:27])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15].C(N(C(C)C)CC)(C)C.[F:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=1[C:40](Cl)=[O:41]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:24][N:25]([C:40]([C:39]1[C:38]([F:37])=[CH:46][CH:45]=[CH:44][C:43]=1[F:47])=[O:41])[CH2:26][CH3:27])([OH:23])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: CCNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 5-amino-N-{2-[(ethylamino)methyl]-3,3,3-trifluoro-2-hydroxypropyl}-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.277 g, 0.712 mmol) in dry dichloromethane (ca. 11 ml), diisopropylethylamine (0.245 ml, 1.42 mmol) was added and then cooled in a freezer to −10 to −15° C. before a similarly cooled solution of 2,6-difluorobenzoyl chloride (0.123 g, 0.712 mmol) in dichloromethane (2 ml) was added with stirring. The mixture was stirred for 1 minute and then allowed to stand in the fridge for approx. 2 hours and then allowed to warm to room temperature. The next day the mixture was evaporated under reduced pressure and purified on a column of silica. Elution with 2% ethanol in chloroform gave, upon evaporation under reduced pressure, a clear glass (0.421 g) which, upon scraping, gave the title compound (0.356 g) as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([C:9]1([C:41]([O:43]CC)=[O:42])[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23](/[C:36](/[CH3:40])=[N:37]/[O:38][CH3:39])[C:24]4[S:28][C:27]([NH:29][C:30](=[O:34])[NH:31][CH2:32][CH3:33])=[N:26][C:25]=4[CH:35]=3)=[CH:17][N:16]=2)[CH2:11][CH2:10]1)[CH3:8]>CS(C)=O>[CH2:7]([C:9]1([C:41]([OH:43])=[O:42])[CH2:14][CH2:13][N:12]([C:15]2[N:16]=[CH:17][C:18]([C:21]3[CH:22]=[C:23](/[C:36](/[CH3:40])=[N:37]/[O:38][CH3:39])[C:24]4[S:28][C:27]([NH:29][C:30](=[O:34])[NH:31][CH2:32][CH3:33])=[N:26][C:25]=4[CH:35]=3)=[CH:19][N:20]=2)[CH2:11][CH2:10]1)[CH3:8]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(/C(C)=N/OC)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(/C(C)=N/OC)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
Potassium tertiary butoxide (71 mg, 0.63 mmol) was added to a solution of ethyl 4-ethyl-1-[5-[2-(ethylcarbamoylamino)-7-[(E)-N-methoxy-C-methyl-carbonimidoyl]-1,3-benzothiazol-5-yl]pyrimidin-2-yl]piperidine-4-carboxylate (87 mg, 0.16 mmol) in DMSO (1.5 mL). The mixture was stirred at rt for 2 h after which time LCMS indicated clean conversion to the acid. The mixture was filtered through cotton wool to remove solid particulates and purified by preparative HPLC to give Compound 116 as a white solid, 27 mg, 25% yield. 1H NMR (DMSO-d6): δ 12.49 (1H, s), 10.66 (1H, s), 8.85 (2H, s), 7.95 (1H, d, J=1.58 Hz), 7.76 (1H, d, J=1.64 Hz), 6.94 (1H, t, J=5.58 Hz), 4.49 (2H, dt, J=13.57, 3.98 Hz), 4.10 (3H, s), 3.30-3.15 (4H, m), 2.42 (3H, s), 2.10 (2H, dt, J=13.97, 2.91 Hz), 1.57 (2H, q, J=7.49 Hz), 1.38 (2H, ddd, J=13.34, 11.14, 4.02 Hz), 1.14 (3H, t, J=7.17 Hz), 0.85 (3H, t, J=7.43 Hz). MS: 526 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([NH:21][C:22](=[O:31])[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1>C1COCC1.[OH-].[Na+]>[Cl:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=1[C:22]([NH:21][CH:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:20])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([OH:32])=[O:2])=[O:31]
Reactant: COC(=O)C(C/C=C/c1ccc(C2(O)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC(C/C=C/c1ccc(C2(O)CCOCC2)cc1)C(=O)O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
To a solution of (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-hydroxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (56 mg) in THF (1.76 ml), 0.1N aqueous sodium hydroxide solution (1.76 ml) was added, and the resulting mixture was stirred at room temperature for 2 hours. After washing the reaction solution with ether, aqueous layer was acidified by adding 1N hydrochloric acid thereto and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(4-hydroxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid (48 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:7]2[C:14]3[CH2:15][CH2:16][CH2:17][C:13]=3[S:12][C:8]2=[N:9][C:10]=1[CH3:11].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH3:11][C:10]1[N:9]=[C:8]2[S:12][C:13]3[CH2:17][CH2:16][CH2:15][C:14]=3[C:7]2=[C:6]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[C:5]=1[CH:4]([CH2:37][CH2:36][CH3:40])[C:3]([O:2][CH3:1])=[O:25]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Yield: 58.6 %

Procedure:
This compound was prepared according to the procedure C from methyl[2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.189 g; 0.538 mmol), LHMDS 1N in THF (0.594 mL; 0.594 mmol), 1-iodopropane (0.080 mL; 0.823 mmol) in DMF (8 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.124 g (59%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12](Cl)Cl.S(Cl)(Cl)=O>CO>[C:1]1([C:7]#[C:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C:7]#[C:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCl
Agent: O=C(O)C#Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)C#Cc1ccccc1
Reaction time: 8 h

Procedure:
Phenylpropiolic acid was synthesized according to the method as described in J. Chem. Soc., Vol. 83, page 1154. To a mixture of 42 g of phenylpropiolic acid and 50 ml of methylene chloride was added 42 ml of thionyl chloride, and the mixture was mildly refluxed by heating on a water bath. After the completion of the generation of gas, the solvent and excessive thionyl chloride were distilled off under reduced pressure. The pale yellow liquid thus obtained was gradually added to 300 ml of methanol under cooling with ice. After being allowing to stand overnight, the solvent was distilled off under a reduced pressure, and the residual liquid was washed with water and dried to obtain 44.5 g of almost pure methyl phenylpropiolate.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:20]=[CH:19][CH:18]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:3]1[C:2]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11](=[O:16])[C:10]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)=[N:9]1
Reactant: COc1cn(-c2cccc(Br)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: COc1cn(-c2cccc(-c3cccnc3)c2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 48.2 %

Procedure:
A solution of 1-(3-bromo-2-fluorophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (177 mg, 0.400 mmol), 3-pyridineboronic acid (54.1 mg, 0.440 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.020 mmol) and Na2CO3 (93 mg, 0.88 mmol) in DME (3.6 mL) and water (0.9 mL) was stirred at 85° C. for 5 h under Ar atmosphere. The mixture was poured into 5% NaHCO3 aqueous solution (20 mL) and extracted with AcOEt (20 mL×3). The combined organic phase was washed with brine (30 mL), dried with MgSO4, and evaporated. The residue was purified by basic silica gel column chromatography (MeOH/AcOEt=0%-10%) and crystallized from AcOEt to give the title compound (84.8 mg, 48% yield) as a colorless solid: mp 147-153° C.; 1H NMR (300 MHz, DMSO-d6): δ ppm 3.78 (3H, s), 7.01 (1H, d, J=1.9 Hz), 7.04-7.17 (1H, m), 7.28-7.51 (6H, m), 7.56 (1H, dd, J=7.7, 5.1 Hz), 7.63-7.75 (1H, m), 7.79 (1H, d, J=1.9 Hz), 8.03 (1H, dd, J=7.9, 1.9 Hz), 8.58-8.68 (2H, m), 8.81 (1H, s). LC-MS (ESI) m/z 440 [M+H]+. Anal. Calcd for C25H18FN5O2: C, 68.33; H, 4.13; N, 15.94. Found: C, 68:04; H,