Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][Si:14]([CH3:25])([CH3:24])[N:15]([CH2:20][CH2:21][CH2:22]Br)[Si:16]([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O>[CH3:19][Si:16]([N:15]([Si:14]([CH3:13])([CH3:24])[CH3:25])[CH2:20][CH2:21][CH2:22][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])([CH3:17])[CH3:18]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[Si](C)(C)N(CCCBr)[Si](C)(C)C
Agent: [K]
Solvent: CN(C)C=O
Product: C[Si](C)(C)N(CCCN1C(=O)c2ccccc2C1=O)[Si](C)(C)C
Temperature: 80 °C
Reaction time: 6 h
Yield: 75.7 %

Procedure:
About 4.60 g of potassium phthalimide, 6.37 g of N,N-bis(trimethylsilyl)-3-bromo-1-propylamine, and 15 mL of N,N-dimethylformamide were mixed in a flask. The mixture was stirred for 6 hour while the flask was kept in an oil bath maintained at 80° C. The N,N-dimethylformamide was removed under vacuum. The residue was extracted with 90 mL of cyclohexane and filtered. The filtrate was evaporated under vacuum. The residue was triturated with 80 mL of hexane, cooled with dry ice, and then filtered to give N-[3-bis(trimethylsilyl)amino-1-propyl]phthalimide (BTMSAPPI) as a white solid (5.95 g, 76% yield). 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product: δ 7.41 (multiplet, 2H, aromatic protons), 6.85 (multiplet, 2H, aromatic protons), 3.44 (triplet, J=7.1 Hz, 2H, CH2 protons), 2.81 (multiplet, 2H, CH2 protons), 1.75 (multiplet, 2H, CH2 protons), 0.06 (singlet, 18H, Si—CH3 protons).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][NH:20][CH3:21])=[C:13]([C:22]([F:25])([F:24])[F:23])[CH:12]=3)[N:7]=[C:6]([C:26]#[N:27])[C:5]=2[N:4]=[CH:3]1.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>C1COCC1>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([C:37](=[O:40])[CH2:38][CH3:39])[CH3:21])=[C:13]([C:22]([F:23])([F:25])[F:24])[CH:12]=3)[N:7]=[C:6]([C:26]#[N:27])[C:5]=2[N:4]=[CH:3]1
Reactant: CNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CCC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(=O)N(C)CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-methyl-6-(4-(2-(methylamino)ethoxy)-3-(trifluoromethyl)-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.053 mmol, 20 mg) in THF (1 mL) was added DIPEA (0.266 mmol, 47 μL) and propionyl chloride (0.16 mmol, 15 mg). The mixture was stirred at r.t. for 16 h and the product was then purified by HPLC to give 1-methyl-6-(4-(2-(N-propionyl-N-methylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (CD3OD) δ: 8.37-8.46 (m, 4H), 7.31 (d, 1H), 4.31-4.37 (m, 2H), 3.90 (s, 3H), 3.82-3.90 (m, 2H), 3.01, 3.30 (2xs, 3H), 2.42-2.58 (m, 2H), 1.10-1.15 (m, 3H). MS m/z 432 (M+H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([F:26])=[CH:28][CH:29]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.79 mmol) in methylene chloride (25 mL) was added dropwise 4-fluorobenzoyl chloride (89 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with diluted aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 130 mg (65%) of the title compound as white crystals: mp 189-190° C.; [α]21D -30° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 367 (11, M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18](Cl)=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].[NH3:26]>CCO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[C:18]([NH2:26])=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(OCc3cnc(C)nc3Cl)ccc12
Reactant: N
Solvent: CCO
Product: CCOC(=O)Cc1csc2cc(OCc3cnc(C)nc3N)ccc12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl(6-((4-chloro-2-methylpyrimidin-5-yl)methoxy)-1-benzothiophen-3-yl)acetate (100 mg) and 2M ammonia in EtOH (10 mL) was stirred at 100° C. for 5 h under microwave irradiation. The mixture was concentrated in vacuo. The residual solid was recrystallized from EtOAc-IPE to give the title compound (92 mg).
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].C[S:7][CH2:8][C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH:26](OC(C)C)(C)C>CO>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:26][C:8]([C:9]1[C:19]2[O:18][CH2:17][CH2:16][C:15]([C:20]([NH:22][C:23]([NH2:25])=[NH:24])=[O:21])=[CH:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)=[S:7]
Reactant: CC(C)OC(C)C
Reactant: CSCc1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Agent: CS(=O)(=O)O
Solvent: CO
Product: CC(=S)c1cccc2c1OCCC(C(=O)NC(=N)N)=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonic acid (0.04 ml) was added to the mixture of (2,3-dihydro-9-methylthiomethyl-1-benzoxepin-4-carbonyl)guanidine (0.15 g) in methanol (1.5 ml) and the mixture was stirred at ambient temperature for 30 minutes. To the mixture was added diisopropyl ether (3 ml). The isolated crystalline was collected by filtration and recrystallized from a mixture of methanol and diisopropyl ether to give (2,3-dihydro-9-methylthiocarbonyl-1-benzoxepin-4-carbonyl)guanidine methanesulfonate (0.12 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](O)=[O:12])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1.S(Cl)([Cl:25])=O.CN(C)C=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([Cl:25])=[O:12])=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[S:8][C:7]=2[CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)Cl)cc1
Yield: 97.2 %

Procedure:
To a slurry of 6-methoxy -2-(4-methoxyphenyl)benzo[b]thiophene-3-carboxylic acid (0.0484 g, 0.154 mmol) in methylene chloride (5 ml) is added thionyl chloride (0.025 ml, 0.356 mmol), and a catalytic amount of N,N-dimethylformamide. The reaction is heated to reflux for 2 hours, then cooled and concentrated in vacuo. The residual material is dissolved in toluene (10 ml), and reconcentrated in vacuo. This dissolution/reconcentration procedure is repeated two more times to afford 0.0498 g (97%) of title compound as a solid: mp 135.5-137.9° C. IR (KBr) 2965, 1678, 1610, 1525, 1478, 1253, 815; 1H NMR (CDCl3): δ8.13 (d, 1 H, J=9 Hz), 7.48 (d, 2 H, J=8.7 Hz), 7.27 (d, 1 H, J=2.4 Hz), 7.13 (dd, 1 H, J=9.0, 2.4 Hz), 7.00 (d, 2 H, J=8.7 Hz); 13C NMR (CDCl3): d 163.4, 161.0, 158.2, 139.1, 131.3, 131.2, 129.1, 128.3, 125.1, 124.6, 115.9, 114.2, 104.4, 55.7, 55.5; Exact mass calcd. for C18H16O4S (in situ-derived methyl ester): 328.0769. Found: 328.0760.
Reaction SMILES: [CH2:1]([C:3]1[CH:24]=[C:23]([CH3:25])[C:22]([CH:26]=[O:27])=[CH:21][C:4]=1[C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:2].[O-:28][Mn](=O)(=O)=O.[K+]>O1CCCC1.O>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:5]([C:4]3[C:3]([CH2:1][CH3:2])=[CH:24][C:23]([CH3:25])=[C:22]([CH:21]=3)[C:26]([OH:28])=[O:27])=[O:6])[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCc1cc(C)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a round-bottom flask was added a solution of 4-(1-(2-ethyl-5-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 211.5, 720 mg, 2.00 mmol, 1.00 equiv) in tetrahydrofuran (20 mL). A solution of KMnO4 (640 mg, 4.05 mmol, 2.00 equiv) in water (20 mL) was added dropwise. The resulting solution was stirred for 15 h at 60° C. then cooled to rt with a water bath. The solids were removed with filtration. The filtrate was extracted with 3×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. This resulted in 600 mg (80%) of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-4-ethyl-2-methylbenzoic acid as a light yellow solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]1[N:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[C:19]([CH2:20][O:21]C(=O)C)=[C:18]([F:25])[CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:10])=O)(C)(C)C.[ClH:32]>CO.O1CCOCC1>[ClH:32].[ClH:32].[NH2:8][C@H:9]([C:11]1[N:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[C:19]([CH2:20][OH:21])=[C:18]([F:25])[CH:17]=[CH:16][C:14]=2[N:15]=1)[CH3:10]
Reactant: CC(=O)OCc1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(-c3ccccc3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1nc2ccc(F)c(CO)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of acetic acid 2-((S)-1-tert-butoxycarbonylaminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazol-4-ylmethyl ester (190 mg, 0.44 mmol) in methanol (2 mL) was added HCl in dioxane (4N, 5 mL) and the reaction stirred at RT for 2 h. The reaction mixture was concentrated in vacuo to give the title compound as a beige solid (159 mg, 100%). LCMS (Method C): RT=1.61 min, [M+H]+=372.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[N:9]([CH2:18][O:19][CH3:20])[C:8]=2[CH:21]=1)[CH3:3]>C(O)C.ClCCl.[Pd]>[OH:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[C:16]3[NH:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10](=[O:17])[N:9]([CH2:18][O:19][CH3:20])[C:8]=2[CH:21]=1)[CH3:3]
Reactant: COCn1c(=O)c2cccnc2c2ccc(C(C)O)cc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: COCn1c(=O)c2c(c3ccc(C(C)O)cc31)NCCC2
Reaction time: 24 h
Yield: 48.5 %

Procedure:
The compound (650 mg, 2.29 mmol) prepared in step 4 was dissolved in ethanol (10 ml)/dichloromethane (10 ml) and added with 10%-palladium (Pd) (200 mg) at room temperature. The resulting mixture was stirred for one day under hydrogen gas and 10%-palladium was removed by using celite-filter. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (chloroform:methanol=30:1) to obtain the title compound (320 mg, yield: 49%, white solid).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[F:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:24]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: COc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
3-Fluorophenylacetic acid (7.33 g, 47.56 mmoles) was dissolved in 25 ml dichloromethane. To this mixture, oxalylchloride (7.54 g, 59.46 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 25 ml dichloromethane. To this mixture, 4-fluoroanisole (5.00 g, 39.64 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (7.95 g, 59.46 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as colourless solid (4.5 g, 45% yield. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 11.34(s,1H), 7.75(dd, J=9.4,3.1Hz, 1H), 7.42(m, 2H), 7.12(m, 3H), 7.05(dd, J=9.0,4.5Hz, 1H), 4.47(s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:20][C:21]1C=C2C(C(C3C=CC=CC=3)CC2=O)=C[CH:22]=1>>[C:21]([O:18][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][CH:15]=1)[CH:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH2:10][C:11]2=[O:19])(=[O:20])[CH3:22]
Reactant: O=C1CC(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1CC(c2cc(F)cc(F)c2)c2ccc(O)cc21
Product: CC(=O)Oc1ccc2c(c1)C(=O)CC2c1cc(F)cc(F)c1
Reaction time: 2 h
Yield: 83 %

Procedure:
The procedure of Step 3 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-2,3-dihydro-6-hydroxyinden-1-one obtained in Step 2 as a starting material instead of 2,3-dihydro-6-hydroxy-3-phenylinden-1-one and being stirred for 2 h to obtain the title compound (83%).
Reaction SMILES: COC[O:4][CH:5]([CH2:26][N:27]1[C:32](=[O:33])[CH:31]=[N:30][C:29]2[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[N:37][C:28]1=2)[CH2:6][NH:7][CH2:8][C@@H:9]1[CH2:13][N:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=3[N:23]=2)[C:11](=[O:25])[CH2:10]1.Cl>CO.O1CCCC1>[OH:4][CH:5]([CH2:26][N:27]1[C:32](=[O:33])[CH:31]=[N:30][C:29]2[CH:34]=[CH:35][C:36]([O:38][CH3:39])=[N:37][C:28]1=2)[CH2:6][NH:7][CH2:8][C@@H:9]1[CH2:13][N:12]([C:14]2[CH:15]=[CH:16][C:17]3[O:18][CH2:19][C:20](=[O:24])[NH:21][C:22]=3[N:23]=2)[C:11](=[O:25])[CH2:10]1
Reactant: COCOC(CNC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1)Cn1c(=O)cnc2ccc(OC)nc21
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2ncc(=O)n(CC(O)CNC[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 18.3 %

Procedure:
In a mixed solution (2 ml) of methanol/tetrahydrofuran (1:1) was dissolved 6-[(4R)-4-({[2-(Methoxymethoxy)-3-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)propyl]amino}methyl)-2-oxopyrrolidin-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (41.3 mg, 0.077 mmol). To this solution was added a 4N hydrochloric acid aqueous solution (1 ml) under cooling on ice and the mixture was stirred at 60° C. for 4 hours. The reaction solution was cooled in the air, and the solvent was then removed under reduced pressure. The residue was dissolved in a lower layer solvent of the chloroform/methanol/water (7:3:1) and alkalized by adding saturated sodium bicarbonate water under cooling on ice. The mixture was extracted with a lower layer solvent of chloroform/methanol/water (7:3:1), the extract was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by preparative layer chromatography (chloroform/methanol) to yield 7 mg (18%) of the title compound in the form of an orangish solid.
Reaction SMILES: [CH3:1][C:2](=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[C:21]=1[N:29]=[C:30]=[O:31])([CH3:19])[CH3:18].C([N-]C(C)C)(C)C.[Li+]>>[CH3:19][CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([CH3:27])[CH3:28])[C:21]=1[NH:29][C:30](=[O:31])[CH2:1][C:2](=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:18]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCCC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCCC(=O)CC(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
The title compound was prepared from 2-pentadecanone (3.0 g, 0.013 mol), 2,6-diisopropylphenyl isocyanate (2.64 g, 0.013 mol), and lithium diisopropylamide (0.013 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 15% EtOAc/hexane) yielded 1.92 g (0.004, 34%) of the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[OH:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2.[H-].[Na+]>CN(C=O)C>[CH:25]1[C:26]2[C:21](=[C:20]([O:19][C:5]3[N:4]=[N:3][C:2]([O:19][C:20]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:21]=4[CH:22]=[CH:23][N:24]=[CH:25]5)=[C:7]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)[CH:6]=3)[CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][N:24]=1
Reactant: Oc1cccc2cnccc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4cnccc34)nnc2Oc2cccc3cnccc23)cc1
Temperature: 140 °C

Procedure:
To a solution of 3,6-dichloro-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 45(d)), (100 mg, 0.3 mmol) and 5-hydroxyisoquinoline (112 mg, 0.7 mmol, Aldrich) in DMF (2.5 mL) was added NaH (32 mg, 0.8 mmol, 60% suspension in mineral oil, Aldrich) and the reaction mixture was heated at 140° C. for 10 min in a microwave synthesizer. The reaction mixture was allowed to cool to room temperature and partitioned between H2O/CH2Cl2. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were concentrated in vacuum. The residue was evaporated onto SiO2 and purified by flash silica gel chromatography with 2M NH3 in MeOH/CH2Cl2 (0:1→1:49) as eluant to give the title compound as an white amorphous solid. Mp: 197–199° C. MS (ESI, pos ion.) m/z: 511 (M+1).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([N:53]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:49][CH:48]=2)(=O)=O)=CC=1.O.NN>CN(C=O)C.O>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N3C(=O)c4ccccc4C3=O)cc2)cc1
Reactant: Oc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: NN
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of the 2-(1-trityl-1H-imidazol-4-yl)phenol (1.1 g, 2.73 mmol) in DMF (15 mL) was added NaH (83 mg, 3.28 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. 4-(1,3-dioxoisoindolin-2-yl)phenethyl 4-methylbenzenesulfonate (1.15 g, 2.73 mmol) was added to the mixture. After stirring overnight under a nitrogen atmosphere, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water (2×20 mL), brine (20 mL) and dried. The solvent was removed under reduced pressure and, the crude product was dissolved in ethanol (15 mL) and treated with hydrazine hydrate (0.3 mL, 5.46 mmol). The mixture was heated at 80° C. for 2 h and filtered. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (silica gel, 30%-50% EtOAc/hexanes as eluent) to afford the desired product as a yellow solid (862 mg, 60% over two steps). 1H NMR: 2.63 (t, 2H, J=7.6 Hz), 4.03 (t, 2H, J=7.6 Hz), 6.46 (d, 1H, J=8.4 Hz), 6.80 (dd, 2H, J=12.4 Hz, 8 Hz), 6.99 (t, 1H, J=7.6 Hz), 7.10-7.19 (m, 7H), 7.28-7.31 (m, 9H), 7.41 (s, 1H), 7.52 (s, 1H), 8.18-8.21 (m, 1H), 8.63 (s, 1H), 9.11 (s, 1H).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH:20]=[CH:19]2)[C:12]1=[O:27])C1C=CC=CC=1.C[OH:30]>CC(O)=O.[Pd]>[C:12]([OH:27])(=[O:30])[CH3:11].[NH2:10][C@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:26]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[CH:20]=[CH:19]2)[C:12]1=[O:27]
Reactant: O=C(N[C@H]1CCN(CCn2ccc3cnccc32)C1=O)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Solvent: CC(=O)O
Product: N[C@H]1CCN(CCn2ccc3cnccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(S)-benzyloxycarbonylamino-4-(2-pyrrolo[3,2-c]pyridin-1-yl-acetylamino)-butyric acid methyl ester (0.51 g, 1.20 mmol) in THF (5 mL) is added diborane (5 mL, 0.500 mmol, 1 M solution in THF). The resulting mixture is stirred at room temperature for 4 hours and then concentrated in vacuo. The residue is suspended in EtOAc (10 mL), treated with 10 drops of H2O, 5 drops of 1 N NaOH and further quenched with saturated NH4Cl solution. The mixture is concentrated in vacuo to about 1/2 volume, partitioned between EtOAc and 10% Na2CO3 solution and the layers are separated. The aqueous layer is extracted with EtOAc. The combined organic phases are washed with saturated NaCl, dried over MgSO4, filtered and concentrated in in vacuo. The crude product obtained is partially purified by column chromatography in a gradient of 2% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2 to afford [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester. FAB MS, [M+H]+=379. To a solution of this crude [2-oxo-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-3-(S)-yl]-carbamic acid benzyl ester in MeOH (10 mL) and AcOH (3 mL) is added a catalytic amount of 10% palladium on activated carbon. The heterogenous mixture is stirred at room temperature under a balloon of H2 for 18 hours. The reaction mixture is filtered through a pad of Celite and washed with MeOH (3x). The crude product is concentrated in vacuo and then azeotroped with toluene to give 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate as a residue (wet with excess HOAc). FAB MS, [M+H]+=245. The title compound is prepared in CH2Cl2 instead of CH3CN as described in EXAMPLE 1, Part K using the above 3-(S)-amino-1-(2-pyrrolo[3,2-c]pyridin-1-yl-ethyl)-pyrrolidin-2-one acetate in place of 7-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)-1-chloro-isoquinoline hydrochloride and 7-methoxynaphthalene-2-sulfonyl chloride as prepared in EXAMPLE 1. Part J. The crude product is partially purified by column chromatography eluting in a gradient of 3% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2. The residue obtained is further purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are lyophilized to provide the title compound as a white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][S:15][C:13]1[O:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[N:11][N:12]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: Sc1nnc(-c2ccc3ncsc3c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(CSc2nnc(-c3ccc4ncsc4c3)o2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
A suspension of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol (235 mg, 1.00 mmol), 3-(trifluoromethyl)benzyl chloride (0.186 mL, 1.20 mmol), and potassium carbonate (207 mg, 1.50 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (321 mg, yield 82%) as colorless crystals.