Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH2:4][C:5]1[O:12][C:11]2[CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[NH:8][C:7]=2[CH:6]=1)C.CI.[BH4-].[Na+].Cl.CC1CCCCC1.C>>[CH3:4][C:5]1[O:12][C:11]2[CH:10]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[NH:8][C:7]=2[CH:6]=1
Reactant: COC(=O)c1cc2oc(CN(C)C)cc2[nH]1
Agent: C
Agent: Cl
Agent: [BH4-]
Solvent: CC1CCCCC1
Solvent: CI
Product: COC(=O)c1cc2oc(C)cc2[nH]1
Reaction time: 1 h
Yield: 53.5 %

Procedure:
Under N2, to methyl 2-[(dimethylamino)methyl]-4H-furo[3,2-b]pyrrole-5-carboxylate (0.58 g, 2.61 mmol) was added methyl iodide (3 mL, 4.82 mmol). The mixture was allowed to stand at rt for 1 h, and then the methyl iodide was removed. The resulting salt was dissolved in absolute methanol (5 mL). To this solution was carefully added sodium borohydride (2.21 g, 5.84 mmol) in small portions. After the addition was complete, the reaction mixture was dilute to a volume of 25 mL by the addition of 3N hydrochloric acid. The mixture was stored in the refrigerator overnight, and then the blue precipitate was dissolved in boiling methylcyclohexane, and the solution was treated with Darco and filtered. The filtrate was evaporated and purified by chromatography over silica gel (0 to 40% EtOAc/heptane over 30 min) to give methyl 2-methyl-4H-furo[3,2-b]pyrrole-5-carboxylate (0.25 g, 53%). 1H NMR (400 MHz, CDCl3) δ ppm 2.42 (s, 3H) 3.87 (s, 3H) 6.09 (d, J=0.49 Hz, 1H) 6.74 (s, 1H) 8.56 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12.[CH3:17][C:18]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:19]=1[NH2:20]>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:20][C:19]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:18]=3[CH3:17])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[N:7][C:6]=12
Reactant: CCOC(=O)c1cnc2c(Br)cnn2c1Cl
Reactant: Cc1ccc(C)c(N)c1
Product: CCOC(=O)c1cnc2c(Br)cnn2c1Nc1cc(C)ccc1C
Yield: 67.7 %

Procedure:
In the same manner as in Example 1, step 4 and using ethyl 3-bromo-7-chloropyrazolo[1,5-a]pyrimidine-6-carboxylate (400 mg, 1.31 mmol) obtained in Example 22, step 1 and 2,5-dimethylaniline (0.19 mL, 1.57 mmol), the title compound (345 mg, 68%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:24]=1[C:25]#[N:26].C([O:35][C:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[CH2:43][CH2:44][CH2:45]O)=[O:37])(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]([CH3:9])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:45][CH2:44][CH2:43][N:39]2[CH2:40][CH2:41][CH2:42][C@H:38]2[C:36]([OH:37])=[O:35])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:20]=[N:21][C:22]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:24]=1[C:25]#[N:26]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1CCCO
Reactant: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C(=O)c1ccc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)c1)c1ccccc1OCCCN1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-N-(2-hydroxy-phenyl)-N-methyl-benzamide (30 mg, 0.069 mmol) dissolved in THF (700 μL), (S)-1-(3-hydroxy-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester (18 mg, 0.078 mmol), triphenylphosphine (26 mg, 0.1 mmol) and DIAD (20 μL, 0.1 mmol) were added. The mixture was stirred at rt overnight, concentrated, diluted with 1 mL MeOH and purified by prep HPLC. The resulting (S)-1-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propyl]-pyrrolidine-2-carboxylic acid tert-butyl ester was treated with 50% TFA in DCM (2 mL), stirred at rt for 4 hrs and concentrated yielding (S)-1-[3-(2-{[4-chloro-3-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-benzoyl]-methyl-amino}-phenoxy)-propyl]-pyrrolidine-2-carboxylic acid 50-1. MS: 587.4 (M+H)+, tR=4.34 min (method 3).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[N:34]1([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]4[O:20][C:21]([C:24]5[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=5)=[CH:22][N:23]=4)=[O:18])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCCC5)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (19 mg, 0.043 mmol) and pyrrolidine (0.005 mL, 0.07 mmol) were dissolved in dichloroethane (2 mL) and NaBH(OAc)3 (18 mg, 0.086 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 3 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 2.5% Et3N/EtOAc) to furnish methyl 6-(2-(3-(4′-(pyrrolidin-1-ylmethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a cloudy oil (16 mg, 75%): 1H NMR (CDCl3, 600 MHz) δ 8.11 (d, 1H, J=7.7 Hz), 8.02 (d, 2H, J=9.0 Hz), 7.96 (t, 1H, J=7.8 Hz), 7.53-7.51 (m, 4H), 7.38 (d, 2H, J=8.0 Hz), 7.33 (d, 2H, J=8.0 Hz), 4.03 (s, 3H), 3.65 (s, 2H), 3.51 (t, 2H, J=7.6 Hz), 3.15 (t, 2H, J=7.6 Hz), 2.54 (s, 4H), 1.81-1.79 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.5, 139.2, 139.1, 138.3, 138.3, 129.3, 128.8, 128.0, 127.1, 126.8, 125.2, 123.3, 60.4, 54.2, 53.1, 40.6, 29.3, 23.4; HR ESI-TOF m/z 496.2233 (M+H+, C30H29N3O4, requires 496.2231).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]([C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1)=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.Cl>O1CCOCC1.[OH-].[Na+]>[NH2:18][C:15]1[S:16][CH:17]=[C:13]([C:5](=[CH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([OH:19])=[O:3])[N:14]=1
Reactant: CCOC(=O)C(=Cc1ccccc1)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nc(C(=Cc2ccccc2)C(=O)O)cs1
Yield: 10.3 %

Procedure:
216 g of the crude product from Example 30 were dissolved in a mixture of 1.2 liters of dioxane and 800 ml of 12 percent strength sodium hydroxide solution. The solution was boiled under reflux for 15 hours and the dioxane was then stripped off and the residue was adjusted to pH 8 with 2 N hydrochloric acid. The mixture was extracted three times with ethyl acetate, the aqueous solution was adjusted to pH 3 to 4 and the product which had precipitated was filtered off. 20 g of the desired product of melting point 138° could be obtained directly by recrystallization from methanol. The mother liquor consisted of an E/Z mixture, which could not be separated by crystallization.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[N:10][N:9]([CH3:12])[C:8](=[O:13])[C:7]=1Cl)[CH2:2][CH2:3][CH3:4].[F:15][C:16]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:17]=1[C:18]([N:20]=[C:21]=[S:22])=[O:19]>O1CCOCC1>[CH2:1]([N:5]1[C:6]2[CH:11]=[N:10][N:9]([CH3:12])[C:8](=[O:13])[C:7]=2[S:22]/[C:21]/1=[N:20]\[C:18](=[O:19])[C:17]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:16]=1[F:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cnn(C)c(=O)c1Cl
Reactant: O=C(N=C=S)c1cc(C(F)(F)F)ccc1F
Solvent: C1COCCO1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2c(=O)n(C)ncc21
Temperature: 100 °C
Yield: 22.1 %

Procedure:
A mixture of 5-(butylamino)-4-chloro-2-methylpyridazin-3(2H)-one from Example 4A (250 mg, 1.16 mmol) and 2-fluoro-5-(trifluoromethyl)benzoyl isothiocyanate (375 mg, 1.51 mmol) in dioxane (20 mL) was heated at 70° C. for 12 hours and at 100° C. for 6 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (CH2Cl2-Et2O 19:1)) to afford 110 mg of the title compound. MS (ESI) m/z 429 (M+H)+.
Reaction SMILES: C([S:9][CH:10]([CH2:21][S:22][CH3:23])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])(=O)C1C=CC=CC=1.C(SCC(CSC)C(N1CCC[C@H]1C(O)=O)=O)(=O)C>>[SH:9][CH:10]([CH2:21][S:22][CH3:23])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: CSCC(SC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CSCC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Product: CSCC(S)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[2-benzoylthio-3-(methylthio)-propanoyl]-L-proline for the 1-[3-acetylthio-2-(methylthiomethyl)propanoyl]-L-proline in the procedure of Example 17, 1-[2-mercapto-3-(methylthio)propanoyl]-L-proline is obtained.
Reaction SMILES: C(OC(=O)[CH:10]([C:22]#[N:23])[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([F:18])=[CH:13][C:12]=1[N+]([O-])=O)C1C=CC=CC=1.C(O)(=O)C.O.[H][H]>C(O)C.[C].[Pd]>[F:18][C:14]1[CH:13]=[C:12]2[C:11]([CH:10]=[CH:22][NH:23]2)=[CH:16][C:15]=1[CH3:17]
Reactant: Cc1cc(C(C#N)C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Cc1cc2cc[nH]c2cc1F
Temperature: 25 °C
Reaction time: 60 h
Yield: 76.6 %

Procedure:
To a solution of cyano-(4-fluoro-5-methyl-2-nitrophenyl)acetic acid benzyl ester (1.54 g), acetic acid (7 mL) and water (7 mL) in ethanol (15 mL) was added 10% palladium-carbon (0.154 g) under an argon atmosphere. This reaction mixture was stirred at room temperature for 60 hours under a hydrogen atmosphere. After water was added to this reaction mixture, hydrogen was exchanged by argon. The insoluble material was removed by filtration, and this filtrate was extracted with diethyl ether. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (0.536 g).
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[NH:7]/[C:6](=[CH:11]\[C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]([CH3:20])([CH3:19])[CH3:18])/[C:5]1=[O:21])(=O)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[C:17]([C:16]1[O:15][CH:14]=[N:13][C:12]=1/[CH:11]=[C:6]1/[C:5](=[O:21])[NH:4]/[C:9](=[CH:27]\[C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)/[C:8](=[O:10])[NH:7]/1)([CH3:18])([CH3:19])[CH3:20]
Reactant: CC(=O)N1CC(=O)N/C(=C\c2ncoc2C(C)(C)C)C1=O
Reactant: COc1cccc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(/C=c2\[nH]c(=O)/c(=C/c3ncoc3C(C)(C)C)[nH]c2=O)c1

Procedure:
To a solution of 4 (50 mg, 0.17 mmol) in DMF (4 mL) was added 3-methoxybenzaldehyde (31.4 μL, 0.26 mmol) and the solution was repeatedly evacuated in a short time to remove oxygen and flushed with Ar, followed by the addition of Cs2CO3 (111.9 mg, 0.34 mmol) and the evacuation-flushing process was repeated again. The resultant mixture was heated for 3 h at 85□. After the solvent was removed by evaporation, the residue was AcOEt, washed with water for two times and saturated NaCl for three times, dried over Na2SO4 and concentrated in vacuo. The resulting residue was dissolved in 70% MeCN aq and applied to reverse-phase HPLC column (μBondasphere 5C18 100 A, 19×150 mm) and eluted using a linear gradient from 30 to 100% CH3CN in 0.1% TFA aq over 30 min at a flow rate of 12 mL/min, and the desired fraction was collected and concentrated by evaporation to give a 35.3 mg (55.9%) of yellow colored KPU-201. mp 114-116° C.; 1H NMR (300 MHz, CDCl3) δ11.40 (br s, 1H), 8.14 (br s, 1H), 7.88 (s, 1H), 6.96-7.00 (m, 2H), 6.92 (s, 1H), 6.88 (s, 1H), 6.88-6.92 (m, 1H), 3.83 (s, 3H), 1.44 (s, 9H); HRMS (EI) m/z 367.1538 (M+) (calcd for C20H21N3O4: 367.1532).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].Br[Mg][CH:17]1[CH2:26][CH2:25][C:20]2([O:24][CH2:23][CH2:22][O:21]2)[CH2:19][CH2:18]1.O1CCCC1.Cl.O>O1CCCC1>[O:21]1[C:20]2([CH2:25][CH2:26][CH:17]([CH:7]([C:6]3[CH:5]=[C:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:3][C:2]=3[CH3:1])[OH:8])[CH2:18][CH2:19]2)[O:24][CH2:23][CH2:22]1
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Reactant: Br[Mg]C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(O)C1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-3-carbaldehyde (2.4 g) in tetrahydrofuran (30 mL) was added dropwise 0.4N bromo(1,4-dioxaspiro[4.5]dec-8-yl)magnesium-tetrahydrofuran solution (33.5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 30% ethyl acetate/hexane) to give the title compound (3.9 g, 91%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12](Cl)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1.[CH2:19]([NH2:21])[CH3:20]>>[Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:21][CH2:19][CH3:20])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:18])[N:3]=1
Reactant: O=C(Nc1ccc(Cl)nc1Cl)c1cccnc1Cl
Reactant: CCN
Product: CCNc1ncccc1C(=O)Nc1ccc(Cl)nc1Cl
Temperature: 165 °C
Yield: 59.8 %

Procedure:
A mixture of N-(2,6-dichloro-3-pyridinyl)-2-chloro-3-pyridinecarboxamide (12.0 g, 39.8 mmol), ethylamine (3.6 g, 80.7 mmol), and 30 mL of xylenes in a sealed vessel was heated at 165° C. for 6 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate to give 7.4 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.C(=O)([O-])[O-].[K+].[K+].ClCCl>CO.O>[CH2:7]1[C:8]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)=[CH:12][C:9]=2[CH2:10][CH2:11][NH:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCNCC3)CC1
Temperature: 25 °C

Procedure:
400 mg tert-butyl 4-[3-(2,2,2-trifluoracetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy]-piperidine-1-carboxylate (see 38.2) are placed in 17 ml of methanol, then a mixture of 151.2 mg potassium carbonate in 3.3 ml of water is added. The reaction mixture is stirred at ambient temperature, until there is no further reaction. The methanol is then spun off. The residue is combined with dichloromethane and water. The organic phase is dried and evaporated to dryness. 310 mg are obtained as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[N:9][NH2:10])[NH2:8].[O:11]1[C:15](=O)[CH2:14][CH2:13][C:12]1=[O:17]>CC(N(C)C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[C:15]([CH2:14][CH2:13][C:12]([OH:17])=[O:11])[NH:10][N:9]=1
Reactant: O=C1CCC(=O)O1
Reactant: NN=C(N)c1ccccn1
Solvent: CC(=O)N(C)C
Product: O=C(O)CCc1nc(-c2ccccn2)n[nH]1

Procedure:
2-Pyridinecarbohydrazonamide (0.136 g) and dihydro-2,5-furandione (0.100 g) in 1 ml of dimethylacetamide was heated for 10 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W under nitrogen to leave 3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanoic acid in 1 ml of dimethylacetamide.
Reaction SMILES: FC1C=[C:4](C=CC=1F)[CH2:5][N:6]1C=CN=C1S.[CH3:16][O:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[SH:28])=[CH:20][CH:19]=1>>[NH2:6][CH2:5][CH2:4][S:28][C:24]1[N:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:30][CH:29]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COc1ccc(Cn2ccnc2S)cc1
Reactant: Fc1ccc(Cn2ccnc2S)cc1F
Product: COc1ccc(Cn2ccnc2SCCN)cc1

Procedure:
The Example 1 process wherein 1-(3,4-difluorobenzyl)-2-mercaptoimidazole is replaced by 1-(4-methoxybenzyl)-2-mercaptoimidazole yields 2-(2-aminoethylthio)-1-(4-methoxybenzyl)imidazole. Treatment of this compound in methylene chloride with boron tribromide yields 2-(2-aminoethylthio)-1-(4-hydroxybenzyl)imidazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:2].CC(C)([O-])C.[K+].[CH2:20]([O:22][C:23](=[O:35])[C:24]([CH3:34])=[C:25]=[CH:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH3:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C(=O)C>[CH2:20]([O:22][C:23](=[O:35])[CH:24]([CH3:34])/[C:25](=[CH:26]\[C:27]1[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=1)/[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH3:21]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(C)=C=Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(C)/C(=C\c1ccc(F)cc1)C(C(=O)OCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Malonic acid tert-butyl ester ethyl ester (30.08 g, 151.8 mmol) was added to a solution of potassium tert-butoxide (16.30 g, 138.0 mmol) in 200 mL of N,N-dimethyl acetamide, while the reaction temperature was maintained at ˜25° C. To the resulting mixture was then added the solution of 4-(4-fluoro-phenyl)-2-methyl-buta-2,3-dienoic acid ethyl ester prepared above, at such a rate that the reaction temperature was maintained between 20-28° C. After the addition was complete, the reaction mixture was stirred at room temperature for 20 minutes, when HPLC indicated completed reaction. The mixture was then treated with 100 mL of 1M citric acid and 150 mL of ice-water, and then extracted with 400 mL of methyl tert-butyl ether. The organic extract was separated and washed with 2×200 mL of water, and then concentrated to produce 56.36 g of a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24](Cl)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH2:1]([O:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C:24]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Cl)cc1
Reactant: NCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)NCc2ccccn2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a 0° C. solution of 3.0 g of product from Example 87 is added 50 ml of methylene chloride, 0.829 g of 2-(aminomethyl)pyridine and 2.31 g of pyridine. The reaction is stirred at 0° C. for 3 hours; followed by 20 hours at room temperature. The mixture is poured into chloroform and saturated sodium bicarbonate. The aqueous layer is extracted with chloroform and the combined chloroform layers are washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 75% ethyl acetate/hexane) to give 2.90 g of the desired product as a colorless solid.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:13][CH2:14]Cl)[CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:23]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:2]([N:9]1[CH2:13][CH2:14][N:28]([C@H:25]2[CH2:26][CH2:27][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:24]2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](N2CCN(Cc3ccccc3)CC2)C1

Procedure:
6.23 g (26.8 mmol) of benzylbis(2-chloroethyl)amine hydrochloride were dissolved in ethanol (100 ml) and, while stirring, 5.00 g (26.8 mmol) of (S)-(−)-N-Boc-3-aminopyrrolidine and 9.02 g (107 mmol) of sodium bicarbonate were added. The resulting reaction solution was heated under reflux for 4 h. The cooled reaction mixture was concentrated in vacuo, 100 ml of water were added, and the aqueous phase was extracted with ethyl acetate (4×60 ml). The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 0-5% methanol in dichloromethane). Yield: 6.99 g (75%) of yellow solid
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=1.Cl.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]3[CH3:17])[C:19]([CH2:20][C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[N:18][C:6]=2[CH:5]=1)=[O:27]
Reactant: COC(=O)c1ccc(NC2CCCCC2C)c(NC(=O)Cc2ccco2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)nc(Cc1ccco1)n2C1CCCCC1C
Yield: 93 %

Procedure:
1.48 g 3-(2-Furan-2-yl-acetylamino)-4-(2-methyl-cyclohexylamino)-benzoic acid methyl ester with 15 ml of 4M hydrochloric acid in dioxane were heated in a microwave reactor to 130° C. for 15 min. Water was added to the reaction mixture and the pH was adjusted to 7 by the addition of saturated sodium bicarbonate solution. The phases were separated, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate, concentrated and 1.31 g (93%) of 2-Furan-2-ylmethyl-1-(2-methyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid methyl ester were obtained.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([C:29]([OH:31])=O)=[CH:24][CH:23]=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:32][C:33]1[CH:34]=[C:35]([CH:44]=[CH:45][CH:46]=1)[O:36][CH2:37][C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39]>C(Cl)Cl>[CH2:13]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([C:29]([NH:32][C:33]1[CH:34]=[C:35]([CH:44]=[CH:45][CH:46]=1)[O:36][CH2:37][C:38]([O:40][CH:41]([CH3:42])[CH3:43])=[O:39])=[O:31])=[CH:24][CH:23]=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Reactant: CCCCCCc1ccc2c(C(=O)O)cccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCc1ccc2c(C(=O)Nc3cccc(OCC(=O)OC(C)C)c3)cccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.1 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride (EDCI, 157 mg) was added to a solution of 6-hexyl-1-naphthoic acid (161 mg, 0.63 mmol) and isopropyl 2-(3-aminophenoxy)acetate (131 mg, 0.63 mmol) in CH2Cl2 (6.3 mL) and the solution was stirred at room temperature overnight. The reaction was concentrated in vacuo, diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was washed with 1 N aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and brine (20 mL), then dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified on 40 g silica (100% hexanes→100% EtOAc, gradient) to afford 65 mg (23%) of isopropyl 2-(3-(6-Hexyl-1-naphthamido)phenoxy)acetate.