Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH2:9]([SnH:13]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1>[CH2:18]([Sn:13]([CH2:9][CH2:10][CH2:11][CH3:12])([CH2:14][CH2:15][CH2:16][CH3:17])/[CH:2]=[CH:1]/[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH2:19][CH2:20][CH3:21]
Reactant: C#Cc1cccnc1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C/c1cccnc1)(CCCC)CCCC
Yield: 53 %

Procedure:
3-Ethynyl-pyridine (1.03 g, 10 mmol) and tributyltin hydride (3.2 mL, 12 mmol) were stirred in dry THF (10 mL) with a catalytic amount of AIBN at 50° C. for 18 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10% EOAc/hexanes) to give 2.09 g (53%) of the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 8.45 (d, 1H, J=3.2 Hz), 7.75 (d, 1H, J=7.6 Hz), 7.25-7.29 (m, 1H), 6.93 (AB q, 2H, J=57.2, 19.6 Hz), 1.49-1.59 (m, 6H), 1.28-1.39 (m, 6H), 0.87-1.00 (m, 15H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][CH:3]=1.[C:9]1([S:15][CH:16]([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N12CCCN=C1CCCCC2.ClCCl>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl.O>[C:9]1([S:15][CH:16]([S:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1c2ccccc2CCC1C(Sc1ccccc1)Sc1ccccc1
Reactant: Cc1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(N=C2c3ccccc3CCC2C(Sc2ccccc2)Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Under argon, 341 mg (3.19 mmol) of p-toluidine are added to 400 mg (1.06 mmol) of 2-[bis(phenylsulphanyl)methyl]-3,4-dihydronaphthalen-1(2H)-one in 20 ml of toluene. After cooling to 0° C., 0.53 ml (0.53 mmol) of a titanium(IV) tetrachloride solution (1 M in dichloromethane) is added slowly. After 1 h of stirring at 0° C. and a further 1 h at 25° C., 809 mg (5.31 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 5 ml of dichloromethane are added. This mixture is poured into water and extracted with ethyl acetate. After washing with saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate) gives 298 mg of N-{2-[bis(phenylsulphanyl)methyl]-3,4-dihydronaphthalen-1(2H)-ylidene}aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=1[C:15]1[NH:19][N:18]=[N:17][N:16]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>C(#N)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=2[C:15]2[NH:19][N:18]=[N:17][N:16]=2)=[CH:23][C:22]=1[C:30]([F:31])([F:32])[F:33]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(C)C(=O)CCc1ccc(N)c(-c2nnn[nH]2)c1
Solvent: CC#N
Product: CN(C)C(=O)CCc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)c(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-Amino-3-(1H-tetrazol-5-yl)-phenyl]-N,N-dimethyl-propionamide (90 mg) dissolved in acetonitrile at 65° C. under Ar was treated with 4-chloro-3-trifluoromethylphenylisocyanate (85.6 mg) and the mixture was stirred overnight. Cooling to room temperature and filtration afforded 3-[4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-3-(1H-tetrazol-5-yl)-phenyl]-N,N-dimethyl-propionamide. Mp.=184.5-189.3° C.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NNC(=O)c1ccco1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)N(NC(=O)c1ccco1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-t-butyl-N-(2-furoyl)hydrazine (1.0 g) was dissolved in 10 ml toluene and 2 ml water. 50% aqueous sodium hydroxide (1.0 g) was added followed by benzoylchloride (0.8 g). After stirring for 14 hours at room temperature, the solid product, N'-t-butyl-N-(2-furoyl)-N'-benzoylhydrazine, was removed by filtration and washed with water. m.p. 160°-162° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:44]=[CH:43][C:22]([O:23][CH2:24][CH2:25][N:26]([CH2:30][CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[C:27]([NH2:29])=[O:28])=[CH:21][CH:20]=1)#[N:18].C(Cl)Cl>C(#N)C>[CH2:1]([N:8]1[CH2:15][CH:14]2[O:16][CH:10]([CH2:11][N:12]([CH2:31][CH2:30][N:26]([CH2:25][CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:44][CH:43]=3)[C:27]([NH2:29])=[O:28])[CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCN(CCOc2ccc(C#N)cc2)C(N)=O)cc1
Reactant: c1ccc(CN2CC3CNCC(C2)O3)cc1
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1ccc(OCCN(CCN2CC3CN(Cc4ccccc4)CC(C2)O3)C(N)=O)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
3-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (0.18 g, 0.82 mmol; see WO 01/28992) and toluene-4-sulfonic acid 2-{1-[2-(4-cyanophenoxy)ethyl]-ureido}ethyl ester (0.50 g, 1.24 mmol; see Preparation D above) were mixed in dry acetonitrile (15 mL) and stirred at 60° C. overnight. DCM (10 mL) was added, together with 0.5 g of PS—NCO (polymer-supported isocyanate). The mixture was stirred for 2 h, then filtered and evaporated. The crude product was put on a SCX-II (cation exchanger)-plug, which plug was then eluted with DCM:MeOH (NH3-saturated), 80:20. The product was further purified on a Horizon prep. column (40 g, A: DCM(1% MeOH), B: DCM/MeOH(NH3-sat.), 80:20. Gradient 0-30% B over 1080 mL). The product was then further purified by prep. HPLC and finally extracted with DCM/Na2CO3 (aq.) to give 193 mg (51.9%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=1>>[CH3:34][O:33][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([O:31][CH3:32])[CH:28]=1)[CH2:24][N:15]1[C:16]([CH3:19])([CH3:20])[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:22])[CH:12]=2)[C:14]1=[O:21]
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Reactant: COc1cc(CCl)cc(OC)c1
Product: COc1cc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)cc(OC)c1

Procedure:
Prepared as in Example 12-16 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) and 1-(chloromethyl)-3,5-dimethoxybenzene. MS 454 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.3 μM.
Reaction SMILES: [CH3:1][O-].[Na+].CO.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[CH:11][C:10]2=[O:24].C=O.[BH4-].[Na+]>CO>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[O:13][C:12]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][CH3:1])=[CH:19][CH:18]=1)=[CH:11][C:10]2=[O:24]
Reactant: C[O-]
Reactant: Nc1ccc(-c2cc(=O)c3cc(Br)ccc3o2)cc1
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc(-c2cc(=O)c3cc(Br)ccc3o2)cc1

Procedure:
A sodium methylate-methanol solution (0.27 ml) was slowly added dropwise to a methanol solution (15 ml) that contained compound 5 (300 mg, 0.949 mmol) and paraformaldehyde (154 mg, 5.13 mmol), while stirring. The obtained mixture was heated to reflux for 1 hour. Thereafter, sodium borohydride (180 mg, 4.75 mmol) that was in the form of a solid was added to the reaction solution by slow degrees, and the obtained mixture was further heated to reflux for 2 hours. Thereafter, the reaction solvent was distilled away under reduced pressure, and the residue was then subjected to silica gel column chromatography using ethyl acetate/hexane (3/5) as an elution solvent, so as to obtain a product of interest, 6-bromo-4′-methylaminoflavone (compound 6). Yield: 121 mg (yield constant: 38.6%) 1H NMR (300 MHz, CDCl3) δ8.31 (s, 1H), 7.69-7.75 (m, 3H), 7.39 (d, J=8.7 Hz, 1H), 6.62-6.66 (m, 3H), 4.18 (s, 1H). 2.91 (s, 3H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>O>[C:1]1([NH:7][C:8]([N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH3:17])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nccn1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A solution of 11.9 g. (0.1 mol.) of phenylisocyanate in 120 ml. of toluene is added to the stirred solution of 8.61 g. (0.105 mol.) of 2-methyl-imidazole in 60 ml. of water under cooling at a temperature of 10 to 12° C. The reaction mixture is stirred at room temperature for one hour, thereafter the separated product is filtered off, washed and dried. 14.0 g. (69.6%) of 1-phenylcarbamoyl-2-methyl-imidazole are obtained; m.p.: 205°-207° C.
Reaction SMILES: [N:1]1([NH:10][C:11]2[C:16]([N+:17]([O-])=O)=[C:15]([NH:20][N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22]3)[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:30](O)C>C(OCC)(OCC)OCC.C(O)(=O)C>[N:1]1([N:10]2[CH:30]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CCO
Reactant: O=[N+]([O-])c1c(Nn2ccc3ccccc32)ncnc1Nn1ccc2ccccc21
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: c1ccc2c(c1)ccn2Nc1ncnc2c1ncn2-n1ccc2ccccc21
Reaction time: 4 h
Yield: 252.2 %

Procedure:
A mixture of N,N'-bis(1H-indol-1-yl)-5-nitro-4,6-pyrimidinediamine (4 g, 10.4 mmole) in 250 ml ethanol containing 200 mg PtO2 was hydrogenated at 55 psi for four hours, then was filtered and evaporated to 4 g of a solid, m.p. 198°-200° C. A solution of 4-[N-(1H-indol-1-yl)-6-[N-(1H -indol-1-yl)]-4,5,6-pyrimidinetriamine (6 g, 17 mmole) in 25 ml triethyl orthoformate and 9 ml glacial acetic acid stirred one hour at 90° C. then was cooled and evaporated. The residue was dissolved in ether and washed with water, sodium carbonate solution, again with water and saturated sodium chloride, then was dried (anhydrous MgSO4), filtered and evaporated to 6 g of an oil. This oil was purified by flash chromatography to give 4 g of a solid. This solid was recrystallized twice from ethyl acetate-petroleum ether to give 2.8 g (49% overall) of 9-(1H-indol-1-yl)-N-(1H-indol-9H-purin-6-amine, m.p. 196°-198° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([NH2:16])=[CH:10][C:9]=1[OH:17].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[S:19]([O:17][C:9]1[CH:10]=[C:11]([NH:16][S:19]([CH3:18])(=[O:21])=[O:20])[C:12]([O:14][CH3:15])=[CH:13][C:8]=1[CH3:7])(=[O:21])(=[O:20])[CH3:18]
Reactant: COc1cc(C)c(O)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C)c(OS(C)(=O)=O)cc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 175.7 %

Procedure:
20 ml of pyridine was cooled to 0° C. and 2.10 g (3.70 mmol) of 2-methyl-4-methoxy-5-aminophenol and 5.3 g of methanesulfonyl chloride were added thereto. The mixture was adjusted to room temperature followed by stirring for 1 hour. Then 200 ml of water was poured thereto and the mixture was extracted with 300 ml of chloroform, and the extra was washed with 2N hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, brown crystals were obtained. These crystals were purified by column chromatography (the same as the one used in Example 3) and recrystallized from the solvent mixture of ethyl acetate/hexane (2:1). Thus 2.01 g (6.50 mmol) of 2-methyl-4-methoxy-5-mesylaminophenyl mesylate was obtained. The yield was 47%.
Reaction SMILES: CN(C)CCN(C)C.C([Li])(CC)C.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[F:24])[C:18]([OH:20])=[O:19].[Cl:25]C(Cl)(Cl)C(Cl)(Cl)Cl>O.O1CCCC1>[Cl:25][C:16]1[C:15]([F:14])=[C:23]([F:24])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(F)c(F)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a mixture of N,N,N′,N′-tetramethylethylenediamine (8.40 mL) and tetrahydrofuran (75 mL) was added sec-butyllithium (1.0 mol/L cyclohexane solution, 55.7 mL) under an argon atmosphere at −78° C., and the mixture was stirred for 30 min. A mixture of 3,4-difluorobenzoic acid (4.00 g) and tetrahydrofuran (25 mL) was added dropwise to the reaction mixture at the same temperature over 30 min. After the reaction mixture was stirred for 30 min, a mixture of hexachloroethane (24.0 g) and tetrahydrofuran (40 mL) was added dropwise to the reaction mixture at the same temperature over 30 min. After stirring for 30 min while raising the temperature to room temperature, the reaction mixture was poured into water. The aqueous layer was washed with diisopropyl ether, acidified with 6 mol/L hydrochloric acid and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was washed with diethyl ether to give the title product as a solid (yield: 2.95 g).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1.CC(C)(C(=O)CC(=O)C(C)(C)C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>CN1C(=O)CCC1.CO.[Cu]Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=2[F:19])[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=2)=[C:26]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:25]=1
Reactant: Oc1ccc(Cl)cc1Oc1ccccc1
Reactant: COC(=O)CCc1ccc(Oc2ccc(F)c(Br)c2)cc1C
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2ccc(F)c(Oc3ccc(Cl)cc3Oc3ccccc3)c2)ccc1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
A solution of 3-[4-(3-bromo-4-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.1 g, 0.27 mmol), 4-chloro-2-phenoxy-phenol (60 mg, 0.27 mmol), copper(I) chloride (13 mg, 0.13 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.01 mL, 0.07 mmol), and cesium carbonate (105 mg, 0.32 mmol) in NMP (3 mL) is heated to 120° C. The reaction is stirred overnight and cooled to rt. The reaction is then quenched with 1N aqueous HCl and extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude ester intermediate. The intermediate is treated with 5N NaOH (0.4 mL, 2.2 mmol) in MeOH (5 mL) and heated to reflux. The reaction is stirred at reflux for 2 hours and then cooled. The reaction is quenched with 1N aqueous HCl to obtain pH=4. The aqueous layer is extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude product. The crude is purified by prep HPLC to afford 15 mg (11%) of desired product.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:25][C:26]([NH2:38])([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH3:27]>>[CH3:27][C:26]([NH:38][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)=[CH:18][CH:19]=1)([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=1)[CH3:25]
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: CC(C)(N)c1ccc(C(F)(F)F)cc1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNC(C)(C)c3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 78 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1-methyl-1-[4-(trifluoromethyl)phenyl]ethylamine gave the title compound as a colorless oil (78%). 1H NMR (CDCl3, 300 MHz) δ 8.07 (d, J=7.9 Hz, 2H), 7.73-7.59 (m, 4H), 7.49 (d, J=8.3 Hz, 2H), 3.57 (s, 2H), 2.80 (t, J=7.5 Hz, 2H), 1.89-1.74 (m, 2H), 1.57 (s, 3H), 1.47-1.17 (m, 19H), 0.88 (t, J=7.0 Hz, 3H). M+(LC/MS(ESI)): 516.3. HPLC (Condition A), Rt: 5.02 min (HPLC purity: 98.2%).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1>[Pd].CO>[NH2:9][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(O)c(N)n1

Procedure:
3-Hydroxy-6-methyl-2-nitropyridine (3.5 g.) in 75 ml. of methanol was reduced over 1 g. of 5% palladium-on-carbon catalyst. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 2-amino-3-hydroxy-6-methylpyridine which was used directly in the next stop.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])[N:9]=1.[OH-].[K+]>CO.O>[CH3:1][NH:2][C:3](=[O:16])[NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[N:9]=1
Reactant: CCOC(=O)Cc1csc(NC(=O)NC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CNC(=O)Nc1nc(CC(=O)O)cs1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
To a solution of ethyl 2-(3-methylureido)thiazol-4-ylacetate (12.8 g.) in a mixture of methanol (240 ml.) and water (240 ml.) was dropwise added 1 N potassium hydroxide aqueous solution (52.7 ml.) with stirring at room temperature, and the solution was stirred for overnight at the same temperature, and then methanol was distilled off therefrom under reduced pressure. The remaining aqueous layer was washed with ethyl acetate, and then 1 N hydrochloric acid (52.7 ml.) was added thereto under ice-cooling. The precipitated crystals were collected by filtration, washed with water and then dried to give colorless crystals of 2-(3-methylureido)thiazol-4-ylacetic acid (9.7 g.), mp 190° C. (dec.).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:11][C:10]2([CH3:35])[CH3:34])=[O:4].Cl>CO.O1CCCC1.[OH-].[Na+].O>[F:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:16]=1)[CH2:11][C:10]2([CH3:35])[CH3:34]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)CC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1N1CCN(c2cccc(C3CC(C)(C)c4cc(F)cc(C(=O)O)c4N3)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
A mixture of 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.36 g, 0.74 mmol) in methanol (3 mL) and tetrahydrofuran (10 mL), 30% sodium hydroxide in water (1 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-fluoro-4,4-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (0.32 g, 90%) as a white solid which was used for next step without further purification: MS (ESI) M+1=474.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH2:17][C:18]([Cl:20])=[CH2:19])(C(OC)=O)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[K+]>CO.O>[CH3:1][O:2][C:3](=[O:21])[CH:4]([CH2:17][C:18]([Cl:20])=[CH2:19])[CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: C=C(Cl)CC(CC(=O)OC(C)(C)C)(C(=O)OC)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(Cl)CC(CC(=O)OC(C)(C)C)C(=O)OC
Reaction time: 24 h

Procedure:
The title compound of Example 2B (1502 g, 4.18 mol) was dissolved in MeOH (2650 mL). While maintaining a temperature of 30° or below for the ensuing mixture, a cold solution of KOH (329 g, 5.85 mol) in H2O (1335 mL) was added dropwise over 20 min. The mixture was stirred vigorously for 24 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:15][C:7]1[C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:9][C:8]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1oc2ccc(Cl)cc2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1oc2ccc(Cl)cc2c1CBr
Yield: 75.6 %

Procedure:
A mixture of ethyl 5-chloro-3-methyl-2 -benzofurancarboxylate (52.5 g, 0.22 mol), N-bromosuccinimide (39.15 g, 0.22 mol) and benzoyl peroxide (0.4 g) in carbon tetrachloride (750 ml) was stirred and refluxed for 10 hours. The mixture was cooled, filtered and the filtrate was concentrated. The crude product was recrystallized from hexane to give 52.8 g (76%) of ethyl 3-bromomethyl-5-chloro-2-benzofurancarboxylate: mp 112-114° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C>[Pt]=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:21]([F:24])([F:22])[F:23])=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(Cl)c2C(F)(F)F)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(Cl)c2C(F)(F)F)CC1
Reaction time: 16 h
Yield: 26.1 %

Procedure:
A mixture of tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.438 g, 1.21 mmol), platinum oxide (0.082 g, 0.363 mmol), acetic acid (0.073 g, 1.21 mmol), and ethyl acetate (20 mL) was hydrogenated using a balloon for 20 h and filtered. The material was re-submitted to hydrogenation at 80° C. for 16 h and filtered. After concentration, the residue was chromatographed over silica gel (0-30% EtOAc in hexanes) to give tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate as colorless thick oil (0.115 g, 26%): 1H NMR (300 MHz, CDCl3) δ7.42-7.30 (m, 3H), 4.25 (br, 2H), 3.21 (m, 1H), 2.81 (m, 2H), 1.80-1.60 (m, 4H), 1.49 (s, 9H); MS (ESI+) m/z 308 [M+H]+.