Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C1COCC1.[CH3:7][O:8][C:9]1[C:18]2[O:17]C(C)(C)[O:15][CH2:14][C:13]=2[CH:12]=[C:11]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:10]=1>O>[OH:17][C:18]1[C:9]([O:8][CH3:7])=[CH:10][C:11]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])=[CH:12][C:13]=1[CH2:14][OH:15]
Reactant: COc1cc(N2CCCC2=O)cc2c1OC(C)(C)OC2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CCCC2=O)cc(CO)c1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.5 %

Procedure:
10% hydrochloric acid (4 ml) was added to a THF solution (7 ml) of 1-(8-methoxy-2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)pyrrolidin-2-one (0.36 g, 1.3 mmol) and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction solution, which was then extracted with dichloromethane. The extracted material was dried over magnesium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol:=300:1→30:1). The purified product was concentrated to dryness under reduced pressure to obtain 1-(4-hydroxy-3-hydroxymethyl-5-methoxyphenyl)pyrrolidin-2-one (0.31 g) as light brown powder.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].CCCCCC.C(OCC)(=O)C>C(#N)C>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[O:13][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:2]
Reactant: CCc1c(O)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCc1c(OCCNC(=O)OC(C)(C)C)ccc2ccccc12

Procedure:
To a solution of 1-ethylnaphthalen-2-ol (780 mg, 4.53 mmol) and K2CO3 (626 mg, 4.53 mmol) in 15 mL of acetonitrile was added tert-butyl (2-bromoethyl)carbamate (1.015 g, 4.53 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 7:3) showed the disappearance of 1-ethylnaphthalen-2-ol, solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (5 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {2-[(1-ethylnaphthalen-2-yl)oxy]ethyl}carbamate which was dissolved in 10 mL of 4M HCl in dioxane and stirred for 1 h. The solvent was removed under vacuum and the residue was diluted with n-hexane (20 mL) and triturated at room temperature for 2 h. The solid was filtered and dried under vacuum at 50° C. to afford 2-[(1-ethylnaphthalen-2-yl)oxy]ethanaminium chloride as brown solid (821 mg, 72% yield). To a solution of 2-[(1-ethylnaphthalen-2-yl)oxy]ethanaminium chloride (100 mg, 0.397 mmol) in 10 mL of MeOH, K2CO3 (65 mg, 0.47 mmol) was added. After 10 min, 48 μL (0.58 mmol) of furan-2-carbaldehyde were added. The resulting solution was stirred for 1 h at room temperature, added with sodium borohydride (15 mg, 0.397 mmol) and allowed to stir for further 2 h at room temperature. The solvent was evaporated under vacuum. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 97:3) to afford 2-[(1-ethylnaphthalen-2-yl)oxy]-N-(furan-2-ylmethyl)ethanamine as a brown solid (91 mg, 78% yield).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.[NH2:13][C@H:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1.Br.Br[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[C@H:14]1([NH:13][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:8]=3)[N:3]=2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: BrCc1cccnc1
Agent: Br
Product: c1cncc(COc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)c1

Procedure:
The title compound, MS: m/e=368.6 (M+H+), was prepared in accordance with the general method of example 1 from 2-chloro-6-hydroxy-quinoline, (R)-1-aminoindane and 3-(brommethyl)pyridine-HBr.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH2:19]([O:26][CH2:27][C:28](Cl)=[O:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:28](=[O:29])[CH2:27][O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: O=C(Cl)COCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)COCc3ccccc3)c(O)c21
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (251 mg, 0.928 mmol) was dissolved in pyridine (10 mL), (benzyloxy)acetyl chloride (160 μL, 1.01 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=80/20→100/0) to give the title compound (285 mg, yield 80%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C.[CH2:14]([NH:18][C:19]([NH2:21])=[S:20])[CH2:15][CH2:16][CH3:17]>CC(C)=O>[ClH:1].[CH3:12][C:11]1[C:2]([S:20][C:19](=[NH:21])[NH:18][CH2:14][CH2:15][CH2:16][CH3:17])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1nc2ccccc2nc1Cl
Reactant: CCCCNC(N)=S
Agent: C
Solvent: CC(C)=O
Product: CCCCNC(=N)Sc1nc2ccccc2nc1C
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Chloro-3-methylquinoxaline (3.572 g., 0.02 mole) was dissolved in 50 ml. of acetone treated with Norit and filtered. The filtrate was added to a solution of 2.645 g. (0.02 mole) n-butylthiourea in 25 ml. acetone. After the mixture was stirred at room temperature for 31/2 hours, the solid which had formed was filtered, washed with acetone, then ether and dried to give 4.86 g. (78.2%) of product as an off-white solid, m.p. 118.5°-119.5°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH2:4][C:5](=O)[C:6]([F:9])([F:8])[F:7].Cl.[NH:15]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[NH2:16].[CH2:26](O)[CH3:27]>>[CH2:26]([O:22][C:21](=[O:23])[C:20]1[CH:19]=[CH:18][C:17]([N:15]2[C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][C:5]([C:6]([F:9])([F:8])[F:7])=[N:16]2)=[CH:25][CH:24]=1)[CH3:27]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A mixture of 1,1,1,5,5,5-hexafluoro-pentane-2,4-dione (3.16 g, 15.2 mmol) and 4-hydrazinobenzoic acid hydrochloride (2.86 g, 15.2 mmol) in ethanol (5 mL) was stirred at 100° C. in a sealed tube for 4 hours. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was purified by chromatography (SiO2, 4:1 to 3:1 hexane/EtOAc) to give 4-(3,5-bis-trifluoromethyl-pyrazol-1-yl)-benzoic acid ethyl ester, (3.1 g, 58% yield) as a syrup: 1H-NMR (CDCl3) δ 1.40 (t, 3H, J=7), 4.35-4.50 (m, 2H), 7.10 (s, 1H), 7.60 (d, 2H, J=7), 8.21 (d, 2H, J=7) ppm.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:6]1[N:7]=[C:2]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:3]=[CH:4][CH:5]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: N#Cc1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C#N)n2)CC1
Temperature: 130 °C

Procedure:
6-Bromo-2-pyridinecarbonitrile (1.00 g, 5.46 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (1.10 g, 5.46 mmol), Pd(OAc)2 (61 mg, 0.27 mmol), 2-(di-t-butylphosphino)biphenyl (98 mg, 0.328 mmol) and Cs2(CO3) (3.56 g, 10.93 mmol) were mixed in toluene (20 ml). The reaction was stirred under an N2 atmosphere and heated to 130° C. on an oil bath for 24 h. The solvent was evaporated in vacuo and the remaining separated between EtOAc (500 ml) and water (500 ml). The aqueous phase was extracted with EtOAc (500 ml). The combined organic phases were washed with water (500 ml), dried with Na2SO4 (s), filtered and evaporated in vacuo. Purification by silica gel flash chromatography using a 40 g Biotage column with a gradient of 5-30% EtOAc in heptane giving the title compound as a white solid. Yield: 605 mg (37%). 1H NMR (400 MHz, CDCl3) δ 7.63 (dd, 1H, J=8.4 Hz, J=7.3 Hz), 7.25 (d, 1H, J=7.3 Hz), 6.90 (d, 1H, J=8.4 Hz), 5.21 (m, 1H), 3.74 (m, 2H), 3.25 (m, 2H), 1.95 (m, 2H), 1.68 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6].[CH3:12]OS(OC)(=O)=O>O>[CH3:12][O:6][C:5]1[C:4]([CH3:3])=[C:10]([OH:11])[CH:9]=[CH:8][CH:7]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1c(O)cccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(O)c1C
Temperature: 95 °C
Reaction time: 2 h

Procedure:
3-Methoxy-2-methyl-phenol was prepared according to published procedure: J. Org. Chem. 55, 5, 1990, 1469. To a solution of 2.0 g (50 mmol) NaOH and 2-methylresorcinol (6.2 g, 50 mmol) in water (50 mL), dimethylsulfate (4.8 mL, 50 mmol) was added at 95° C. over 30 min, then reaction was stirred for 2 h at 95° C. After cooling to RT, the reaction mixture was poured into aqueous NaOH (8.0 g in 200 ml H2O). Extracted with Et2O (2×100 mL). The aqueous phase was acidified with 5 N aq. HCl, extracted with Et2O (2×100 mL), extracts were dried over Na2SO4 and evaporated. The residue was purified on SiO2 (200 g) column, hexane—EtOAc (0 to 20%). Yield 3.37 g (24.0 mmol, 49%), colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccccc1F
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccccc3F)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-2-fluoro-benzene.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27].CO>C[O-].[Na+]>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:4]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 89.1 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (185 mg, 0.55 mmol), beta-alanine (489 mg, 5.5 mmol) in 0.5 M NaOMe in MeOH solution (8.8 mL, 4.4 mmol) was refluxed overnight. After cooled, the reaction mixture was concentrated and residue was dissolved in water (80 mL). It was acidified by 1 N HCl solution to pH ca. 3-4. Resulting gummy solid was collected by filtration, rinsed with water and then dissolved in EtOAc. The organic solution was dried over MgSO4, filtered and concentrated to provide the title compound (173 mg, 0.49 mmol) as an off-white solid in 89% yield. LC-MS ESI−: 351.14 (M−1)−.
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])[CH:3]([CH3:5])[CH3:4].CN1CCOCC1.[NH2:30][C@H:31]([C:35]([C:37]([C:40]([F:43])([F:42])[F:41])([F:39])[F:38])=[O:36])[CH:32]([CH3:34])[CH3:33].Cl>C(Cl)Cl.CC#N>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:2]([C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:30][C@H:31]([C:35]([C:37]([C:40]([F:41])([F:42])[F:43])([F:38])[F:39])=[O:36])[CH:32]([CH3:33])[CH3:34])=[O:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)[C@H](N)C(=O)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
To a stirred solution of Boc-Val-Pro-OH (1.10 g, 3.5 mmole) in CH2Cl2 (20 ml) under argon, cooled to -17° C., was added NMM (0.40 ml, 3.68 mmole). After 5 minutes, 1 equivalent (0.45 ml, 3.5 mmole) of IBCF was added and a light suspension formed several minutes later. After 20 minutes NMM (0.4 ml, 3.68 mmol) was added followed by a suspension of H-Val-CF2CF3.HCl (0.88 g, 3.50 mol) in CH2Cl2 (10 ml) plus CH3CN (10 ml) dropwise (from an addition funnel) over ca. 15 minutes. The reaction was stirred at -14° to -18° C. for 1 hour and then the cooling bath was removed. The reaction was allowed to warm to room temperature (ca. 40 min.) and diluted with CH2Cl2 (100 ml). The organic phase was washed with 1 N HCl (3×75 ml), satd. NaHCO3 (2×75 ml), and brine (50 ml). Drying (Na2SO4) and concentration gave a colorless oil which was placed under high vacuum to give the desired product as a white foam (1.59 g, 88%). Elemental analysis; calculated for C22H34F5N3O5 : % C=51.26, % H=6.65; % N=8.15. Found: % C=50.80, % H=6.57, % N=7.85.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][NH:31][CH3:32]>O1CCOCC1>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[CH2:30][N:31]([CH3:32])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(=O)Nc1ccc(C(=O)CBr)cc1
Reactant: CNCc1ccc(Cl)cc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C(=O)CN(C)Cc2ccc(Cl)cc2Cl)cc1
Temperature: 20 °C
Yield: 105 %

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(4-(2-bromoacetyl)phenyl)acetamide (1 g, 3.91 mmol, 1.00 equiv) in 1,4-dioxane (40 mL). This was followed by the addition of triethylamine (1.58 g, 15.64 mmol, 4.00 equiv) dropwise with stirring at 20° C. To this was added (2,4-dichlorophenyl)-N-methylmethanamine (880 mg, 4.63 mmol, 1.19 equiv) dropwise with stirring at 20° C. The resulting solution was stirred for 4 h at 20° C. The solids were filtered out. The resulting mixture was concentrated under vacuum to give 1.5 g (84%) of N-(4-(2-((2,4-dichlorobenzyl)(methyl)amino)acetyl)phenyl)acetamide as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)=[CH:5][C:4]=1N)#[N:2].N([O-])=O.[Na+].[ClH:25]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[CH2:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][CH2:14]2)[CH2:11][CH2:10]3)=[CH:5][C:4]=1[Cl:25])#[N:2]
Reactant: Cl
Reactant: CCCC12CCC(c3ccc(C#N)c(N)c3)(CC1)CC2
Agent: O=N[O-]
Agent: [Na+]
Product: CCCC12CCC(c3ccc(C#N)c(Cl)c3)(CC1)CC2

Procedure:
A diazonium salt solution prepared from 20.1 g of 1-(4-cyano-3-aminophenyl)-4-n-propylbicyclo[2.2.2]octane, 5.2 g of sodium nitrite and 40 ml of 20 per cent hydrochloric acid is added dropwise at 0oto a solution of 9.9 g of Cu(I) chloride in 40 ml of concentrated hydrochloric acid, the mixture is then heated on a boiling water bath until the evolution of gas is complete and is allowed to cool, giving 1-(4-cyano-3-chlorophenyl)-4-n-propylbicyclo[2.2.2]octane by extracting and working up.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.Cl.[C:16]1([C:22]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:32]1([C:22]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]3[CH:26]([CH2:27][N:28]([C:12](=[O:14])[CH2:11][C:4]4[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:29]3)[C:25](=[O:31])[CH2:24][CH2:23]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(OC)c(CC(=O)N2CC3C(=O)CCC(c4ccccc4)(c4ccccc4)C3C2)c1
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution of 2,5-dimethoxyphenylacetic acid (1.34 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×200 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (20 cc) and isopropyl ether (80 cc). The crystals are drained, washed with isopropyl ether (25 cc) and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2,5-dimethoxyphenyl)acetyl]-4-perhydroisoindolone (1.5 g) is obtained in the form of white crystals melting at 209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[N:10][CH:11]=[C:12]([CH:17]=2)[C:13](OC)=[O:14])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].[NH2:32][CH:33]([CH:38]([CH3:40])[CH3:39])[CH2:34][C:35]([OH:37])=[O:36]>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:12]([C:13]([NH:32][CH:33]([CH:38]([CH3:40])[CH3:39])[CH2:34][C:35]([OH:37])=[O:36])=[O:14])[CH:11]=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:4][C:3]=1[O:25][CH2:26][CH2:27][CH2:28][N:29]([CH3:30])[CH3:31]
Reactant: COC(=O)c1cnc(-c2ccccc2C)c(-c2ccc(Cl)c(OCCCN(C)C)c2)c1
Reactant: CC(C)C(N)CC(=O)O
Product: Cc1ccccc1-c1ncc(C(=O)NC(CC(=O)O)C(C)C)cc1-c1ccc(Cl)c(OCCCN(C)C)c1
Product: Cl
Yield: 23.8 %

Procedure:
According to the saponification/peptide coupling steps described in examples 1.7 and 10.6 respectively, starting from 835 mg (1.90 mmol) of methyl 5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)nicotinate and 258 mg (1.97 mmol) of racemic 3-amino-4-methylpentanoic acid, we obtain 130 mg of 3-({[5-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-6-(2-methylphenyl)pyridin-3-yl]carbonyl}amino)-4-methylpentanoic acid hydrochloride in the form of a white solid.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:9][C:10]([CH2:12][O:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][N+:29]([O-:31])=[O:30])=[O:11])([CH3:8])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:3][CH2:4][C:5]([NH:9][C:10]([CH2:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][N+:29]([O-:31])=[O:30])=[O:11])([CH2:6][OH:7])[CH3:8]
Reactant: CC1(NC(=O)COC(=O)c2ccccc2OC(=O)CCCCCO[N+](=O)[O-])COC(C)(C)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(CO)(CO)NC(=O)COC(=O)c1ccccc1OC(=O)CCCCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a solution of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid (2,2,5-trimethyl-[1,3]dioxan-5-yl carbamoyl)-methyl ester (5.5 grams) in a mixture of Methanol (55 ml) and water (2.5 ml), was added p-toluenesulfonic acid (0.2 grams) and stirred at room temperature for 2 hours. The reaction mixture poured onto cold water, extracted with Ethyl acetate, washed the organic layer with water, dried over Sodium sulphate and distilled under vacuum to get crude compound which was purified by column chromatography using Hexane:Ethyl acetate as eluant to get 1 grams of 2-(6-Nitrooxy-hexanoyloxy)-benzoic acid (2-hydroxy-1-hydroxy methyl-1-methyl-ethylcarbamoyl)-methyl ester as light yellow syrup. The product was characterized by IH NMR (DMSO-d6) δ 1.16 (s, 3H, CH3), 1.45 (m, 2H, CH2), 1.70 (m, 4H, CH2X2), 2.64 (t, 2H, CH2), 3.50 (m, 4H, CH2X2), 4.55 (t, 2H, CH2), 4.70 (s, 2H, CH2), 4.80 (t, 2H, OHX2), 7.25 (d, 1H, Ar), 7.40 (m, 2H, Ar & NH), 7.70 (t, 1H, Ar), 8.00 (d, 1H, Ar).
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:32][CH3:33])=[C:14]([C:16](=[N:30][OH:31])[CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1>[C:34]([O:31][N:30]=[C:16]([C:14]1[CH:15]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:11]=[CH:12][C:13]=1[NH:32][CH3:33])[CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[O:28][CH3:29])(=[O:36])[CH3:35]
Reactant: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CNc1ccc(C(=O)NCC2CCCC2)cc1C(Cc1ccc(C(=O)OC)cc1OC)=NOC(C)=O
Yield: 85 %

Procedure:
A solution of methyl 4-[2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]-2-(hydroxyimino)ethyl]-3-methoxybenzoate (79.9 mg), 4-(dimethylamino)pyridine (22 mg), and acetic anhydride (0.17 ml) in dischloromethane (11 ml) was stirred under a nitrogen atmosphere for 15 hours. The solution was diluted with dischloromethane, washed with 5% w/v sodium hydrogen sulfate, water, and brine, then dried (MgSO4), and evaporated to give methyl 4-[2-(acetoxyimino)-2-[5-(N-cyclopentylmethylcarbamoyl)-2-methylaminophenyl]ethyl]-3-methoxybenzoate (74.1 mg, 85%) as a pink solid; NMR (80 MHz, CDCl3): 1.2-1.8 [8H, (CH2)4 ], 2.1 (s, 3H, CH3CO), 3.0 (d, 3H, NCH3), 3.3. (dd, 2H, CH2NH), 3.9 (2s, 6H 2×OCH3), 4.3(s, 2H, ArCH2), 5.8 (broad, 1H, NHCO), 6.7(d, 1H), 7.0 (d, 1H), 7.4-7.6 (m, 3H), 7.8 (d, 1H), 8.5 (broad, 1H, CH3NH).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([Br:17])[N:3]=1.C(N(CC)CC)C.Br[CH2:26][C:27]1[CH:41]=[CH:40][C:30]([CH2:31][P:32](=[O:39])([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])=[CH:29][CH:28]=1>C(#N)C>[Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:31][P:32]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])=[O:39])=[CH:40][CH:41]=2)[C:12](=[O:16])[O:13][CH2:14][CH3:15])[CH:5]=[C:4]([Br:17])[N:3]=1
Reactant: CCOC(=O)Nc1cc(Br)nc(Br)c1[N+](=O)[O-]
Reactant: CCOP(=O)(Cc1ccc(CBr)cc1)OCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)N(Cc1ccc(CP(=O)(OCC)OCC)cc1)c1cc(Br)nc(Br)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 38 %

Procedure:
To a solution of ethyl (2,6-dibromo-3-nitropyridin-4-yl)carbamate (1 equiv.) (described in ref. 18, Preparation 67) in acetonitrile (0.40 M) was added triethyl amine (1.5 equiv.) and diethyl 4-(bromomethyl)benzylphosphonate (1.3 equiv.) (described in ref. 88, Ex 25 Step 1). The reaction mixture was then heated to 60° C. for 18 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (38%) as a solid.