Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:5][CH:4]1[CH2:6][OH:7].[CH2:8](Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>CN(C=O)C.[Na+].[I-]>[CH2:8]([O:7][CH2:6][C@@H:4]1[CH2:3][O:5]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC1CO1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COC[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
A slurry of NaH (267 g) and NaI (26.5 g) in DMF (3000 mL) was cooled to between −15° C. and −10° C. with ice-brine mixture. A solution of glycidol (480 g) in DMF (1000 mL) was added with stirring for 10 minutes. BnCl (745.5 g) in DMF (800 mL) was added (slightly exothermic) and the reaction was warmed to room temperature followed by stirring for approximately 16 hours. The solution was stirred for a further time period until HPLC analysis showed less than 1% of BnCl remained. The reaction was cooled to −5° C. and water (4 L) was added. MBTE (5 L) was added with stirring for 30 minutes. The organic and aqueous layers were separated and two additions of MBTE (5 L; 3.5 L) were used to extract the aqueous layer. The combined organic layer was washed with brine (1.8 L (×2)) and dried over Na2SO4 for 1 hour. The organic layer was concentrated to dryness, distilled under vacuum (5 mm Hg, 85° C.) to give the product as a yellow liquid (760 g). 1H NMR (CDCl3, 400 MHz): δ 7.27-7.37 (m, 5H), 4.51 (s, 2H), 3.74 (dd, 1H), 3.29 (dd, 1H), 3.14 (m, 1H), 2.72 (dd, 1H), 2.55 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([C:11](=[O:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[F:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:26])[NH:24][NH2:25])[CH:18]=[C:19]([F:21])[CH:20]=1>CO>[F:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:26])[NH:24][N:25]=[C:8]([OH:10])[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[C:11](=[O:13])[CH3:12])[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: NNC(=O)Nc1cc(F)cc(F)c1
Reactant: CC(=O)c1cccc(F)c1C(=O)O
Solvent: CO
Product: CC(=O)c1cccc(F)c1C(O)=NNC(=O)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3 g of 6-fluoro-2-acetyl benzoic acid and 3 g of 4-(3,5-difluorophenyl)semicarbazide are mixed in 20 ml of methanol and heated until clear. The solution is then stirred at R.T. for 24 hr. A white solid forms which is filtered and dried in vacuum at 60° to yield the title product m.p. 227° (decomp.). The corresponding sodium salt is made by reaction of the free acid with 25% sodium methoxylate/methanol.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[H-].[Na+].Br[CH2:21][CH2:22][O:23]C1CCCCO1>CN(C)C=O>[C:1]([N:11]1[CH2:16][CH2:15][N:14]([CH2:21][CH2:22][OH:23])[C:13](=[O:17])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)OCc2ccccc2)CCN1CCO
Reaction time: 20 h

Procedure:
To a solution of 1-carbobenzoxypiperazin-3-one (234 mg, 1.0 mmol) in dimethylformamide (10 ml) under nitrogen was added in one portion, 50% sodium hydride (48 mg, 1 mmol). After stirring at 20°-25° for 30 minutes until all of the sodium hydride had reacted, a solution of 2-(2-bromoethoxy)-tetrahydropyran (209 mg, 1 mmol) in dimethylformamide (2 ml) was added and the reaction mixture stirred at 20°-25° for 20 hours. Solvent was removed at 40°-45° and 0.1 mm and the residue chromatographed over silica gel. Elution with 2% isopropanol -98% methylene chloride gave the pure protected alcohol as an oil.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([O:17][CH3:18])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([O:17][CH3:18])[C:10]=2[N:14]=1
Reactant: CCC(CC)c1ccc(OC)c2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCC(CC)c1ccc(OC)c2nc(Cl)n(C)c12
Temperature: 110 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
A mixture of 7-(1-ethylpropyl)-4-methoxy-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (190 mg, 0.765 mmol) in phosphorous oxychloride (2.14 mL) was stirred at 110° C. for 6 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate 10:1-1:1) and crystallized from ethyl acetate/n-hexane to afford the title compound as colorless crystals (123 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]([C:16]1[N:17]=[N:18][NH:19][N:20]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][C:9](=[O:21])[NH:10][C@H:11]([C:16]1[N:20]=[N:19][N:18]([CH3:22])[N:17]=1)[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)c1nn[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cn1nnc([C@@H](NC(=O)OCc2ccccc2)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
A suspension of benzyl[(1S)-2,2-dimethyl-1-(2H-tetrazol-5-yl)propyl]carbamate (0.41 g, 1.4 mmol), potassium carbonate (1.0 g, 7.0 mmol) and methyl iodide (0.35 mL, 5.6 mmol) in acetone (7 mL) was stirred at 0° C. for 10 min and warmed to rt. After 5 h, the reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (8/1-4/1-1/1) to afford 0.29 g (68%) of the title compound.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)[C:4]#[N:5].[CH3:19][O-].[Na+].CI.[Cl-].[NH4+]>CO>[CH3:1][S:2][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)([CH3:19])[C:4]#[N:5]
Reactant: CSC(C#N)c1cccc(Oc2ccccc2)c1
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSC(C)(C#N)c1cccc(Oc2ccccc2)c1
Yield: 82 %

Procedure:
956 ml of alpha-(methylthio)(m-phenoxyphenyl)-acetonitrile was dissolved in 5 ml of anhydrous methanol, and 1.7 ml of a 2.5 M methanol solution of sodium methoxide was added at room temperature in an atmosphere of argon. The mixture was stirred, and 0.34 ml of methyl iodide was added dropwise. The mixture was further stirred for 1 hour at room temperature. An aqueous solution of ammonium chloride (3 g/20 ml) was added, and the mixture was extracted with 20 ml of ether three times. The extract was washed with 25 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; hexane and methylene chloride) to afford 817 mg (yield 82%) of alpha-(methylthio)-alpha-(m-phenoxyphenyl)-propionitrile as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:22](C)=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16](O)[CH3:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[C:24]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:24])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[CH2:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(CNc2cccn3c(C(C)O)c(C)nc23)c1C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=Cc1c(C)nc2c(NCc3c(C)cccc3C)cccn12
Yield: 141.8 %

Procedure:
A mixture of 1-[8-(2,3-dimethylbenzylamino)-2-methylimidazo[1,2-a]pyridine-3-yl]-1-ethanol (0.2 g, 0.65 mmol) and p-toluenesulfonic acid (0.029 g, 0.15 mmol) in benzene (40 ml) was refluxed for 20 h with Dean-Stark water separation. The solvent was evaporated under reduced pressure, the residue was solved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using methylene chloride:ethyl acetate (10:1) gave 0.062 g (33%) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[O:3][C:4]1[CH:9]=CC[CH2:6][CH:5]=1.[C:12]([O:17][CH3:18])(=[O:16])[C:13]#[C:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:15][C:14]1[CH:9]=[C:4]([O:3][Si:2]([CH3:11])([CH3:10])[CH3:1])[CH:5]=[CH:6][C:13]=1[C:12]([O:17][CH3:18])=[O:16]
Reactant: C[Si](C)(C)OC1=CCCC=C1
Reactant: CC#CC(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(O[Si](C)(C)C)cc1C
Temperature: 150 °C
Yield: 67.1 %

Procedure:
A 50 mL round bottom flask equipped with magnetic stir bar and condenser was charged with 6.0 g of 2-trimethylsilyloxy-1,3-cyclohexadiene, 3.5 g methyl tetrolate in 3 mL dry toluene. The reaction was heated to 150° C. for 50 hours at which point 1H-NMR indicated no starting diene. The raction was concentrated in vacuo to provide 5.7 g (67%) methyl 2-methyl-4-trimethylsilyloxybenzoate.
Reaction SMILES: C(O)C(C)C.[O:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12].[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=2)[N:23]=[C:22](Cl)[N:21]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:20]([NH2:19])=[N:21][C:22]([N:16]3[CH2:15][CH2:14][N:13]([C:11]([CH:7]4[O:6][CH2:10][CH2:9][CH2:8]4)=[O:12])[CH2:18][CH2:17]3)=[N:23][C:24]2=[CH:25][C:26]=1[O:32][CH3:33]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Solvent: CC(C)CO
Solvent: O
Product: COc1cc2nc(N3CCN(C(=O)C4CCCO4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Yield: 109.2 %

Procedure:
To a solution of iso-butanol (306 ml), water (34 ml) and N-(2-tetrahydrofuroyl)piperazine (20 g) were added, while stirring, 4-amino-2-chloro-6,7-dimethoxyquinazoline (22.2 g). The reaction mixture was heated to reflux and the reflux was maintained for about 13 hours. Then the reaction mixture was cooled to room temperature and stirred at this temperature for about 12 hours. The crystals were collected by filtration, washed with iso-butanol and dried in vacuo at 40° C. to yield 39.2 g (91.9%) of Terazosin.HCl dihydrate. See Trial A in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]2[NH:6][C:7]([CH:9]([CH:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[NH:10][C:11](=[O:26])[C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:19])=[C:14]([CH3:25])[CH:13]=3)=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[C:37](Cl)(=[O:39])[CH3:38].O>O1CCCC1>[C:37]([N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([CH:9]([C:7]2[NH:6][C:5]3[CH:33]=[CH:34][C:2]([Cl:1])=[CH:3][C:4]=3[N:8]=2)[NH:10][C:11](=[O:26])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[C:14]([CH3:25])[CH:13]=2)[CH2:28]1)(=[O:39])[CH3:38]
Reactant: Cc1cc(C(=O)NC(c2nc3cc(Cl)ccc3[nH]2)C2CCCNC2)ccc1C(=O)N1CCCC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCCC(C(NC(=O)c2ccc(C(=O)N3CCCC3)c(C)c2)c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
90 mg (0.16 mmol) of rac.-N-[(5-chloro-1H-benzimidazol-2-yl)-(piperidin-3-yl)methyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is dissolved in 3 mL of tetrahydrofuran and, after the addition of 8.4 mg (0.17 mmol) of sodium hydride (50% solution in oil), stirred for one hour at 40° C. Then the mixture is cooled to ambient temperature and stirred for a further 16 hours with 11.4 μL (0.16 mmol) of acetyl chloride. Then water is added and the mixture is extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with dichloromethane/ethanol (100:0 and 90:10). The 4 possible stereoisomers were separated into one pair of enantiomers with a high Rf value (Example 189) and one pair of enantiomers with a low Rf value (Example 190). Yield: 30 mg (36% of theory); Rf value: 0.37 (silica gel; dichloromethane/ethanol=9:1); C28H32ClN5O3 (522.05); mass spectrum: (M+H)+=522/524 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([OH:19])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:29][O:30][CH2:31]Cl.Cl>ClCCl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([O:19][CH2:29][O:30][CH3:31])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2]
Reactant: COCCl
Reactant: CCOC(=O)Nc1c(F)ccc(O)c1C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Nc1c(F)ccc(OCOC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
26.6 g of the resulting ethyl 2-(N-ethoxycarbonylamino)-3-fluoro-6-hydroxybenzoate was dissolved in 300 ml of dichloromethane under argon atmosphere, 20.5 ml of diisopropylethylamine and 9.0 ml of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. Additional 20.5 ml of diisopropylethylamine and 9.0 ml of chloromethyl methyl ether were added and the mixture was stirred for 1.6 hours. Additional 5.1 ml of diisopropylethylamine and 2.2 ml of chloromethyl methyl ether were added and the mixture was stirred for 1 hour. An aqueous dilute solution of hydrochloric acid was added to the reaction solution, the mixture was extracted with dichloromethane, the organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 2-(N-ethoxycarbonylamino)-3-fluoro-6-methoxymethoxybenzoate.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=3)[C:11]=2[CH2:12][CH2:13][CH2:14][OH:15])=[O:6])[CH2:3][CH2:2]1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28].C(N(CC)CC)C>ClCCl>[CH3:30][S:27]([O:15][CH2:14][CH2:13][CH2:12][C:11]1[N:10]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:21]=2)[N:9]=[N:8][C:7]=1[C:5]([NH:4][CH:1]1[CH2:2][CH2:3]1)=[O:6])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCCOS(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 97.6 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-(3-hydroxypropyl)-1H-1,2,3-triazole-4-carboxamide (3.57 g, 10 mmol) obtained in Example 113 and mesyl chloride (1.37 g, 12 mmol, 1.2 eq.) were dissolved in dichloromethane (50 ml) and triethylamine (1.21 g, 12 mmol, 1.2 eq.) was added dropwise over 10 min while stirring at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. The reaction mixture was washed with 10% brine and saturated brine, dried over anhydrous sodium sulfate and concentrated. Diethyl ether was added and the precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (4.25 g, 97.6%).
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24].Cl>C(#N)C>[C:22]([CH:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:4]([O:12][CH2:13][CH3:14])=[O:11])(=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)CC)C(=O)OCC
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
To magnesium chloride (2.96 g, 31.2 mmol) was added dry acetonitrile (5 mL) and the mixture was then cooled in ice and treated with diethyl malonate (5 g, 31.2 mmol). Once the mixture was cold, triethylamine (8.6 mL, 62.5 mmol) was added and the resulting suspension was stirred for 15 mins. Propionyl chloride (2.71 mL, 31.2 mmol) was added dropwise and the mixture was stirred at 0° C. for 1.5 h and at ambient temperature for 5 h. The mixture was cooled in an ice-bath and treated with aqueous hydrochloric acid (2M, 10 mL) and the product extracted with ether. The organic phase was washed with water then brine, dried and evaporated to afford 6.31 g of a yellow oil. This was dissolved in ether and washed with aqueous hydrochloric acid (2M) then brine, dried and evaporated to afford 5.93 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][N:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[N:12][CH:13]=1)=[O:19]
Reactant: NCc1ccccn1
Reactant: CCc1cc(-c2ccc(C(=O)O)cn2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)NCc3ccccn3)cn2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-5-carboxylic acid and (pyridin-2-ylmethyl)-amine to afford the title compound. MS: m/e=349 (M+H). 1H NMR (δ ppm): 11.71 (s, 1H); 9.28 (t, 1H, J=5.8 Hz); 9.07 (s, 1H); 858 (s, 1H); 8.47 (dd, 1H, J=4.6 and 1.5 Hz); 8.24 (dd, 1H, J=8.3 and 2.5 Hz); 7.75 (m, 1H); 7.63 (d, 1H, J=8.3 Hz); 7.54 (s, 1H); 7.37 (dd, 1H, J=7.7 and 4.6 Hz); 4.53 (d, 2H, J=5.8 Hz); 2.42 (q, 2H, J=7.4 Hz); 2.35 (s, 3H); 1.11 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([C:8]([OH:10])=O)[CH:7]=1)=[O:2].[C:11](N1C=CN=C1)([N:13]1C=CN=[CH:14]1)=O.CNC>O1CCCC1>[CH3:11][N:13]([C:8]([C:6]1[CH:7]=[C:3]([CH:1]=[O:2])[S:4][CH:5]=1)=[O:10])[CH3:14]
Reactant: O=Cc1cc(C(=O)O)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1csc(C=O)c1
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 2-formyl-4-thiophenecarboxylic acid (prepared according to Gronowitz, S., et al., Arkiv. for Kemi. 21:265 (1963)) (1.24 g, 7.94 mmoles) in 50 ml of tetrahydrofuran was added 1,1'-carbonyldiimidazole (1.80 g, 11.10 mmoles) the solution stirred under dry argon for 11/2 hours and treated with excess gaseous dimethylamine. The solution was concentrated in vacuo to an oil which was dissolved in ethyl acetate (60 ml) and extracted with 1N hydrochloric acid (1×30 ml) followed by 5% sodium bicarbonate (1×30 ml). Each of the aqueous extracts was backwashed with ethyl acetate (2×50 ml) and the combined organic layers were dried (magnesium sulfate). Concentration in vacuo furnished a tan solid (1.15 g, 79%). EIMS (m/z): 183 (M+, 31%), 155 (M+ -CO, 38%), 139 (M+ -(CH3)2N, base) and 111 (M+ -(CH3) 2 NCO, 25%); 1HNMR (DMSO-d6) delta, 9.89 (1H, d, J=1.4Hz), 7.89 (1H, dd, J=1.5, 1.4Hz), 7.86 (1H, d, J=1.5Hz), 3.08 (6H, s). This material was used directly without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH:11]([NH:14][CH:15]([CH3:17])[CH3:16])([CH3:13])[CH3:12]>ClCCl>[CH:11]([N:14]([CH:15]([CH3:17])[CH3:16])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)NC(C)C
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)N(C(=O)c1ccc(Br)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromobenzoyl chloride (10.0 g) in dry dichloromethane (60 mL) at 0° C. was slowly added diisopropylamine (19 mL; 3.0 eq). The reaction was stirred overnight under nitrogen and gradually warmed to room temperature. The solution was washed with two portions of water and the organics were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 15% ethyl acetate. Near quantitative yield of product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1.B(F)(F)F.[CH3:17][CH2:18][O:19]CC.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][CH2:17][CH2:18][OH:19])=[CH:6][CH:5]=1
Reactant: CCOCC
Reactant: COC(=O)c1ccc(CO)cc1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(COCCO)cc1
Temperature: -5 °C
Reaction time: 0.58 h
Yield: 60329.8 %

Procedure:
To a flame-dried 2-neck flask was added a solution of methyl-4-(hydroxymethyl)benzoate (2.5 g, 15 mmol) in dichloromethane (30 mL). The reaction was purged with nitrogen and brought to −5° C. A dewar condenser (also flame-dried) containing a dry ice/acetone bath (−78° C.) was affixed to the flask and ethylene oxide-tetradeuterate was added (˜55 drops). Then BF3.Et2O (510 μL, 0.0041 mmol) was added dropwise and the reaction stirred at −5° C. for 35 minutes under nitrogen atmosphere. Monitoring by TLC (100% ethyl acetate) showed complete consumption of the starting material. The reaction was warmed to room temperature and vented to remove any excess ethylene oxide gas. The reaction was then diluted with brine and extracted with dichloromethane (2 times). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude oil. Purification by flash column chromatography (4:1 pentane:ethyl acetate) provided the product as a clear oil (520 mg, 16% yield). 1H NMR (600 MHz, CDCl3) δ 8.02 (d, 2H, J=8.2 Hz), 7.41 (d, 2H, J=8.1 Hz), 4.62 (s, 2H), 3.92 (s, 3H); 13C NMR (150 MHz, CDCl3167.1, 143.5, 130.8) δ 129.9, 127.5, 72.8, 52.4.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C.[NH2:39][C@@H:40]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[CH:67][CH:66]=1)[C:41]([N:43]([C@@H:55]([CH3:63])[CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)=[O:42]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:39][C@@H:40]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[CH:67][CH:66]=1)[C:41]([N:43]([C@@H:55]([CH3:63])[CH:56]([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])[CH2:44][C:45]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:48]=[CH:47][CH:46]=1)=[O:42])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To the solution of 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-3) 182 mg (0.77 mmol), hydroxybenzotriazole 104 mg (0.77 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 148 mg (0.77 mmol) in dichloromethane 3 ml, a solution of (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 260 mg (0.51 mmol) and 4-dimethylaminopyridine 31 mg (0.26 mmol) in dichloromethane 3 ml was added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on Buch silica gel column chromatography (chloroform:methanol=95:5) to obtain the title compound 333 mg (90%).