Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9](Br)=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[CH2:19](B(O)O)[CH:20]([CH3:22])[CH3:21].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH2:19]([C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][C:9]([CH2:4][CH:5]([CH3:16])[CH3:6])=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: Brc1ccc2ccc3c(Br)ccc4ccc1c2c43
Reactant: CC(C)CB(O)O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc2ccc3c(CC(C)C)ccc4ccc1c2c43
Yield: 154.2 %

Procedure:
A mixture of 1,6-dibromopyrene (15.13 g, 42.0 mmol), isobutyl boronic acid (27.58 g, 270 mmol), potassium phosphate tribasic monohydrate (53.94 g, 254 mmol), Pd2(dba)3 (3.02 g, 3.30 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.00 g, 2.45 mmol) in toluene (300 mL) was fully degassing by bubbling through with nitrogen. The reaction mixture was maintained at reflux under nitrogen for 16 h. The reaction mixture was cooled, then filtered through a pad of Celite and washed with toluene. The solvent was removed in vacuo and the residue was purified by flash chromatography using hexane to yield 1,6-diisobutylpyrene (10.18 g, 77% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[F:21])C(OC)=O.[Cl-].[Li+].O.C(OCC)(=O)C>CS(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[N:17]=2)[N:12]=[CH:11][C:10]=1[F:21]
Reactant: COC(=O)C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1c(F)cnc2ccc(OC)nc12
Temperature: 100 °C

Procedure:
A mixture of dimethyl[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]propanedioate (52 g, 169 mmol), lithium chloride (14.5 g, 340 mmol) and water (3.43 ml, 190 mmol) in DMSO (1175 ml) was heated at 100° C. for 24 hours and cooled. The solution was shaken with water and ethyl acetate, separated and the organic phase washed twice with water. The total aqueous was re-extracted with ethyl acetate and this water-washed. The combined organic phase was dried and evaporated and the residue chromatographed, using a hexane/ethyl acetate gradient, to give the desired product containing about 10% of starting material (35.79 g).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]([OH:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][N:7]=[CH:6]1>C(OCC)(=O)C>[C:1]([O:16][CH:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:10]([O:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)C(O)C(Oc1ccccc1)n1ccnc1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C(Oc1ccccc1)n1ccnc1)C(C)(C)C
Yield: 68.1 %

Procedure:
8.0 g (0.1 mol) of acetyl chloride are added to 20.6 g (0.1 mol) of 1-imidazol-1-yl-1-phenoxy-3,3-dimethyl-butan-2-ol in 100 ml of ethyl acetate at room temperature. The mixture is then heated under reflux for 4 hours. It is allowed to cool and concentrated by distilling off the solvent in vacuo. The residue is taken up in benzene and the solution is washed with aqueous sodium bicarbonate solution and dried over sodium sulphate. The solvent is distilled off under a water pump vacuum and the residue is recrystallized from petroleum ether. 20.6 g (45% of theory) of 2-acetoxy-1-phenoxy-1-imidazol-1-yl-3,3-dimethyl-butane are obtained as a mixture of isomers with a melting point of 114°-121° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[C:9][CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1>C(OCC)(=O)C.[Pt]=O>[CH3:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]([NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1
Reactant: CCCC#Cc1cnc(NC(=O)C(C)(C)C)cc1C
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCCCCc1cnc(NC(=O)C(C)(C)C)cc1C
Reaction time: 1.5 h

Procedure:
A solution of 4-methyl-2-(trimethylacetyl)amino-5-(1-pentynyl)-pyridine (225 mg, 0.87 mmol) in ethyl acetate (4.5 mL) containing platinum oxide (45 mg) was hydrogenated at atmospheric pressure for 1.5 h. The catalyst was removed by filtration through a Millex-HV 0.45 um Filter Unit. Evaporation of the filtrate gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCN(CCCOc1ccc(C(=O)OC)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CCCOc1ccc(C(=O)O)cc1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 13 h
Yield: 91.3 %

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)-N-ethylamino]propoxy]benzoate (1.37 g) was dissolved in methanol (20 ml), and a solution of sodium hydroxide (0.48 ml) in water (5 ml) was added thereto, the mixture was heated with stirring at 60° C. for 13 hours. The reaction mixture was cooled, and was added a neutralization amount of conc. hydrochloric acid thereto, then the mixture was concentrated under reduced pressure. The residue was suspended in water, and collected by filtration, and washed with water to give the desired product (1.20 g). mp. 146°-149° C.
Reaction SMILES: Cl(O)(=O)(=O)=[O:2].[CH3:6][C:7]1[N:11]([CH2:12][CH:13]2[C:26](=[O:27])[C:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[N:24]([CH3:25])[C:16]=3[CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1.[C:28]([OH:31])(=[O:30])[CH3:29]>>[CH3:25][N:24]1[C:16]2[CH2:15][CH2:14][CH:13]([CH2:12][N:11]3[CH:10]=[CH:9][N:8]=[C:7]3[CH3:6])[C:26](=[O:27])[C:17]=2[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2.[C:28]([OH:31])(=[O:30])[CH:29]=[O:2]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CC(=O)O
Agent: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Product: O=CC(=O)O

Procedure:
A mixture containing 2.83 g (0.01 mole) of 3-hydroxy-methyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylic acid lactone [compound of the formula (Ic)]and 1.64 g (0.02 mole) of 2-methylimidazole in 6.0 ml of sulfolane (tetramethylenesulfone) is heated in an oil bath of 150 to 160° C. for 15 minutes while stirring. After cooling down and diluting with 60 ml of acetone the precipitate is filtered off, washed with acetone and dried to give 0.95 g of the title compound, m.p.: 190°-200° C. (with decomposition). The active agent content of this product measured by titration with perchloric acid in glacial acetic acid was found to be 96%. In the combined filtrate of the reaction, ondansetron could be detected by thin layer chromatography. The most important characteristics of the title product are as follows:
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH:30]([CH3:32])[CH3:31])[CH3:14])=[CH:7][C:6]=1[CH3:33].[OH-].[Li+].O1CCCC1.CO>Cl.O>[CH:30]([C:16]1[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=2)[O:19][C:15]=1[CH:13]([CH3:14])[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:34])=[O:2])=[C:6]([CH3:33])[CH:7]=1)([CH3:31])[CH3:32]
Reactant: COC(=O)Cc1ccc(OCC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C(C)C)ccc1CC(=O)O

Procedure:
(4-{2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propoxy}-2-methyl-phenyl)-acetic acid methyl ester (0.065 g, 0.1367 mmol), lithium hydroxide (0.020 g, 0.8333 mmol) and 3:2:1 tetrahydrofuran:methanol:water (15 mL) is stirred at 60 deg C. 1 hr. The mixture is cooled on ice/water and diluted with 0.2 N aqueous hydrochloric acid. The product is extracted to ethyl acetate (2×50 mL), the extracts combined, dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound as a white solid, 55 mg, 87%. MS M++1 462. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[Br:14]N1C(=O)CCC1=O>>[Br:14][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([CH:1]=[O:2])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Product: COC(=O)c1cc(Br)c(O)c(C=O)c1
Yield: 73 %

Procedure:
Proceeding as in Reference 9, but substituting methyl 3-formyl-4-hydroxybenzoate (12.0 g, 66.6 mmol, 1 eq.) and N-bromosuccinimide (12.45 g, 69.9 mmol, 1.05 eq.) gave methyl 3-bromo-5-formyl-4-hydroxybenzoate (12.6 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.S(=O)(=O)(O)O.O.[CH3:21]COCC>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:21])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Cl)ccc2c1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 72 h

Procedure:
A suspension of the 6-chloro-2-naphthoic acid (41.2 g.) in a mixture of methanol (500 ml.) and concentrated sulphuric acid (50 ml.) is heated under reflux for 3 hours, stored at ambient temperature for 3 days, then warmed until a solution is obtained. Water (2 1.) and ether (1 1.) are added. The ethereal layer is separated, and is washed in turn with water, N-aqueous sodium hydroxide, and water, dried with magnesium sulphate, and evaporated to give methyl 6-chloro-2-naphthoate (38.8 g.) m.p. 97°-98° C., which may be further purified by recrystallisation from light petroleum (b.p. 40°-60° C.) to give material of m.p. 100°-101° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:41]=[CH:40][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=2[C@@H:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]([O:33]C(=O)C(C)(C)C)[CH:27]=[CH:26][C:25]=3[CH2:24]2)=[CH:7][CH:6]=1)(O)=O.[NH:42]1[CH2:45][CH2:44][CH2:43]1>>[N:42]1([CH2:1][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=3[C@@H:23]3[CH2:32][CH2:31][C:30]4[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26][C:25]=4[CH2:24]3)=[CH:40][CH:41]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: COc1cc(NCCCc2ccc(CC(=O)O)cc2)c([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)cc1OC
Reactant: C1CNC1
Product: COc1cc(NCCCc2ccc(CCN3CCC3)cc2)c([C@@H]2CCc3cc(O)ccc3C2)cc1OC
Yield: 19.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and azetidine (10 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (3.3 mg) was obtained.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1>CN(C)C=O.C(OCC)C>[Br:1][C:18]1[CH:17]=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)[CH:22]=[CH:21][C:19]=1[NH2:20]
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Nc1ccc(Cc2ccncc2)cc1Br
Reaction time: 1 h

Procedure:
A solution of 18.34 g (0.103 mol) of N-bromosuccinimide in 60 ml of dimethylformamide is added dropwise, shielded from light, to a solution of 20 g (0.1084 mol) of 4-(4-pyridylmethyl)aniline in 180 ml of dimethylformamide. After 1 hour, the solvent is evaporated off under reduced pressure and the solid is taken up in 200 ml of dichloromethane. The solution is subsequently washed with 100 ml of water and then with 100 ml of a saturated sodium chloride solution. After customary treatment of the organic phase, an oil is obtained which is taken up in 500 ml of diethyl ether, and the whole is left in a refrigerator for 2 days. After filtration, the expected product is obtained.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([NH:10][C@@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:12]([OH:15])[CH2:13][OH:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[S:22]1[C:26]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.CN1C(=O)CCC1>O>[S:22]1[C:26]2[CH:27]=[C:28]([NH:31][C:2]3[CH:9]=[C:8]([NH:10][C@@H:11]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([OH:15])[CH2:13][OH:14])[C:5]([C:6]#[N:7])=[CH:4][N:3]=3)[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: N#Cc1cnc(Cl)cc1N[C@@H](c1ccccc1)[C@H](O)CO
Reactant: Nc1ccc2ncsc2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cnc(Nc2ccc3ncsc3c2)cc1N[C@@H](c1ccccc1)[C@H](O)CO
Temperature: 150 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A mixture of 6-chloro-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile (0.108 g, 0.356 mmol), benzo[d]thiazol-6-amine (0.187 g, 1.244 mmol) and NMP (1.422 mL) was stirred at 150° C. for 1 hour in a microwave reactor. The vessel was cooled to room temperature, diluted with water and filtered. Following drying on a buchner funnel, 6-(benzo[d]thiazol-6-ylamino)-4-((1S,2S)-2,3-dihydroxy-1-phenylpropylamino)nicotinonitrile (0.122 g, 0.292 mmol, 82% yield) was collected as a yellowish solid. LC-MS (m/z, M+1=418), Waters sunfire 4.6×50 mm C18 5 um 4 min/1 min hold time 0-100% (A-B) A=10% MeOH-90% water-0.1% TFA, B=90% MeOH-10% water-0.1% TFA RT=2.06.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1cccc(OCCCBr)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(F)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.723 g of 1-(3-bromopropoxy)-3-fluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.29.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[OH:11])[CH3:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)=[O:11])[CH3:5])[CH3:2]
Reactant: CCOC(C)OCC#CC(O)c1ccc(Cl)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(C)OCC#CC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 7.1 g (26.4 mmol) of 4-(1-ethoxyethoxy)-1-(4-chlorophenyl)-2-butyn-1-ol in 40 ml of methylene chloride was added dropwise at 0° to a suspension of 68 g (0.78 mol) of manganese dioxide in 110 ml of methylene chloride. The reaction mixture was stirred at 0° for lo minutes, filtered over magnesium sulphate and concentrated. Chromatography of the residue on 300 g of silica gel (elution agent ether/hexane 1:1) yielded 4-(1-ethoxyethoxy)- 1-(4-chlorophenyl)-2-butyn-1-one as an oil.
Reaction SMILES: [OH-].[Na+].C1(S([N:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[C:14]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]4)=[C:27]([CH3:37])[CH:26]=3)(=[O:24])=[O:23])=[CH:13]2)(=O)=O)C=CC=CC=1>CO>[F:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[NH:12][CH:13]=[C:14]2[S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]2)=[C:27]([CH3:37])[CH:26]=1)(=[O:23])=[O:24]
Reactant: Cc1cc(S(=O)(=O)c2cn(S(=O)(=O)c3ccccc3)c3ccc(F)cc23)ccc1C1CCN(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(S(=O)(=O)c2c[nH]c3ccc(F)cc23)ccc1C1CCN(C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.7 %

Procedure:
An aqueous solution of NaOH (2 M, 0.8 mL) was added to a solution of 1-benzenesulfonyl-5-fluoro-3-[3-methyl-4-(1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-1H-indole (0.209 g, 0.4045 mmol) in MeOH (1 mL) and the resulting mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure and the crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.102 g of 5-fluoro-3-[3-methyl-4-(1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-1H-indole as a white foam. MP=86.5-93.5° C.; MS (M+H)=378.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[CH2:6][C:7]1[C:12]([CH2:13][CH3:14])=[C:11]([CH3:15])[N:10]=[C:9]([O:16]C)[C:8]=1[NH:18]C(=O)C(C)(C)C.[NH4+]>O>[NH2:18][C:8]1[C:9](=[O:16])[NH:10][C:11]([CH3:15])=[C:12]([CH2:13][CH3:14])[C:7]=1[CH2:6][C:5]1[CH:4]=[C:3]([CH3:2])[CH:27]=[C:26]([CH3:28])[CH:25]=1
Reactant: CCc1c(C)nc(OC)c(NC(=O)C(C)(C)C)c1Cc1cc(C)cc(C)c1
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: CCc1c(C)[nH]c(=O)c(N)c1Cc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3M aqueous hydrochloric acid (150 mL) was added to a suspension of 4-(3,5-dimethylbenzyl)-5-ethyl-2-methoxy-6-methyl-3-pivaloylaminopyridine (2.36 g) in water (300 mL). The mixture was refluxed for 3.5 h and then stirred at room temperature for 12 h. The solution was basified by adding concentrated ammonium hydroxyde and was extracted with 3×800 mL ethyl acetate. The combined organic layers were washed with 110 mL brine, dried over magnesium sulfate and concentrated under reduced pressure giving 3-amino-4-(3,5-dimethylbenzyl)-5-ethyl-6-methylpyridin-2(1H)-one. (1.79 g, 100%). mp 204-205° C.
Reaction SMILES: [CH2:1]1[O:17][C:16]2[CH:15]=[CH:14][C:5]([CH2:6][NH:7][CH2:8][CH:9](OC)OC)=[CH:4][C:3]=2[O:2]1.[CH:18](=O)[C:19]1[CH:28]=[CH:27][C:24]([O:25][CH3:26])=[C:21]([O:22][CH3:23])[CH:20]=1.[ClH:30]>>[ClH:30].[CH3:23][O:22][C:21]1[C:24]([O:25][CH3:26])=[CH:27][C:28]2[CH2:19][C:18]3[C:14]4[C:5](=[CH:4][C:3]5[O:2][CH2:1][O:17][C:16]=5[CH:15]=4)[CH:6]=[N:7][C:8]=3[C:9]=2[CH:20]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC(CNCc1ccc2c(c1)OCO2)OC
Agent: Cl
Product: COc1cc2c(cc1OC)-c1ncc3cc4c(cc3c1C2)OCO4
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Concentrated HCl (20 mL) was added to a mixture of (3,4-methylenedioxybenzyl)-(2,2-dimethoxyethyl)amine (12b, 1.79 g, 7.49 mmol) and veratraldehyde (10a, 3.04 g, 0.018 mol). The reaction mixture was stirred at 100° C. for 3 h. The reaction mixture was then cooled and washed with ether (50 mL×3). Then it was brought to a basic pH with NH4OH. The mixture was extracted with chloroform (50 mL×4), washed with water (100 mL), dried (Na2SO4) and concentrated. The residue was dissolved in an organic solvent (200 mL chloroform). The mixture was filtered and HCl (2 M in ether, 40 mL) was added to the filtrate. The yellow precipitate that formed (0.7649 g, 29%) was collected by filtration. An analytical sample was prepared by recrystallizing 0.3655 g from methanol (50 mL), mp 257-259° C. 1H NMR (300 MHz, TFA) δ 8.88 (s, 1H), 7.69 (s, 1H), 7.39 (s, 1H), 7.33 (s, 2H), 6.21 (s, 2H), 4.18 (s, 2H), 4.02 (s, 3H), 4.01 (s, 3H); low resolution ESIMS m/z (rel intensity) 322 (100, MH+); high resolution ESIMS m/z (rel intensity) 322.1084 (100, MH+) (calculated mass 322.1079); IR (KBr) 3435, 3043, 2966, 2841, 2648, 2027, 1623, 1589, 1494, 1470, 1458, 1419, 1379, 1323, 1291, 1275, 1256, 1220, 1198, 1147, 1122, 1092, 1035, 969, 935, 902, 872, 835, 818, 785, 762, 743, 572 cm−1. Anal. Calcd for C19H16NO4Cl(H2O)0.7: C, 61.61; H, 4.74; N, 3.78. Found: C, 61.40; H, 4.98; N, 3.75.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[C:6]1[CH:11]=[C:10]([S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[N:9]=[C:8]([NH:18][CH:19]([CH2:21][CH3:22])[CH3:20])[CH:7]=1>CO>[C@@H:19]([NH:18][C:8]1[CH:7]=[C:6]([CH:11]=[C:10]([S:12]([CH:15]([CH3:16])[CH3:17])(=[O:14])=[O:13])[N:9]=1)[C:5]([OH:23])=[O:4])([CH2:21][CH3:22])[CH3:20]
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(S(=O)(=O)C(C)C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(S(=O)(=O)C(C)C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
Add 2 N NaOH (7.0 mL, 14.0 mmol) to a solution of 2-sec-butylamino-6-isopropanesulfonyl-isonicotinic acid methyl ester (1.46 g, 4.65 mmol) in methanol (10 mL) at 0° C. Stir the mixture at room temperature for 3 h and acidify the solution to about pH=2 and concentrate the solvent to one half volume. Partition the residue between ethyl acetate and water, and extract the aqueous layer with ethyl acetate (2×50 mL). Wash the combined organic extracts with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound in 90% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]([NH:22][C@H:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)[CH3:24])=[O:21])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.Cl>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:20]([NH:22][C@H:23]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)[CH3:24])=[O:21])[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(CCN(C)C)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(CCN(C)C)cc1)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 83 from methyl 4-((1S)-1-{[(5-chloro-2-{4-[2-(dimethylamino)ethyl]phenoxy}pyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1) and then converted into the hydrochloride salt with 4 M solution of hydrogen chloride in ethyl acetate: 1H-NMR (DMSO-d6) δ 9.04 (1H, d, J=7.9 Hz), 8.26 (1H, d, J=2.8 Hz), 8.12 (1H, d, J=2.6 Hz), 7.85 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.3 Hz), 7.34 (2H, d, J=8.6 Hz), 7.17 (2H, d, J=8.6 Hz), 5.22–5.12 (1H, m), 3.29–3.25 (2H, m), 3.04–2.99 (2H, m), 2.80 (6H, s), 1.45 (3H, d, J=7.0 Hz); MS (ESI) m/z 468 (M+H)+, 466 (M−H)−.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:30][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:20]=1[NH:19][CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:24]([OH:26])=[O:25]
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C(=O)O)ccc1NC(CC(C)C)c1cc(-c2ccccc2)oc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.1 g), methyl 4-amino-3-methylbenzoate (1.0 g), sodium carbonate (0.6 g) and sodium iodide (2.4 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.5 g, 31%) as an amorphous compound.