Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.7 %

Procedure:
38.1 A solution of 530 mg (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 5 ml pyridine was cooled to 0° C. under an argon atmosphere and treated with 664 mg 4-toluenesulfonyl chloride. The mixture was slowly warmed to room temperature and stirred for 6 hrs. The pyridine was distilled off. The residue was taken up in CH2Cl2 and 10% aq. Na2CO3. The organic phase was washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: cyclohexane->cyclohexane/EtOAc 7:3) to give 628 mg (3S,4S)-3-azido-4-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester as viscous yellow oil. MS 405.3 ([M+Na]+)
Reaction SMILES: [N:1]1([C:6]2[C:7]([C:12]([NH:14][C@H:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[NH:20][C:21]3[CH:26]=[N:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)=[O:13])=N[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.BrC1C=CC=[C:53]([O:57][CH3:58])C=1C(N[C@H]1CCC[C@@H]1NC1C=NC(C(F)(F)F)=CN=1)=O.N1C=CC=N1>>[CH3:53][O:57][C:58]1[CH:9]=[CH:10][CH:11]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[C:7]=1[C:12]([NH:14][C@H:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:20][C:21]1[CH:26]=[N:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][N:22]=1)=[O:13]
Reactant: COc1cccc(Br)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1-n1cccn1
Agent: c1cn[nH]c1
Product: COc1cccc(-n2cccn2)c1C(=O)N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1

Procedure:
Prepared according to the procedure for 3-(1H-pyrazol-1-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]pyridine-2-carboxamide (Example 43) from 2-bromo-6-methoxy-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 49; 100 mg, 0.218 mmol) and 1H-pyrazole (30 mg, 0.435 mmol) to afford the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].CO.Cl>O1CCCC1>[NH2:6][CH2:5][C:4]1[C:3]([NH:2][CH3:1])=[N:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNc1ncccc1C#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ncccc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
Borane/THF complex (1.44 mol) as a 1 M solution in tetrahydrofuran was added, dropwise, to a solution of 2-(methylamino)-nicotinonitrile (63.9 g, 480 mmol) in tetrahydrofuran (480 mL). This mixture was stirred at room temperature for 1 hour then heated to reflux for 3 hours. The reaction mixture was quenched by dropwise addition of methanol (136 mL, 3.36 mol) followed by 6M HCl (80 mol, 480 mmol) and 10% HCl (400 mL). The phases were separated and the organic phase washed with brine (2×480 mL). The aqueous phase was made alkaline with 50% aqueous NaOH (250 g). The aqueous phase was extracted with dichloromethane (2×480 mL) and the organic extracts dried over Na2SO4. Concentration in vacuo gave 44.85 g of 3-(aminomethyl)-2-methylaminopyridine as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[O:19][CH:18]=[N:17][CH:16]=3)[N:10]=2)[CH:3]=1.Br[CH:21]=[CH:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.O(C(C)(C)C)[Li].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:10]=[C:11]([C:15]3[O:19][C:18]([CH:21]=[CH:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)=[N:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: N#Cc1ccc(C=CBr)cc1
Reactant: Cc1ccnc(Nc2cccc(-c3cnco3)n2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3cnc(C=Cc4ccc(C#N)cc4)o3)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
A sealed tube was charged with a mixture of (4-methyl-pyridin-2-yl)-(6-oxazol-5-yl-pyridin-2-yl)-amine (200 mg, 0.793 mmol), 4-(2-bromovinyl)-benzonitrile (330 mg, 1.59 mmol), Pd(PPh3)4 (46 mg, 0.0396 mmol), LiOtBu (127 mg, 1.59 mmol) and anhydrous 1,4-dioxane (5 ml) and heated to 100° C. with stirring for 2 h. The cooled reaction mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2, eluting with 50% EtOAc in cyclohexane to afford the title compound as a yellow solid (76 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ=9.79 (s, 1H), 8.12 (d, J=5.1 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 7.86-7.61 (m, 5H), 7.46 (d, J=16.3 Hz, 1H), 7.36 (d, J=7.3 Hz, 1H), 6.78 (d, J=4.7 Hz, 1H), 2.35 (s, 3H). (ESI+) m/z 380 (M+H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@@H:13](O)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.P(Br)(Br)[Br:19].Br>>[Br:19][C@@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1)[CH3:14]
Reactant: BrP(Br)Br
Reactant: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Br
Product: C[C@@H](Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 20.5 °C
Reaction time: 0.5 h
Yield: 170.2 %

Procedure:
Under an argon atmosphere, (S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (1.0 g, 3.87 mmol, >99.5% ee) was added dropwise with phosphorus tribromide (0.52 g, 1.94 mmol) on a water bath at a temperature lower than 20° C., and the mixture was stirred at 19 to 22° C. for 30 minutes. The reaction mixture was cooled, and added dropwise with hydrogen bromide (30% solution in acetic acid, 0.76 mL, 3.87 mmol) at a temperature lower than 0° C., and the mixture was stirred at 13 to 15° C. for 18 hours. The reaction mixture was poured into ice water, and the mixture was extracted with n-hexane (15 mL×2). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate (15 mL×1) and then with saturated brine (15 mL×1), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by column chromatography (silica gel, 8 g; developing solvent, n-hexane) to obtain 1.06 g of (R)-1-bromo-1-[3,5-bis(trifluoromethyl)phenyl]ethane as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[CH3:8][O:9][C:10](=[O:14])[C:11]([CH3:13])=O.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>C(O)(=O)C.CO>[CH3:8][O:9][C:10]([C:11]1[C:6]2[C:5]([CH3:7])=[N:4][NH:3][C:2]=2[N:1]=[C:20]([C:19]2[CH:22]=[CH:23][C:16]([OH:15])=[CH:17][CH:18]=2)[CH:13]=1)=[O:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc(N)n[nH]1
Reactant: COC(=O)C(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C)c12
Temperature: 75 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
A mixture of 3-amino-5-methylpyrazole (50.0 g), pyruvic acid methyl ester (58.4 g) and 4-hydroxybenzaldehyde (62.9 mL) in acetic acid/methanol (v/v=1/1, 300 mL) was stirred at 75° C. for 15 h, cooled to r.t.; and the precipitate formed was isolated by suction filtration and dried in vacuo at 60° C. 15 g (10%) of the title compound were obtained as pale yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]([NH:19][P:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)([CH3:3])[CH3:2].[CH2:27]([Li])CCC.CI>C(OCC)C>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]([N:19]([P:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[CH3:27])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)([CH3:3])[CH3:2]
Reactant: [Li]CCCC
Reactant: Cc1ccc(C(=Nc2ccccc2C(C)C)NP(C(C)C)C(C)C)cc1
Solvent: CCOCC
Solvent: CI
Product: Cc1ccc(C(=Nc2ccccc2C(C)C)N(C)P(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
N′-(2-isopropylphenyl)-N-(diisopropylphosphino)-4-methylbenzamidine (1.40 g, 3.0 mmol) was dissolved in 25 mL of diethylether and cooled to 0° C. Butyllithium (1.50 mL of 2.0 M solution in pentane, 3.0 mmol) was added dropwise, producing a cloudy yellow suspension. The slurry was warmed to room temperature and stirred for 2 hours. Methyliodide (1.5 mL of 2.0 M solution in THF) was added dropwise at room temperature and stirred continued for 1 hour. The solution became clear yellow. The solvent was removed under vacuum and replaced with 20 mL of diethylether. A small amount of solid (presumably LiI) was removed by filtration and the filtrate was taken to dryness, yielding 0.94 g (65%) of sticky yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=[O:16].[C:19]1([CH3:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:22]3[CH:23]=[CH:24][C:19]([CH2:25][OH:16])=[CH:20][CH:21]=3)=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1
Reactant: OCc1ccc(-c2ccccc2)cn1
Product: OCc1ccc(OCc2ccc(-c3ccccc3)cn2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
A mixture of 5-phenyl-2-pyridylmethanol (1.98 g), thionyl chloride (1.6 ml) and toluene (30 ml) was stirred at 70° C. for 2 hours. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. A mixture of the residue, 4-hydroxybenzyl alcohol (1.37 g), potassium carbonate (3.18 g) and N,N-dimethylformamide (50 ml) was stirred at 80° C. overnight. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain 4-(5-phenyl-2-pyridylmethoxy)benzyl alcohol (2.69 g, yield 86%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 159–160° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([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)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:33])[CH2:29][C:30](O)=[O:31])[CH:4]=[N:3]1.[NH2:34][CH:35]([CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].Cl.CN(C)CCCN=C=NCC.O>O1CCCC1.C(Cl)Cl>[CH3:1][N:2]1[C:6]([NH:7][C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:33])[CH2:29][C:30]([NH:34][CH:35]([CH2:45][NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:31])[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)NCC(N)CNC(=O)OC(C)(C)C
Reactant: Cn1ncc(NC(=O)CC(=O)O)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cn1ncc(NC(=O)CC(=O)NC(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of 3-{[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}-3-oxopropanoic acid (600 mg), di-tert-butyl (2-amino-1,3-propanediyl)biscarbamate (434 mg) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (522 mg) in tetrahydrofuran (12 ml) and methylene chloride (6 ml) was stirred overnight at room temperature. Water was added and the whole mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a residue, which was triturated with diisopropyl ether-ethyl acetate (2:1) to give di-tert-butyl {2-[(3-{[1-methyl-5-(tritylamino)pyrazol-4-yl]amino}-3-oxopropanoyl)amino]-1,3-propanediyl}biscarbamate (699 mg) as a white solid.
Reaction SMILES: C1([C@H]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C@@H:22]4[CH2:26][CH2:25][O:24][CH2:23]4)=[CH:17][CH:16]=3)[CH2:10]2)C)C=CC=CC=1.C([O-])=O.[NH4+].O1CCCC1.CO>[Pd].O>[O:24]1[CH2:25][CH2:26][C@@H:22]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([C@@H:11]3[O:12][CH2:13][CH2:14][NH:9][CH2:10]3)=[CH:20][CH:19]=2)[CH2:23]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N[C@@H]3CCOC3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: c1cc([C@H]2CNCCO2)ccc1N[C@@H]1CCOC1
Temperature: 95 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
To a solution of 4-((1R)-1-phenylethyl)-(2S)-2-(4-[N-{(3R)-tetrahydrofuran-3-yl}amino]phenyl)morpholine (0.40 g, 1.09 mmol) and ammonium formate (0.69 g, 10.9 mmol) in mixture of tetrahydrofuran (50 ml), methanol (100 ml) and water (16 ml) was added 10% palladium on carbon (wet, 150 mg) and stirred at 95° C. for one hour. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give (2S)-2-[4-{N-((3R)-tetrahydrofuran-3-yl)amino}phenyl]morpholine (0.28 g, quant.) as a colorless oil.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][CH2:16]2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:4]([C:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][N:18]([S:21]([CH3:24])(=[O:22])=[O:23])[CH2:17][CH2:16]3)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1nc(N2CCN(S(C)(=O)=O)CC2)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1
Product: Cn1c(N2CCN(S(C)(=O)=O)CC2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
N-[(4-fluorophenyl)methyl]-1,6-dihydro-5-hydroxy-1-methyl-2-[4-(methylsulfonyl)-1-piperazinyl]-6-oxo-4-pyrimidinecarboxamide was synthesized from 5-hydroxy-2-(4-methanesulfonyl-piperazin-1-yl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester and 4-fluorobenzylamine as described in example to yield the title compound as a white solid 1H NMR (300 MHz, MeOD) δ: 8.88 (1H, t, J=5.9 Hz), 7.37 (2H, dd, J=8.6, 5.3 Hz), 7.05 (2H, t, J=8.8 Hz), 4.55 (2H, d, J=6.2 Hz), 3.55 (3H, s), 3.39–3.36 (4H, m), 3.26–3.23 (4H, m), 2.88 (3H, s). HRMS (M+H) calcd for C18H23FN5O5S: 440.14040. found: 440.1386.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.C(OCC)(=O)C>[O-:34][N+:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:12][CH2:11]2)=[O:9])=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccncc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc[n+]([O-])cc1)C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Benzyl 4-[(4-pyridinylamino)carbonyl]-1-piperidinecarboxylate (EXAMPLE 1, Step 1) (615 mg, 1.81 mmol) was dissolved in CH2Cl2 and treated with mCPBA (3.12 g, 18.10 mmol) and aged 18 h. The reaction was diluted with ethyl acetate and washed with sat. NaHCO3. The organics were separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to afford benzyl 4-{[(1-oxido-4-pyridinyl)amino]carbonyl}-1-piperidinecarboxylate as a clear oil.
Reaction SMILES: C(OC([NH:11][CH2:12][C:13](O)=O)=O)C1C=CC=CC=1.NC1C=CC=CC=1O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:26]=1[NH2:38].C(OC(NCC(N[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C1)=O)=O)(C)(C)C.C(OC([NH:73][CH2:74][C@@H:75]1[CH2:79][N:78](C(OC(C)(C)C)=O)[C@@H:77]([C:87]([OH:89])=O)[CH2:76]1)=O)(C)(C)C>>[NH2:73][CH2:74][C@H:75]1[CH2:79][NH:78][C@@H:77]([C:87]([NH:11][CH2:12][C:13]2[NH:38][C:26]3[CH:27]=[C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:29]=[CH:30][C:25]=3[N:24]=2)=[O:89])[CH2:76]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nc1ccc(Oc2ccccc2)cc1N
Agent: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: Nc1ccccc1O
Product: NC[C@H]1CN[C@@H](C(=O)NCc2nc3ccc(Oc4ccccc4)cc3[nH]2)C1

Procedure:
This compound was prepared as in Compound M77, replacing N-(Benzyloxycarbonyl)-D-homophenylalanine with N-(Benzyloxycarbonyl)glycine, 2-aminophenol with 1,2-diamino-4-phenyloxybenzene and trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline with trans-4-(N-tert-butoxycarbonylaminomethyl)-N-tert-butoxycarbonyl-D-proline.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C(OP(CC(OCC)=O)(OCC)=O)C.C(O[K])(C)(C)C.[C:35]([O:38][CH2:39][CH3:40])(=[O:37])[CH3:36]>O1CCCC1>[CH2:39]([O:38][C:35](=[O:37])[CH2:36][CH:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)[CH3:2])[CH3:40]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Agent: CC(C)(C)O[K]
Agent: CCOC(=O)CP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 4-acetylbenzate (5.00 g, 26.0 mmol) was added to a solution (130 ml) of ethyl diethylphosphonoacetate (6.71 ml, 33.8 mmol) and tert-butoxy potassium (4.38 g, 39.0 mmol) in tetrahydrofuran at 0° C., and the mixture was stirred at room temperature for 16 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate). The mixture of the obtained oil and 10% palladium carbon (1 g) in ethanol (150 ml) was stirred under a hydrogen atmosphere for 2 hrs, and filtered through celite. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (5.67 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.COCCCO.[F:45][C:46]1[CH:47]=[C:48]2[C:53](=[C:54]([OH:56])[CH:55]=1)[N:52]=[C:51]([CH3:57])[CH:50]=[CH:49]2>O>[F:45][C:46]1[CH:47]=[C:48]2[C:53](=[C:54]([O:56][CH2:23][CH2:22][CH2:21][O:20][CH3:24])[CH:55]=1)[N:52]=[C:51]([CH3:57])[CH:50]=[CH:49]2
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Reactant: C1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COCCCOc1cc(F)cc2ccc(C)nc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 80.2 %

Procedure:
Triphenylphosphine (0.74 g, 2.8 mmol) was dissolved in tetrahydrofuran (0.94 mL, 1.1 mmol) and diisopropyl azodicarboxylate (0.35 mL, 1.8 mmol), 3-methoxypropan-1-ol (0.14 mL, 1.5 mmol) and 6-fluoro-2-methylquinolin-8-ol (0.20 g, 1.1 mmol) were added. The vessel was sealed and the mixture was stirred at 50° C. for 12 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (10-50% ethyl acetate/hexanes) to provide the title compound (0.22 g, 77%).
Reaction SMILES: [OH-:1].[Na+].[OH2:3].[C:4]([O-:11])(=[O:10])/[CH:5]=[CH:6]\[C:7]([O-:9])=[O:8].[Ca+2:12]>[OH-].[Ca+2].[OH-].C(O)(=O)C>[C:7]([CH:6]([CH:5]([C:4]([O-:11])=[O:10])[OH:3])[OH:1])([O-:9])=[O:8].[Ca+2:12]
Reactant: [OH-]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Reactant: O
Agent: [Ca+2]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Temperature: 27 °C
Reaction time: 1 h

Procedure:
D,L-tartaric acid, 44.7 g, 101.05 g of 50% sodium hydroxide, 50 g water, and 1.5 g calcium hydroxide were placed in a 500 ml round bottom flask fitted with a thermometer, condenser, addition funnel and mechanical stirrer. A calcium tartrate filter cake from a previous reaction (133.2 g,50% solids) was added to the reactor. The mixture was stirred at 120 rpm and heated to 80°±2° C. The calcium maleate solution was added and the reaction continued at 88°±2° C. Water, 73 g, was stripped from the reaction mixture with a flowing air stream over the 40 minutes of reaction. The reaction solution clarified after about one hour. Total reaction time was three hours. 250 g of water was added and the mixture cooled slowly while slowly adding acetic acid, 13.8 g over30 minutes. At the end of this time the pH of the mixture had been reduced to 9.13 and the temperature reached 68° C. Then the mixture was slowly cooled over 75 minutes from 68° C. to 35° C. Finally,the mixture was cooled to 27° C. in an ice bath. The mixture was filtered using a fritted glass filter funnel. The filtration took only five minutes and provided 485.5 g of filtrate and 59.1 g of calcium tartrate wet cake. On standing overnight, additional calcium tartrate crystallized out and was filtered off, weight, 17.6 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1.[C:30](Cl)(=[O:32])[CH3:31].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:11][C@@H:10]2[CH2:12][O:13][C:14]2[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:32])[CH3:31])[CH2:25]3)=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][N:20]=3)[N:15]=2)=[N:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCNC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc3cccnc3cc2C2CCCN(C(C)=O)C2)nc1
Reaction time: 0.08 h

Procedure:
To a solution of 2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-3-(piperidin-3-yl)-1,5-naphthyridine (RR3) (12 mg, 0.03 mmol) in DMF (0.3 mL) was added acetyl chloride (0.006 mL, 0.09 mmol) and Hunig's Base (0.015 mL, 0.09 mmol). After five minutes, the mixture was purified directly by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.78 (s, 1 H), 8.13 (s, 3 H), 7.64 (s, 1 H), 7.26 (m, 2 H), 4.50 (m, 2 H), 4.26 (brs, 2 H), 3.77 (s, 3 H), 3.49-3.40 (m, 2 H), 3.08 (m, 2 H), 2.27 (m, 2 H), 2.24-2.19 (m, 1 H), 2.05 (s, 3 H), 1.80 (s, 1 H), 1.23-1.15 (m, 2 H), 1.08 (dt, J=8.7, 4.6 Hz, 1 H); HRMS m/z (M+H) 433.2228 found, 433.2234 required.