Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[CH2:23](O)[C:24]([F:27])([F:26])[F:25].[C:29](=O)([O-])O.[Na+]>ClCCl>[CH:10]([N:8]1[CH2:9][CH:6]([O:5][CH2:29][CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:7]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC(F)(F)F
Reactant: O=C([O-])O
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)CCOC1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 1-benzhydrylazetidin-3-yl methanesulfonate (500 mg, 1.57 mmol) in trifluoroethanol (3.5 mL, 30.7 mmol) was stirred under microwaves at 110° C. for 30 minutes. The reaction mixture was diluted by addition of dichloromethane (100 mL) and a saturated solution of sodium hydrogencarbonate (25 mL). The aqueous layer was separated and extracted with dichloromethane (2×10 mL). The combined organic phase was dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/ethyl acetate (90:10) as eluent. The title product was obtained as a light yellow gum (170 mg, 32%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:13]3[CH:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1.CCCCCC.C(O)C.C(NCC)C>>[CH3:1][C:2]1[O:3][C:4]2[C:13]3[C@H:12]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:11][CH2:10][C:9]=3[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Solvent: CCCCCC
Solvent: CCNCC
Solvent: CCO
Product: CC(=O)NCC[C@@H]1CCc2ccc3nc(C)oc3c21
Yield: 49.2 %

Procedure:
Racemic N-[2-(2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethyl]acetamide (768 mg, 3.00 mmol) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K. K.), column: CHIRALPAK AD (50 mmID×500 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 60 mL/min, column temperature: 30° C., sample concentration: 1.02 mg/mL, injection weight: 31 mg). A fraction containing an optically active compound having a shorter retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was added again, and the mixture was concentrated to dryness to give the title compound (381 mg, 99.9% ee). Enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD (4.6 mmID×250 mL, manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=90/10/0.1, flow rate: 0.5 mL/min, column temperature: 30° C., sample concentration: 0.65 mg/mL (hexane/ethanol), injection volume: 10 μL).
Reaction SMILES: CO[C:3]([C:5]1[N:13]=[CH:12][C:11]2[NH:10][C:9]3[N:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([CH2:24][N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:20][CH:19]=4)=[CH:17][C:8]=3[C:7]=2[CH:6]=1)=[O:4].O.[NH2:32][NH2:33]>C(O)C>[N:25]1([CH2:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]3[CH:15]=[N:14][C:9]4[NH:10][C:11]5[CH:12]=[N:13][C:5]([C:3]([NH:32][NH2:33])=[O:4])=[CH:6][C:7]=5[C:8]=4[CH:17]=3)=[CH:23][CH:22]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of 3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid methyl ester (425 mg, 1.06 mmol) and hydrazine hydrate (1.29 mL, 26.5 mmol) in ethanol (4.6 mL) was heated under reflux for 1 h under a nitrogen atmosphere. The solution was allowed to cool to ambient temperature and the resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford a yellow solid (337 mg, 79%). The solid was used without purification.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-:3].[Cl-].[C:5]1([OH:15])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.O>ClC1C=CC=C(Cl)C=1>[Cl:1][C:5]1[CH:14]=[C:9]([Cl:3])[CH:8]=[CH:7][C:6]=1[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[CH2:6][CH2:7]1
Reactant: Oc1cccc2ccccc12
Reactant: [Cl-]
Agent: [Al+3]
Solvent: O
Solvent: Clc1cccc(Cl)c1
Product: O=C1CCC(c2ccc(Cl)cc2Cl)c2ccccc21
Temperature: 65 °C
Yield: 142.5 %

Procedure:
In a suspension of 60 g (0.45 mole) of aluminium chloride in 100 ml of metadichlorobenzene, 28.8 g (0.2 mole) of α-naphthol are introduced in 10 minutes: the temperature rises from 20° to 45° C. The medium is heated for 1 hour 30 mins at 65° C. then hydrolysed with 400 ml of water. After decantation, the organic phase is separated and concentrated in a vacuum from 2 to 5 torrs at 80° C. The residue is dissolved in 100 ml of isopropanol and the resultant solution cooled at 0° C. for 2 hours. The light beige solid formed is separated by filtration and dried to obtain 41.5 g of the expected compound.
Reaction SMILES: [F:1][C:2]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([C:16]#[C:17][CH2:18][OH:19])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5].CN(C)CC#CC1NC2=NC=C(NC(=O)C3C(F)=CC=C(NS(CCC)(=O)=O)C=3F)C=C2C=1>>[F:1][C:2]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:26])=[O:27])=[CH:22][CH:21]=[C:20]([F:31])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([CH2:16][CH2:17][CH2:18][OH:19])[NH:13][C:10]2=[N:11][CH:12]=1)=[O:5]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C#CCO)cc3c2)c1F
Agent: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C#CCN(C)C)cc3c2)c1F
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(CCCO)cc3c2)c1F

Procedure:
2,6-Difluoro-N-(2-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide was prepared according to the general procedure of Example 95 substituting 2,6-difluoro-N-(2-(3-hydroxyprop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide for N-(2-(3-(dimethylamino)prop-1-ynyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide. 1H NMR (400 MHz, CD3OD) δ 8.28-8.21 (m, 2H), 7.67-7.61 (m, 1H), 7.15-7.09 (m, 1H), 6.24 (s, 1H), 3.66-3.62 (m, 2H), 3.13-3.09 (m, 2H), 2.90-2.85 (m, 2H), 2.01-1.84 (m, 2H), 1.08-1.03 (m, 3H); m/z (APCI-pos) M+1=453.1.
Reaction SMILES: [OH-].[K+].[CH:3]1([CH:8]([NH:14][C:15]([O:17][CH3:18])=[O:16])[C:9]([O:11]CC)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1>O.C(O)C>[CH:3]1([CH:8]([NH:14][C:15]([O:17][CH3:18])=[O:16])[C:9]([OH:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C(NC(=O)OC)C1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)NC(C(=O)O)C1CCCC1
Yield: 89.1 %

Procedure:
KOH (3.87 g, 69.0 mmol) in water (50 mL) was added to ethyl 2-cyclopentyl-2-(methoxycarbonylamino)acetate (Compound I2.1) (7.6 g, 33.2 mmol) in ethanol (20 mL). The resultant mixture was stirred at rt for 5 h. Part of the solvent was removed under reduce pressure. The remaining mixture was extracted with Et2O (2×50 mL). The pH of the water layer was acidified by additions of HCl (1N, 20 mL) and the resultant mixture was extracted with DCM (3×50 mL), dried (MgSO4) and concentrated under reduce pressure. The residue was purified via Biotage (gradient: 10-80% of DCM/MeOH/HOAc (1: 0.05: 0.01) in DCM, KP-SIL 340 g column), KP-SIL 340 g column) to give the title product (5.95 g, 85%). 1H NMR (600 MHz, CDCl3) 1.26-1.48, 1.49-1.68, 1.68-1.85, 2.28, 3.69, 4.31, 5.12. Total no of protons: 14.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:26][CH2:25]1.N1CCCCC1>CN(C=O)C.CO>[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]([C:37]2[CH:43]=[CH:42][C:40]([NH:41]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:39][CH:38]=2)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:26][CH2:25]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(N)cc1
Solvent: CO
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Examples 1 and 187 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-[N-(2-morpholinoethyl)-N-methylsulphonyl-amino]-aniline in DMF and subsequent treatment with piperidine in methanol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])=[O:27].O>C1COCC1>[C:8]([C:6]1[CH:5]=[C:4]([CH2:12][OH:13])[C:3]([O:14][CH3:15])=[C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]([Cl:33])([Cl:32])[Cl:31])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COc1c(N)cc(C(C)(C)C)cc1CO
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
A solution of (3-amino-5-tert-butyl-2-methoxyphenyl)methanol (1.72 g, 8.23 mmol) and N,N-diisopropylethylamine (2.15 mL, 12.3 mmol) in THF (27.4 mL) was cooled to 0° C., and 2,2,2-trichloroethyl chloroformate (1.24 mL, 9.01 mmol) was added, followed by stirring the mixture for 10 minutes. Water was added to the reaction solution and the aqueous layer was extracted with ethyl acetate and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=75/25-50/50) to obtain 2.23 g of the captioned compound (71% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].C=O.[C:14]([O-])(=[O:16])C>O.C(O)(=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:14][OH:16])[C:5]=1[OH:11]
Reactant: Cc1ccc(O)c(C)c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)c(O)c(CO)c1
Reaction time: 8 h
Yield: 97.4 %

Procedure:
75 g of NaOH were dissolved in 300 ml of deionized (DI) water. 183.3 g 2,4-dimethylphenol were added, and the mixture was cooled to 15°-20° C. 188 g of aqueous formaldehyde (made from 152g 37% formalin diluted with 36 g water) were added over half an hour, while the temperature was maintained below 20° C. After stirring overnight, Thin Layer Chromotography (TLC) in 2:1 hexane/ethyl. acetate showed a single spot, and no remaining 2,4-dimethylphenol. The pH was then adjusted to 6-7 with about 200 ml of 50% aqueous acetic acid. The mixture was transferred to a 2 liter beaker, and extracted with ethyl acetate (400 ml). Removal of the ethyl acetate in a vacuum gave 221.0 g (97.4%) of the desired product as a clear oil or a low-melting solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:19](O)[CH2:20][OH:21].CC1C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)N1CCC(C2(c3ccc(F)cc3)OCCO2)CC1
Reaction time: 108 h
Yield: 56.8 %

Procedure:
A mixture of 74.7 parts of 1-acetyl-4-(4-fluorobenzoyl)piperidine, 46.5 parts of 1,2-ethanediol, 3 parts of 4-methylbenzenesulfonic acid and 810 parts of benzene was stirred for 108 hours at reflux temperature using a water separator. After cooling, the reaction mixture was washed successively with 250 parts of water, 22.5 parts of ammonium hydroxide and 250 parts of water. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3COCH3 50:50). The eluent of the desired fraction was evaporated, yielding 50 parts (56.8%) of 1-acetyl-4-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]piperidine (interm. 45).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C(N)CC(C)C.[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5N(CC)C6C=[CH:49][C:50]([C:52](O)=O)=[CH:51][C:43]=6[N:42]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:58]=[CH:57][C:24]([C:25]2[C:30]([C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41]5[N:42]([CH2:43][CH2:51][CH:50]([CH3:52])[CH3:49])[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:37]=4)[N:32]=3)=[CH:29][C:28]([O:55][CH3:56])=[CH:27][CH:26]=2)=[CH:23][CH:22]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(C)CCN
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4CCC(C)C)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and isoamylamine according to the procedure described in the preparation Compound 534.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1.[F:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][N:22]2[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:24]=[C:23]2[C:19]([CH2:20][CH2:21][N:22]2[CH:25]2[CH2:30][CH2:29][N:28]([C:8]3[N:9]=[N:10][C:11]([N:4]4[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]4)=[CH:12][CH:13]=3)[CH2:27][CH2:26]2)=[CH:18][CH:17]=1
Reactant: Fc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: Cc1cn[nH]c1
Reactant: Clc1ccc(Cl)nn1
Product: Cc1cnn(-c2ccc(N3CCC(N4CCc5ccc(F)cc54)CC3)nn2)c1

Procedure:
The title compound was prepared following the procedure as described in Example 14, reacting 4-methylpyrazole, 3,6-dichloropyridazine, and 6-fluoro-1-(piperidin-4-yl)indoline.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]2[N:7]([C@@H:10]3[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]3[O:12][C:13](=[O:15])[CH3:14])[CH:8]=[N:9][C:5]=2[CH:4]=1.[Br:28]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:28][C:8]1[N:7]([C@@H:10]2[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]2[O:12][C:13](=[O:15])[CH3:14])[C:6]2[CH:24]=[CH:25][C:3]([C:2]([F:1])([F:26])[F:27])=[CH:4][C:5]=2[N:9]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cnc2cc(C(F)(F)F)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 115.7 %

Procedure:
To a refluxing solution of 0.2 g (0.52 mmol) of 5-Trifluoromethyl-1-(2,3-di-O-Acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole in 10 mL of dry THF was added 0.2 g (1.1 mmol) of N-bromosuccinimide (NBS). The reaction mixture was further refluxed for 10 min. Additional 0.1 g of NBS was added. After 5 min, the mixture was poured into an ice-cooled solution of 20 mL CHCl3 and 20 mL sat. NaHCO3. The CHCl3 solution was separated and was further washed with sat. NaHCO3. After drying (MgSO4) and solvent removal, 0.28 g of the title compound was obtained as a semi-solid which was used without further purification in the following reaction.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:13])[CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]([O:20]CC)=[O:19].Cl>O.C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]([OH:20])=[O:19])=[C:8]([Cl:13])[CH:7]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(O)c(Cl)c1
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1Cl)C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 37.2 g of 4-t-amyl-2-chlorophenol, 200 ml of toluene, and 20.4 g of sodium hydroxide was heated to 80° C., and 40.3 g of ethyl 2-bromooctanoate was added dropwise thereto over a period of one hour, followed by reacting the mixture at that temperature for 3 hours. After cooling the mixture with water, 300 ml of water was added thereto, and 40 ml of concentrated hydrochloric acid was dropwise added. The organic layer was separated, washed twice with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 55 g of an oily substance.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].[OH-].[Na+].[CH2:21](O)[CH3:22]>>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH:13]([CH3:12])[CH2:14][CH2:15][C:16]([O:18][CH2:21][CH3:22])=[O:17]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=C(O)CCCCBr
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)CCC(C)Sc1nc2ccccc2[nH]1
Yield: 83 %

Procedure:
11 g of 2-mercaptobenzimidazole and 14.6 g of 5-bromovaleric acid were dissolved in 50 ml of ethanol and the mixture was refluxed under heating for 24 hours. After cooling, the mixture was added with wafer and adjusted to pH 8 with aqueous sodium hydroxide. The deposited crystals were collected by filtration and washed with water-containing methanol to obtain 16.9 g of the title compound (yield: 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:44])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH3:33])=[C:25]([S:27]([NH:30][CH3:31])(=[O:28])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:44])=[N:7]1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CNS(=O)(=O)c1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cccc(F)c5)c4C)c3c2)ccc1OC
Yield: 35.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (80 mg, 0.118 mmol) was hydrolyzed by lithium hydroxide (143 mg, 0.593 mmol), THF/Methanol/water (1/1/0.5 mL) to afford 22 mg (36.06% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.47-8.46 (d, 1H), 8.029-8.024 (d, 1H), 7.89-7.86 (m, 2H), 7.41 (s, 1H), 7.38-7.30 (m, 2H), 7.05-6.96 (m, 2H), 6.90-6.85 (m, 1H), 5.36 (s, 2H), 4.00 (s, 3H), 2.53 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H). MS: m/z=520.1 (M+1), HPLC Purity: 93.81% (Method B).
Reaction SMILES: COC1C=C(CNCCCNCCCCNCCCN[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27](OC)[CH:26]=2)C=CC=1O.CNC1N[C:45](=[O:47])[C:44]2[NH:43]CCNC=2N=1.C(S)C(O)C([OH:53])CS>>[NH2:43][C@H:44]([C:45]([OH:47])=[O:53])[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1
Reactant: CNc1nc2c(c(=O)[nH]1)NCCN2
Reactant: OC(CS)C(O)CS
Reactant: COc1cc(CNCCCNCCCCNCCCNCc2ccc(O)c(OC)c2)ccc1O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 0 °C

Procedure:
TH enzymatic activity was assayed using a method modified from Reinhard et al. (Life Sci. 39 (1986) 2185). Frozen cell pellets were sonicated for 30 s in ice cold 0.2%/100 mM Na HEPES, pH 6.99 and centrifuged (10,000 x g, 10 min). A fraction of the supernatant (10 μl) was used to assay TH activity by measuring the amount of 3H2O formed from L-[3,5-3H]tyrosine during the incubation (10 min, 37° C.) in 100 μl of reaction medium (100 mM Na HEPES, pH 6.99, catalase (Sigma) 50 μg, 25 μM L-tyrosine (free-base, Sigma) and 0.2 μCi L-[3,5-3H]tyrosine (Amersham), 1 mM FeSO4, 0.5 mM DL-6-methyl-5,6,7,8-tetrahydropterine, 5 mM dithiotreitol). The reaction was stopped by addition of 1 ml of 7.5% (w/v) charcoal (activated, Sigma) in 1 M HCl. The mixtures were then vortexed (3 s) and centrifuged (10,000 x g, 10 min). Aliquots (100 μl) of the supernatant were then transferred to scintillation vials containing 10 ml of scintillation cocktail (aqueous counting scintillant, Amersham) to measure the amount of 3H2O formed. To make L-tyrosine stock solution, L-[3,5-3H]tyrosine was first speed-vacuum dried to eliminate the contaminating 3H2O before adding 500 μl of cold L-tyrosine 500 μM. Results are expressed in pmol of 3H2O formed by [3H]tyrosine hydroxylation per hour per mg of protein. Protein quantitation was performed according to the method of Bradford et al.
Reaction SMILES: Cl.[NH2:2][C:3](N)([CH3:7])[C:4]([OH:6])=[O:5].[C:9]([C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)(=O)[C:10]([CH3:12])=O.C([N:32](CC)CC)C>CO>[CH3:29][O:28][C:26]([C@H:23]1[CH2:24][CH2:25][C@H:20]([C:17]2[CH:18]=[CH:19][C:14]([C:9]3[N:2]=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=[N:32][C:10]=3[CH3:12])=[CH:15][CH:16]=2)[CH2:21][CH2:22]1)=[O:27]
Reactant: CCN(CC)CC
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)=O)cc2)CC1
Reactant: CC(N)(N)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](c2ccc(-c3nc(C(=O)O)cnc3C)cc2)CC1

Procedure:
Diaminopropionic acid hydrochloride (496 mg, 3.52 mmol) was added to a stirred solution of methyl trans-4-(4-pyruvoylphenyl)cyclohexanecarboxylate (Intermediate 65-2, 844 mg, 2.93 mmol) and triethylamine (1.6 mL, 11.72 mmol) in MeOH (6 mL). After 48 h the reaction mixture was concentrated and the residue was triturated with ether to give the title compound (751 mg, 72%) as a solid that was used without further purification; 1H NMR δ9.04 (1H, s), 7.62 (2H, d), 7.40 (2H, d), 3.64 (3H, obs. s), 2.70-2.55 (1H, m), 2.66 (3H, s), 2.50-2.36 (1H, m), 2.08-1.96 (2H, m), 1.95-1.85 (2H, m), 1.65-1.45 (4H, m); MS 355.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][N:8]=1)=[O:6].[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C:24]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][S:22][C:21]=2[CH:31]=1.CN1CCCC1=O.[OH-].[Na+]>O>[ClH:1].[F:16][C:17]1[CH:18]=[CH:19][C:20]2[C:24]([N:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][NH:4][C:5]([C:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[O:9][N:8]=4)=[O:6])[CH2:29][CH2:30]3)=[CH:23][S:22][C:21]=2[CH:31]=1
Reactant: Fc1ccc2c(N3CCNCC3)csc2c1
Reactant: O=C(NCCCl)c1noc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cl
Product: O=C(NCCN1CCN(c2csc3cc(F)ccc23)CC1)c1noc2ccccc12
Temperature: 160 °C
Yield: 23.6 %

Procedure:
A mixture of N-(2-chloroethyl)-1,2-benzisoxazole-3-carboxamide (4.40 g), 6-fluoro-3-(1-piperazinyl)benzo[b]thiophene (5.90 g), and N-methylpyrrolidinone (100 ml) was heated at 160° C. for 3.0 hr. The reaction mixture was allowed to cool, diluted with water (350 ml), basified with 25% sodium hydroxide to pH-8, and extracted with ether. The combined extracts were washed with water, brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The residue was chromatographed on silica gel, using 75% ethyl acetate in hexanes as the eluant. The appropriate fractions were collected and concentrated. Ethanolic hydrogen chloride was added to the residue. Recrystallization of the precipitate from methanol/ethanol gave 2.13 g (23.6%) of product, mp 225°-228° C. dec.