Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([F:36])[C:30]=1[CH2:29][C@H:16]([NH:15][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: N[C@@H](Cc1c(F)cccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2c(F)cccc2F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,6-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (231 mg, 0.69 mmol) [prepared according to the procedure of Preparation 18] and PyBrop (353 mg, 0.75 mmol) in chloroform (8 mL). DIEA (0.64 mL, 3.66 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (149 mg, 0.21 mmol, 30%): LC-MS (ES) m/z=507 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:22][CH3:23].[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>O>[CH3:23][O:22][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][NH:28][CH2:27][CH2:26][O:25][CH3:24])[N:12]=[CH:11][N:10]=[C:9]2[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCBr
Reactant: COCCN
Solvent: O
Product: COCCNCCOc1cc2ncnc(Oc3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of 7-(2-bromoethoxy)-6-methoxy-4-phenoxyquinazoline (1.1 g, 2.9 mmol), (prepared as described for the starting material in Example 22), in 2-methoxyethylamine (8 ml) was stirred at ambient temperature for 4 hours. The mixture was diluted with water and extracted with methylene chloride (5×25 ml). The combined extracts were washed with brine and passed through phase separating paper. The solvent was removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (100/8/1) to give 6-methoxy-4-phenoxy-7-(2-(2-methoxyethylamino)ethoxy)quinazoline (760 mg, 70%) as a white solid.
Reaction SMILES: C1(C)C=CC(P(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[Cl:43][C:44]1[CH:49]=[C:48]([S:50][CH2:51][CH3:52])[CH:47]=[CH:46][C:45]=1I>CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:43][C:44]1[CH:49]=[C:48]([S:50][CH2:51][CH3:52])[CH:47]=[CH:46][C:45]=1[C:25]1[C:24]([OH:23])=[CH:29][CH:28]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:26]=1
Reactant: CCSc1ccc(I)c(Cl)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: CO
Product: CCSc1ccc(-c2cc(C(F)(F)F)ccc2O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of palladium acetate (0.045 g) and tri-p-tolylphosphine (0.213 g) in methanol (10 ml) was stirred at RT for 30 min. The product from step (iii) (1 g), sodium carbonate (1.27 g), the product from example (26) step (i) (1.19 g) and methanol (20 ml) were added and the mixture heated under reflux for 6 h. The solvent was removed under reduced pressure and the residue partitioned between diethylether and 2M hydrochloric acid. The organics were separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% ethylacetate/isohexane. Yield 0.503 g
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH2:11]>>[C:1]([O:6][CH2:7][CH:8]([CH2:9][OH:11])[OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O
Reactant: C=C(C)C(=O)OCC1CO1
Product: C=C(C)C(=O)OCC(O)CO

Procedure:
Glycidyl methacrylate is immiscible with water, but as the reaction proceeds, solubility is increased until a clear solution is obtained. As the reaction proceeds, glyceryl methacrylate is formed which co-dissolves the unreacted glycidyl methacrylate.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:6]([OH:26])([CH2:23][CH:24]=[CH2:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])[CH:4]=[CH2:5].Cl>>[CH2:3]([C:6]([OH:26])([CH2:23][CH:24]=[CH2:25])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH3:21])([CH3:22])[C:19]([OH:1])=[O:20])[CH:4]=[CH2:5]
Reactant: [OH-]
Reactant: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C=O
Agent: Cl
Agent: [Na+]
Product: C=CCC(O)(CC=C)CCCCCCCCCCCC(C)(C)C(=O)O
Yield: 46 %

Procedure:
The NaOH extracts from the product of Example 7 were brought to pH 2 with dilute HCl and extracted with ether. These extracts were dried (Na2SO4), evaporated and the yellow glass dried at 30° centigrade/0.5 mm. yielding 18.4 g (46%) of the title compound. A 0 28 g-sample prepared in this manner was flash chromatographed on a 1×15 cm column of silica gel in 20% C2H5OCOCH3 --CH2Cl2 and furnished 0.13 g of the title compound.
Reaction SMILES: I.[C:2]([NH:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:22])SC)[S:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH3:3].[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>C(O)C>[C:2]([NH:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]2[N:14]=[C:15]([N:18]=[C:19]([NH2:22])[NH:27][CH2:23][CH2:24][CH2:25][CH3:26])[S:16][CH:17]=2)[CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH3:3]
Reactant: CCCCN
Reactant: CSC(N)=Nc1nc(-c2cccc(CNC(C)=O)n2)cs1
Agent: I
Solvent: CCO
Product: CCCCNC(N)=Nc1nc(-c2cccc(CNC(C)=O)n2)cs1

Procedure:
A mixture of 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino)(methylthio)methyleneamino]thiazole hydriodide (1.5 g) and n-butylamine (1.6 ml) in ethanol (30 ml) was heated under reflux for 40 hours. The solvent was removed by concentration and residue was added to a mixture of ethyl acetate, tetrahydrofuran and water. The mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate and a separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (19:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was recrystallized from a mixture of methanol, dioxane and diisopropyl ether to give 4-(6-acetylaminomethylpyridin-2-yl)-2-[(amino) (n-butylamino)methyleneamino]thiazole (0.48 g).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15]([NH2:17])=[C:14]1[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]1)=[N:8]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27]>CN(C)C=O.O>[OH2:2].[NH2:17][C:15]1[C:16]2[C:7]([N:8]=[C:9]3[C:14]=1[CH2:13][CH2:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH:25]([CH3:30])[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C(C)Br
Reactant: Nc1c2c(nc3cccc(O)c13)CCCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)Oc1cccc2nc3c(c(N)c12)CCCC3
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 8-hydroxy-1,2,3,4-tetrahydro-9-acridinamine hydrochloride (3.77 g) in dry dimethylformamide (100 ml) was added potassium carbonate (4.7 g), with stirring. After one hr, methyl 2-bromopropionate (2.51 ml) was added and stirring was continued overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and the residue was flash chromatographed (ethyl acetate, then 5% triethylamine/ethyl acetate) to yield 4.05 g (86.7%) of methyl α-[(9-amino-1,2,3,4-tetrahydroacridin-8-yl)oxy]propionate hydrate.
Reaction SMILES: I[C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[CH:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[CH3:10][C:3]1[C:4]([CH2:5][OH:6])=[CH:7][CH:8]=[CH:9][C:2]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1c(I)cccc1CO
Reactant: c1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: Cc1c(CO)cccc1-c1ccccc1

Procedure:
In a photoreactor was placed 3-iodo-2-methylbenzyl alcohol (5.0 g, 0.02 mole) and 800 ml of benzene. To this was added sodium thiosulfate (5.0 g, 0.04 mole) in 15 ml of water. The mixture was purged with argon for 30 minutes, then irradiated with a 200 watt medium pressure ultraviolet lamp for 36.5 hours. The reaction mixture was then transferred to a separatory funnel. The photoreactor was washed with approximately 20 ml each of water, chloroform, and acetone. These washes were added to the separatory funnel. The organic layer was washed with aqueous 0.5 M sodium thiosulfate, then with an aqueous solution saturated with sodium chloride. The organic layer was then dried and filtered. The filtrate was evaporated under reduced pressure to an oily residue. The residue was purified by column chromatography on silica gel, elution with 1:1 hexane:chloroform, to give 2-methyl[1,1'-biphenyl]-3-methanol (2.4 g). The nmr and ir spectra were consistent with that expected for the named compound.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[K+].C[O-].[K+].O>OCC(CO)O>[C:16]1(=[O:17])[O:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(O)CCCCCSCCCCCCCCO
Agent: C[O-]
Agent: [K+]
Agent: [OH-]
Solvent: OCC(O)CO
Solvent: O
Product: O=C1CCCCCSCCCCCCCCO1
Temperature: 153 °C

Procedure:
22 g of crude 15-hydroxy-7-thiapentadecanoic acid (9, n=3, m=7, R=H) was treated with 0.45 ml (4.0 mmol) of 50 percent potassium hydroxide solution and byproducts were distilled off at 180° C./20-23 mbar for 1 h. Thereupon, the reaction vessel was fitted with a condenser and separator and 1.2 g (17 mmol) of potassium methylate in 300 ml of anhydrous glycerol was added to the reaction mixture. The mixture was heated to reflux at 153° C./4-6 mbar over the separator for 2 d., with 1.2 g (17 mmol) of potassium methylate again being added after 14 h. The separated glycerol was poured into 800 ml of water and the crude product was extracted twice with 500 ml of MTBE each time and once with 500 ml of n-pentane. The combined organic extracts were dried over magnesium sulphate and concentrated to dryness on a rotary evaporator. After flash chromatography (n-pentane/MTBE, 19:1, hRf=46) on silica gel, 2.9 g (11% overall yield) of 7-thia-pentadecanolide as a colorless wax-like solid with an intensive, linear musk odor accompanied by green-mossy aspects with a threshold value of 0.2 ng/l air was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc2c(c1)CCC2O
Reaction time: 2 h
Yield: 100.5 %

Procedure:
1-Oxo-2,3-dihydro-1H-inden-5-carbonitrile (7.85 g, 50 mmol) was dissolved in 50 mL of methanol. To it was added sodium borohydride (2.3 g, 60 mmol) gradually within about 30 minutes. The solution was concentrated after being stirred for 2 hours. The residue was dissolved in ethyl acetate and the solution obtained was washed with sodium bicarbonate twice and then with brine twice, dried over magnesium sulfate, filtered, and concentrated to obtain 8 g of the desired compound (100% yield). MS (M+1)=160.07.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]([CH3:15])[CH3:14])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:18]>O1CCCC1.O>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([CH:13]([CH3:14])[CH3:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:18])[NH2:2]
Reactant: COC(=O)c1cc(C#N)c(C)cc1C(C)C
Reactant: CCOP(=S)([S-])OCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(N)=S)c(C)cc1C(C)C
Temperature: 85 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
To a round-bottom flask was added a solution of methyl 5-cyano-2-isopropyl-4-methylbenzoate (compound 196.3, 800 mg, 3.68 mmol, 1.00 equiv) in tetrahydrofuran/H2O (10/5 mL). O,O′-diethyl dithiophosphate (2.05 g, 11.0 mmol, 3.00 equiv) was added to the reaction mixture. The resulting solution was stirred for 15 h at 85° C. in an oil bath (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to ambient temperature, the mixture was extracted with 2×100 mL of ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:100-1:50-1:0) as eluent to furnish 0.800 g (86%) of methyl 5-carbamothioyl-2-isopropyl-4-methylbenzoate as a yellow oil.
Reaction SMILES: [C:1]([NH:8]CC=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Mg]Cl)C(C)C.C([O:20]CC)C>C(OCC)(=O)C>[C:1]([NH:8][OH:20])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: CCOCC
Agent: CC(C)C[Mg]Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NO
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 39 %

Procedure:
To a -78° C. solution of 547 mg (3.44 mmol) of N-Boc glycinal (20) in 17 mL of diethyl ether was added 5.16 mL (10.3 mmol, 3 equiv) of isobutylmagnesium chloride (2.0M in diethyl ether). After five minutes, the solution was warmed to 0° C. and stirred for 24 h. The reaction mixture was then diluted with 300 mL of ethyl acetate, washed with 1N aqueous sodium bisulfate, dried over magnesium sulfate and concentrated. Purification by flash chromatography (20×150 mm silica gel, 30% ethyl acetate/hexane) gave 291 mg (39%) of the title compound as a clear oil: Rf 0.20 (30% ethyl acetate/hexane); 1H NMR (300 MHz, CDCl3) δ5.19 (br t, J=5.4 Hz, 1H), 3.69 (br m, 1H), 3.24-3.19 (br m, 1H), 3.09 (br s, 1H), 2.92 (br pent, J=6.4 Hz, 1H), 1.72 (hept, J=6.4 Hz, 1H), 1.45-1.29 (m, 1H), 1.39 (s, 9H), 1.15 (ddd, J=4.8, 8.7, 13.4 Hz, 1H), 0.86 (t, J=6.3 Hz, 6H); MS(FAB) 218 (M+1), 162.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Cl.[NH2:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([NH:18][C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
3-Acetylthio-2-benzylpropanoyl chloride and (L)-tyrosine, methyl ester, hydrochloride are reacted in the presence of diisopropylethylamine according to the procedure of Example 26 to give (±)-N-[2-(acetyl-thiomethyl) -1-oxo-3-phenylpropyl]-L-tyrosine, methyl ester.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:10]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[OH:8][C:9]1[C:13]([OH:14])=[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C:10]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(-c2ccccn2)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(O)c(O)c(-c2ccccn2)n1-c1ccc(OC)cc1
Yield: 88.9 %

Procedure:
A solution of ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(pyridin-2-yl)-1H-pyrrole-2-carboxylate (UL1-082) (146 mg, 0.273 mmol) in MeOH/THF (9:1; 20 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 30° C. under H2 (full H2 mode). The output was concentrated in vacuo and the resulting oil was purified by silica gel chromatography (12 g, 0-2% MeOH in DCM) to afford ethyl 3,4-dihydroxy-1-(4-methoxyphenyl)-5-(pyridin-2-yl)-1H-pyrrole-2-carboxylate (UL1-083) (86 mg, 89%) as a pale orange solid: m/z 355 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 10.84 (s, 1H), 8.62 (s, 1H), 8.56-8.47 (m, 1H), 7.67-7.55 (m, 1H), 7.26-7.12 (m, 3H), 7.01-6.89 (m, 2H), 6.62-6.49 (m, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 1.02 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]([O:12]CC)=[O:11])[C:6](=[O:8])[CH:7]=1.[OH-].[Li+].FC(F)(F)C(O)=O>O1CCCC1.CO.O>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:6](=[O:8])[CH:7]=1
Reactant: CCOC(=O)Cn1ncc(C)cc1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn(CC(=O)O)c(=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To ethyl [4-methyl-6-oxopyridazin-1(6H)-yl]acetate (0.575 g, 2.93 mmol) in tetrahydrofuran (3 mL), methanol (2 mL) and water (2 mL) was added 1 N lithium hydroxide solution (2.9 mL). The reaction mixture was stirred at ambient temperature for 1.5 h. After neutralized with trifluoro acetic acid, the reaction mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-45% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to yield the title compound. LC/MS 169.2 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][OH:29].ClN1C(=O)CCC1=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]=2[O:29][CH2:28][CH2:27][CH2:26][CH2:25][Cl:24])=[O:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCC(CNC(=O)c2c[nH]c3ccccc23)CC1
Reactant: OCCCCCl
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCN1CCC(CNC(=O)c2c(OCCCCCl)[nH]c3ccccc23)CC1
Reaction time: 0.67 h
Yield: 49.9 %

Procedure:
A stirred suspension of N-[(l-n butyl-4-piperidyl)methyl] indole-3-carboxamide (Description 1b, 1.0 g, 0.0032 mole) in chloroform (25 ml) was treated with 4-chlorobutanol (0.69 ml, 0.0064 mole) followed by N-chlorosuccinimide (470 mg, 0.0035 mole) and a yellow solution was produced inside 5 minutes. After a further 40 minutes the solution was observed to darken in colour to orange. The mixture was kept at room temperature for a further 1 h then treated with 10% Na2CO3 solution (30 ml) and extracted with chloroform (2×30 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford an orange oil, which was chromatographed on silica gel eluting with 5% methanol/chloroform to give N-[(1-n butyl-4-piperidyl)methyl] 2-(4-chlorobutoxy)indole-3-carboxamide (0.67 g, 50%) as a yellow oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[CH:28]=[N:27][N:26]=1.[CH:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[S:56](Cl)(=[O:58])=[O:57].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[CH:28]=[N:27][N:26]=[C:25]1[CH2:24][NH:23][S:56]([C:47]1[CH:48]=[CH:49][C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:46]=1)(=[O:58])=[O:57])=[O:43]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CNS(=O)(=O)c2ccc3ccccc3c2)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazole di-p-toluenesulfonate (5.0 g) was dissolved in dimethylformamide (20 ml). 2-Naphthalenesulfonyl chloride (1.8 g) and triethylamine (5.0 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and then saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 2.73 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethyl)naphthalene-2-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][C:24](=[O:26])[CH2:23][N:22]=3)[C:9]=2[CH2:27][CH3:28])=[CH:4][CH:3]=1.[CH2:29](Br)[CH2:30][CH2:31][CH3:32]>>[CH2:29]([N:25]1[C:24](=[O:26])[CH2:23][N:22]=[C:21]1[C:10]1[C:9]([CH2:27][CH3:28])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCBr
Reactant: CCc1c(C2=NCC(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Product: CCCCN1C(=O)CN=C1c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1CC

Procedure:
Compound 30 was synthesized from 26 (102 mg, 0.23 mmol) and n-butyl bromide (500 mg, 3.65 mmol) as a white solid (55 mg, 49%) in a manner similar to that described in Example 59. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 1H), 7.30 (d, 2H), 7.25 (dd, 1H), 7.17 (d, 1H), 7.09 (d, 2H), 4.83 (s, 0.82H), 4.45 (s, 1.18H), 3.80 (s, 1.18H), 3.67 (s, 0.82H), 2.65 (q, 2H), 1.69 (br s, 2H), 1.42-1.25 (m, 2H), 1.13 (t, 3H), 0.97-0.86 (m, 3H); ESMS m/: 489.1 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:12]([O:14]C)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(#N)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OC)c(OCc2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(C(=O)O)cc1OCc1ccccc1
Temperature: 40 °C

Procedure:
A 25 g quantity of the methyl 3-benzyloxy-4-methoxybenzoate obtained in Reference Example 2 was dissolved in 100 ml of acetonitrile, and a solution of 11 g of sodium hydroxide in 100 ml of water was added. The mixture was stirred with heating at 40° C. for 5 hours. The reaction mixture was cooled with ice, and concentrated hydrochloric acid was added to give a pH of about 3. The precipitated crystals were collected by filtration and dried under reduced pressure to give 22.1 g of white crystalline 3-benzyloxy-4-methoxybenzoic acid.