Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[N:24][N:23]([CH2:34][CH2:35]O)[C:22](=[O:37])[CH:21]=2)=[CH:16][CH:15]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[K+].[Br-]>N1C=CC=CC=1.O>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[N:24][N:23]([CH2:34][CH2:35][N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[C:22](=[O:37])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(=O)n(CCO)nc2-c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cc(=O)n(CCN3CCN(C)CC3)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of para-toluenesulfonyl chloride (357 mg, 4 eq) in pyridine (0.5 ml), a solution of 5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one (165 mg, 0.47 mmol) in pyridine (1.0 ml) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed successively with water and a brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off, and N-methylpiperazine (0.15 ml, 3 eq) was added to the residue. The resulting mixture was stirred at 90-100° C. for 2 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and ethanol was added to the residue. The resulting mixture was azeotropically boiled three times with ethanol to drive off water. The thus-obtained residue (256 mg) was separated and purified by chromatography on a silica gel column [silica gel: 8 g, chloroform/methanol (20/1)], whereby a yellow oil (165 mg, 81%) was obtained. The oil was left over in a refrigerator. Precipitated crystals were washed with a mixed solvent of methanol and diethyl ether, whereby the title compound (65 mg, 32%) was obtained as pale yellow prisms. Melting point: 109.7-110.8° C. 1H-NMR (CDCl3) δ: 2.29(3H,s), 2.46(4H,brs), 2.64(4H,brs), 2.87(2H,t,J=6.83 Hz), 3.80(3H,s), 3.81(3H,s), 4.40(2H,t,J=6.84 Hz), 6.79(2H,d,J=9.03 Hz), 6.81(2H,d,J=8.78 Hz), 6.87(1H,s), 7.02(2H,d,J=8.79 Hz), 7.12(2H,d,J=9.03 Hz). IR (KBr) cm−1: 1659,1608,1513,1295,1250,1177,1013.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[O:6].[C:12]([OH:17])(=[O:16])[C:13]([CH3:15])=O.O>ClCCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:7][C:13]([C:12]([OH:17])=[O:16])=[CH2:15])=[O:6]
Reactant: COc1ccccc1C(N)=O
Reactant: CC(=O)C(=O)O
Solvent: ClCCCl
Solvent: O
Product: C=C(NC(=O)c1ccccc1OC)C(=O)O
Yield: 8.5 %

Procedure:
A suspension of 2-methoxybenzamide in 1,2-di-chloroethane (24.5 ml/g) is brought to reflux in the presence of 3 equivalents of freshly distilled pyruvic acid in a round-bottomed flask surmounted by a system which makes it possible to remove the water formed during the reaction. When the formation of water has finished 15 (approximately 7 hours), the reaction mixture is left at room temperature. After filtering off the insoluble materials, the filtrate is extracted with an aqueous sodium bicarbonate solution. The combined aqueous phases are extracted with dichloromethane and then acidified with hydrochloric acid. The precipitate formed is filtered off, dried and then taken up in ethyl acetate. After filtering off the insoluble material, the filtrate is concentrated under vacuum, dissolved in dichloromethane and then precipitated with heptane, thus providing pure N-(2-methoxybenzoyl)dehydroalanine. (Nonoptimized yield 8.5%).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[F:12][C:13]([F:17])([F:16])[CH2:14]I>O>[F:12][C:13]([F:17])([F:16])[CH2:14][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: FC(F)(F)CI
Reactant: O=C1Nc2ccccc2C1=O
Solvent: O
Product: O=C1C(=O)N(CC(F)(F)F)c2ccccc21
Temperature: 55 °C

Procedure:
Sodium hydride (8.65 g of a 60% oil dispersion, 0.22 mol) was washed with hexane and suspended in hexamethylphosphoramide (200 mL). Isatin (29.4 g, 0.20 mol)) was added carefully. After the gas evolution subsided, 2,2,2-trifluoroethyl iodide (46.2 g, 0.22 mol) was added and the mixture was heated to 55° C. for 4 hours. The solution was cooled, diluted with water (1 L), and the precipitate was collected. The filtrate was acidified with 6 N HCl and a new precipitate formed and was collected. The combined solids were recrystallized from 95% ethanol. Yield 22.5 g (49%). mp 161-163° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Br[C:15]1[C:16]([NH2:22])=[N:17][CH:18]=[C:19]([Br:21])[N:20]=1.CCN(C(C)C)C(C)C>C(O)C>[Br:21][C:19]1[N:20]=[C:15]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[CH:3][C:2]([Br:1])=[CH:11]3)[C:16]([NH2:22])=[N:17][CH:18]=1
Reactant: NCc1ccc2ncc(Br)cc2c1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1ncc(Br)nc1NCc1ccc2ncc(Br)cc2c1
Temperature: 120 °C

Procedure:
A microwave tube was charged with (3-bromoquinolin-6-yl)methanamine (237 mg, 1.0 mmol), 3,5-dibromopyrazin-2-amine (253 mg, 1.0 mmol), DIPEA (0.6 mL) and 5 mL of ethanol. The tube was heated at 120° C. under microwave irradiation for 15 h. After cooling, the solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with DCM/methanol gradient to afford the title compound. LCMS (method E): [MH]+=406/408/410, tR=5.803 min.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[F:29])[CH:20]=[CH:19][C:18]=2[O:30][CH3:31])[CH2:11][CH2:10]1)C)(C)(C)C.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[F:29][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:23]=1[C:21]1[CH:20]=[CH:19][C:18]([O:30][CH3:31])=[C:17]([CH:22]=1)[CH2:16][N:15]([CH:12]1[CH2:11][CH2:10][CH:9]([NH:7][CH3:6])[CH2:14][CH2:13]1)[C:39]([C:38]1[S:37][C:36]2[C:42]([F:47])=[CH:43][CH:44]=[C:45]([F:46])[C:35]=2[C:34]=1[Cl:33])=[O:40]
Reactant: COc1ccc(-c2ccncc2F)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: CNC1CCC(N(Cc2cc(-c3ccncc3F)ccc2OC)C(=O)c2sc3c(F)ccc(F)c3c2Cl)CC1

Procedure:
Following the synthetic protocol described in Method D′; 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carboxylic acid [5-(3-fluoro-pyridin-4-yl)-2-methoxy-benzyl]-(4-methylamino-cyclohexyl)-amide is prepared starting from {4-[5-(3-Fluoro-pyridin-4-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester and 3-Chloro-4,7-difluoro-benzo[b]thiophene-2-carbonyl chloride. The desired product is isolated in 54%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11](Cl)=[O:12])=[CH:2]1.[CH2:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC#N>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:14])[C:11]([NH:23][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: NCCc1ccccc1
Solvent: CC#N
Product: O=C(NCCc1ccccc1)C(=O)c1c[nH]c2ccccc12

Procedure:
2-(1H-Indol-3-yl)-2-oxo-N-phenethyl-acetamide was synthesized following scheme I above starting from (1H-indol-3-yl)-oxo-acetyl chloride and phenethylamine. Yield (61%). HPLC ret. time 3.17 min, 10-99% CH3CN, 5 min run; 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 8.79 (t, J=5.9 Hz, 1H), 8.67 (s, 1H), 8.23 (m, 1H), 7.53 (m, 1H), 7.33-7.19 (m, 7H), 3.47 (m, 2H), 2.85 (t, J=7.4 Hz, 2H); ESI-MS 293.3 m/z (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.C([Sn](CCCC)(CCCC)[C:18]([O:20][CH2:21][CH3:22])=[CH2:19])CCC>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[CH2:19])[CH:6]=[CH:5]2
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2cc(Br)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2cc(Br)ccc2n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Dichlorobis(triphenylphosphine)-palladium(II) (0.289 g, 0.412 mmol) was added to a solution of 6-bromo-2-chloroquinoline (1.0 g, 4.1 mmol) and tributyl(1-ethoxyvinyl)stannane (1.79 g, 4.95 mmol) in dioxane (8 mL) and the mixture was stirred at 100° C. for 5 h, desired product was identified by LCMS. The crude reaction mixture was concentrated and purified by flash silica gel chromatography (eluted with 1:1 hexanes/DCM) to yield product 6-bromo-2-(1-ethoxyvinyl)quinoline (720 mg) as white solid. LC-MS retention time 4.091 min; m/z 279.84 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29].CO[Na].CO>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:27][C@@H:28]([CH3:29])[C:30]([OH:32])=[O:31])=[O:7])[N:9]=[CH:10]3)=[CH:15][CH:14]=2)=[CH:21][CH:22]=1
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: CO[Na]
Solvent: CO
Product: C[C@H](NC(=O)c1ncc2cc(Oc3ccc(F)cc3)ccc2c1O)C(=O)O
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
A mixture of 7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (154 mg, 0.43 mmol), (S)-alanine (225 mg, 2.5 mmol) and a 0.5 N solution of MeONa in MeOH (5 ml, 2.5 mmol) was heated in a microwave oven with stirring for 20 min at 130° C. before the mixture was concentrated in vacuo. To the residue was added water (15 ml) and the mixture was washed with Et2O (3×30 ml). The purified aq. solution was acidified by the addition of 6 N HCl and extracted with EtOAc (1×30 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (79 mg); MS-(−)-ion M−1=369.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([O:25][CH3:26])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([O:25][CH3:26])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([CH:19]=[CH:20][C:21]=3[CH3:22])[O:23][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(O)c1C
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(OCC(=O)OC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.4 %

Procedure:
To a solution of 3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (115 mg, 0.31 mmol, 1.0 eq) in acetone (4 mL) was added Cs2CO3 (154 mg, 0.47 mmol, 1.5 eq). The reaction mixture was stirred for 30 min at room temperature then isopropyl bromoacetate (68.4 mg, 0.38 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 2 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 30:1 to 20:1) to give the title compound as a colorless oil (155 mg, 100%).
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]([OH:17])=[CH:5][C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15].[OH-].[Na+].CO.Cl>CCOC(C)=O>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6](=[O:16])[CH:5]=[C:4]([OH:17])[C:3]([OH:18])=[O:2]
Reactant: COC(=O)C(O)=CC(=O)CCc1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(C=C(O)C(=O)O)CCc1ccccc1Cl
Reaction time: 2 h
Yield: 78.5 %

Procedure:
Intermediate 1B (320 mg, 1.2 mmol) was treated with 1.31 ml of 1 N NaOH, a small amount of MeOH was added to aid dissolution of the ester. The resulting suspension was stirred for 2 h then acidified with 1N HCl and EtOAc was added. The organic layer was separated, washed with brine, dried over Na2SO4 then filtered and the solvent removed to yield 240 mg oil. The crude product was purified by reverse phase preparative HPLC (C18, MeOH/H2O (0.1% TFA)-gradient). MS (M−H) calcd for C12H10NO4Cl: 253.0268; found: 253.0267.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.C(OCC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a cold (0° C.) stirred solution of 1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in anhydrous THF (50 mL) under argon was added dropwise 1.0 M 4-chlorophenylmagnesium bromide in diethyl ether (10 mL, 10 mmol). The reaction was warmed to RT for 2 hrs then quenched with sat'd aqueous NH4Cl (5 mL). The reaction mixture was extracted with EtOAc (2×50 mL), the organic layers combined and dried over Na2SO4. Pure 1-t-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopiperidine (2.1 g, 96%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 1H NMR CDCl3 δ 1.43 (9H,s), 1.61–2.22 (6H, m), 3.21–3031 (2H, m), 3.48–3.82 (2H, m).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([O:12]CC)=[O:11])=[N:6]1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[N:6]1
Reactant: CCOC(=O)c1ccn(CCOC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCn1ccc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.2 %

Procedure:
Ethyl 1-(2-methoxyethyl)-1H-pyrazole-3-carboxylate (Preparation 28, 360 mg, 1.8 mmol) was dissolved in ethanol (6 ml), a solution of sodium hydroxide (90 mg, 2.3 mmol) in water (3 ml) was added and the solution was stirred at room temperature for 3 hours. The ethanol was removed in vacuo and the residue was acidified with 2M HCl (approximately 1.5 ml), the aqueous solution was evaporated to dryness in vacuo and the residue was extracted with a mixture of dichloromethane (15 ml) and 3 drops of methanol. The mixture was filtered to remove the inorganics and the solvent removed in vacuo to give 310 mg of a yellow oil which crystallized on standing.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[CH2:18]([SH:20])[CH3:19]>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([S:20][CH2:18][CH3:19])=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: CCS
Reactant: C[n+]1ncc(N)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCSc1cc(N)cn[n+]1C

Procedure:
24.4 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 250 parts of acetonitrile is stirred with 10 parts of ethylmercaptan and 10 parts of triethylamine for four hours at 50° to 60°C. After the solvent has been distilled off the residue is washed with 100 parts of water. 18.3 parts (67.9% of theory) of 1-methyl-4-amino-6-ethylmercaptopyridazinium perchlorate is obtained; C7H12O4N3SCl, melting point 136° to 137°C after having been recrystallized from alcohol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@H:13]3[CH2:15][C@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.Cl.[F:20][C:21]([F:28])([F:27])[C:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1>>[F:20][C:21]([F:28])([F:27])[C:22]1([NH:26][C:16]([C:9]2[C:10]3[CH2:11][C@@H:12]4[CH2:15][C@@H:13]4[C:14]=3[N:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[N:8]=2)=[O:18])[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21
Reactant: NC1(C(F)(F)F)CCC1
Agent: Cl
Product: O=C(NC1(C(F)(F)F)CCC1)c1nn(-c2cnccn2)c2c1C[C@@H]1C[C@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method UU using Intermediate 4 and 1-(trifluoromethyl)cyclobutanamine hydrochloride. LCMS m/z=364.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 0.47 (td, J=4.6, 3.2 Hz, 1H), 1.23-1.29 (m, 1H), 2.04-2.14 (m, 2H), 2.27-2.33 (m, 1H), 2.64-2.70 (m, 4H), 2.74-2.80 (m, 1H), 2.93 (d, J=16.9. Hz, 1H), 3.02 (dd, J=16.6 and 6.2 Hz, 1H), 6.99 (s, 1H), 8.42 (dd, J=2.5 and 1.5 Hz, 1H), 8.52 (d, J=2.5 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[CH2:8][CH2:7][C:5]=2[CH:6]=1.OS(O)(=O)=O.C([O-])([O-])=O.[K+].[K+].[CH3:23][OH:24]>O>[OH:24][C:23]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[CH2:7][CH2:8][C:9]([O:11][CH3:4])=[O:10]
Reactant: O=C1CCc2ccccc2O1
Reactant: CO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: COC(=O)CCc1ccccc1O
Temperature: 55 °C
Yield: 90 %

Procedure:
To a stirred solution of dihydrocoumarin (10 mL, 78.9 mmol) and a catalytic amount of conc. H2SO4 in dry methanol (300 mL) was added and the reaction mixture was then heated at 55° C. for 8 hours. Methanol was evaporated to dryness to give crude product which was subjected to neutralize with K2CO3. The residue was diluted with water and extracted with dichloromethane. Purification of the crude product by column chromatography (20% CH2Cl2:3% EtOAc:77% Hexane as eluent) gave the desired ester as colorless oil (12.80 g, 90%). 1H NMR (400 MHz, CDCl3): 2.71 (3H, t, J=6.4 Hz), 2.89 (2H, t, J=6.4 Hz), 3.67 (3H, s), 6.83-6.87 (2H, m), 7.06-7.12 (2H, m),
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:25]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:27]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])C.[OH-].[Na+]>>[C:41]([CH2:40][CH2:39][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:25]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:46])=[O:3])([OH:43])=[O:42]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccccc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccccc3)cc(-c3ccsc3)c2)c1CCC(=O)O
Yield: 72.1 %

Procedure:
A similar procedure as described in Example 12, step 9 was used, starting from 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-thiophen-3-yl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (85 mg, 0.13 mmol) and 1.0 N aqueous NaOH (8 mL) to afford 4-{2-(2-carboxy-ethyl)-3-[6-(5-thiophen-3-yl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid (55 mg, 71%) as an amorphous white solid: ES(+)-HRMS m/e calculated for C35H38O6S (M+H)+ 587.2462, found 587.2461.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:20]>C(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7]([CH3:8])=[O:20])=[N:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc(-c2ccncc2)n1C
Solvent: ClCCl
Product: Cn1c(-c2ccncc2)nnc1S(C)=O
Reaction time: 8 h

Procedure:
To a stirred, 0° C., solution of 4-methyl-5-methylthio-3-(4-pyridyl)-4H-1,2,4-triazole (4.54 g, 2.2×10-2 mole) and CH2Cl2 (125 ml) was added portionwise m-chloroperoxybenzoic acid (4.83 g, 2.24×10-2 mole, 80% active MCPBA). After stirring overnight the reaction was diluted with CH2Cl2 until homogeneous. The CH2Cl2 solution was then washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. After drying over anhydrouse Na2SO4, the CH2Cl2 was evaporated at reduced pressure to give the desired product.
Reaction SMILES: [Mg].I[C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14].C1(OC)C=CC=CC=1.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.[Cl-].[NH4+]>C(OCC)C>[OH:30][CH:23]([C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[O:13][CH3:14])[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(C(C)(C)C)cc1I
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: COc1ccccc1
Solvent: CCOCC
Product: COc1ccc(C(C)(C)C)cc1C(O)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
270 mg of magnesium was suspended in 2 ml of anhydrous diethyl ether and 0.5 ml of a solution of 2-iodo-4-tert-butylanisole (prepared by dissolving 2.90 g of the anisole in 5 ml of diethyl ether), followed by warming the mixture to initiate the reaction. Upon addition of the remaining ethereal solution of the anisole, the mixture began to reflux. The mixture was refluxed for 30 minutes and then cooled to 0° C., and 1.03 ml of nicotinaldehyde dissolved in 5 ml of diethyl ether was added dropwise to the mixture. After stirring for one hour at 0° C., a saturated aqueous solution of ammonium chloride was added to the mixture which was then extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and an aqueous sodium chloride solution, dried and concentrated. The residue was chromatographed on silica gel column using a mixed solvent of methylene chloride and ethyl acetate (1:1 by volume) as an eluting agent to give 1.76 g of the title compound having the following physical properties.