Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:23][CH2:22][C:21](=[C:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:19]2)=[CH:14][C:13]=1[Cl:31])=O)C1C=CC=CC=1>C(OCC)(=O)C.[Pt]=O>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C@H:18]2[CH2:19][CH2:20][C@H:21]([CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:22][CH2:23]2)=[CH:14][C:13]=1[Cl:31]
Reactant: CCOC(=O)C(C)=C1CCC(c2ccc(NC(=O)OCc3ccccc3)c(Cl)c2)CC1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)[C@H]1CC[C@H](c2ccc(N)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
Platinum oxide (300 mg) was added in one portion to a stirred solution of ethyl 2-[4-(4-{[(benzyloxy)carbonyl]amino}-3-chlorophenyl)cyclohexylidene]propanoate (1.7 g, 3.85 mmol) in ethyl acetate (50 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 9 h. The reaction mixture was filtered and concentrated in vacuo to leave a residue, which was purified by column chromatography, using a gradient of 11-66% ethyl acetate:isohexane as eluent, to give the aniline product as a mixture of cis- and trans-cyclohexane isomers. Recrystallisation from a mixture of ethanol and diethyl ether gave the title compound (0.37 g, 28%) as a white solid; 1H NMR δ 1.08 (3H, d), 1.2-1.3 (1H, m), 1.27 (3H, t), 1.31-1.49 (1H, m), 1.52-1.7 (1H, m), 1.71-1.81 (1H, m), 1.81-1.97 (3H, m), 2.2-2.32 (1H, m), 2.33-2.48 (1H, m), 4.15 (2H, dq), 7.02 (1H, dd), 7.2 (1H, d), 7.22 (1H, d); MS m/e MH+ 310.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:22]=[N:21][C:20]4[C:19]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)=[N:18][C:17]([C:29]5[CH:30]=[N:31][C:32]([NH:35]C(=O)OC(C)(C)C)=[N:33][CH:34]=5)=[N:16][C:15]=4[CH:14]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO.C(Cl)(Cl)Cl>[NH2:35][C:32]1[N:31]=[CH:30][C:29]([C:17]2[N:18]=[C:19]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:20]3[N:21]=[CH:22][C:13]([C:10]4[CH:9]=[CH:8][C:7]([C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:6])=[CH:12][CH:11]=4)=[CH:14][C:15]=3[N:16]=2)=[CH:34][N:33]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4ccc(C(=O)NC5CC5)cc4)cc3n2)cn1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4ccc(C(=O)NC5CC5)cc4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19 %

Procedure:
To a 50 mL round bottom flask, tert-butyl (5-(7-(4-(cyclopropylcarbamoyl)phenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (0.1 g, 0.00018 mol) and DCM (10 mL) were added. To the same reaction flask, TFA (0.055 mL, 0.00072 mol) was added and the reaction mixture was stirred at room temperature for 12 hours. The volatiles were evaporated under reduced pressure to provide crude residue. The residue was dissolved in 10% methanol in chloroform, washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by flash column chromatography (3-4% methanol in chloroform) to provide the title compound (0.016 g, 12%). 1H NMR (400 MHz, DMSO-d6): δ 9.19 (br s, 2H), 9.12 (d, J=1.6 Hz, 1H), 8.58 (d, J=4.0 Hz, 1H), 8.43 (d, J=1.6 Hz, 1H), 8.07 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.4 Hz, 2H), 7.22 (br s, 2H), 4.52 (br s, 4H), 3.83 (s, 4H), 2.93-2.86 (m, 1H), 0.72 (d, J=5.2 Hz, 2H), 0.61 (d, J=2.4 Hz, 2H): LC-MS (ESI): Calculated mass: 468.2; Observed mass [M+H]+: 469.0. (RT=0.19 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][OH:40]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:37][CH2:38][CH2:39][OH:40])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[C:16]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[N:17][C:18]([CH3:22])=[C:19]([CH3:21])[CH:20]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
6-Methoxy-4-(5,6,5′-trimethyl-[2,2′]bipyridin-3-yloxy)-quinolin-7-ol (compound 453) (50 mg) was suspended in N,N-dimethylformamide (2 ml). Potassium carbonate (54 mg) and 3-bromo-1-propanol (0.03 ml) were added to the suspension, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (26 mg, yield 46%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=2)=[CH:5][N:4]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35]Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:35][CH2:34][CH2:33][S:30]([C:27]3[CH:28]=[CH:29][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:25][CH:26]=3)(=[O:31])=[O:32])[CH:12]=2)=[CH:5][N:4]=1
Reactant: COc1ccc(Cc2cnc(N)nc2N)cc1O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)CCCCl)cc1
Agent: Cl
Product: COc1ccc(Cc2cnc(N)nc2N)cc1OCCCS(=O)(=O)c1ccc(NC(C)=O)cc1
Yield: 80 %

Procedure:
Following substantially the procedure of Example 1, Step B, 2,4-diamino-5-(3'-hydroxy-4'-methoxybenzyl)pyrimidine hydrochloride is treated with 3-(p-acetamidophenylsulfonyl)propyl chloride to afford 2,4-diamino-5-{3'-[3"-(p-acetamidophenylsulfonyl)propoxy]-4-methoxybenzyl}pyrimidine in 80% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:25](O)(=[O:28])[CH2:26][CH3:27]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[C:25](=[O:28])[CH2:26][CH3:27]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(=O)c1c(O)cc(C)oc1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 4-hydroxy-6-methyl-2H-pyran-2-one (18 g; 143 mmol; Aldrich) in 300 ml DCM at 0° C., was added TEA (20 ml; 143 mmol; Aldrich), DCC (30 g; 145 mmol; Aldrich), DMAP (5.25 g; 42.7 mmol; Aldrich) and propionic acid (11 ml; 147 mmol; Aldrich). The reaction mixture was stirred at 0° C. for 1 h, stirred at 25° C. for 18 h, and filtered via vacuum filtration. The filtrate was washed with 5% HCl, dried with brine and anhydrous Na2SO4, and evaporated to a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:43]=[C:42]([F:44])[C:41]([F:45])=[CH:40][C:37]=1[CH2:38]Br.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:10][C@H:9]1[CH2:33][O:34][CH2:38][C:37]1[CH:40]=[C:41]([F:45])[C:42]([F:44])=[CH:43][C:36]=1[F:35])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: Fc1cc(F)c(CBr)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A solution of 15.5 g (32.59 mmol) (2S,4R)-2-hydroxymethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester and 24.7 g (109.77 mmol) 2,4,5-trifluorobenzylbromide in 700 ml DMF at 0° C. was treated with 2.28 g (52.14 mmol) of 55% NaH in 4 portions and warmed up to room temperature during 7 h. The reaction was cooled to 0° C. and treated with 500 ml aqueous saturated NH4Cl solution, extracted with EtOAc (3×). The organic phase was washed with 10% NaCl dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with hexane/EtOAc (9:1 to 8.5:1.5) gave 9.37 g (46%) of (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 620 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10]C(C)(C)C)=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+]>O1CCOCC1>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([O:28][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)c1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(OC2CCN(Cc3ccccc3)CC2)n1
Yield: 58.8 %

Procedure:
Tert-butyl 6-chloropyridine-2-carboxylate (1.00 g, 4.68 mmol) and N-benzylpiperidin-4-ol (1.88 g, 9.83 mmol) were dissolved in dioxane (10 mL). NaH (393 mg, 60% dispersion in mineral oil, 9.83 mmol) was added and the reaction mixture was heated using a microwave (80° C., absorption high) for 1 h. The solvents were removed in vacuo and the residue was dissolved in MeOH (100 mL), filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography to give the title compound (860 mg, 59%) as a white solid. LCMS (ES+): 313.1 [MH]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:10]([OH:21])[CH2:9]1)=O)(C)(C)C.[ClH:22]>CO>[ClH:22].[OH:21][C@@H:10]1[C@@H:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCc2ccccc2)[C@@H](O)C1
Agent: Cl
Solvent: CO
Product: O[C@H]1CNC[C@@H]1CCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a suspension of benzyltriphenylphosphonium bromide (1.75 g, 4.97 mmol) in dry THF (10 mL) under argon at 0° C. was added 1.6 M BuLi in THF (2.33 mL, 3.73 mmol) and the deep red solution left stirring without cooling for 10 min. After re-cooling to 0° C., the aldehyde 46 (335 mg, 1.56 mmol) [G. B. Evans, R. H. Fumeaux, A. Lewandowicz, V. L. Schramm, and P. C. Tyler, Second-Generation Transition State Analogues of Human Purine Nucleoside Phosphorylase, J. Med. Chem., 46 (2003) 5271-5276] in THF (5 mL) was added and the mixture stirred at r.t. for 12 h. The reaction was then quenched with water (1 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with sat. aq. NaHCO3 (15 mL) then water (15 mL), dried (MgSO4) and concentrated in vacuo. The residue was subjected to chromatography to afford a ca. 1:3 cis/trans mixture of (3R,4S)-N-tert-butoxycarbonyl-3-hydroxy-4-(2-phenylethenyl)-pyrrolidine (47) as a syrup (290 mg, 64%). 1H NMR (300 MHz, CDCl3): δ ppm: trans: 7.28 (m, 5H), 6.49 (d, J=15.9 Hz, 1H), 6.03 (dd, J=15.9, 8.1 Hz, 1H), 4.11 (m, 1H), 3.67 (m, 2H), 3.32 (m, 2H), 2.83 (m, 1H), 1.46 (s, 9H); cis: 7.27 (m, 5H), 6.58 (d, J=11.6 Hz, 1H), 5.43 (dd, J=11.6 Hz, 10.0 Hz, 1H), 4.11 (m, 1H), 3.65 (m, 2H), 3.21 (m, 2H), 2.88 (m, 1H), 1.44 (s, 9H). To a solution of intermediate 47 (290 mg, 1.00 mmol) in ethanol (20 mL) was added 10% Pd/C (250 mg) and the suspension was stirred under an atmosphere of hydrogen for 12 h. After filtration, the solvent was removed in vacuo to give (3R,4S)-N-tert-butoxycarbonyl-3-hydroxy-4-(2-phenylethyl)pyrrolidine (48) as a syrup, 254 mg (87%). 1H NMR (300 MHz, CDCl3): δ ppm: 7.10 (m, 5H), 4.00 (m, 1H), 3.47 (m, 2H), 3.07 (m, 2H), 2.67 (m, 2H), 2.04 (m, 1H), 1.83 (m, 1H), 1.54 (m, 1H), 1.45 (s, 9H). 13C NMR (300 MHz, CDCl3): δ ppm (note that some peaks are doubled due to slow conversion of rotamers): 155.17, 142.03, 128.83, 128.71, 126.37, 79.88, (74.94, 71.26), (53.17, 52.90), (49.90, 49.34), (46.11, 45.52), 34.41, 33.69, 28.91. To a solution of intermediate 48 (254 mg, 0.87 mmol) in methanol (10 mL) was added 12N (conc.) HCl (4 mL) and the solution stirred at 40° C. for 30 min. After removal of the solvent in vacuo and azeotroping with toluene, the crude title compound (3R,4S)-3-Hydroxy-4-(2-phenylethyl)pyrrolidine hydrochloride 49 was obtained as a solid (202 mg, 0.89 mmol, 102%). 1H NMR (300 MHz, MeOH-d4): δ ppm: 7.14 (m, 5H), 4.22 (m, 1H), 3.52 (dd, J=11.8, 7.4 Hz, 1H), 3.39 (dd, J=12.3, 4.9 Hz, 1H), 3.14 (dd, J=12.3, 2.8 Hz, 1H), 3.02 (dd, J=11.8 Hz, 1H), 2.71 (m, 2H), 2.20 (m, 1H), 1.84 (m, 1H), 1.62 (m, 1H). 13C NMR (300 MHz, MeOH-d4): δ ppm: 142.94, 129.93, 129.89, 127.56, 75.56, 52.90, 48.55, 47.28, 35.18, 34.44.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].C(O)C.[NH:12]1[CH:16]=[C:15]([C:17]2[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=2[C:19]#[N:20])[N:14]=[CH:13]1>O.C1COCC1>[OH:3][NH:2][C:19](=[NH:20])[C:18]1[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=1[C:15]1[N:14]=[CH:13][NH:12][CH:16]=1
Reactant: NO
Reactant: N#Cc1ccccc1-c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: N=C(NO)c1ccccc1-c1c[nH]cn1
Temperature: 80 °C
Yield: 25 %

Procedure:
Hydroxylamine hydrochloride (56 mg, 0.804 mmol) was added to a solution of NaHCO3 (68 mg, 0.804 mmol) in water (0.5 mL). Ethanol (1.5 mL) was added followed by 2-(1H-imidazol-4-yl)benzonitrile in THF (0.5 mL) and the reaction mixture was heated at 80° C. for 18 h. Solvents were removed under reduced pressure and the remaining solution poured into water and extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (10 mL), dried, and concentrated. The residue was purified by flash column chromatography (silica gel, 5%-30% MeOH/DCM) to afford the desired product as a white solid (20 mg, 0.099 mmol, 25%). 1H NMR (DMSO-d6): 3.13 (s, 1H), 5.75 (s, 1H), 7.16-7.38 (m, 3H), 7.65 (s, 1H), 7.79 (s, 1H), 7.92 (d, 1H, J=7.6 Hz), 9.27 (s, 1H)
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[O:1]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccccn1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-hydroxymethylpyridine (19.3 ml), t-butyldimethylsilyl chloride (36.2 g) and imidazole (27.2 g) in dimethylformamide (190 ml) was stirred for two hours at room temperature. Water was added to the reaction mixture and extracted with n-hexane. The organic layer was washed with water, dried over magnesium sulfate and then evaporated. The residue was distilled to give 2-t-butyldimethylsiloxymethylpyridine (42.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][N:14]=1)[C:5]([NH:7][NH:8][C:9]([NH2:11])=[S:10])=O.N>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[S:10][C:9]([NH2:11])=[N:8][N:7]=2)[CH:12]=[CH:13][N:14]=1
Reactant: NC(=S)NNC(=O)c1ccnc(Cl)c1
Agent: N
Product: Nc1nnc(-c2ccnc(Cl)c2)s1
Temperature: 0 °C
Yield: 93 %

Procedure:
To a flask was weighed 42 g of PPA. Preheated the flask to 100° C. and then 2.4 g (10 mmol) of 8.1.B were added in portions into the flask. After an hour, ice water was added to dilute the reaction and the pH was adjusted to 7 with aqueous NH3. Bright yellow precipitates were generated. Filtered and the precipitates were dried. LC/MS of the precipitates showed to be the product. 2.05 g of 8.1.C was generated with a yield of 93%.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([O:5][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])=[O:4]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Z-Pro (7.5 gm, 0.03 mole) and N-Hydroxysuccinimide (3.45 gm, 0.03 mole) were dissolved in cold dioxane and dicyclohexylcarbodiimide (DCC) (6.18 gm, 0.03 mole) was added with rapid stirring. The mixture was stirred overnight at room temperature and the next day the solid dicyclohexylurea (DCU) was filtered off. The solvent was removed and the oil was recrystallized from isopropyl alcohol. Crystals of Z-Pro-OSu formed with scratching. Yield 8.4 gm. Melting point 86.5°-87.5° C.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)[CH2:2]2>[Pd]>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][N:8]=1)[CH2:2]2
Reactant: O=[N+]([O-])c1ccc(N2CC3CC3C2)nc1
Agent: [Pd]
Product: Nc1ccc(N2CC3CC3C2)nc1
Yield: 0.1 %

Procedure:
The process is carried out according to the method used in example 5.2, using 0.2 g (0.97 mol) of 2-(3-azabicyclo[3.1.0]hex-3-yl)-5-nitropyridine, described in step 12.1, and 0.5 g of 10% palladium-on-charcoal. 0.1 g of the expected product is thus isolated, which product will be used as it is in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][C:19](=[O:21])[N:18]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])[CH2:17][C:16]1([CH3:31])[CH3:30])=O)(C)(C)C>C(Cl)Cl>[F:28][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:29])[C:22]=1[N:18]1[CH2:17][C:16]([CH3:30])([CH3:31])[NH:15][CH2:20][C:19]1=[O:21]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2c(F)cccc2F)CC1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN(c2c(F)cccc2F)C(=O)CN1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
4.2 ml of trifluoroacetic acid (54.7 mmol) was added to a solution of 1.80 g of 4-(2,6-difluorophenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (60c) (5.47 mmol) in methylene chloride (8.4 ml) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=10/1) to obtain 1.25 g of the title compound (yield: quant.).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:10][OH:11])[CH2:4][C:3]1([CH3:13])[CH3:12].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[CH3:31][C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=[O:34]>>[C:33]([O:35][C:5]1([N:10]=[O:11])[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:13])([CH3:12])[CH2:4]1)(=[O:34])[C:32]([CH3:37])([CH3:36])[CH3:31]
Reactant: CN1C(C)(C)CC(=NO)CC1(C)C
Reactant: CC(C)(C)C(=O)O
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CN1C(C)(C)CC(N=O)(OC(=O)C(C)(C)C)CC1(C)C

Procedure:
1,2,2,6,6-Pentamethyl-4-nitrosopiperidin-4-yl pivalate was prepared from 1,2,2,6,6-pentamethyl-piperidin-4-one oxime, lead tetraacetate and trimethylacetic acid using conditions of General Method 3. 1H NMR (250 MHz, CHLOROFORM-d) δ 2.43-2.64 (5H, m), 2.09 (3H, s), 1.91 (2H, d, 14.2 Hz), 1.39 (6H, d, 5.9 Hz), 1.30 (9H, s), 1.25 (6H, d, 2.6 Hz).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[Cl:27][C:28]1[S:29][C:30]([S:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)(=[O:36])=[O:35])=[CH:31][C:32]=1[NH2:33]>>[Cl:27][C:28]1[S:29][C:30]([S:34]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)(=[O:35])=[O:36])=[CH:31][C:32]=1[NH:33][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:13]
Reactant: CN1CCN(S(=O)(=O)c2cc(N)c(Cl)s2)CC1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN1CCN(S(=O)(=O)c2cc(NC(=O)c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)c(Cl)s2)CC1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-chloro-5-(4-methyl-piperazine-1-sulfonyl)-thiophen-3-ylamine (example B.22) according to general procedure II.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[C:21]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)(=[O:23])[CH3:22]>>[C:21]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:30]1)(=[O:23])[CH3:22]
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CC(=O)CNCCCC1CCCNC1
Product: CC(=O)CNCCCC1CCCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1

Procedure:
Prepared analogously to Example 8 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[3-[(acetyl)methylamino]-propyl]piperidine. Purification is carried out by chromatography on silica gel (Baker) using methylene chloride to which increasing amounts of methanol are added.
Reaction SMILES: [CH3:1][NH2:2].F[C:4]1[N:9]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1>>[CH3:1][NH:2][C:4]1[N:9]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: NS(=O)(=O)c1cccc(F)n1
Product: CNc1cccc(S(N)(=O)=O)n1

Procedure:
To 10 ml of condensed methylamine was added 1.86 g (10 mmol) of 6-fluoropyridine-2-sulfonamide. The mixture was allowed to reflux under a dry-ice condenser for 4 hr, then excess amine was allowed to evaporate overnight. The residue was crystallized with water to yield 1.64 g of tan solid, m.p. 124° C. to 126° C. NMR (CDCl3): δ 2.64 (s, 3H), 6.12 (br s, 2H), 6.30 (d, 1H), 6.86 (d, 1H), 7.23 (dd, 1H).
Reaction SMILES: C([Li])CCC.[Br-].[CH2:7]([O:9][C:10]([CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:11])[CH3:8].[CH2:32]([C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]=O)=[CH:36][C:35]=1[O:44][CH3:45])[CH3:33].[Cl-].[Na+]>CCCCCC.O1CCCC1>[CH2:32]([C:34]1[C:41]([O:42][CH3:43])=[CH:40][C:37]([CH:38]=[CH:12][C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:36][C:35]=1[O:44][CH3:45])[CH3:33]
Reactant: CCc1c(OC)cc(C=O)cc1OC
Reactant: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1cc(OC)c(CC)c(OC)c1
Reaction time: 1 h
Yield: 78.8 %

Procedure:
39.4 ml (63 mmol) of a 1.6N solution of n-butyllithium in hexane were added over a period of 15 minutes while stirring at −40° to a suspension of 28.3 g (66 mmol) of ethoxycarbonylmethyl-triphenylphosphonium bromide in 200 ml of tetrahydrofuran. The reaction mixture was stirred at 0° for one hour, cooled to −70° and treated dropwise over 30 minutes with a solution of 11.6 g (60 mmol) of 4-ethyl-3,5-dimethoxybenzaldehyde in 100 ml of tetrahydrofuran. Subsequently, the mixture was stirred at room temperature for a further 16 hours, poured into 600 ml of saturated sodium chloride solution and extracted twice with 800 ml of diethyl ether each time. The combined organic phases were washed once with 600 ml of saturated sodium chloride solution, dried (MgSO4) and concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (hexane/ethyl acetate 5:1). 12.5 g (79%) of ethyl 3-(4-ethyl-3,5-dimethoxy-phenyl)-acrylate were obtained as a white solid.