Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[O:1]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCOc1ccccc1
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A mixture of N-(4-phenoxybutyl)phthalimide (7.8 g), hydrazine hydrate (7 ml) and ethanol (150 ml) was stirred for one hour under reflux. Crystalline precipitate was filtered off, then the filtrate was concentrated under reduced pressure to give 4-phenoxybutylamine (4.2 g, 95%) as an oily product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([C:12]2[N:17]=[C:16]3[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]3=[N:14][CH:13]=2)=[N:3]1.Cl.[NH2:25][C:26]1([C:29]#[N:30])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:29]([C:26]1([NH:25][C:21]([C:18]2[C:16]3=[N:17][C:12]([C:4]4[C:5]5[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=5)[N:2]([CH3:1])[N:3]=4)=[CH:13][N:14]=[C:15]3[NH:20][CH:19]=2)=[O:22])[CH2:28][CH2:27]1)#[N:30]
Reactant: N#CC1(N)CC1
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)nn(C)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC5(C#N)CC5)c4n3)nn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.8 %

Procedure:
To a stirred mixture of 2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (80 mg, 0.26 mmol) and 1-aminocyclopropanecarbonitrile hydrochloride (46 mg, 0.39 mmol) in DMF (3 mL) was added EDCI (100 mg, 0.52 mmol) followed by DMAP (63 mg, 0.52 mmol). The mixture was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered, the solid was washed with DMSO and MeOH then dried to give N-(1-cyanocyclopropyl)-2-(1,6-dimethyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (22 mg, 23%) as a white solid. MS: (M+H)+=372; 1H NMR (300 MHz, DMSO): δ 12.98 (s, 1H), 9.14 (s, 1H), 8.95 (s, 1H), 8.55 (s, 1H), 7.58 (s, 1H), 7.25 (d, 1H, J=8.4 Hz), 4.17 (s, 3H), 2.56 (s, 3H), 1.77 (d, 2H, J=6.0 Hz), 1.48-1.44 (m, 2H).
Reaction SMILES: [OH:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](O)=[O:4].S(Cl)(Cl)=O.[C:13]1([S:19]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C>CC(N(C)C)=O>[C:13]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([NH:26][C:3](=[O:4])[C:2]([OH:1])([CH3:8])[CH2:6][CH3:7])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(C)(O)C(=O)O
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: C
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CCC(C)(O)C(=O)Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 2-hydroxy-2-methyl butyric acid (0.76 g, 6.4 mmol) in dry dimethylacetamide (15 ml) was stirred under a nitrogen atmosphere at -10° C. Thionyl chloride (0.76 g, 6.4 mmol) was added and the resulting mixture was allowed to stir at -10° C. for 1 hour. 4-Phenylsulfonylaniline (1.0 g, 4.29 mmol) was then added and the reaction mixture was stirred at -10° C. for a further 15 mins. The solution was then allowed to warm to room temperature where it was stirred overnight. The reaction mixture was poured onto water, extracted with ethyl acetate, and the combined ethyl acetate portions were washed with water, and brine. After drying (Na2SO4) the ethyl acetate was removed by evaporation. Crystallization from ethyl acetate/hexane yielded the title tertiary carbinol (0.89 g, 62.5%) as a colorless crystalline solid; mp=163.0°-165.0° C. 1H--NMR (250 MHz, d6 --DMSO): 0.82 (t, J=7Hz, 3H, CH3), 1.32 (s, 3H, CH3), 1.56 (m, J=7 Hz, 1H, CH2), 1.76 (m, J=7 Hz, 1H, CH2), 5.65 (s, 1H, OH), 7.64 (m, 3H, ArH), 7.91 (m, 4H, ArH, 8.01 (d, J=11.1 Hz, 2H, ArH), 9.98 (s, 1H, NH). MS (CI, CH4): 334(M+1, 100).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[N:9][N:8]=1>O1CCCC1>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH2:6][O:4][CH2:1][C:2]#[CH:3])=[N:8][N:9]=1
Reactant: Clc1nnc(CBr)c2ccccc12
Reactant: C#CCO
Solvent: C1CCOC1
Product: C#CCOCc1nnc(Cl)c2ccccc12
Reaction time: 3 h
Yield: 23.1 %

Procedure:
A solution of propargyl alcohol (46 mg, 0.81 mmol) and KN(TMS)2 (1.63 mL, 0.81 mmol) in tetrahydrofuran (1.5 mL) is stirred under argon for 30 min before 1-bromomethyl-4-chlorophthalazine (2) (140 mg, 0.54 mmol) is added. The mixture is stirred for 3 h, quenched with 2 N HCl (5 mL) and H2O (15 mL), and extracted with ethyl acetate (80 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (20% to 25% ethyl acetate/hexane) to give 29 mg (23%) of 3 as a colorless solid, mp 131-132° C. IR 3079, 1406, 1325 cm−1; 1H NMR (CDCl3) δ 2.60 (t, J=2.4 Hz, 1H, CH≡CCH2O), 5.17 (s, 2H, CH2), 5.36 (d, J=2.4 Hz, CH≡CCH2O), 7.90-8.02 (m, 2H, 6,7-PhthH), 8.21 (m, 1H, 5-PhthH), 8.36 ppm (m, 1H, 8-PhthH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:17][N:14]1[CH2:15][CH2:16][CH:11]([S:8][C:4]2[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:13]1
Reactant: CN1CCC(Cl)CC1
Reactant: Nc1cccc(S)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1CCC(Sc2cccc(N)c2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
Combine 3-amino-benzenethiol (1.87 mL, 17.83 mmol), 4-chloro-1-methyl-piperidine hydrochloride (2.0 g, 11.76 mmol), cesium carbonate (8.42 g, 25.87 mmol), and dimethylformamide (60 mL), stir and heat at 80° C. After 18 hr., cool to ambient temperature and filter. Wash the filtrate with water (3×20 mL) and extract with diethyl ether (2×30 mL). Combine the organic layers, dry over magnesium sulfate, filter and concentrate. Purify through a plug of silica gel using dichloromethane/2.0 M ammonia in methanol (20:1 mixture ratio) to give the title compound as a pale orange oil (1.52 g, 58%): Mass spectrum (ion spray): m/z=223.1 (M+1), 1H NMR (free base, CDCl3): 7.10 (t, J=7.8 Hz, 1H), 6.84-6.80 (m, 1H), 6.77 (t, J=2.0 Hz, 1H), 6.58 (ddd, J=0.8, 2.2, 8.0 Hz, 1H), 3.69 (bs, 2H), 3.09 (bs, 1H), 2.85 (m, 2H), 2.31 (s, 3H), 2.16-1.99 (m, 4H), 1.79-1.64 (m, 2H). 13C NMR (free base, CDCl3): 146.7, 135.2, 129.4, 122.0, 118.4, 113.7, 55.1, 46.1, 43.6, 32.5.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[O:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39]OS(C)(=O)=O)=[CH:35][C:34]=1[Cl:45])[Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[O:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:35][C:34]=1[Cl:45])[Si:15]([C:28]([CH3:29])([CH3:30])[CH3:31])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1
Reactant: CC(C)(C)[Si](OCc1ccc(COS(C)(=O)=O)cc1Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1ccc(COc2ccccc2)cc1Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
To a solution of phenol (969 mg) in N,N-dimethylformamide (27 ml) was added potassium carbonate powder (1.92 g) and the mixture was stirred at room temperature for 5 min. 1-((tert-Butyldiphenylsiloxy)methyl)-2-chloro-4-((methanesulfonyloxy) methyl)benzene (3.39 g) was added and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was allowed to cool to room temperature. Water was added and the mixture was extracted twice with hexane. The organic layers were combined, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate=50/1) to give 1-((tert-butyldiphenylsiloxy)-methyl)-2-chloro-4-(phenoxymethyl)benzene (2.65 g) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][O:10][CH2:9]2)[N:5]=[C:4]([NH2:13])[N:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].N1C=CC=CC=1>CCO>[C:17]([O:16][C:14]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:12][CH2:11][O:10][CH2:9]3)[N:5]=[C:4]([NH2:13])[N:3]=2)[CH2:23][CH2:22]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1nc(Cl)cc(C2CCOC2)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C3CCOC3)nc(N)n2)CC1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A solution of 4-chloro-6-(tetrahydro-furan-3-yl)-pyrimidin-2-ylamine (500 mg, 2.51 mmol), N-BOC piperazine (960 mg, 5.15 mmol) and pyridine (500 uL, 6.1 mmol) in EtOH (10 mL) was heated at 90° C. for 4 h. Upon cooling to rt a thick precipitate formed which was collected by filtration. The material was rinsed with EtOAc to afford 125 mg of a white solid. The filtrate was concentrated and triturated with Et2O-EtOAc (1:1) to yield an additional 600 mg of material (82% combined). MS (ESI): mass calcd. for C17H27N5O3, 349.2; m/z found, 350.3 [M+H]+. 1H NMR (CDCl3): 5.86 (s, 1H), 4.70 (br s, 2H), 3.90-4.07 (m, 2H), 3.83-3.90 (m, 2H), 3.55-3.60 (m, 4H), 3.45-3.50 (m, 4H), 3.18-3.26 (m, 1H), 2.20-2.30 (m, 1H), 2.09-2.18 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](B(O)O)=[CH:8][C:7]=2[CH:14]=1.Br[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=1.CCN(CC)CC>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=3)=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1ccc2oc(B(O)O)cc2c1
Reactant: NC(=O)c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2oc(-c3ccc(C(N)=O)cn3)cc2c1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 31.7 %

Procedure:
5-methoxybenzofuran boronic acid (1.2 mmol), 6-bromonicotinamide (1.0 mmol), Pd(PPh3)2Cl2 (0.024 mmol) and NEt3 (317 μL) were mixed in EtOH (10 mL) in a 20 mL microwave vial. The mixture was stirred at 140° C. for 10 min in a microwave reactor. The mixture was filtered, the obtained precipitate was washed with water and EtOAc and dried under vacuum to afford the title compound (85 mg). 1H NMR δ ppm 9.14 (d, 1 H) 8.42 (dd, 1 H) 7.97-8.25 (m, 2 H) 7.63-7.80 (m, 2 H) 7.58 (d, 1 H) 7.22 (d, 1 H) 6.98 (dd, 1H) 3.81 (s, 3 H); MS m/z 269 (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][NH:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:18][N:19]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:6](=[O:7])[C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
3,5-Bis-trifluoromethylbenzoyl chloride (36 mg, 0.13 mmol, CAS RN 1271-19-8) was added to a solution of methyl-(4-o-tolyl-pyridin-3-yl)-amine (20 mg, 0.10 mmol) and DIPEA (40 μL, 0.23 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred overnight and then loaded directly onto a silica gel column and eluted with 50% EtOAc in n-hexane to yield the desired product as a waxy solid (23 mg, 41%). MS (ESI): m/z=439.0 [M+H]+.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[CH2:13][O:14][CH3:15].[NH2:16][C:17]1([O:32][CH3:33])[C:23](=[O:24])[N:22]2[CH:18]1[S:19][C:20]([CH3:31])([CH3:30])[CH:21]2[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:16][C:17]2([O:32][CH3:33])[C:23](=[O:24])[N:22]3[CH:18]2[S:19][C:20]([CH3:30])([CH3:31])[CH:21]3[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:12])=[CH:5][C:4]=1[CH2:13][O:14][CH3:15]
Reactant: COCc1cc(CC(=O)O)ccc1O
Reactant: CCOC(=O)C1N2C(=O)C(N)(OC)C2SC1(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C1N2C(=O)C(NC(=O)Cc3ccc(O)c(COC)c3)(OC)C2SC1(C)C
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Equivalent amouts (0.05 mole) of the sodium salt of 4-hydroxy-3-(methoxymethyl)benzeneacetic acid and 6-amino-6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylic acid, ethyl ester, are added to dimethylformamide (DMF). The temperature is maintained at 0° C. Then about 1.2 equivalents of dicyclohexylcarbodiimide in DMF is added. The mixture is stirred at 0° C. for from 0.5 to 3 hours and an additional 2 to 5 hours at room temperature. Filtration of the reaction mixture removes the formed dicyclohexylurea. The filtrate is then diluted with chloroform, methylene chloride or ethyl acetate, washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:6][O:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20].Cl>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:6][O:7][CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(COCCO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(COCCOS(C)(=O)=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 19.0 g of 1-acetoxy-1-(3-chlorophenyl)-2-(2-hydroxyethoxy)ethane and 95.0 ml of methylene chloride containing 9.1 ml of methanesulfonyl chloride was dropwise added 16.4 ml of triethylamine with ice cooling over 1 hour. The resulting mixture was stirred for 10 minutes at the same temperature and further for 1 hour at room temperature. The reaction mixture was added to a mixture of 50.0 ml of methylene chloride and 50.0 ml of ice water. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 24.5 g of oily 1-acetoxy-1-(3-chlorophenyl)-2-(2-methanesulfonyloxyethoxy)ethane.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([C:25](C)(C)[O:26][SiH2]C(C)(C)C)=[CH:21][CH:20]=2)[C:12]=1[F:35])[CH2:9][CH3:10])(C)(C)C.N[C@@H](C1C(F)=[C:43]([C:48](C2C=CC(CO)=CC=2)=[O:49])C(Cl)=CC=1)CC>>[NH2:7][C@@H:8]([C:11]1[C:12]([F:35])=[C:13]([C:14]([Cl:17])=[CH:15][CH:16]=1)[C:18]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:48](=[O:49])[CH3:43])=[CH:23][CH:24]=1)=[O:34])[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(C(C)(C)O[SiH2]C(C)(C)C)cc2)c1F
Reactant: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(CO)cc2)c1F
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(COC(C)=O)cc2)c1F

Procedure:
Step 2 ((R)-1-{3-[4-(tert-Butyl-dimethyl-silanyloxymethyl)-benzoyl]-4-chloro-2-fluoro-phenyl}-propyl)-carbamic acid tert-butyl ester was deprotected as Step 2 in the preparation of Example 2. A mixture of the doubly deprotected product [3-((R)-1-amino-propyl)-6-chloro-2-fluoro-phenyl]-(4-hydroxymethyl-phenyl)-methanone (=Example 50) and the trans-esterified product acetic acid 4-[3-((R)-1-amino-propyl)-6-chloro-2-fluoro-benzoyl]-benzyl ester (=Example 49) was obtained. Separation was achieved by column chromatography with 0-8% ammonia in methanol/dichloromethane.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28].C(N(CC)CC)C.Cl>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[C:24]([C:23]([F:22])([F:33])[F:34])[CH:25]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4cccc(C(F)(F)F)c4)ccc3C2=O)C(=O)N1
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (1.00 g, 3.20 mmol) and 3-(trifluoromethyl)benzoyl chloride (0.67 g, 3.20 mmol) in N,N-dimethylformamide (25 mL), was added triethylamine (0.90 mL, 6.40 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (50 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (50 mL) and water (50 mL). The solids were dissolved in EtOAc (75 mL) and washed with water (75 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-trifluoromethyl-benzamide as an off-white solid (0.95 g, 66% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.69 min (98.71%); mp: 244-246° C.; 1H NMR (DMSO-d6) δ 1.94-2.06 (m, 1H), 2.27-2.46 (m, 1H), 2.53-2.68 (m, 1H), 2.80-3.04 (m, 1H), 4.32 (d, J=17.4 Hz, 1H), 4.45 (d, J=17.4 Hz, 1H), 4.63 (d, J=5.9 Hz, 2H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 7.57 (s, 1H), 7.66-7.82 (m, 2H), 7.94 (d, J=7.7 Hz, 1H), 8.16-8.34 (m, 2H), 9.42 (t, J=5.8 Hz, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.90, 47.14, 51.59, 122.21, 122.99, 123.86 (q, J=3.6 Hz), 123.90 (q, J=270 Hz), 127.18, 127.94 (q, J=3.5 Hz), 129.2 (q, J=32 Hz), 129.71, 130.47, 131.44, 134.97, 142.42, 143.50, 164.79, 167.91, 170.98, 172.85. LCMS: MH=446; Anal Calcd for C22H18N3O4F3+0.6H2O: C, 57.92; H, 4.24; N, 9.21. Found: C, 57.87; H, 4.08; N, 9.16.
Reaction SMILES: [OH:1][CH:2]1[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@@H:3]1[CH2:4][C@@H:5]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@H:6]2/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1.O>C(Cl)Cl.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1>[O:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]1[O:1][CH:2]1[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@@H:3]1[CH2:4][C@@:5]([C:3]([CH3:7])([CH3:4])[CH3:2])([O:27][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])[C@H:6]2/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C1=COCCC1
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: O
Solvent: ClCCl
Product: C=C1C[C@H]2[C@H](C[C@](O[Si](C)(C)C(C)(C)C)(C(C)(C)C)[C@H]2/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)C1OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 176 %

Procedure:
(1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (127 mg, 0.25 mmole) obained in Example 3 was dissolved in 2 ml of methylene chloride. Dihydropyrane (42 mg, 0.50 mmole) and pyridium p-toluenesulfonate (5 mg) were added to the solution, and the mixture was stirred at room temperature for 8 hours. Water and methylene chloride were added to the reaction mixture to perform extraction. The resulting organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The resulting crude product was subjected to column chromatography (silica gel 15 g, hexane/ethyl acetate=30/1) to give (1S,2RS,5S,6S,7R)-2-(2-tetrahydropyranyloxy)-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyl-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (130 mg, 0.22 mmole, 88%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[F:23][C:24]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:28][C:25]=1[C:26]#[N:27].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:27]=[C:26]([C:25]2[CH:28]=[C:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:30]=[CH:31][C:24]=2[F:23])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCCCCCCc1ccc(F)c(C#N)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCc1ccc(F)c(-c2nc(-c3c(F)cccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 60.9 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.34 g), 2-fluoro-5-undecylbenzonitrile (1.09 g), anhydrous aluminum chloride (0.55 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.04 g of desired compound (refractive index: 1.5419).
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:46])([F:45])[C:33]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.Cl>CC(N(C)C)=O>[F:31][C:32]([F:45])([F:46])[C:33]1[CH:40]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:38]=[CH:37][C:34]=1[CH2:35][N:9]1[C:10](=[O:23])[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])=[C:12]([OH:13])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:24]
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)n(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1=O
Reaction time: 8 h
Yield: 33.5 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. potassium carbonate (750 mg, 5.35 mmoles) and 2,4-bis(trifluoromethyl)benzyl bromide (375 uL, 2.0 mmoles) in dimethylacetamide (6 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate (×2). The combined organic solutions were washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (3.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated. Recrystallization from acetic acid-water gave the title compound (180 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.11 (br. s., 1 H), 8.06 (s, 1 H), 7.98 (d, J=8.59 Hz, 1 H), 7.53 (d, J=8.34 Hz, 1 H), 5.23 (s, 2 H), 4.64 (t, J=12.00 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.24 (q, 2 H), 1.78 (d, J=12.63 Hz, 2 H), 1.52-1.73 (m, 3 H), 1.28 (q, J=13.05 Hz, 2 H), 1.10 (q, 1 H).