Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C@@H:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1.C(O)(=O)C.O=[C:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30]1.[Na]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH:29]3[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30]3)[CH2:13][CH2:12]2)[C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: CCOC(=O)N1CCC(=O)C1
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCNCC1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (3aR,7aR)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one TFA salt (400 mg, 1.24 mmol) in dichloromethane (10 mL) was added acetic acid (0.35 mL 6.12 mmol)-ethyl 3-oxopyrrolidine-1-carboxylate (0.35 mL 2.23 mmol). Sodium triacetoxyoborohydride (0.8 g, 3.77 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with ice water, then diluted with dichloromethane (200 mL) and was washed successively with 1N NaOH (10 mL), water (10 mL) and brine. The solvent was removed under reduced pressure and the residue was purified by high pH prep LCMS (acetonitrile/water) to provide the mixture of two diastereoisomers (260 mg 58%).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Na].[N+:7]([C:10]1[CH:11]=[C:12]([C:16]2[N:20]=[C:19](C(Cl)(Cl)Cl)[O:18][N:17]=2)[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8]>C(O)C>[NH:4]([C:19]1[O:18][N:17]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=2)[N:20]=1)[C:3]([NH2:5])=[NH:2]
Reactant: N=C(N)N
Reactant: O=[N+]([O-])c1cccc(-c2noc(C(Cl)(Cl)Cl)n2)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N=C(N)Nc1nc(-c2cccc([N+](=O)[O-])c2)no1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
7.3 gm of guanidine hydrochloride were added in portions to a solution of 1.8 gm of sodium in 100 ml of ethanol. After 30 minutes of stirring, 22.5 gm of 3-(3-nitro-phenyl)-5-trichloromethyl-1,2,4-oxadiazole were added. The solid which separated out overnight was filtered off and dried, yielding 15.2 gm of the title compound, m.p. 290°-291° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([N:30]4[CH:35]=[CH:34][C:33]([C:36]([O:38]C)=[O:37])=[C:32]([CH3:40])[C:31]4=[O:41])[CH2:26][CH2:25]3)[CH:7]=2)[CH2:5][CH2:4]1>C(O)C>[CH:3]1([C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)=[C:10]([F:19])[C:9]([O:20][CH2:21][CH3:22])=[C:8]([CH2:23][N:24]3[CH2:25][CH2:26][CH:27]([N:30]4[CH:35]=[CH:34][C:33]([C:36]([OH:38])=[O:37])=[C:32]([CH3:40])[C:31]4=[O:41])[CH2:28][CH2:29]3)[CH:7]=2)[CH2:5][CH2:4]1
Reactant: CCOc1c(CN2CCC(n3ccc(C(=O)OC)c(C)c3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(CN2CCC(n3ccc(C(=O)O)c(C)c3=O)CC2)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A 2 M aqueous sodium hydroxide solution (2 mL) was added at room temperature to an ethanol (8 mL) solution of methyl 1-(1-((6-cyclopropyl-3-ethoxy-2,4′-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (283 mg), and the mixture was stirred at 80 C for 3 hours in a nitrogen atmosphere. Then, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was neutralized with 2 M hydrochloric acid. The deposited crystal was collected by filtration and dissolved in ethanol. The obtained solution was filtered, and then, the filtrate was concentrated under reduced pressure. The obtained residue was crystallized (hexane/ethyl acetate) and further recrystallized (hexane/ethyl acetate) to obtain the title compound (151 mg).
Reaction SMILES: [CH2:1]([CH:3]([N:17]1[C:21](=[O:22])[C:20]2=[C:23]([N+:27]([O-])=O)[CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])[CH3:2].[N-:31]=[N+:32]=[N-].[Na+]>CS(C)=O>[CH2:1]([CH:3]([N:17]1[C:21](=[O:22])[C:20]2=[C:23]([N:27]=[N+:31]=[N-:32])[CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc(N=[N+]=[N-])c2C1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
A mixture of 20.9 g (0.05 mol) of N-(1-ethyl-10,10-dimethyl-11-hydroxyundecyl)-3-nitrophthalimide and 3.55 g (0.055 mol) of sodium azide in 100 ml of dimethylsulphoxide is stirred for 24 hours at 80° C. The solution is evaporated in vacuo and the residue is diluted with 300 ml of water. The resulting emulsion is extracted with twice 100 ml of diethyl ether. The ether extracts are first dried with anhydrous sodium sulphate, and then evaporated. 14.7 g (71% of theory) of N-(1-ethyl-10,10-dimethyl-11-hydroxyundecyl)-3-azidophthalimide are obtained in the form of a viscous oil which cannot be distilled.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH2:11].[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][N:23]([C:26]2[S:27][C:28]([C:32](O)=[O:33])=[C:29]([CH3:31])[N:30]=2)[C:22](=[O:35])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:32]([C:28]1[S:27][C:26]([N:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:21][C:22]2=[O:35])=[N:30][C:29]=1[CH3:31])=[O:33]
Reactant: NCc1nc2ccccc2s1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1nc2ccccc2s1
Yield: 69 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use benzo[d]thiazol-2-ylmethanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 69% yield: 1H NMR (300 MHz, DMSO-d6) δ 9.23 (t, J=5.8 Hz, 1H), 8.63 (d, J=8.1 Hz, 1H), 8.04-8.02 (m, 1H), 7.93-7.91 (m, 1H), 7.49-7.31 (m, 7H), 6.40 (dd, J=8.1, 2.7 Hz, 1H), 6.24 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 4.78 (d, J=5.8 Hz, 2H), 2.58 (s, 3H); MS (ES+) m/z 489.1 (M+1).
Reaction SMILES: N1CCC[CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)C>C(OCC)(=O)C>[CH:2](=[C:10]([C:9](=[O:16])[CH2:8][Cl:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:3]
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC(=O)CCl
Agent: CC=O
Solvent: CCOC(C)=O
Product: CC=C(C(=O)CCl)C(=O)OCC
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
0.25 part by weight of piperidine is added dropwise to a mixture of 32.9 parts by weight of ethyl 4-chloroacetoacetate and 9.6 parts by weight of acetaldehyde at -20° C. The mixture is left to stand at -20° C. for 5 to 6 hours and ice-cold 1N hydrochloric acid and ethyl acetate are then added. The ethyl acetate phase is separated off, extracted twice more with 1N hydrochloric acid and then once with water, dried over magnesium sulphate and concentrated. 35.6 parts by weight of a yellow oil are obtained, and are distilled using a bulb tube (oven temperature 80° to 110° C. under 0.07 mm). 15.5 parts by weight of product are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]=[C:18]=[O:19]>C1(C)C=CC=CC=1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([NH:1][C:2]1[C:3]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][S:5][CH:6]=1)=[O:19]
Reactant: COC(=O)c1cscc1N
Reactant: O=C=NCCCCCBr
Solvent: Cc1ccccc1
Product: COC(=O)c1cscc1NC(=O)NCCCCCBr
Yield: 98 %

Procedure:
Methyl 4-aminothiophene-3-carboxylate was reacted with one equivalent of 5-bromopentylisocyanate in toluene at room temperature for 4 hours to produce N-(5-bromopentyl)-N'-(4-carbomethoxythien-3-yl]urea as a tan solid (98%). This material was recrystallized from CH2Cl2 /ether/hexane to afford the urea as a white solid, mp 92°-93.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][Si:60]([C:73]([CH3:76])([CH3:75])[CH3:74])([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[CH:57]=2)[CH:52]=[CH:51][CH:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:10])[C:11]([NH:48][C:49]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([O:59][Si:60]([C:73]([CH3:76])([CH3:75])[CH3:74])([C:61]3[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)[CH:57]=2)[CH:52]=[CH:51][CH:50]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](Oc1ccc2cccc(N)c2c1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Reaction time: 3 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)alanine (220 mg, 1.16 mmol) in dry CH2Cl2 (2 mL) under argon were added PYBOP (604 mg, 1.16 mmol), 1-amino-7-(tert-butyldiphenylsilyloxy)naphthalene hydrochloride, as described above in Step C, (250 mg, 0.58 mmol), and N,N-diisopropylethylamine (0.40 mL, 2.3 mmol). The reaction mixture was stirred for 3 hrs, then partitioned between CH2Cl2 (250 mL) and 10% aqueous citric acid (75 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with CH2Cl2-20% ethyl acetate to yield the desired product as a white foam.
Reaction SMILES: [CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH:16]([C:21]([O:23]CC)=[O:22])[CH2:15][CH2:14]2)[CH2:2][CH3:3].I[CH3:38]>>[CH2:1]([C:4]1[CH:29]=[C:28]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]=[CH:26][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16]([CH3:38])([C:21]([OH:23])=[O:22])[CH2:15][CH2:14]2)[CH2:2][CH3:3]
Reactant: CI
Reactant: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)CCC(C(=O)OCC)O2
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCOc1ccc2c(c1)CCC(C)(C(=O)O)O2

Procedure:
The title compound was prepared from ethyl 6-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate (Example 13) following the procedures described in Example 2, Step A, employing iodomethane instead of iodopropane, and subsequently hydrolyzed following the procedure in Example 1, Step C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11]2)=[CH:6][C:5]=1[O:19][CH3:20].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:11]2)=[CH:6][C:5]=1[O:19][CH3:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCc2cc(OC)c(O)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCc2cc(OC)c(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 8.9 mmol of a 60% strength suspension of sodium hydride in paraffin oil are added a little at a time to 1.86 g of ethyl 7-hydroxy-6-methoxy-2-chromancarboxylate in 23 ml of dimethylformamide. The mixture is stirred at room temperature for 60 minutes, and 8.1 mmol of benzyl bromide are then added. The reaction mixture is stirred at room temperature for 5 hours. For aqueous work-up (three times washing with water, once with saturated sodium chloride solution), the mixture is diluted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. Two recrystallizations from cyclohexane give pure ethyl 7-(benzyloxy)-6-methoxy-2-chromancarboxylate; further product fractions are obtained from the mother liquors of the recrystallizations by preparative HPLC purification (column; chromsil, mobile phase: acetonitrile/water).
Reaction SMILES: I[C:2]1[N:14]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[N:31]=[C:30]2[Sn](C)(C)C>CN(C=O)C.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>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH3:36])[N:31]=[C:30]2[C:2]1[N:14]([S:15]([C:18]2[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=2)(=[O:16])=[O:17])[C:5]2=[N:6][CH:7]=[C:8]3[CH:12]=[N:11][N:10]([CH3:13])[C:9]3=[C:4]2[CH:3]=1
Reactant: COc1ccc2c(c1)c([Sn](C)(C)C)nn2C
Reactant: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)cnn4C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)nn2C
Temperature: 80 °C
Yield: 46.2 %

Procedure:
To a flask was added 7-iodo-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.090 g, 0.20 mmol, Preparation #1), Pd(Ph3P)4 (0.018 g, 0.016 mmol) and 5-methoxy-1-methyl-3-(trimethylstannyl)-1H-indazole (0.071 g, 0.22 mmol) in DMF (3 mL) and the mixture was heated to about 80° C. for about 17 h. The mixture was cooled to rt and then loaded directly on 12 g silica column and eluted with 0 to 100% EtOAc/DCM to provide 7-(5-methoxy-1-methyl-1H-indazol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.045 g, 47%): LC/MS (Table 2, Method c) Rt=1.47 min; MS m/z 487 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1>C(Cl)Cl>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[NH:18][C:13]([C:12]1[N:8]([CH2:7][C:6]2[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:9]=[N:10][N:11]=1)=[O:14]
Reactant: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Reactant: Nc1cnccn1
Solvent: ClCCl
Product: COc1ccc(Cn2nnnc2C(=O)Nc2cnccn2)cc1

Procedure:
1-(4-Methoxybenzyl)-1H-tetrazole-5-carbonyl chloride is reacted in methylene chloride with 2-aminopyrazine to obtain N-(2-pyrazinyl)-1-(4-methoxybenzyl)-1H-tetrazole-5-carboxamide. The protected intermediate is deprotected and worked up by the techniques described in Example 1 to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:46])[C@@H:7]([NH:35]C(OCC1C=CC=CC=1)=O)[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:34])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[Pd]>[C:1]([O:5][C:6](=[O:46])[C@@H:7]([NH2:35])[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:34])[CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:12]1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CC(=O)N1CCCC(NC(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)CC(=O)N1CCCC(NC(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Reaction time: 6 h
Yield: 100.1 %

Procedure:
The solution of 4-(3-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionylamino}-1-piperidyl]-4-oxo-2(S)benzyloxycarbonylaminobutyric acid tert-butyl ester (1.35 g) in tetrahydrofuran (10 ml) and methanol (10 ml) was added 10% Pd—C (0.27 g, 50% wet) was hydrogenated at atmospheric pressure for 6 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo to give 4-[3-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionylamino}-1-piperidyl]-4-oxo-2(S)-aminobutyric acid tert-butyl ester (1.07 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([N+:19]([O-])=[O:20])([CH3:18])[CH2:13][O:14][CH2:15][O:16][CH3:17].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N+:19]([C:12]([CH3:18])([CH3:11])[CH2:13][O:14][CH2:15][O:16][CH3:17])[O-:20]
Reactant: O=Cc1ccc(F)cc1F
Reactant: COCOCC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: COCOCC(C)(C)[N+]([O-])=Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 64.3 %

Procedure:
A suspension of 2,4-difluorobenzaldehyde (293.3 mg, 2.06 mmol), 2-methyl-2-nitro-1-(methoxymethoxy)propane (382.7 mg, 2.35 mmol) and zinc (266 mg, 4.07 mmol) in ethanol (5 ml) was cooled to 0° C. in ice-water bath. Acetic acid (0.46 ml, 8.0 mmol) was added dropwise to the mixture. The mixture was gradually warmed to room temperature and stirred for 19 hours. The mixture was filtered through Celite® bed and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1) to give the title compound (361.9 mg; 56%).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C([BH3-])#N.[Na+]>CO>[CH:16]1([CH2:21][NH:22][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCC1CCCC1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(Oc2ccc(CNCC3CCCC3)cc2)cc1
Reaction time: 48 h
Yield: 80 %

Procedure:
4-Phenoxybenzaldehyde (3.0 g, 15.1 mmol) and cyclopentylmethylamine (1.49 g, 15.1 mmol) were dissolved in methanol (85 mL) under nitrogen at room temperature. Sodium cyanoborohydride (0.95 g, 15.1 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 3.4 g (80%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.10-1.24 (m, 2H), 1.45-1.67 (m, 2H), 1.71-1.90 (m, 3H), 2.06 (p, J=7.5 Hz, 1H), 2.58 (d, J=7.5 Hz, 2H), 3.79 (s, 2H), 6.95-7.05 (m, 4H) 7.09 (tt, J=7.5, 1.5 Hz, 1H), 7.28-7.38 (m, 4H). MS (DCl/NH3) m/e 282 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23]CC)=[O:22])[C:6](=[O:20])[N:7]2[C:12]=1[CH:11]=[C:10]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[CH:9]=[CH:8]2)[CH3:2].[OH-].[Na+].[ClH:28]>C1COCC1>[ClH:28].[CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[N:7]2[C:12]=1[CH:11]=[C:10]([N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1)[CH:9]=[CH:8]2)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)c2cc(N3CCN(C)CC3)ccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)c(=O)n2ccc(N3CCN(C)CC3)cc12
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 68 %

Procedure:
To a solution of 171 mg (0.5 mmol) of ethyl 1-ethyl-8-(4-methylpiperazin-1-yl)-4H-quinolizin-4-one-3-carboxylate, from Step 1, in 4 mL of THF was added 4.0 mL of a 1.0N aqueous sodium hydroxide solution and the reaction mixture was heated, with stirring, at 75° C. for 4.5 hours. The reaction mixture was cooled to ambient temperature and adjusted to pH 2 with 5 mL of 1N aqueous hydrochloric acid solution. The aqueous solution was concentrated in vacuo to ~5 mL and the solid was collected by filtration and dried in vacuo to afford 120 mg (68% yield) of the title compound, m.p. 293°-294° C. (dec); MS DCI-NH3 : 316 (M-Cl)+ 90%, 272 ((M-Cl)--CO2H)+ base; IR (KBr): 3420 (OH), 1695 (C=O), 1640 (C=O) cm-1 ; 1H NMR (TFA) d 1.47 (t, 3H, J=7.5 Hz), 3.00 (q, 2H, J=7.5 Hz), 3.23 (s, 3H), 3.55 (dd, 2H, J=9 Hz), 4.12 (m, 4H), 4.65 (d, 2H, J=15 Hz), 7.40 (s, 1H), 7.67 (d, 1H, J=9 Hz), 8.18 (s, 1H), 9.20 (d, 1H, J=7.5 Hz). Analysis calculated for C17H22ClN3O3 : C, 56.59; H, 6.42; N, 11.64. Found: C, 56.86; H, 6.19; N, 11.60.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)C.[OH-].[Na+].Cl>O.C(O)C>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][C:4]([OH:28])=[O:3])[CH2:11][CH2:10]2)=[O:27])=[CH:14][CH:15]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CN1CCC(C(=O)c2ccc(OCc3ccccc3)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CN1CCC(C(=O)c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 40 °C
Yield: 156.5 %

Procedure:
To a solution of [4-(4-benzyloxy-benzoyl)-piperidin-1-yl]-acetic acid ethyl ester (180 mg, 0.47 mmol) in water (2 mL) and ethanol (2 mL) was added a 4N solution of NaOH (0.24 mL, 0.94 mmol). The reaction was heated up to 40° C. for 3 hours. The reaction was acidified to pH 3 using 1N HCl, then the solvent was then evaporated under vacuum to afford the crude title compound (260 mg). LRMS m/z: ES+=354.4 (M+H), retention time 1.11.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:14])([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[CH3:6])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:14][C:5]([C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=1)([CH3:6])[CH2:4][OH:3]
Reactant: CCOC(=O)C(C)(C)c1ccc(C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)CO)cc1
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of 2-methyl-2-p-tolyl-propionic acid ethyl ester (510 mg, 2.47 mmol) in THF (10 mL) at 0° C. was added lithium aluminum hydride (1M in Et2O, 2.6 mL, 2.6 mmol). The reaction was stirred for 0.5 h and the reaction was quenched by consecutive addition of water (0.1 mL), 15% NaOH (0.1 mL), and water (0.3 mL). The reaction was diluted with EtOAc, dried (MgSO4), filtered and concentrated to yield 2-methyl-2-p-tolyl-propan-1-ol (405 mg). 1H NMR (400 MHz, CDCl3) δ 7.27 (d, 2H), 7.15 (d, 2H), 3.58 (s, 2H), 2.32 (s, 3H), 1.31 (s, 6H); MS 165 (M+1).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[CH3:38][O:37][C:35]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9]1)=[O:36]
Reactant: c1ccc(C(NC2CCCNC2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCCC(NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Yield: 72.9 %

Procedure:
Add triethylamine (3.73 mL, 26.7 mmol) to a solution of piperidin-3-yl-trityl-amine (7.63 g, 22.3 mmol) in dichloromethane (125 mL), follow by dropwise addition of methyl chloroformate (1.76 mL, 22.7 mmol). Stir the reaction at room temperature under nitrogen overnight. Wash the reaction is wash with saturated aqueous sodium bicarbonate solution, brine, dry over magnesium sulfate and concentrate. Purify by flash chromatography on silica gel (eluting with 0–20% ethyl acetate/hexane) to give 6.51 g of the title compound as a white solid, 73% yield. 1H NMR: consistent with structure.