Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:19]([N:21]([CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH3:20].C1(O)C=CC=CC=1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:28][CH3:29])[CH2:19][CH3:20])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: CCN(CC)CCCCCN
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Solvent: Oc1ccccc1
Product: CCN(CC)CCCCCNc1c2ccc(Cl)cc2nc2ccc(OC)nc12
Product: Cl

Procedure:
A mixture of 2.8 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 1.7 g. of 5-diethylaminopentylamine and 6.5 g. of phenol was treated as in Example 5 to obtain the title compound, m.p. 232°-233° C.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2O)[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH3:27].[F:29][C:30]([F:53])([C:49]([F:52])([F:51])[F:50])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]C1C=C(C)C=CC=1S([O-])(=O)=O.[OH2:54]>CN(C)C=O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:54])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:28])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]([CH3:27])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][C:30]([F:29])([F:53])[C:49]([F:50])([F:51])[F:52]
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCCCCCC(F)(F)C(F)(F)F)c1
Reactant: CNCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F
Solvent: CN(C)C=O
Product: CN(CCCCCCCC(F)(F)C(F)(F)F)CCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CC[C@H](O)[C@@]1(C)C[C@@H]2F

Procedure:
A solution of 1.77 g of 11β-fluoro-7α-[5-(methyl-amino)-pentyl]-estra-1,3,5(10)-triene-3,17β-diol in 18 ml of dimethylformamide is stirred with 1.4 g of 8,8,9,9,9-pentafluoro-nonyltosylate for 1 hour at a bath temperature of 80° C. Then, it is added to water, extracted three times with ethyl acetate, washed with water and common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/methanol. 11β-Fluoro-7α-{5-[methyl-(8,8,9,9,9-pentafluoro-nonyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol is obtained as crystals with a melting point of 110° C.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]2=[O:14].[C:15]1([CH:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30]Br)[CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1C[O:41]CC1>>[C:15]1([CH:21]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][O:14][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]4[C:10]=3[CH2:11][CH2:12][C:13](=[O:41])[CH2:4]4)[CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: C1CCOC1
Reactant: BrCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Product: O=C1CCc2c(cccc2OCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A suspension of sodium hydride (11 mg 60% oil dispersion, 0.28 mmol) and 5-hydroxy-1-tetralone (43 mg, 0.27 mmol) in 5 mL of THF was warmed to about 50° C. for about 30 min. After addition of N-diphenylmethyl-N'-(3-bromopropyl)piperazine (100 mg, 0.27 mmol) the mixture was stirred at about 50° C. for about 3 h. Evaporation of the solvent and silica gel chromatography of the residue (diethyl ether-CH2Cl2 =1:4) gave 100 mg (83%) of the title compound as an oil; MS 455.4.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>O.CCOCC>[O:15]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: Cc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: Cc1cccc(Oc2ccccc2)n1
Temperature: 210 °C
Yield: 124.3 %

Procedure:
A mixture containing 50.28 g of 6-bromo-2-picoline, 83.01 g of phenol and 120.86 g of potassium carbonate under an atmosphere of nitrogen was heated in an oil bath maintained at 210° C. for 20 hrs. After cooling to room temperature, the reaction mixture was dissolved in 1000 ml of H2O and 500 ml of ether. The layers were then separated and the aqueous layer extracted with ether. The combined etheral extracts were washed three times with 5% NaOH and then once with H2O. After drying the etheral layer over anhydrous Na2SO4, removal of the solvents afforded 67.3 g of an orange oil. Distillation afforded 44.32 g of colorless oil, b.p. 80°-85° at 5 mm.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1)[CH2:2][CH3:3].[N+:15]([C:18]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Br:35])=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16].O>CN(C)C=O>[N+:15]([C:18]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Br:35])=[CH:23][C:19]=1[C:20]([N:10]1[C:11](=[O:12])[C:6]2=[CH:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=[C:7]2[C:8]1=[O:9])=[O:21])([O-:17])=[O:16]
Reactant: CCCc1ccc2c(c1)C(=O)NC2=O
Reactant: O=C(Cl)c1cc(Oc2ccc(Br)cc2Br)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc2c(c1)C(=O)N(C(=O)c1cc(Oc3ccc(Br)cc3Br)ccc1[N+](=O)[O-])C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of 4-propylphthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-nitro-5-(2,4-dibromophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-nitro-5-(2,4-dibromophenoxy)benzoyl]-4-propylphthalimide.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:8]([C:9]([O:11][CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[N:7]2[C:25](=[O:36])[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C@H:6]2[S:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:45])C=1>C(Cl)(Cl)Cl>[F:1][CH2:2][C:3]1[CH2:4][S:5](=[O:45])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CF)=CS[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CF)CS(=O)[C@H]12
Reaction time: 2.5 h

Procedure:
To a solution of 1.04 g of benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-2-cephem-4-carboxylate in 10 ml of CHCl3 at 0° is added dropwise a solution of 0.35 g of m-chloroperbenzoic acid in 5 ml of CHCl3. The solution is stirred at 0° for 2.5 hours, then diluted with CHCl3 and washed with NaHCO 3, the dried (MgSO4) and evaporated in vacuo. The residue is recrystallized from methanol to yield benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][C:14]([CH3:27])([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1cccnc1

Procedure:
N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2,2-dimethylpropanoate (77) is synthesised from 3-pyridine sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate according to Scheme 2. (0.99 g, 58%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.16-9.26 (1H, m), 8.89 (1H, d, 4.4 Hz), 8.36 (1H, d, 8.2 Hz), 7.54 (1H, dd, 8.2, 4.9 Hz), 1.42 (9H, s), 1.37 (9H, s)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([OH:35])=O)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C(O)=O)=CC=5)C=4N=[C:68]([N:70]4[CH2:75][CH2:74][O:73][CH2:72][CH2:71]4)N=3)=CN=2)=CC=1.[NH2:99][CH2:100]CCN1CCOCC1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([NH:99][CH2:100][CH2:68][N:70]5[CH2:71][CH2:72][O:73][CH2:74][CH2:75]5)=[O:35])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: NCCCN1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)NCCN4CCOCC4)c3)cn2)cc1

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (69.6 mg, 0.105 mmol) obtained in Step A in Example 1-D-53 instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and N-(3-aminopropyl)morpholine (31.0 μl, 0.212 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-morpholin-4-yl-ethyl)-benzamide as a yellow solid (66.5 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-124) as a colorless powder (23.0 mg, 40%).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:3]=12.[Cl:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[ClH:20].[CH2:24]([O:23][C:21]([N:17]1[CH2:18][CH2:19][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:15][CH2:16]1)=[O:22])[CH3:25]
Reactant: Cc1c2c(nc3ccc([N+](=O)[O-])cc13)CCNCC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3ccc([N+](=O)[O-])cc3c(C)c2CC1
Product: Cl
Yield: 51 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-9-nitro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-11-methyl-9-nitro-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10]O)[CH2:6][CH2:5]1)[CH2:2][CH3:3].P(Br)(Br)[Br:13]>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][Br:13])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](CO)CC1
Reactant: BrP(Br)Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCC[C@H]1CC[C@H](CBr)CC1
Temperature: 0 °C

Procedure:
Compound (31) obtained according to section (A) (15.6 g, 0.1 mole) was added at 0° C. to 150 ml of pyridine-benzene mixture (1:1), and while being stirred, the solution was added to 9.0 g (0.033 mole) of PBr3. The reaction mixture was stirred for 2 hours at 0° C. and then 2 hours at room temperature, poured over ice/2 N HCl and extracted with diethyl ether. The ether extract was washed once each with 2 N HCl, 2 N NaOH, and NaCl solution, dried with Na2SO4, and concentrated. The bromide of formula (32) was purified chromatographically with silica gel.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3C(OC(C)(C)C)=O)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>CN(C)C=O>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:26]1([S:32]([N:1]2[C:9]3[C:4](=[C:5]([O:10][CH2:11][C@@H:12]4[CH2:16][CH2:15][CH2:14][NH:13]4)[CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc2[nH]ncc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ncc2c(OC[C@@H]3CCCN3)cccc21
Reaction time: 0.17 h

Procedure:
A solution of t-butyl (2S)-2-[(1H-indazol-4-yloxy)methyl]pyrrolidine-1-carboxylate (0.317 g, 1.0 mmol) in dimethylformamide is treated with sodium hydride (0.08 g, 2.0 mmol, 60% in mineral oil) at room temperature, stirred for 10 min, treated with benzenesulfonyl chloride (0.264 g, 1.5 mmol), stirred for 18 h under nitrogen at room temperature, quenched with water and diluted with ether. The organic phase is separated, washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a white foam residue. The residue is purified by chromatography (silica gel, EtOAc:hexanes, 15:85) to give a white solid. This solid is dissolved in trifluoroacetic acid at 0° C., stirred at room temperature for 90 min and concentrated in vacuo. The resultant residue is triturated under ether to afford the title compound as a white solid, 300 mg, mp 218-219° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [N+:1]([O-:4])([OH:3])=[O:2].C(O)(=O)C.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14]>C(OCC)C>[N+:1]([O-:4])([OH:3])=[O:2].[N+:1]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][NH2:9])([O-:3])=[O:2]
Reactant: NCCCCO
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O=[N+]([O-])O
Product: NCCCCO[N+](=O)[O-]
Temperature: -8 °C
Reaction time: 0.17 h

Procedure:
Fuming nitric acid (1.5 mL) was added dropwise to acetic acid (25 mL) which had been cooled to an inner temperature of −8° C. with keeping an inner temperature of 0° C. or lower. After stirring the mixed solution for 10 minutes, 4-amino-1-butanol (3.1 mL) was added dropwise with keeping an inner temperature of 0° C. or lower. After stirring the mixture for 10 minutes, a temperature was raised to room temperature with a water bath. After stirring the mixture for 10 minutes, diethyl ether (100 mL) was added, followed by concentration under reduced pressure. To the resulting concentrated material, diethyl ether (100 mL) was added, followed by stirring and removing the supernatant. The resulting residue was concentrated under reduced pressure to obtain a titled compound (6.31 g) having the following physical property values.
Reaction SMILES: [Si]([O:8][CH:9]([C:19]1[CH:20]=[CH:21][C:22]([C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH:29]([C:36]2[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][N:37]=2)[CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:23][CH:24]=1)[CH2:10][O:11][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.C([O-])(=O)C.[NH4+:50].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[CH:31]1([CH2:30][CH:29]([C:28]2[NH:50][C:25]([C:22]3[N:23]=[CH:24][C:19]([CH:9]([OH:8])[CH2:10][OH:11])=[CH:20][CH:21]=3)=[CH:26][CH:27]=2)[C:36]2[CH:41]=[CH:40][C:39]([S:42][CH3:43])=[CH:38][N:37]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: [NH4+]
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)CCC(=O)c2ccc(C(CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)cn2)nc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1ccc(C(CC2CCCC2)c2ccc(-c3ccc(C(O)CO)cn3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 53.4 %

Procedure:
To a solution of 1-[5-(1,2-bis{[tert-butyl(dimethyl)silyl]oxy}ethyl)pyridin-2-yl]-6-cyclopentyl-5-[5-(methylsulfanyl)pyridin-2-yl]hexane-1,4-dione (682 mg) in acetic acid (7 mL) was added ammonium acetate (1.26 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. To a solution of the obtained residue in tetrahydrofuran (4 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 8.16 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (230 mg, yield 53%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (99:1, volume ratio). MS: 424 (MH+).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Br.[CH3:47][C:48]1[CH:53]=[C:52]([NH:54][NH2:55])[CH:51]=[CH:50][N:49]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:52]3[CH:51]=[CH:50][N:49]=[C:48]([CH3:47])[CH:53]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: Cc1cc(NN)ccn1
Agent: Br
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: Cc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
500 mg (1.03 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 315 mg (1.54 mmol) of 2-methylpyridin-4-yl-hydrazine hydrobromide. After hydrolysis, 182 mg (40% of theory) of the title compound is obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1F
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.145 g, 3.13 mmol) (from example 101, step 1) was dissolved in methanol (10 mL) and cooled to −40° C. Sodium hydroxide (0.194 g, 4.84 mmol) dissolved in water (1.000 mL) was added dropwise and continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.192 mL, 3.13 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (15 mL, 90.00 mmol) and the mixture continued to stir at 80° C. for 55 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to a yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (468 mg, 45%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.46-1.77 (m, 2H), 1.80-2.13 (m, 2H), 2.28-3.23 (m, 4H), 3.38-3.80 (m, 3H), 4.04-4.34 (m, 1H), 4.50-4.80 (m, 1H), 5.65 (s, 1H), 6.99-7.12 (m, 2H), 7.12-7.30 (m, 2H). MS m/z 335 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=2)[N:3]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:11]([C:12]#[N:13])[C:2]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: C1CCNCC1
Reactant: COc1ccc2c(-c3ccccc3)c(C#N)c(Cl)nc2c1
Product: COc1ccc2c(-c3ccccc3)c(C#N)c(N3CCCCC3)nc2c1

Procedure:
The title compound was prepared in analogy to example 27 step C from 2-chloro-7-methoxy-4-phenyl-quinoline-3-carbonitrile and piperidine. Light yellow solid. MS (ESI): 344.5 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O)(=O)C>CO.[C].[Pd]>[C:13]([O:17][C:18]([NH:20][CH:21]1[CH2:22][CH2:23][N:24]([CH:10]2[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]2)[CH2:25][CH2:26]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.3 %

Procedure:
To 1-Boc-azetidin-3-on (1.00 g) and 4-(tert-butoxycarbonylamino)piperidine (1.17 g) dissolved in methanol (50 ml) were added acetic acid (0.368 ml) and 10% palladium carbon (1.0 g), followed by stirring under hydrogen atmosphere at room temperature for 12 hours. The reaction mixture was stirred under hydrogen atmosphere (0.4 MPa) at room temperature for 4 hours. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added thereto, followed by partition. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated. The resultant crystals were suspended in diethyl ether-hexane, collected by filtration, and washed with hexane. There crystals were dried under aeration to provide the title compound (1.21 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.CO[C:13](=O)[C@@H:14]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1.S(=O)(=O)(O)O>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:13]([C@H:14]2[NH:15][C:16](=[O:19])[CH2:17][CH2:18]2)[O:5][N:4]=1
Reactant: CC(C)=NO
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc([C@@H]2CCC(=O)N2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a cooled (0°-5° C.) solution of acetone oxime (11.74.g, 160.8 mmol) in THF (200 mL) was slowly added n-butyl lithium (128.6 mL, 2.5M, 321.6 mmol) in hexanes. After being stirred at 0°-5° C. for one hour, a solution of pyroglutamic methyl ester (10.0 g, ~69.9 mmol, the product of step 13a) in THF (50 mL) was added. After stirring for 4 hr, the solution was allowed to slowly warm up to room temperature, and the stirring was continued for 16 hr. Sulfuric acid (35 g, 98%) was slowly added with cooling, followed by the addition of water (35 mL), The resulting mixture was refluxed for one hour. The organic layer was decanted and the slurry was washed with ethyl acetate (5×50 mL). To the mixture was added ethyl acetate (400 mL) and sodium carbonate until basic. Again, the organic layer was decanted and the slurry was washed with ethyl acetate (4×20 mL), The combined organics were then dried over magnesium sulfate. Evaporation of the solvents gave the title product (5.33 g, 46%), which was taken directly to the next step. HPLC (analytical Chiralark AD column) analysis indicated >99.6% ee.