Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]([C@H:14]1[CH2:17][C@H:16](CS([O-])(=O)=O)[CH2:15]1)[C:5]([CH:11]([CH3:13])[CH3:12])([CH:8]([CH3:10])[CH3:9])[O:6][SiH3:7])([CH3:3])[CH3:2].[N:23]1[C:31]([NH2:32])=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[N:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]([CH:4]([C@@H:14]1[CH2:15][C@H:16]([N:27]2[CH:28]=[N:29][C:30]3[C:26]2=[N:25][CH:24]=[N:23][C:31]=3[NH2:32])[CH2:17]1)[C:5]([CH:8]([CH3:9])[CH3:10])([CH:11]([CH3:12])[CH3:13])[O:6][SiH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)C([C@H]1C[C@H](CS(=O)(=O)[O-])C1)C(O[SiH3])(C(C)C)C(C)C
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)C([C@H]1C[C@@H](n2cnc3c(N)ncnc32)C1)C(O[SiH3])(C(C)C)C(C)C
Temperature: 120 °C

Procedure:
In a 25 mL three-neck flask with trans-3-(triisopropyl-siloxyethyl)cyclobutyl-mesylate (0.27 g, 7.7 mmol), adenine (0.16 g, 1.18 mmol) and Cs2CO3 (0.38 g, 1.17 mmol) inside, dry DMF 5 mL was added under argon. Then began to heat to 120° C. and after 24 hr, the solvent was removed and directly applied to silica gel flash chromatography to give 0.14 g (47%) the desired product. 1H NMR (CDCl3, 400 MHz): δ 0.99-1.05 (m, 21H), 1.72-1.78 (m, 2H), 2.15-2.23 (m, 2H), 2.60-2.79 (m, 3H), 3.67-3.70 (t, J=6.0, 2H), 4.81-4.90 (m, 1H), 6.37-6.39 (bs, 2H), 7.88 (s, 1H), 8.31 (s, 1H). 13C NMR (CDCl3, 100 MHz): δ 12.08, 18.17, 26.60, 37.03, 39.84, 45.86, 61.64, 138.76, 140.09, 150.07, 152.91, 155.93. MS (FAB): expected for C20H35N5OSi (M+H)+ 390.61. Found 390.26828. IR (neat) νmax 2942, 2865, 1670, 1604, 1571, 1463, 1415, 1308, 1246, 1108, 882, 681, 658.
Reaction SMILES: B(Br)(Br)Br.[CH3:5][O:6][C:7]([C:9]1[C:17]2[O:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH:12]=[C:11]([O:19]C)[CH:10]=1)=[O:8].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[C:17]2[O:16][C:15]([CH3:18])=[CH:14][C:13]=2[CH:12]=[C:11]([OH:19])[CH:10]=1)=[O:8]
Reactant: COC(=O)c1cc(OC)cc2cc(C)oc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(O)cc2cc(C)oc12
Temperature: 25 °C
Yield: 83.9 %

Procedure:
BBr3 (10 mL, 10.08 mmol, 1.0 M in CH2Cl2) was added drop-wise to a solution of 5-methoxy-2-methyl-benzofuran-7-carboxylic acid methyl ester (4c) (951 mg, 4.31 mmol) and 2,6-lutidine (1.17 mL, 10.08 mmol) in CH2Cl2 (20 mL) at 0° C. The mixture was stirred and warmed to RT overnight. The mixture was quenched with H2O (60 mL) and extracted with CH2Cl2 (2×60 mL). The combined organic layers were dried over MgSO4 and concentrated. The residue was purified by flash column chromatograph eluting with 5% CH3OH/CH2Cl2 to afford a white solid (746 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=2.53 Hz, 1 H) 7.13 (d, J=2.53 Hz, 1 H) 6.33 (d, J=1.01 Hz, 1 H) 5.50 (s, 1 H) 4.00 (s, 3 H) 2.49 (d, J=1.01 Hz, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:32][CH:33]1[CH:40]2[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:42][CH:34]1[CH2:35]3)[CH2:39]2.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:32][CH:33]2[CH:34]3[CH2:42][CH:38]4[CH2:37][CH:36]([CH2:41][CH:40]2[CH2:39]4)[CH2:35]3)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: NC1C2CC3CC(C2)CC1C3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 4-fluorobenzoic acid (15.0 g, 0.11 mol) in DMF (400 mL) was added HOBt (24.59 g, 0.16 mol) and EDAC (20.53 g, 0.11 mol). The resulting mixture was stirred for 1 hr at room temperature at which time a solution of 2-amino-adamantane.HCl (20.1 g, 0.11 mol) and DIPEA (20.52 mL) in DMF (100 mL) was added dropwise. The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in AcOEt and washed with aq. NaHCO3, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo affording 28.66 g, (98%) of 4-fluoro-N-adamantan-2-yl-benzamide as a solid.
Reaction SMILES: C([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:23][NH:24][C:25]2[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:18][C@H:17]([CH3:19])[CH2:16][C@H:15]([CH3:20])[CH2:14]1)[CH:10]=[O:11])C1C=CC=CC=1>CO.[Pd]>[CH3:20][C@H:15]1[CH2:16][C@@H:17]([CH3:19])[CH2:18][C:13]([CH2:12][N:9]([OH:8])[CH:10]=[O:11])([C:21]([NH:23][NH:24][C:25]2[N:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=2)=[O:22])[CH2:14]1
Reactant: C[C@@H]1C[C@H](C)CC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)C1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@H](C)CC(CN(O)C=O)(C(=O)NNc2nccc(C(F)(F)F)n2)C1
Reaction time: 1 h
Yield: 71.6 %

Procedure:
To a solution of N-Benzyloxy-N-{(3S,5R)-3,5-dimethyl-1-[N′-(4-trifluoromethyl-pyrimidin-2-yl)-hydrazinocarbonyl]-cyclohexylmethyl}-formamide (0.09 g, 0.19 mmol) in methanol (10 mL) was added 10% Pd/C (0.028 g). The reaction mixture was subjected to hydrogenation for 1 h at room temperature. The reaction mixture was then filtered through a pad of Celite@, and washed with methanol (20 mL). Removal of the solvent provided the title compound as a beige solid (0.053 g, 73%). MH+390.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@:3]([OH:21])([CH3:20])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10](Br)[N:9]=1)=[O:7].[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.CC#N.O.CCOC(C)=O>C1COCC1.C([O-])([O-])=O.[Cs+].[Cs+]>[F:1][C:2]([F:23])([F:22])[C@:3]([OH:21])([CH3:20])[CH2:4][NH:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)[N:9]=1)=[O:7]
Reactant: C[C@](O)(CNC(=O)c1nc(Br)c(C(F)(F)F)cc1N)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@](O)(CNC(=O)c1nc(-c2ccc(F)cc2)c(C(F)(F)F)cc1N)C(F)(F)F
Temperature: 160 °C

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide (Ex. 3) (100 mg, 0.244 mmol), 4-fluorophenylboronic acid (37.5 mg, 0.268 mmol) and 1,1′ bis(diphenylphosphoshio)ferrocenepalladium dichloride (19.90 mg, 0.024 mmol) was suspended in THF (2 ml) and 1M Cs2CO3 (0.667 ml). The vial was flushed with N2, sealed and heated at 160° C. using microwave radiation for 15 minutes. The mixture was partitioned between EtOAc (50 ml) and water (50 ml). The organic portion was separated and washed with brine (30 ml), dried (MgSO4), filtered through Celite® (filter material) and concentrated in vacuo. The crude residue was dissolved in DMSO (2 ml) and purified by mass directed LCMS using MeCN/Water/0.1% TFA eluent to afford clean product. The product fraction obtained as MeCN/Water/0.1% TFA solution was poured into EtOAc (50 ml) and washed with saturated NaHCO3 (50 ml) to free base the product. The organic portion were combined, dried (MgSO4) and concentrated in vacuo to afford the title compound as a pale orange crystalline solid; 1H NMR (400 MHz, DMSO-d6) δ 8.4 (1H, m), 7.7 (1H, s), 7.49 (2H, m), 7.29 (2H, t), 7.2 (2H, br s), 6.22 (1H, s), 3.68 (1H, m), 3.44 (1H, m), 1.22 (3H, s); LC-MS Rt 4.41 mins [M+H]+ 426 (Method 10minLC_v003).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])OC2C=CC=CC=2)=[C:19]([CH3:33])[C:18]=1[CH3:34])(=[O:3])[NH2:2].[CH3:35][NH2:36]>>[CH3:34][C:18]1[C:19]([CH3:33])=[C:20]([NH:23][C:24]([NH:36][CH3:35])=[O:32])[CH:21]=[CH:22][C:17]=1[O:16][C:7]1[C:6]2[C:11](=[CH:12][C:13]([O:14][CH3:15])=[C:4]([C:1]([NH2:2])=[O:3])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C)c3C)c2cc1C(N)=O
Reactant: CN
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)c(C)c1C

Procedure:
The title compound (30 mg) was obtained as colorless crystals from phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2,3-dimethylphenyl)carbamate) (56 mg) and methylamine (2M tetrahydrofuran solution), by the same procedure as in Example 11.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:14])[NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:15]([C:27](OCC)=[O:28])([C:22](OCC)=[O:23])[CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C[O-].[Na+].Cl>O.CO>[OH:23][C:22]1[C:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[C:27]([OH:28])[N:13]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=2)[N:14]=1
Reactant: N=C(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)Cc1c(O)nc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A 250 mL round bottom flask was charged with 2-(4-nitrophenyl)ethanimidamide hydrochloride (approximately 6.47 g, 30.0 mmol, 48% purity), triethyl ethane-1,1,2-tricarboxylate (7.60 mL, 33.0 mmol) and methanol (43 mL). To this solution was added a 25% sodium methoxide solution in methanol (24.0 mL, 105.2 mmol) immediately resulting in a dark purple thick suspension. After stirring for three hours under reflux the dark purple mixture was cooled to 0° C. using an ice bath and carefully treated with 30 mL water. This mixture was slowly treated with 35 mL 6N hydrochloric acid giving a pale green suspension. The suspension was stirred for additional 30 minutes, filtered and the obtained fawn solid was washed with 100 mL water. The product was dried in a desiccator under vacuum for two days. The crude product was used without purification in the next step.
Reaction SMILES: CN(C=O)C.[H-].[Na+].[C:8]1([CH3:15])[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1.[NH2:16][C:17]1[N:25]=[C:24](Cl)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>[Cl-].[Na+].O>[NH2:16][C:17]1[N:25]=[C:24]([S:14][C:11]2[CH:12]=[CH:13][C:8]([CH3:15])=[CH:9][CH:10]=2)[N:23]=[C:22]2[C:18]=1[N:19]=[CH:20][N:21]2[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(S)cc1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2nc(N)c3ncn(Cc4ccccc4)c3n2)cc1
Temperature: 100 °C
Yield: 91.5 %

Procedure:
To DMF suspension (10 ml) containing sodium hydride (300 mg, 7.5 mmol, 60% in mineral oil) were added p-toluenethiol (1.9 g, 15 mmol) and 6-amino-9-benzyl-2-chloropurine (100 mg, 0.39 mmol) in order. The mixture was stirred under heating at 100° C. for 3 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (124 mg, yield 93%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=3[Cl:29])[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]=12)C1C=CC=CC=1.Cl.C(OCC)(=O)C>CO>[Cl:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[C:17]1([CH2:16][C:12]2[N:11]3[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)N1CCn2c(CC3(c4cc(Cl)ccc4Cl)CCCC3)nc(=O)c(O)c2C1=O
Reaction time: 20 h
Yield: 7.6 %

Procedure:
To a stirred solution of 9-benzyloxy-6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (208) (500 mg, 0.93 mmol) in methanol (5.5 mL) was added concentrated HCl (4 mL) and the mixture was stirred for 20 h. Silica thin layer chromatography was performed (100% ethyl acetate, Rf=0.3). Methanol was removed, water was added, the mixture was basified (pH˜8) with solid NaHCO3, extracted with ethyl acetate (3×20 mL), and the organic part was dried and concentrated. The crude product was purified by preparative HPLC purification to get 6-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (209) (32 mg, 11.34%) as a light brown solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.O>CN(C=O)C>[O:17]1[CH2:16][CH:15]1[CH2:13][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: BrCC1CO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CC1CO1
Temperature: 120 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
Step1: To a suspension of potassium phthalimide (5.0 g, 27 mmol) in DMF (75 ml) was added epibromohydrin (2.5 ml, 29 mmol), and the mixture was stirred at 120° C. for 3 h. After adding water, the mixture was extracted with (hexane/ethyl acetate=3/1), washed with brine, dried over magnesium sulfate, and then filtered. Concentrating under vacuum gave N-(2,3-epoxypropyl)phthalimide (2.81 g, 51%) which was used in the next step without further purification.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:17])[CH2:11][NH:12][C:13](=[O:16])[CH2:14][NH2:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClC1C(Cl)=CC(Cl)=CC=1[O:27][C:28](=O)[C@H:29]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].CN1CCOCC1>C(Cl)Cl>[CH2:2]([O:9][C:10](=[O:17])[CH2:11][NH:12][C:13](=[O:16])[CH2:14][NH:15][C:28](=[O:27])[C@H:29]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1)[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1cc(Cl)cc(Cl)c1Cl
Reactant: NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)NCC(=O)NCC(=O)OCc1ccccc1

Procedure:
A solution of 4.4 parts glycylglycine benzyl ester hydrochloride, 9.1 parts N-t-butoxycarbonyl-L-tyrosine 2,3,5-trichlorophenyl ester and 1.8 parts N-methylmorpholine in 150 parts methylene chloride is stirred overnight at room temperature. The solvent is then removed by evaporation under reduced pressure. The crude material is subjected to low-pressure column chromatography on silica gel to afford N-t-butoxycarbonyl-L-tyrosylglycylglycine benzyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH2:5]([CH:7]1[O:9][CH2:8]1)[Cl:6]>>[Cl:1][CH2:2][CH:3]([OH:4])[CH2:8][O:9][CH2:7][CH2:5][Cl:6]
Reactant: ClCC1CO1
Reactant: OCCCl
Product: OC(CCl)COCCCl
Yield: 74.9 %

Procedure:
A mixture consisting of 100 g 2-chloroethanol (12.4 mol), 573 g epichlorohydrin (6.2 mol) and 20 g of an acidic ion exchange resin was refluxed for 24 hours. The mixture was then filtered to remove the ion exchange resin and the excess alcohol and unreacted epichlorohydrin were removed by distillation. The residue was distilled under vacuum and the product 1-chloro-3-(2-chloroethoxy)-2-propanol (804 g, 75% yield) distilled between 89° and 91° C. at 0.05 mm Hg.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:20][C:19](=[N:21][O:22][CH3:23])[CH2:18][C@H:17]2[C:24]#[N:25])=[O:15])=[CH:10][CH:9]=1.Cl.[NH2:33][OH:34]>C(O)C>[C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:20][C:19](=[N:21][O:22][CH3:23])[CH2:18][C@H:17]2[C:24](=[N:33][OH:34])[NH2:25])=[O:15])=[CH:12][CH:13]=1
Reactant: NO
Reactant: CON=C1C[C@@H](C#N)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 81.8 %

Procedure:
According to the general method outlined above for the synthesis of Intermediates 8, triethylamine (1.94 ml, 13.94 mmol) was slowly added to a suspension of (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-4-(methoxyimino)-2-pyrrolidinecarbonitrile (3.71 g, 11.62 mmol) and hydroxylamine.hydrochloride (0.97 g, 13.94 mmol) in ethanol (150 ml), under stirring. The reaction mixture was allowed to stir at 80° C. for 16 h, and then cooled to ambient temperatures. The solvent was removed by evaporation and the solid was suspended in water (100 ml) then filtered. The solid was washed with diethyl ether (2×100 ml) whilst on the sinter and then dried in vacuo at 40° C., to give the desired product, (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (3.35 g, 82%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[C:4]([CH3:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[C:11]([Cu])#[N:12].C(N)CN>CC(N(C)C)=O>[NH2:8][C:5]1[C:4]([CH3:9])=[C:3]([CH3:10])[C:2]([C:11]#[N:12])=[CH:7][N:6]=1
Reactant: N#C[Cu]
Reactant: Cc1c(Br)cnc(N)c1C
Solvent: NCCN
Solvent: CC(=O)N(C)C
Product: Cc1c(C#N)cnc(N)c1C
Temperature: 170 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
A mixture of 5-bromo-3,4-dimethyl-pyridin-2-ylamine (500 mg, 2.49 mmol), CuCN (445 mg, 4.97 mmol) and DMA (3.5 mL) was stirred under nitrogen for 20 h at 170° C. The reaction mixture was cooled and added to 50 mL of a 20% aqueous solution of ethane-1,2-diamine. The layers were separated and the aqueous layer was extracted 3× with EtOAc. The combined organics were washed with water, followed by brine and dried over MgSO4. Concentration in vacuo afforded compound 850A (362 mg, 99%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16].O>O1CCOCC1>[CH:30]1[C:31]2[CH:19]([CH2:18][O:17][C:15]([N:1]3[CH2:4][CH2:3][C@H:2]3[C:5]([OH:7])=[O:6])=[O:16])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 0.50 g of (S)-(-)-2-azetidine carboxylic acid in 15 ml of 10 aqueous sodium carbonate solution was added 1.3 g of 9-fluorenylmethyl chloroformate in 10 ml of dioxane, dropwise, while maintaining the temperature of the reaction mixture at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours, then poured into water and the aqueous solution was washed with ether. The aqueous layer was cooled to 0° C. and adjusted to a pH of 2 with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give (S)-N-(9-fluorenylmethoxycarbonyl) azetidine-2-carboxylic acid.
Reaction SMILES: O.[ClH:2].[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.Cl.[CH3:11][O:12][NH2:13].C(=O)([O-])[O-].[K+].[K+].Cl>O.C(O)C>[ClH:2].[CH3:11][O:12][N:13]=[C:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: O=C1CCNCC1
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CON=C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Piperidinone hydrochloride monohydrate (5 g, 32.5 mmol), methoxyamine hydrochloride (4.18 g, 50 mmol) and potassium carbonate (13.82 g, 100 mmol) were taken into 100 mL of ethanol and stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate evaporated to afford a white solid. The crude solid was dissolved in water, made basic with solid potassium carbonate, and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate and evaporated in vacuo to afford a clear, colorless liquid. It was converted to its hydrochloride salt by treating with ethereal hydrogen chloride to give 233 g, m.p. 140°-141° C. C6H12N2O·HCl: Calc.: C, 43.77; H, 7.96; N, 17.02. Found: C, 43.78; H, 7.96; N, 17.08.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Oc1cccc(Cl)c1
Reactant: O=Cc1ccccc1F
Product: O=Cc1ccccc1Oc1cccc(Cl)c1
Yield: 69 %

Procedure:
Preparation analogous to Example 12a) from 2-fluoro-benzaldehyde and 3-chlorophenol. Yield: 69%; yellow oil after bulb tube distillation (150°-180° C., 0.001 torr); 1H-NMR (CDCl3, 200 MHz): 6.92-7.38 (m, 6H); 7.95 (m, 1H); 10.48 (s, 1H).
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](O)[CH:34]=[CH:35][CH:36]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH:34]=[CH:33][CH:32]=1)[O:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: COc1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cccc(O[C@@H](CCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.5 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-methoxyphenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.1 mg, 46.6% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.47 (d, 1H, J=6.7 Hz), 7.42 (s, 1H), 7.3-7.20 (m, 3H), 7.20 (m, 3H), 7.07 (t, 1H, J=8.4 Hz), 6.97 (apparent d, 1H, J=6.7 Hz), 6.40 (m, 3H), 5.27 (apparent dd, 1H, J=5.3, 8.0 Hz), 3.74 (s, 3H), 3.38 (m, 2H), 2.93 (m, 2H), 2.61 (s, 1H), 2.53 (apparent sept, partially hidden, 1H, J=6.5 Hz), 2.30-2.10 (m, 6H), 1.82 (m, 2H), 1.25 (d, 6H, J=6.9 Hz); ESMS m/e: 487.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][N:20]2C(=O)C4C(=CC=CC=4)C2=O)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.NN>O1CCCC1.C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][NH2:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]-ethyl}-isoindole-1,3-dione (87 mg in a mixture of 4 mL tetrahydrofuran and 4 mL ethanol) was added 0.6 mL of 95% aqueous hydrazine and the reaction stirred at room temperature. After 18 hours the mixture was concentrated in vacuo and purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 9:6:1) to provide the title compound (54 mg).