Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([N:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)#[N:3].[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(Cl)Cl>[ClH:1].[CH:25]1([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:16]([CH:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][N:8]=4)[CH2:15][CH2:14]3)=[O:17])[CH2:19][CH2:20]2)[CH2:28][CH2:27][CH2:26]1
Reactant: O=C1CCC1
Reactant: N#Cc1ccc(N2CCC(C(=O)N3CCCNCC3)CC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(N2CCC(C(=O)N3CCCN(C4CCC4)CC3)CC2)nc1
Reaction time: 0.08 h

Procedure:
1-[1-(5-Cyanopyridin-2-yl)-piperidine-4-carbonyl]-[1,4]-diazepane hydrochloride (D14) (0.30 g) was dissolved in DCM (10 ml) and TEA (0.4 ml) was added followed by cyclobutanone (0.14 ml). The reaction was stirred for 5 min under argon and then sodium triacetoxyborohydride (0.41 g) was added and the reaction stirred at rt for 4 h. The reaction mixture was washed with saturated aqueous potassium carbonate (2×30 ml), saturated sodium hydrogen carbonate (2×50 ml) and brine (50 ml). The organic layer was then dried (MgSO4) and evaporated to a crude which was purified by column chromatography [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM] to give the free base product which was converted to the HCl salt by redissolving in DCM and then treating with excess hydrogen chloride (1M solution in diethyl ether) and concentrating to yield the title compound (E37) as a pale yellow solid (0.047 g). MS electrospray (+ve) 368 (MH+). 1H NMR δ [DMSO-d6]: 10.80-10.50 (1H, m), 8.47 (1H, s), 7.83 (1H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 4.44 (2H, m), 4.05 (1H, m), 3.85-3.28 (6H, m), 3.07-2.72 (5H, m), 2.41-2.01 (6H, m), 1.82-1.41 (6H, m).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:28])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:14][C:13]=2[Cl:27])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].[CH2:29]([OH:34])[CH:30]=[CH:31][C:32]#[CH:33]>>[Cl:27][C:13]1[CH:14]=[C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH:16]=[CH:17][C:12]=1[C:10]([C:8]1[CH:9]=[C:4]([N:1]2[CH:33]=[C:32]([CH:31]=[CH:30][CH2:29][OH:34])[N:3]=[N:2]2)[CH:5]=[CH:6][C:7]=1[CH3:28])=[O:11]
Reactant: C#CC=CCO
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Product: Cc1ccc(-n2cc(C=CCO)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 116, using compound 434 (0.15 mmol) and pent-2-en-4-yn-1-ol (0.30 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 30:70 to 50:50 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[CH:14]=[C:13]([CH3:15])[C:12](I)=[CH:11][C:10]=1[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:32]=[O:33].Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]1[C:10]([CH3:17])=[CH:11][C:12]([CH:32]=[O:33])=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1I
Reactant: CN(C)C=O
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C=O
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
To a stirred solution of dibenzyl-(4-iodo-2,5-dimethylphenyl)amine (9.35 g, 21.9 mmol) in toluene (100 mL) under nitrogen at −15° C. was added n-butyllithium in hexanes (1.6 M, 20.5 mL, 32.8 mmol) dropwise via syringe over a 30 min period. The resulting mixture was stirred at −15° C. for 15 min and then N,N-dimethylformamide (1.86 mL, 24.1 mmol) was added dropwise over a 10 min period. After 2 h, aqueous hydrochloric acid (1 M, 46.6 mL) and brine (30 mL) were added and the resulting mixture was stirred for 15 min. The layers were separated and the organic layer was extracted with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-50% DCM in hexanes) to give the title compound (3.60 g, 49% yield) as a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[C:8](Cl)[N:7]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[CH3:70][N:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[C:8]([N:74]2[CH2:75][CH2:76][N:71]([CH3:70])[CH2:72][CH2:73]2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nc(Cl)ccc1C(F)(F)F
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: CCOC(=O)Cc1nc(N2CCN(C)CC2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(6-Chloro-3-trifluoromethyl-pyridin-2-yl)-acetic acid ethyl ester (700 mg, 2.62 mmol), palladium(II) acetate (47 mg, 0.21 mmol) and rac-2,2′-Bis-diphenylphosphanyl-[1,1′]binaphthalene (65 mg, 0.10 mmol) are added to sodium tert-butoxide, which has been dried for 15 minutes at 60° C. under high vacuum (277 mg, 2.88 mmol). This mixture is suspended in dioxane (9 ml, degassed three times under high vacuum and purged with argon), and N-methyl piperazine (288 mg, 2.88 mmol) is added. The flask containing this suspension is immersed in a pre-heated oil bath (85° C.). After 15 minutes at 85° C., TLC analysis indicates complete consumption of starting materials. The reaction mixture is cooled to RT and poured under stirring into a mixture of conc. aqueous NH4Cl (100 ml) and EtOAc (100 ml). The aqueous layer is extracted with EtOAc. The organic layer is then washed once with conc. aqueous NH4Cl, dried over Na2SO4 and concentrated. Purification by FCC (CH2Cl2/MeOH 100:0 to 98:2 to 97:3 to 96:4 to 95:5 to 8:2) yields the title compound. 1H NMR (CDCl3, 400 MHz) δ 1.30 (t, J=7.8 Hz, 3H), 2.35 (s, 3H), 2.50-2.57 (m, 4H), 3.32-3.39 (m, 4H), 3.76 (s, 2H), 4.20 (q, J=7.8 Hz, 2H), 6.90 (d, J=8.9 Hz, 1H), 7.79 (d, J=8.9 Hz, 1H); ES-MS: 332.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[O-:15][C:16]#N.[K+]>O>[Cl:8][C:4]1[C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:16](=[O:15])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(Cl)c1NCCCO
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cccc(Cl)c2n1CCCO
Reaction time: 8 h
Yield: 41 %

Procedure:
To a stirred and cooled (10° C.) mixture of 20 parts of 3-[(2-amino-6-chlorophenyl)amino]-1-propanol, 12 parts of a hydrochloric acid solution and 100 parts of water is added dropwise a solution of 9 parts of potassium cyanate in 30 parts of water: Upon completion, stirring is continued first for 2 hours at room temperature and further overnight at reflux temperature. After cooling, the product is extracted with trichloromethane. The extract is washed with a diluted hydrochloric acid solution, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 9 parts (41%) of 4-chloro-1,3-dihydro-3-(3-hydroxypropyl)-2H-benzimidazol-2-one.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[C:28]([F:31])([F:30])[F:29]>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(C(F)(F)F)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (85 mg, 82%), MS (ISP) m/z=413.4 [(M+H)+], mp 268° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-chloro-3-trifluoromethyl-phenylboronic acid (72.9 mg, 0.325 mmol).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=O.[NH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.CC(O)=O.O>CCO>[N:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:32][C:3]([C:5]2[C:6]([OH:31])=[C:7]3[C:12](=[C:13]([C:15]#[N:16])[N:14]=2)[N:11]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10](=[O:24])[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8]3)=[O:2])=[CH:35][CH:36]=1
Reactant: NCc1ccncc1
Reactant: COC(=O)c1nc(C#N)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1nc(C(=O)NCc2ccncc2)c(O)c2cc(-c3ccccc3)c(=O)n(Cc3ccccc3)c12
Yield: 43.4 %

Procedure:
A mixture of 1-benzyl-8-cyano-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.085 mmol) and 4-(aminomethyl)-pyridine (0.030 mL, 0.30 mmol) in 2 mL of EtOH was refluxed for 16 h. AcOH (0.1 mL) and water (4 mL) were added, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (0-45% EtOAc/CH2Cl2+1% AcOH) to give 18 mg of the title compound as an off-white solid. MS: (+) m/z 488.13 (M+1).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1/[CH:17]=[CH:18]/[CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH:22]([NH:26]C(=O)OC(C)(C)C)[CH2:21]1.BrB(Br)Br>>[NH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][N:20]([CH2:19]/[CH:18]=[CH:17]/[C:4]2[C:5]3[C:6]4[CH:16]=[CH:15][S:14][C:7]=4[C:8](=[O:13])[NH:9][C:10]=3[CH:11]=[CH:12][C:3]=2[OH:2])[CH2:21]1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1/C=C/CN1CCCC(NC(=O)OC(C)(C)C)C1
Agent: BrB(Br)Br
Product: NC1CCCN(C/C=C/c2c(O)ccc3[nH]c(=O)c4sccc4c23)C1
Yield: 32 %

Procedure:
Following General Procedure F, (E)-tert-Butyl 1-[3-(8-Methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)allyl]piperidin-3-ylcarbamate (320 mg, 0.88 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 4.0 mL, 4.0 mmol) to afford the desired product (100 mg, 41%) as a yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.00 (dd, J=19.3, 5.4 Hz, 2H), 7.32 (d, J=8.9 Hz, 1H), 7.24 (d, J=16.0 Hz, 1H), 7.12 (d, J=8.9 Hz, 1H), 6.39-6.25 (m, 1H), 4.25 (d, J=6.8 Hz, 1H), 3.94 (d, J=11.4 Hz, 1H), 3.83 (d, J=11.9 Hz, 1H), 3.76-3.65 (m, 1H), 3.28-3.10 (m, 2H), 2.24 (dd, J=35.1, 13.6 Hz, 2H), 2.06-1.98 (m, 1H), 1.81-1.68 (m, 1H).
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([CH3:16])=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].O>C1C=CC=CC=1>[CH3:16][C:7]1[C:6]([N:5]=[S:1]=[O:2])=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cccc(N)c1C
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1cccc(N=S=O)c1C
Yield: 90 %

Procedure:
To a solution of thionyl chloride (6.63 mL, 91.0 mmol) in benzene (60 mL) was added a solution of methyl 3-amino-2-methylbenzoate (13.1 g, 91.0 mmol) in benzene (31 mL) at room temperature, and the mixture was heated under reflux for 18 hr. Water was added, and the mixture was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (17.3 g, yield 90%).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[CH:10]2[C:11]3[C:16]([CH2:17][CH2:18][N:9]2[CH2:8][CH2:7]1)=[CH:15][CH:14]=[CH:13][CH:12]=3.[N+:19]([O-])([O-:21])=[O:20].[K+].[OH-].[NH4+].[ClH:26].C(O)(C)C>C(O)(C)C>[ClH:26].[N+:19]([C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][N:9]3[CH2:8][CH2:7][CH2:6][CH:10]32)=[CH:15][CH:14]=1)([O-:21])=[O:20]
Reactant: c1ccc2c(c1)CCN1CCCC21
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2c(c1)C1CCCN1CC2
Reaction time: 3 h

Procedure:
To concentrated sulfuric acid (200 ml) at -10° C. was added portionwise 1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (20.5 g, 118 mmol) over 2 h. After addition was complete, potassium nitrate (1 1.6 g, 0.115 mol) was added portionwise over 3 h. The reaction mixture was stirred for an additional 3 h and then poured onto ice and made basic with concentrated ammonium hydroxide. The product was extracted twice with dichloromethane. The dried (magnesium sulfate) organic phase was concentrated to give a red oil which was immediately dissolved in isopropanol (200 ml) and made acidic with saturated isopropanol-HCl. The resulting precipitate was collected to give a tan solid (18.9 g). Recrystallization from 95% ethanol (100 ml) afforded the title compound as an off-white solid (11.5 g, 62%), m.p. 243-5° C. This was converted to the free base by dissolving in water, making basic with dilute base, and extracting with dichloromethane to give 96% recovery of the product.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Br:7][C:8]1[N:9]([CH3:26])[N:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][N:12]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25].C([OH:30])(C)C>O.C(Cl)(Cl)(Cl)Cl.O.[Ru](=O)=O>[Br:7][C:8]1[N:9]([CH3:26])[N:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][C:13](=[O:30])[N:12]2[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=1[CH3:25]
Reactant: CC(C)O
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3Br)c(C)c1
Agent: O=[Ru]=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1cc(C)c(N2C(=O)CCc3c2nn(C)c3Br)c(C)c1
Temperature: 25 °C

Procedure:
Ruthenium(IV) oxide hydrate (22 mg) was dissolved in 35 mL water and sodium periodate (684 mg) was added. This mixture was rapidly stirred while 3-bromo-2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (1-3; 505 mg) in 25 mL carbon tetrachloride was added dropwise. After the mixture had stirred at room temperature over night, isopropanol was added and the mixture was stirred for an additional hour. The mixture was then filtered through diatomaceous earth and extracted with dichloromethane. The organic extracts were dried with magnesium sulfate and concentrated. The residue was chromatographed on silica gel to afford 54.4 mg of 3-bromo-2-methyl-7-(2,4,6-trimethylphenyl)-2,4,5,7-tetrahydro-pyrazolo[3,4-b]pyridin-6-one (9-4).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19](=O)[CH2:20][C:21](=[O:23])[CH3:22])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:7][N:6]1[C:19](=[S:34])[CH2:20][C:21](=[O:23])[CH3:22])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=O)CC(C)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2)CN1C(=S)CC(C)=O

Procedure:
In analogy to the procedure described in example 192 g, (2S,4R)-4-benzenesulfonyl-1-(3-oxo-butyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with Lawesson's reagent to give the title compound as red oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:10]([CH3:11])[C:9]2[C:4](=[C:5]([Cl:14])[C:6]([Cl:13])=[C:7]([OH:12])[CH:8]=2)[C:3]1=[O:15].I[CH2:18][C:19]([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:15]=[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:12][CH2:18][C:19]([OH:21])=[O:20])=[C:6]([Cl:13])[C:5]=2[Cl:14])[CH:10]([CH3:11])[C:2]1([CH3:1])[CH3:16]
Reactant: O=C(O)CI
Reactant: CC1c2cc(O)c(Cl)c(Cl)c2C(=O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1c2cc(OCC(=O)O)c(Cl)c(Cl)c2C(=O)C1(C)C

Procedure:
A mixture of 2,2,3-trimethyl-5-hydroxy-6,7-dichloro-1-indanone (6.1 g., 0.025 mole), iodoacetic acid (5.58 g., 0.03 mole) and potassium carbonate (4.14 g., 0.03 mole) in acetone (80 ml.) is refluxed for 20 hours. The acetone is evaporated and the residue is dissolved in water and acidified with hydrochloric acid. The (1-oxo-2,2,3-trimethyl-6,7-dichloro-5-indanyloxy)acetic acid which separates is filtered, rinsed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1.[OH-].[Li+].O>CO>[CH3:1][O:2][C:3]1[C:8]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc2[nH]c(-c3cccnc3OC)cc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ncccc1-c1cc2cc(C(=O)O)ccc2[nH]1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a suspension of methyl 2-(2-methoxypyridin-3-yl)-1H-indole-5-carboxylate (1.0 g, 0.354 mmol) in methanol (100 ml) was added lithium hydroxide (0.30 g, 1.25 mmol) and water (10 ml). The reaction was heated overnight at 80° C. The reaction was not complete so more lithium hydroxide (0.10 g, 0.42 mmol) was added and heating was continued for 4 hours. The reaction was allowed to cool and stir at room temperature overnight. The reaction was concentrated to about 15 ml and 1 g citric acid dissolved in 10 ml of water was added. The solid was filtered, washed with water (25 ml) and dried under high vacuum at 50° C. The desired product was obtained as a white solid and used in the next reaction without any purification (0.9 g, 94%). 400 MHz 1H NMR (DMSO-d6) δ: 12.56 (bs, 1H), 11.69 (s, 1H), 8.30-8.12 (m, 3H), 7.75 (dd, J=1.6 Hz, 8.5 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 7.24-7.09 (m, 2H), 4.06 (s, 3H). LCMS: 269 [M+H]
Reaction SMILES: [C:1]1([CH:7]([CH2:20][N:21]2CCCC2)[CH2:8][N:9]2[C:17](=O)[C:16]3[C:11](=CC=CC=3)[C:10]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([CH2:8][N:9]2[CH2:17][CH2:16][CH2:11][CH2:10]2)[CH2:20][NH2:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(CN1CCCC1)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCC(CN1CCCC1)c1ccccc1

Procedure:
A solution of 2-(2-phenyl-3-pyrrolidin-1-yl propyl)isoindole-1,3-dione (3 mmol) and hydrazine monohydrate (6 mmol) in ethanol (10 mL) is refluxed for 3.5 h. The reaction mixture is cooled and filtered through celite. The filtrate is concentrated in vacuo to give the title compound, which is directly used for the next reaction without further purification.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:69][CH2:68][CH2:67][C@H:31]1[C:32]([NH:34][C@H:35]([C:37]([NH:39][C@H:40]([C:57]([O:59]CC1C=CC=CC=1)=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][NH:45]C(OCC1C=CC=CC=1Cl)=O)=[O:38])[CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:27])[NH:16]S(C1C=CC(C)=CC=1)(=O)=O)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].C1(OC)C=CC=CC=1>>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:28]([N:30]1[CH2:69][CH2:68][CH2:67][C@H:31]1[C:32]([NH:34][C@H:35]([C:37]([NH:39][C@H:40]([C:57]([OH:59])=[O:58])[CH2:41][CH2:42][CH2:43][CH2:44][NH2:45])=[O:38])[CH3:36])=[O:33])=[O:29])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:27])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
The solution of 102 mg (0.1 mmol) of Boc-Asn-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 17), 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 43 mg (80%) of the title compound. Mp. 168–170° C., FAB-MS (m/e) 585[M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](Cl)=O)=[N:6][CH:7]=1.[C:11]1([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O1CCOCC1.O.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]=2)=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Br)cn1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
To a suspension of 5-bromopyridine-2-carbonyl chloride (10.11 g, 46 mmol), N-phenyl-1,2-diaminobenzene (8.46 g, 46 mmol) in anhydrous dichloromethane (DCM) (100 mL), was added triethylamine (TEA) at 0° C. Then the whole was stirred at room temperature (RT) for about 20 hours. The mixture was poured into water, extracted with dichloromethane (100 mL×2). The organic phase was collected, dried over sodium sulfate (Na2SO4), and passed through a pad of silica gel (hexanes/ethyl acetate 4:1). After removal of solvent, a brown oil was obtained, which was dissolved in dioxane (150 mL), phosphoryl chloride (POCl3) (25 mL) was added at 0° C., and the mixture was then heated at about 100° C. under argon overnight. Then the whole was poured into ice (200 g) after being cooled to RT, then neutralized by sodium carbonate (Na2CO3), and extracted with dichloromethane (DCM) (200 mL×2). The organic phase was dried over Na2SO4, absorbed on silica gel, and purified by a silica gel column (hexanes/ethyl acetate 4:1). The desired fraction was collected, concentrated, and reprecipitated with hexanes. After filtration and being washed with methanol, an off-white crystalline solid (Compound 1) was obtained, 4.02 g, with an overall 25% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CCN(Cc2ccccc2)CC1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
1-Benzylpiperidin-4-one (10 g, 53.0 mmole) was added to the stirred suspension of sodium hydride (1.8 g, 53.0 mmole) in tetrahydrofuran (50 ml) at 10° C. The reaction mixture was stirred for 15 min, benzyl bromide (9.0 g, 53.0 mmole) was added at 10° C. The resulting mixture stirred at room temperature for 4 hr and concentrated to dryness. The residue was triturated with water, extracted with ethyl acetate, dried (Na2SO4) and concentrated to give crude product, which was purified through column chromatography. Elute from 10% ethyl acetate in hexane afforded 1,3-dibenzylpiperidin-4-one. Yield 1.8 g (13%), C19H21NO, m/z 280 (M+1), PMR (CDCl3): 2.22-2.62 (4H, m, H2 & H6), 2.86 (2H, m, H5), 3.2 (1H, dd, H3, j=12 Hz), 3.45 (2H, m, CH2Ar), 3.68 (2H, m, N—CH2Ar), 7.1-7.4 (10, m, ArH).