Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:24][C:25]2[N:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].COC1C=CC(NC2C(C=CC(C3C=C(OC)C(OC)=C(OC)C=3)=O)=CC=CN=2)=CC=1.Cl>CO>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[CH:27][C:26]2[C:25]([NH:24][C:16]3[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=3)=[N:32][CH:31]=[CH:30][CH:29]=2)=[CH:5][CH:6]=1
Reactant: COc1cc(Nc2ncccc2C=O)cc(OC)c1OC
Reactant: COc1ccc(C(C)=O)cc1
Agent: COc1ccc(Nc2ncccc2C=CC(=O)c2cc(OC)c(OC)c(OC)c2)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=O)C=Cc2cccnc2Nc2cc(OC)c(OC)c(OC)c2)cc1
Reaction time: 0.08 h
Yield: 91.2 %

Procedure:
To a solution of 4-methoxy acetophenone (104.16 mg, 0.694 mmol) in methanol (5 mL) was added 2N Ba(OH)2 solution (2 ml) and stirred for 5 minutes. Then added 2-(3,4,5-trimethoxyphenylamino)nicotinaldehyde (200 mg, 0.694 mmol) and the reaction mixture was stirred at a temperature of 30° C. for 6h and the reaction was monitored by TLC. After 8h the reaction mixture is acidified with 2N HCl. The resulting precipitate was filtered, washed thoroughly with water and dried over anhydrous CaCl2. The precipitate was recrystallized using ethanol to obtain pure (6z) (266 mg, 91% yield).
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([F:19])[CH:4]=1)#[N:2].C(O)C.O.[H][H]>[Pd].C(O)(=O)C>[NH2:2][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH:10]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: [H][H]
Reactant: N#Cc1ccc(C(=O)NC2CCCCCC2)c(F)c1
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NCc1ccc(C(=O)NC2CCCCCC2)c(F)c1
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
Add 4-cyano-N-cycloheptyl-2-fluoro-benzamide (1.4 g, 5.4 mmol), 10% Pd/C (Degussa type E101, 415 mg), ethanol (40 mL), water (15 mL) and acetic acid (1.8 mL) to a pressure vessel. Pressurize the vessel to 55 psi with hydrogen, and stir the mixture for 0.5 h (monitor the reaction by TLC). Filter the mixture through Celite® and wash the cake with warm ethanol followed by dichloromethane under a nitrogen atmosphere. Concentrate the filtrate in vacuo to obtain the product as the acetic acid salt. Use SCX chromatography to obtain the title compound (1.36 g, 95%). GC-MS m/z: 264 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[O:15]C=CC=3)=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]([C:24]([F:27])([F:26])[F:25])=[N:10]2)=[CH:5][CH:4]=1.C(Cl)(Cl)(Cl)Cl.C(#N)C.O.I([O-])(=O)(=O)=[O:38].[Na+]>O.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([OH:15])=[O:38])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]([C:24]([F:26])([F:25])[F:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)c1c(C(F)(F)F)nn(-c2ccc(OC)cc2)c1-c1ccco1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nn(-c2ccc(OC)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-(trifluoromethyl)-4-(ethoxycarbonyl)-5-(2-furyl)pyrazole (1.0 g, 2.63 mmol) in 4:4:6 carbon tetrachloride/acetonitrile/water was added sodium periodate (2.5 g, 11.8 mmol) and ruthenium (III) chloride monohydrate (11 mg, 0.05 mmol). The resulting biphasic reaction was stirred vigorously at ambient temperature for 24 h. The reaction was quenched with 10% aq HCl and diluted with ethyl acetate. The organics were washed with brine, dried (MgSO4), filtered through a pad of Celite and concentrated. The residue was dissolved in 1:1 hexanes/ethyl acetate and extracted with sat'd aq Na2CO3 (2 times). The combined aqueous extracts were acidified and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried (MgSO4) and concentrated to afford 0.5 g (53%) of the title compound as a solid. LRMS (ES-): 357.0 (M-H)-.
Reaction SMILES: [CH2:1]([Si:8]([CH2:11]Br)([CH3:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:13].[Na+]>CC(C)=O>[CH2:1]([Si:8]([CH2:11][I:13])([CH3:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(CBr)Cc1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C[Si](C)(CI)Cc1ccccc1
Yield: 94412.4 %

Procedure:
Benzyl(bromomethyl)dimethylsilane [Colm, Earborn and Foad M. S., Malmond J. Organomet. Chem., 209, 13 (1981)](12 g, 0.05 mmol) and sodium iodide (45 g, 0.3 mmol) are refluxed with stirring in acetone (500 ml) during 24 hours. The reaction mixture is cooled, filtered and the solvent is evaporated under reduced pressure. The residue is dissolved in ether and washed with water. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to afford benzyl(iodomethyl)dimethylsilane (13.7 g, 95%) as a slightly yellow oil.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[C:21]12([CH2:31][C:32](Cl)=[O:33])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>>[C:21]12([CH2:31][C:32]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]3=[O:20])=[O:33])[CH2:28][CH:27]3[CH2:26][CH:25]([CH2:24][CH:23]([CH2:29]3)[CH2:22]1)[CH2:30]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(-c2nn(N)c(=O)c3ccccc23)cc1
Product: COc1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3ccccc23)cc1

Procedure:
The product from Example 151A and (adamantan-1-yl)acetyl chloride were treated using a method similar to that described in Example 1C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.23 (s, 1H), 8.39-8.42 (m, 1H), 7.88-8.02 (m, 2H), 7.75-7.78 (m, 1H), 7.52-7.55 (m, 2H), 7.11-7.14 (m, 2H), 3.85 (s, 3H), 2.05 (s, 2H), 1.94-1.97 (m, 3H), 1.59-1.70 (m, 12H); MS (ESI+) M/Z 444 (M+H)+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][N:16]1[C:24]2[N:23]=[C:22]([Br:25])[N:21]([CH2:26][C:27]#[C:28][CH3:29])[C:20]=2[C:19](=[O:30])[NH:18][C:17]1=[O:31].[CH:32]1[C:33]([CH2:41]O)=[CH:34][N:35]2[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(Cl)Cl>[CH:32]1[C:33]([CH2:41][N:18]2[C:19](=[O:30])[C:20]3[N:21]([CH2:26][C:27]#[C:28][CH3:29])[C:22]([Br:25])=[N:23][C:24]=3[N:16]([CH3:15])[C:17]2=[O:31])=[CH:34][N:35]2[C:40]=1[CH:39]=[CH:38][CH:37]=[CH:36]2
Reactant: OCc1cc2ccccn2c1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1cc3ccccn3c1)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.61 ml of diisopropyl azodicarboxylate are added to a mixture of 594 mg of 3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine, 353 mg of (indolizin-2-yl)-methanol and 826 mg of triphenylphosphine in 30 ml of tetrahydrofuran. The reaction mixture is stirred for two hours at ambient temperature. For working up it is diluted with methylene chloride, added to 6 g silica gel and chromatographed through a silica gel column with petroleum ether/ethyl acetate (7:3 to 1:5) as eluant.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:30])(=O)=O)=CC=1>C1COCC1>[CH2:6]([O:10][C:11]1[CH:12]=[C:13]([CH:17]([F:30])[C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH3:9]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCCCOc1cccc(CC#N)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCCOc1cccc(C(F)C#N)c1
Reaction time: 1 h
Yield: 53.4 %

Procedure:
Tert-butyllithium (1268 uL; 2.16 mmol) is added dropwise to a solution of 2-(3-butoxyphenyl)acetonitrile (371 mg; 1.96 mmol) in THF (16 mL) at −78° C., under nitrogen atmosphere. The light yellow solution turned into orange and stirring is continued for 1 hour. A solution of N-fluorobenzenesulfonimide (618 mg; 1.96 mmol) in THF (2 mL) is added dropwise and the reaction is stirred at −78° C. for 2 hours. TLC (petroleum ether/EtAc 9:1) reveals no presence of starting material and two more apolar spots. The reaction is then quenched by adding 0.01N HCl, then more water is added and extracted with DCM (three times). The combined organic layers are dried over Na2SO4, filtered and evaporated. The crude residue is purified by flash chromatography (petroleum ether/EtAc, 99/1) affording 217 mg (53%) of 2-(3-butoxyphenyl)-2-fluoroacetonitrile as a colorless oil.
Reaction SMILES: I[C:2]1[CH:31]=[CH:30][C:5]2[N:6]([CH:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[CH3:11])[C:7]([NH2:9])=[N:8][C:4]=2[CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:10]([N:6]2[C:5]3[CH:30]=[CH:31][C:2]([C:36]4[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=4)=[CH:3][C:4]=3[N:8]=[C:7]2[NH2:9])[CH3:11])[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1
Reactant: COc1ccc(COc2ccc(C(C)n3c(N)nc4cc(I)ccc43)cc2OC)cn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(C(C)n3c(N)nc4cc(-c5cnn(C)c5)ccc43)cc2OC)cn1
Temperature: 125 °C
Reaction time: 0.5 h
Yield: 172.9 %

Procedure:
To stirred mixture of 5-iodo-1-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethyl)-1H-benzo[d]imidazol-2-amine (0.267 g, 0.50 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.138 g, 0.63 mmol), tricyclohexylphosphine (0.014 g, 0.050 mmol), potassium phosphate tribasic (0.381 g, 1.76 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added palladium(II) acetate (0.005 g, 0.025 mmol). The mixture was heated to 125° C. in a microwave reactor. After 30 min, additional portions of catalyst (0.005 g) and ligand (0.014 g) were added, and the mixture was reheated in a microwave reactor to 150° C. After 60 min of reaction time, the crude mixture was transferred to a 20 mL microwave reaction vial and was treated with an additional portions of boronate ester (0.050 g), catalyst (0.005 g), and ligand (0.014 g). The mixture was diluted with additional 1,4-dioxane (8 mL) and water (4 mL). The mixture was heated to 150° C. in a microwave reactor. After a total of 105 min, the reaction was complete. The mixture was diluted with water (30 mL) and extracted with dichloromethane (3×25 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 419 mgs of a brown oil. Chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% 2M ammonia in methanol/dichloromethane elute) provided 109 mgs of an impure tan solid. A second chromatographic purification (CombiFlash, 12 g SiO2 gold column, 1-5% 2M ammonia in methanol/dichloromethane elute) afforded 0.063 g (26%) of the product as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.22-8.16 (m, 1H), 7.75 (d, J=0.8 Hz, 1H), 7.68 (dd, J=8.5, 2.4 Hz, 1H), 7.58 (d, J=0.8 Hz, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.20-7.16 (m, 1H), 7.11-7.06 (m, 1H), 6.96-6.87 (m, 2H), 6.80-6.73 (m, 2H), 5.55 (q, J=7.1 Hz, 1H), 5.05 (s, 2H), 4.33 (br s, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.76 (s, 3H), 1.87 (d, J=7.1 Hz, 3H) ppm; (M+1)=485.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:40][OH:41])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:38]#[N:39])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C([OH:44])C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:40][OH:41])=[C:19]([N:23]3[C:27]4=[N:28][C:29]([N:32]5[CH2:33][CH2:34][O:35][CH2:36][CH2:37]5)=[CH:30][CH:31]=[C:26]4[C:25]([C:38]([NH2:39])=[O:44])=[CH:24]3)[CH:20]=[CH:21][CH:22]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(N6CCOCC6)nc54)c3CO)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(N6CCOCC6)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-6-morpholino-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (75 mg, 136 μmol, Eq: 1.00) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (2 mg, 4.66 μmol, Eq: 0.0343) were combined with ethanol (1 ml) and water (1.00 ml) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h, then concentrated in vacuo. Mixture was diluted with acetonitrile and water and filtered. The resultant filtrate was lyophilized to give 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-6-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (70 mg, 90%, [M+H]+ 571).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I-].C[S+](C)(C)=O.[C:13]1([C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[C:24]([C:31]4[NH:39][C:38]5[CH2:37][CH2:36][NH:35][C:34](=[O:40])[C:33]=5[CH:32]=4)[CH:25]=[CH:26][CH:27]=3)[N:22]=2)=[CH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.Cl>[C:13]1([C:19]2([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([C:31]5[NH:39][C:38]6[CH2:37][CH2:36][NH:35][C:34](=[O:40])[C:33]=6[CH:32]=5)[CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:1][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[O-]
Reactant: C=C(c1ccccc1)c1ccc2cccc(-c3cc4c([nH]3)CCNC4=O)c2n1
Agent: C[S+](C)(C)=O
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(C5(c6ccccc6)CC5)nc34)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
A mixture of potassium tert-butoxide (18.42 mg, 0.164 mmol) and trimethylsulfoxonium iodide (36.1 mg, 0.164 mmol) in anhydrous DMSO (0.5 mL) was stirred under argon at 25° C. for 10 min, providing a colorless solution. A solution of 2-(2-(1-phenylvinyl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 113; 30 mg, 0.082 mmol) in DMSO (1.0 mL) was added (dropwise, over 2 min), and the resulting solution was stirred at 25° C. for 30 min. The reaction solution was diluted with LON aq. HCl (0.1 mL), then partitioned between DCM (50 mL) and water (20 mL). The aq. layer was extracted with additional DCM (20 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(2-(1-phenylcyclopropyl)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (18.8 mg, 0.050 mmol, 60% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.49 (1H, br. s.), 8.08 (1H, dd, J=7.4, 1.0 Hz), 8.00 (1H, d, J=8.6 Hz), 7.57 (1H, d, J=7.2 Hz), 7.44-7.50 (3H, m), 7.42 (2H, t, J=7.3 Hz), 7.33-7.38 (1H, m), 7.19 (1H, d, J=2.0 Hz), 7.07 (1H, d, J=8.8 Hz), 5.40 (1H, br. s.), 3.63 (2H, td, J=6.8, 2.2 Hz), 2.85 (2H, t, J=6.9 Hz), 1.68-1.72 (2H, m), 1.55-1.60 (2H, m). m/z (ESI, +ve) 380.1 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]3[C:20]([O:22][C:23](=O)[C:16]=3[CH:15]=2)=[O:21])=[CH:11][C:10]2[C:25]([O:27][C:28](=O)[C:9]=2[CH:8]=1)=[O:26].[OH-].[Na+].O>C1COCC1.CC(C)=O.CCOCC>[O:13]([C:14]1[CH:15]=[C:16]([CH2:23][OH:22])[C:17]([CH2:20][OH:21])=[CH:18][CH:19]=1)[C:12]1[CH:11]=[C:10]([CH2:25][OH:26])[C:9]([CH2:28][OH:27])=[CH:8][CH:7]=1
Reactant: O=C1OC(=O)c2cc(Oc3ccc4c(c3)C(=O)OC4=O)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCc1ccc(Oc2ccc(CO)c(CO)c2)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of LiAlH4 (1M in THF) (64 mL, 64.0 mmol, 4.0 molar equivalents) in THF (50 mL) cooled to −78° C. is added dropwise a solution of 4,4′-oxydiphthalic anhydride (5.0 g, 9.6 mmol, 1 molar equivalent) in THF (20 ml). The reaction mixture is allowed to warm up to room temperature and then stirred at 70° C. for 2 hrs. To this resulting solution cooled at 0° C. is added a 2M sodium hydroxide solution (40 mL) followed by cold water (25 mL) and THF (50 mL). The reaction mixture is then further extracted with THF (3×50 mL). The organic fractions are combined, washed with brine, dried as added over magnesium sulfate, filtered and concentrated in vacuum to give a light brown oil. The crude oil is dissolved in acetone and Et2O is added until an off-white precipitate started to form. After filtration, the organic layer is concentrated in vacuum to give a light brown oil which crystallises spontaneously. Purification by DCM washes gave the title compound as a light yellow powder (2.75 g, 59%). 1H NMR (300.13 MHz, DMSO-d6) (ppm) 4.47 (d, J=5.40 Hz, 4H) 4.53 (d, J=5.40 Hz, 4H) 5.03 (t, J=5.40 Hz, 2H) 5.12 (t, J=5.40 Hz, 2H) 6.84 (dd, J1=2.70 Hz, J2=8.40 Hz, 2H) 7.04 (d, J=2.70 Hz, 2H) 7.34 (d, J=8.40 Hz, 2H).
Reaction SMILES: [CH:1]([NH:14][C:15](=[O:31])[N:16]([CH:18]1[CH2:22][CH2:21][N:20](C(=O)C2C=CC=CC=2)[CH2:19]1)[CH3:17])([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>CO.[Pd]>[CH:1]([NH:14][C:15](=[O:31])[N:16]([CH3:17])[C@@H:18]1[CH2:22][CH2:21][NH:20][CH2:19]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: CN(C(=O)NC(c1ccccc1)c1ccccc1)C1CCN(C(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)NC(c1ccccc1)c1ccccc1)[C@@H]1CCNC1
Reaction time: 24 h
Yield: 116.4 %

Procedure:
To a solution of 3-benzhydryl-1-(1-benzoyl-pyrrolidin-3-yl)-1-methyl-urea (0.7 g, 1.75 mmol) in CH3OH (25 ml) was added Pd/C 20% (175 mg). The resulting slurry was hydrogenated at 50 psi for 24 hours. The catalyst was filtered through Celite and filtrate evaporated under reduced pressure to, give 0.63 g of desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19]>CC#N>[CH2:18]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:19]
Reactant: CCI
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 82.3 %

Procedure:
To a solution of 3-bromophenylacetic acid (10.0 g, 46.5 mmol) in CH3CN (150 mL) was added K2CO3 (7.39 g, 53.5 mmol) followed by ethyl iodide (5.6 mL, 70.0 mmol). The mixture was heated at reflux for 2.5 h and was cooled to room temperature. The volatiles were removed in vacuo and water was added. The aqueous solution was extracted with EtOAc (3×) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4), filtered, and concentrated to provide (3-bromo-phenyl)-acetic acid ethyl ester (9.30 g) as an oil. 1H NMR (400 MHz, CDCl3) δ7.43 (s, 1H), 7.38 (m, 1H), 7.21-7.16 (m, 2H), 4.14 (q, 2H), 3.56 (s, 2H), 1.24 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:11]2[CH2:12][CH2:13][CH2:14][C@@H:10]2[C:9](=[O:15])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:23]=[CH:24][CH:25]=[CH:26][C:6]1=2)=[O:4].[F:27][C:28]1[CH:29]=[C:30]2[C:35](=O)[O:34][C:32](=[O:33])[C:31]2=[CH:37][CH:38]=1.CCCCCC>C1(C)C(C)=CC=CC=1>[CH2:16]([N:8]1[C:9](=[O:15])[C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[N:5]([C:3](=[O:4])[CH2:2][N:1]2[C:35](=[O:34])[C:30]3=[CH:29][C:28]([F:27])=[CH:38][CH:37]=[C:31]3[C:32]2=[O:33])[C:6]2[CH:26]=[CH:25][CH:24]=[CH:23][C:7]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(F)cc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C(=O)[C@H]2CCC[C@H]21
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
A suspension of (3aR*,10aS*)-4-(aminoacetyl)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta-[e][1,4]diazepin-10(1H)-one (490 mg, 1.4 mmol) and 4-fluorophthalic acid anhydride (233 mg, 1.4 mmol) in xylene (3 mL) was stirred for 30 minutes at 140° C. The reaction mixture was left standing for cooling at room temperature, to which was added hexane (5 mL). The resulting solid was collected by filtration, followed by recrystallization from dichloromethane-hexane to give 436 mg (yield 62%) of the titled compound, m.p. 235°-236° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:25][C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[CH2:18][C:19]2[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH:31]1([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:25][C:26]3[NH:30][CH:29]=[CH:28][N:27]=3)[CH2:18][C:19]3[N:20]([CH3:24])[CH:21]=[CH:22][N:23]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C1CCCCC1
Reactant: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCN)cc1)Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1ccnc1CN(Cc1ccc(S(=O)(=O)NCCCCNC2CCCCC2)cc1)Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
The compound (173.5 mg) obtained in Example 102-4 was dissolved in anhydrous methanol (7.0 ml). Then, the solution was added with cyclohexanone (0.083 ml) and sodium cyanoborohydride (75.4 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 16.5 hours. After the reaction, the solvent was distilled off. Subsequently, the residue was added with a 1 mol/l sodium hydroxide aqueous solution (7.0 ml), followed by extraction with chloroform. The extract was dried with magnesium sulfate and the solvent was then distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol) and then treated with hydrochloric acid, thereby obtaining hydrochloride (161.6 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[Li+].[Cl-].[Mg+2].[Cl-].[CH:12](NC(C)C)([CH3:14])[CH3:13].C([Li])CCC.BrCCC.Cl>CCCCCCC.O.O1CCCC1>[CH2:3]([CH:2]([CH2:13][CH2:12][CH3:14])[C:1]([OH:7])=[O:6])[CH2:4][CH3:5]
Reactant: CC(C)NC(C)C
Reactant: CCCCC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: O
Product: CCCC(CCC)C(=O)O
Temperature: 50 °C
Yield: 1126.8 %

Procedure:
A 2-L flask is charged with 21.6 g (200 mmol) of lithium valerate, 9.5 g (100 mmol) of anhydrous magnesium chloride and 250 mL anhydrous tetrahydrofuran (freshly distilled from sodium, benzophenone). The stirred mixture is warmed to 50° C. allowing the metathetical exchange to occur and a homogeneous solution is produced within 5-15 minutes. The slightly hazy solution is cooled and 5.1 g (200/4 mmol) of diisopropylamine is added. Some precipitate forms and continued stirring fails to effect solution. Finally, 120 mL of a standard solution (1.67M; 200 mmol) of n-butyllithium in heptane is added in four portions at 15-minute intervals at 25°-30° C. After addition of the first portion, a homogeneous solution is produced but addition of the remaining portions yields a turbid mixture. After addition of the final portion, the mixture is permitted to stir for 2 hours at ambient temperature. Then the heterogeneous mixture is cooled to 0° C. and 24.6 g (200 mmol) of 1-bromopropane is added over 10 minutes. Finally, the mixture is warmed to 50° C. for 12 hours overnight. At the conclusion of the reaction period, the mixture is cooled and 200 mL of 6N hydrochloric acid solution is added at a temperature <15° C. followed by 100 mL of water. The phases are separated and the aqueous layer is back-extracted with 100 mL of diethyl ether. The organic layers are combined and the solution is washed with brine, dried (magnesium sulfate), evaporated and the residue is distilled through a 6" heated helices packed column to afford 6.5 g of 2 -propylpentanoic acid; bp 89°-92° C./2 mm.