Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH:12]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[S:6][C:5]([S:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]4[NH:21][N:20]=[N:19][N:18]=4)[CH:12]=3)(=[O:9])=[O:8])=[CH:4][CH:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Br)s1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2cccc(Cl)c2)s1
Yield: 26 %

Procedure:
The product was prepared according to General Procedure 3, described in Example 22, using 5-bromo-N-[3-(1H-tetrazol-5-yl)phenyl]thiophene-2-sulfonamide (Intermediate 17) (19 mg, 0.055 mmol) and 3-chlorophenylboronic acid (9 mg, 0.06 mmol). The title compound was obtained in 26% yield (5.4 mg). MS (ESI+) calcd mass for C17H12ClN5O2S2 417.012094, found 417.012844.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]2[S:23][C:22]([CH:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])=[CH:21][C:20]=2[CH:31]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]2[S:23][C:22]([CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([O:14][CH2:13][C:9]3[NH:10][CH:11]=[CH:12][C:8]=3[CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:26])=[CH:21][C:20]=2[CH:31]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(F)ccc2s1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccccc1)c1cc2cc(F)ccc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzylpyrrolyl methanol (1.8 mmol), 2-(5-fluoro-2-benzothienyl)-3-methylbutanoic acid (2.0 mmol) and 4-dimethylaminopyridine (2.0 mmol) in 20 ml of methylene chloride and 2 ml of DMF is added N,N'-dicyclohexylcarbodiimide (2.0 mml). The reaction mixture is stirred, under nitrogen, for about two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous NaHCO3, water and saturated aqueous NaCl, dried over CaSO4 and solvent evaporated to yield 3-benzylpyrrolylmethyl 2-(5-fluoro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: ClC1C=CC2NC(=O)[O:8][C@:7](C#CC3CC3)([C:12]([F:15])([F:14])[F:13])C=2C=1.Cl[C:23]1[CH:29]=CC(N)=CC=1.C(Cl)(=[O:35])C(C)(C)C.[OH-]>>[F:13][C:12]([F:15])([F:14])[C:7]([O:35][CH2:29][CH3:23])=[O:8]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1Nc2ccc(Cl)cc2[C@@](C#CC2CC2)(C(F)(F)F)O1
Reactant: Nc1ccc(Cl)cc1
Agent: [OH-]
Product: CCOC(=O)C(F)(F)F

Procedure:
Synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one can be accomplished through the use of commercially available 4-chloroaniline. After reaction with pivaloyl chloride in the presence of hydroxide to afford the corresponding amide, treatment with an alkyl lithium and ethyl triflouroacetate is followed by acidification with a mineral acid to provide the salt of the triflouroketone (Scheme 1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH3:14])[C:11]([O-:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:41][CH2:42][C@@H:43]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>C1COCC1.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([CH3:14])[C:11]([NH:41][CH2:42][C@@H:43]([CH2:54][CH:55]([CH3:57])[CH3:56])[C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CNC(=O)OC(C)(C)C)C(=O)[O-]
Reactant: CC(C)C[C@H](CN)C(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](CNC(=O)[C@H](C)CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.8 %

Procedure:
A solution of (2R)-3-(tert-butoxy)carbonylamino-2-methylpropanoate (0.81 g, 4.0 mmol) in THF (20 ml) was cooled under Ar to −15° and successively treated with NMM (0.46 ml, 4.2 mmol), isobutyl chloroformate (0.55 ml, 4.2 mmol) and, after stirring for 5 min, a precooled solution of benzyl (2R)-2-aminomethyl4methylpentanoate toluenesulfonate ((2),1.79 g, 4.4 mmol) and NMM (0.48 ml, 4.4 mmol) in DMF (10 ml). The mixture was allowed to warm to r.t. over a period of 2 h and stirring was continued for further 2 h. The solvent was removed under reduced pressure, the residue dissolved in AcOEt and washed with 10% aq. citric acid (3×), sat. aq. K2CO3 (3×), H2and sat. aq. NaCl soln. The org. phase was dried (MgSO4) and evaporated. Purification by FC (hexane/AcOEt 2:1) yielded The title compound (1.46 g, 87%): White solid.1H-NMR (200 MHz, CDCl3): 0.92 (d, J=5.5, 6H, CH(CH3)2); 1.05 (d, J=6.5, 3H, CHRCH3); 1.23-1.40 (m,1H, CH(CH3)2); 1.44 (s, 9H, C(CH3)3); 1.52-1.77 (m, 2H, CH2CH(CH3)2); 2.30-2.50 (m, 1H, COCHR); 2.68-2.85 (m, 1H, COCHR); 3.08-3.42 (m, 3H, 3 NCH); 3.45-3.60 (m, 1H, NCH); 5.04 (br.,1H, NHCOCHR); 5.16 (s, 2H, CH2Ph); 5.90 (br.,1H, NHCOOtBu); 7.10-7.28 (m, 5H, H-arom.).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].I[CH3:24]>O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[CH2:19][CH2:18][CH:17]([O:20][CH3:24])[CH:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: COc1ccc(C2=CC(O)CC2)cc1OC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2=CC(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-cyclopent-2-en-1-ol (150 mg, 0.55 mmol) (E10) was added to a suspension of powdered potassium hydroxide (89%, 138 mg, 2.2 mmol) under an argon atmosphere and then iodomethane (35μl, 0.56 mmol ) was added. The resulting mixture was stirred at room temperature for 3 hr, poured into water and extracted with ether. The ether extracts were washed three times with water, dried (sodium sulfate) and concentrated under reduced pressure. Purification by flash chromatography, eluting with 2:1 hexanes/ether, provided the title compound as an oil (120 mg, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:9]1[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([N:38]=[N+:39]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:9]1[S:10][CH:11]=[C:12]([C:14](=[N+:38]=[N-:39])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)Cc1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=[N+]=[N-])c1csc(N(Cc2ccc(OC)cc2)C(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
To a solution of ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]acetate (synthesized as per preparation 44; 3.8 g, 9.35 mmol) in dry acetonitrile was added para-toluene sulfonyl azide (2.04 g, 10.3 mmol) followed by DBU (2.09 mL, 14.0 mmol) in dropwise manner. The reaction stirred for 30 min. then poured in ice cold water (20 mL) extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide crude product, which was purified by column chromatography using 5-7% ethyl acetate in hexane to afford Ethyl 2-[2-[tert-butoxycarbonyl-[(4-methoxyphenyl)methyl]amino]thiazol-4-yl]-2-diazo-acetate (3.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=1[CH3:15].OS(O)(=O)=O.[CH3:21]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(C(=O)CCC(=O)O)ccc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(F)c(C)c1
Reaction time: 16 h

Procedure:
To the crude 4-(4-fluoro-3-methyl-phenyl)-4-oxo-butyric acid in 50 mL methanol was added 500 μL concentrated H2SO4 at 25° C. After stirring for 16 h, the mixture was concentrated under reduced pressure and 50 mL water was added. The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic layers washed with brine (2×30 mL) and the product isolated using silica gel chromatography to afford 1.2 g of the title compound as a colorless oil.
Reaction SMILES: C([N:8]1[C:12]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:11][N:10]=[N:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)(=O)C>[C].[Pd].CO>[O:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:12]2[NH:8][N:9]=[N:10][CH:11]=2)[CH2:15][CH2:16]1
Reactant: c1ccc(Cn2nncc2NC2CCOCC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CC(=O)O
Product: c1nn[nH]c1NC1CCOCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A mixture of 1-benzyl-N-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-amine (450 mg), 10% palladium-carbon (containing water by 50%, 450 mg), ammonium formate (631 mg), acetic acid (1.2 mL) and methanol (12 mL) was stirred at 60° C. for 16 hr under a nitrogen atmosphere. The reaction mixture was filtered, and the solvent was evaporated. The residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate-isopropyl alcohol (3:1). The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a white powder (209 mg, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of 4-hydroxybenzoic acid ethyl ester (5.0 g) in N,N-dimethylformamide (50 ml) were sequentially added potassium carbonate (6.2 g) and 1-(2-chloroethyl)piperidine (8.3 g), and the solution was stirred for 1.5 hours at 60° C. The solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to obtain 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (8.3 g). To a solution of 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (34 g) dissolved in ethanol (200 ml) was added an aqueous solution of 2N sodium hydroxide (100 ml), and the solution was refluxed for 1 hour. Ethanol was evaporated in vacuo, water was added and stirred, the solid that was precipitated by adding 2N hydrochloric acid (180 ml) was filtered to provide the title compound (28.2 g).
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH3:8][CH:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[NH:30][CH2:29][CH2:28][C:27]([C:31]([O:33][CH3:34])=[O:32])=[CH:26][C:25]=3[CH:35]=2)=[CH:17][CH:16]=1)[CH3:10].C(OC=O)=O>C1COCC1>[CH:1]([N:30]1[C:24]2[CH:23]=[CH:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][CH:9]([CH3:8])[CH3:10])=[CH:16][CH:17]=3)=[CH:35][C:25]=2[CH:26]=[C:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:28][CH2:29]1)=[O:3]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2NCC1
Reactant: CC(=O)O
Agent: O=COC=O
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(-c3ccc(OCCOC(C)C)cc3)ccc2N(C=O)CC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.51 ml) was added formic acid, (0.25 ml) at 0° C., and the mixture was stirred at 55° C. for 2 hours, air-cooled and diluted with THF (10 ml). In THF (15 ml) was dissolved methyl 7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (462 mg), and the solution was added dropwise to the previously prepared solution of formic anhydride in THF, at 0° C. The mixture was stirred at room temperature for 2 hours, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous, magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give methyl 1-formyl-7-[4-(2-propoxy)ethoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (496 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([O:21][CH3:22])[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)O.S(Cl)(C)(=O)=O>CN(C1C=CN=CC=1)C.ClCCl.CCOCC>[CH3:1][O:2][C:3](=[O:23])[C:4]([O:21][CH3:22])=[CH:5][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: COC(=O)C(OC)C(O)c1cccc(OCc2ccccc2)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OC

Procedure:
A mixture of 3-(3-Benzyloxy-phenyl)-3-hydroxy-2-methoxy-propionic acid methyl ester (1 eq), mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at room temperature overnight. The Reaction mixture was diluted with ether and washed with HCl 1N. Dried and concentrated in vacuo to give a residue which was chromatographed in silica gel to yield the title compound.
Reaction SMILES: C(OC(C1C=C(C2C=CC(C[S:19][CH2:20][CH2:21][OH:22])=CC=2)C=CC=1)=O)C.[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40]Br)=[CH:30][CH:29]=1)=[O:27])[CH3:24].SCCO.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][S:19][CH2:20][CH2:21][OH:22])=[CH:30][CH:29]=1)=[O:27])[CH3:24]
Reactant: CCOC(=O)c1ccc(-c2ccccc2CBr)cc1
Reactant: CCOC(=O)c1cccc(-c2ccc(CSCCO)cc2)c1
Agent: O=C([O-])[O-]
Agent: OCCS
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2ccccc2CSCCO)cc1

Procedure:
2′-(2-Hydroxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester was synthesized as described for 4′-(2-hydroxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester. 2′-Bromomethyl-biphenyl-4-carboxylic acid ethyl ester (5.77 g, 18.1 mmol, 1 eq.) in anhydrous DMF was treated with 2-mercaptoethanol (2.83 g, 36.2 mmol, 2 eq.) and potassium carbonate (7.50 g, 54.3 mmol, 3 eq.). When complete, the reaction was worked up as described leaving a yellow oil
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12](=[O:22])[C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([OH:18])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O.ON1[C:29]2C=CC=C[C:28]=2N=N1.C([N:36]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:37][C:38]([OH:40])=[O:39])C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.O>[CH2:28]([O:40][C:38](=[O:39])[CH2:37][N:36]([C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12](=[O:22])[NH:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[CH:14]=1)[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH3:29]
Reactant: O=C(O)c1cccc(C(=O)NCc2ccc3c(c2)OCO3)c1
Reactant: CCN(CC(=O)O)Cc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CN(Cc1ccccc1)C(=O)c1cccc(C(=O)NCc2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-benzo[1,3]dioxol-5-ylmethyl-isophthalamic acid (3.0 g, 10 mmol) in methylene chloride was added 1-hydroxy-benzotriazole monohydrate (“HOBt”) (1.35 g, 10 mmol) and ethyl N-benzylglycine (1.94 g, 10 mmol). To this was added 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (“EDAC”) (1.92 g, 10 mmol) and the mix stirred at room temperature for 24 hours. The solution treated with water (150 mL) and the organic phase separated, washed with 10% citric acid (100 mL), saturated sodium bicarbonate (100 mL) and brine (100 mL). The organic phase dried over magnesium sulfate and evaporated at reduced pressure to give ({3-[(1,3-benzodioxol-5-ylmethyl)-carbamoyl]-benzoyl}-benzyl-amino)-acetic acid ethyl ester as a solid, 3.69 g. To a solution of this ester (3.6 g, 7.6 mmol) in a mix of water (15 mL), dioxane (60 mL) and ethanol (20 mL) was added sodium hydroxide (0.72 g, 18 mmol). The mixture stirred at 50° C. for 24 hours. The solution cooled to room temperature and evaporated at reduced pressure free of solvents. The residue was diluted with water (100 mL) and washed with ether (2×50 mL). The ether discarded and the aqueous phase made acidic with 6N HCl. This was extracted with ethyl acetate (2×100 mL). The organic phases washed with brine (100 mL) and dried over magnesium sulfate. The solvent was evaporated at reduced pressure to give the title compound, 3.41 g. Microanalysis (C25H22N2O6.0.3H2O): Calc'd: C=66.45; H=5.05; N=6.20. Found: C=66.25; H=5.15; N=5.99.
Reaction SMILES: [C:1]([C:4](=[CH:9][C:10]1[C:11]([CH3:19])=[N:12][N:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=12)[C:5]([O:7][CH3:8])=[O:6])(=O)[CH3:2].[NH2:20]/[C:21](/[CH3:37])=[CH:22]\[C:23]([O:25][CH2:26][CH2:27][N:28]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:29])=[O:24]>C(O)(C)C>[CH3:2][C:1]1[NH:20][C:21]([CH3:37])=[C:22]([C:23]([O:25][CH2:26][CH2:27][N:28]([CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH3:29])=[O:24])[CH:9]([C:10]2[C:11]([CH3:19])=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: C/C(N)=C/C(=O)OCCN(C)Cc1ccccc1
Reactant: COC(=O)C(=Cc1c(C)nn2ccccc12)C(C)=O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)Cc2ccccc2)C1c1c(C)nn2ccccc12

Procedure:
A solution of 24.9 g of methyl 2-acetyl-3-(2-methylpyrazolo[1,5-a]pyridin-3-yl)acrylate and 28.8 g of 2-(N-benzyl-N-methylamino)ethyl 3-aminocrotonate in 125 ml of isopropylalcohol was refluxed for 8.5 hours, then concentrated. The resulting residue was dissolved in 100 ml of ethyl acetate, washed with 1 N-hydrochloric acid, and then extracted with 2 N-hydrochloric acid three times. The resulting hydrochloric acid layer was alkalized with 5 N-aqueous sodium hydroxide at pH 9, and then extracted with ethyl acetate. The ethyl acetate layer was washed with salt water, dried over anhydrous sodium sulfate and then concentrated. Hexane was added to the resulting residue, and insoluble layer was collected, then recrystallized from diethyl ether-hexane mixtures.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9].[NH2:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=1>>[NH2:15][C:16]1[C:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[O:9])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1cccs1
Product: Nc1cccnc1Nc1ccccc1C(=O)c1cccs1

Procedure:
In accordance with the procedure of Intermediate 9, (2-aminophenyl)(2-thienyl)methanone, prepared by the method of Steinkopf & Gunther, Ann. 522, 28-34 (1936), is reacted with 3-amino-2-chloropyridine to give the title compound.
Reaction SMILES: Br[C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][N:6]2[C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[CH3:20][N:3]1[C:2]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([F:33])([F:32])[F:21])=[C:10]2[C:5]([N:6]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])[CH2:7][CH2:8][CH2:9]2)=[N:4]1
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(C)c1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(N2CCCc3c2nn(C)c3-c2ccccc2C(F)(F)F)c(C)c1
Temperature: 100 °C
Yield: 36.4 %

Procedure:
A mixture of 200 mg of 3-bromo-2-methyl-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, 124 mg of 2-trifluoromethylphenylboronic acid, and 14 mg of tetrakistriphenylphosphine palladium (0) in 2 mL of dioxane was treated with a solution of 210 mg of sodium carbonate in 2 mL of water. The mixture was placed under an atmosphere of argon and heated to 100° C. for 20 h. The mixture was cooled to room temperature, diluted with 20 mL of ethyl acetate, washed with 20 mL of 1 M HCl and 20 mL of brine, dried over magnesium sulfate, and evaporated to dryness. The residue was purified by flash silica gel column chromatography using 7% acetone/hexane as solvent yielding 87 mg of 2-methyl-3-(2-trifluoromethylphenyl)-7-(2,4,6-trimethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, mp 59-63° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C)C=O>[N:34]([CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 65 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
The 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl methanesulfonate (169.1 mg, 0.351 mmol) obtained in step C was dissolved in N,N-dimethylformamide (1.3 ml). Thereafter, sodium azide (96.2 mg, 1.33 mmol) was added to the obtained solution, and the mixture was then stirred at 65° C. for 4 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1 to 3:1), so as to obtain 7-(5-azidomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (139.6 mg; yield: 93%) in the form of a colorless solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4]Br.[NH2:7][C:8]([NH2:10])=[S:9].[CH3:11][OH:12]>C(OCC)C>[CH3:11][O:12][CH2:2][C:3]1[N:7]=[C:8]([NH2:10])[S:9][CH:4]=1
Reactant: NC(N)=S
Reactant: CO
Reactant: O=C(CBr)CBr
Solvent: CCOCC
Product: COCc1csc(N)n1
Yield: 9 %

Procedure:
1,3-Dibromo-propan-2-one (9 g, 42 mmol) was dissolved in methanol. (90 mL) followed by the addition of thiourea (3.2 g, 42.5 mmol) and the dark colored mixture was refluxed overnight. The solvent was then removed under reduced pressure and the remaining oil was dissolved in an ethyl acetate/water. The mixture was acidified with 1N HCl to pH 1 and extracted with three portions of ethyl acetate. The aqueous layer was then treated with solid sodium carbonate to pH 8 and again extracted with three portions of ethyl acetate. The combined, organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product. After purification on silica gel (NH2-modified) with ethyl acetate/n-hepatane as eluents, the desired fractions were combined and concentrated under reduced pressure to yield a solid which was stirred in diethyl ether, filtered and dried to give the title compound as a light brown solid. (0.53 g, 9% yield) MS (ISP): m/e 145.1 (M−H)+