Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:12][CH2:13][C:14](Cl)=[O:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:12][CH2:13][C:14]([N:9]1[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCN(C(=O)CCl)CC1
Temperature: 27 °C
Yield: 93 %

Procedure:
piperazine-1-carboxylic acid ethyl ester (200 mg, 1.26 mmol) was treated with chloroacetyl chloride (186 mg, 1.65 mmol) in anhydrous CH2Cl2 (10 mL) containing DIEA (490 mg, 3.80 mmol) at 0° C. The mixture was stirred and warmed to 27° C. for 4 h. The mixture was washed with 1 M HCl(aq). The organic phase was dried over MgSO4, and concentrated under reduced pressure to give ethyl 4-(2-chloroacetyl)piperazine-1-carboxylate (275 mg, 93% yield). C9H15ClN2O3; transparent oil; 1H NMR (400 MHz, CDCl3) δ 4.15 (2H, q, J=7.2 Hz) 4.06 (2H, s), 3.60 (2H, m), 3.54 (2H, m), 3.49 (4H, m), 1.27 (3H, t, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 164.3, 154.3, 61.4, 45.8, 43.5, 43.1, 41.8, 40.8, 14.7; ESI-HRMS calcd for C9H16ClN2O3: 235.0849. found: m/z 235.0852 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([NH:12][C@H:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:14]O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][CH2:20][C@H:9]1[C:10]([NH:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH2:14])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=C(NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OC

Procedure:
31.6 g of methyl t-butoxycarbonylprolylserinate are dissolved in 300 ml methylene chloride. 20.2 g of N-methylmorpholine are added to the solution followed by the addition of 19.1 g toluenesulfonyl chloride. The reaction mixture is chromatographed on silica gel to obtain pure product, methyl t-butoxycarbonylprolyldehydroalaninate.
Reaction SMILES: [NH:1]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:2]([C:24]([OH:26])=O)[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:23])[NH:8][S:9]([C:12]1[C:21]([CH3:22])=[C:19]([CH3:20])[C:16]([O:17][CH3:18])=[CH:15][C:13]=1[CH3:14])(=[O:11])=[O:10].C(N(CC)CC)C.O=S(Cl)Cl.CO>C(Cl)Cl>[C:30]([O:29][C:27](=[O:28])[NH:1][CH:2]1[CH2:3][CH2:4][CH2:5][N:6]([C:7](=[NH:23])[NH:8][S:9]([C:12]2[C:13]([CH3:14])=[CH:15][C:16]([O:17][CH3:18])=[C:19]([CH3:20])[C:21]=2[CH3:22])(=[O:11])=[O:10])[C:24]1=[O:26])([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)NC(=N)N2CCCC(NC(=O)OC(C)(C)C)C2=O)c(C)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Boc-Arg(Mtr)-OH (0.973 g, 2 mmol) and triethylamine (2.02 g, 20 mmol) in CH2Cl2 was added SOCl2 (2.38 g, 20 mmol) at 0° C. The resulting dark brown slurry was stirred at room temperature for 2 hours. The reaction mixture was sampled into methanol and analyzed by HPLC and MS analysis. The major product was identified as the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CC1(C)N([O])C(C)(C)CCC1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[CH:2]([CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reaction time: 3 h

Procedure:
To a flask containing tert-butyl 4-(2 hydroxyethyl)piperidine-1-carboxylate (4.4 g, 19.2 mmol) in CH2Cl2 (20 mL) was added TEMPO (300 mg, 1.92 mmol) followed by iodobenzene diacetate (6.8 g, 21.1 mmol). The reaction was stirred 3 hours and then diluted with CH2Cl2 (100 mL). Saturated aqueous solution of Na2S2O3 (100 mL) was added and extracted with CH2Cl2 (3×50 mL). The combined organics were washed with saturated aqueous NaHCO3 (150 mL) and brine (150 mL), dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40-70% Et2O/pentanes) to provide the title compound, which was identical to the reported literature compound (see Sato et al. (2001) Heterocycle 54: 747). 13C NMR (75 MHz, CDCl3) δ 201.5, 154.7, 79.4, 50.3, 43.7, 31.9, 30.6, 28.4.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][CH2:9]Cl)=[O:7])=[CH:4][CH:3]=1.[I-].[Na+].[N:15]1([C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][CH2:9][CH:16]2[CH2:17][NH:18][CH2:19][CH2:20][N:15]2[C:21]([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:33])[CH2:27][CH2:26]3)=[O:22])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)N3CCNCC3CCC(=O)c3ccc(Cl)cc3)ccc2N1
Temperature: 50 °C

Procedure:
4.12 Grams of 2-(4-chlorobenzoyl)ethyl chloride and 6.08 g of sodium iodide were dispersed in 50 ml of dimethylformamide, and heated at 50° C. for 1.5 hours. Then, to this dispersion was added 50 ml of dimethylformamide solution containing 3 g of 6-(1-piperazinylcarbonyl)-3,4dihydrocarbostyril, and further 9.8 g of potassium carbonate was added thereto and reacted by heating at 70° C. for 3 to 4 hours. After the reaction was completed, the insoluble matters were removed by filtration, and the solvent in the filtrate was removed by evaporation under reduced pressure. The residue thus obtained was extracted with chloroform, and the extract was dried with anhydrous calcium sulfate, then concentrated. The thus obtained residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=50:1), then recrystallzied from ethanol-diethyl ether to yield 2.29 g of 6-{[2-(4-chlorobenzoyl)ethyl]-1-piperazinylcarbonyl}-3,4-dihydrocarbostyril. White powdery substance. Melting point: 198°-200° C. (decomp.)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([Br:28])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:28][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]([C:15]2[NH:14][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[N:17][CH:16]=2)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(Br)c3ccccc23)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(-c2cnc(C3CCCN3)[nH]2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 121.5 %

Procedure:
2-[5-(4-Bromo-naphthalen-1-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g) was dissolved in DCM (12 mL), and trifluoroacetic acid (4 mL) was added. The reaction mixture was stirred at ambient temperature for 3 hours and evaporated under vacuum. Solid was dissolved in DCM (10 mL) and extracted with saturated NaHCO3 solution (30 mL). A solid was collected by vacuum filtration, washed with DCM, and dried under vacuum, giving 5-(4-bromo-naphthalen-1-yl)-2-pyrrolidin-2-yl-1H-imidazole (0.940 g, crude) as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[C:21]1([C@H:27]([NH2:29])[CH3:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:29][C@@H:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:28])=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCCN(CC(=O)N[C@H](C)c1ccccc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and (1R)-1-phenylethanamine: MS (APCI) m/z 390 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]([N:8]2[C:7]([NH:19][C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=4)=[CH:25][CH:24]=3)=[O:21])=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9]2)=[CH:11][CH:12]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A solution of 1-[5-tert-butyl-2-(4-nitrophenyl)-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)phenyl]urea (2.5 g, 5.3 mmol) in anhydrous EtOH (40 mL) was added to a round bottle (100 mL) flask containing 10% Pd/C (30 mg). The reaction vessel was fitted with a balloon adapter and charged with hydrogen and evacuated three times until the reaction was under a H2 atmosphere. The reaction mixture was stirred at room temperature for 18 h, and then filtered through a pad of celite. The celite was washed with EtOH (200 mL) and the filtrate was concentrated at reduced pressure. The residue was purified by MPLC (1:1 hexanes/EtOAc) to give 1.8 g (77%) of the desired product. 1H-NMR (DMSO-d6) δ 9.16 (s, 1H), 8.42 (d, J=5.4 Hz, 2H), 8.17 (s, 1H), 7.47 (d, J=6.9 Hz, 2H), 7.09 to 7.04 (m, 4H), 6.86 (d, J=5.7 Hz, 2H), 6.64 (d, J=6.6 Hz, 2H), 6.28 (s, 1H), 6.38 (s, 2H), 1.18 (s, 9H); MS LC-MS [M+H]+=443, RT=1.95 min.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)=O.[C:16]([O:20][C:21](=[O:37])[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)([CH3:19])([CH3:18])[CH3:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:16]([O:20][C:21]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]([CH2:1][C:3]1[C:8]([C:9]([O:12][C:13](=[O:15])[CH3:14])([CH3:11])[CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)[CH2:28][C:29]1[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][N:30]=1)=[O:37])([CH3:17])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)c1cccnc1C=O
Reactant: Cc1cnc(CNCCCCNC(=O)OC(C)(C)C)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CC(=O)OC(C)(C)c1cccnc1CN(CCCCNC(=O)OC(C)(C)C)Cc1ncc(C)cc1C
Yield: 75 %

Procedure:
Using General Procedure B: Reaction of acetic acid 1-(2-formyl-pyridin-3-yl)-1-methyl-ethyl ester, {4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-carbamic acid tert-butyl ester and NaBH(OAc)3 in CH2Cl2CH2Cl2 gave acetic acid 1-(2-{[(4-tert-butoxycarbonylamino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester (0.83 g, 75%). Deprotection with TFA using General Procedure F gave acetic acid 1-(2-{[(4-amino-butyl)-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-1-methyl-ethyl ester. 1H NMR (CDCl3) δ 1.30 (m, 2H), 1.53 (m, 2H), 1.76 (s, 6H), 1.94 (s, 3H), 2.18 (s, 3H), 2.26 (s, 3H), 2.60 (m, 4H), 3.84 (s, 2H), 3.97 (s, 2H), 7.15 (m, 1H), 7.21 (s, 1H), 7.64 (d, 1H, J=7.0 Hz), 8.18 (s, 1H), 8.50 (d, 1H, J=3.0 Hz).
Reaction SMILES: Cl.[C:2]1([C:8]2[NH:13][C:12]3[CH:14]=[N:15][CH:16]=[CH:17][C:11]=3[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([Cl:26])=[O:25])([O-:20])=[O:19]>>[ClH:26].[N+:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([N:10]1[C:11]2[CH:17]=[CH:16][N:15]=[CH:14][C:12]=2[NH:13][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9]1)=[O:25])([O-:20])=[O:19]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2=NNc3ccncc3N2)cc1
Agent: Cl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1N=C(c2ccccc2)Nc2cnccc21
Yield: 78.6 %

Procedure:
3.8 g (0.015 moles) of 3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride are reacted with m-nitrobenzoyl chloride as described in Example 3 to obtain 1-(m-nitrobenzoyl)-3-phenyl-1,4-dihydropyrido[3,4-e]-as-triazine hydrochloride with a yield of 78.6%; m.p.: 206°-207° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]([C@H:12]2[O:21][C:19](=[O:20])[C:18]3[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=[CH:14][C:13]2=3)[C:10]2[C:9]([O:26][CH3:27])=[C:8]3[O:28][CH2:29][O:30][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1.[BrH:31].O.[Br]>>[CH3:1][N:2]1[C@@H:11]([C@H:12]2[O:21][C:19](=[O:20])[C:18]3[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=[CH:14][C:13]2=3)[C:10]2[C:9]([O:26][CH3:27])=[C:8]3[O:28][CH2:29][O:30][C:7]3=[C:6]([Br:31])[C:5]=2[CH2:4][CH2:3]1
Reactant: Br
Reactant: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(cc3c(c2OC)OCO3)CCN1C
Agent: [Br]
Solvent: O
Product: COc1ccc2c(c1OC)C(=O)O[C@@H]2[C@H]1c2c(c(Br)c3c(c2OC)OCO3)CCN1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Synthesis of 9-aminonoscapine was shown in Scheme 1. Briefly, noscapine (1) was dissolved minimum amount of 48% hydrobromic acid and then cautiously added freshly prepared bromine water. The reaction mixture stirred for 1 h at 25° C. and the resultant mixture was basified to pH 10 to afford 9-bromonoscapine in 82% yield. Refluxing compound 2 in DMF with sodium azide and sodium iodide for 15 hours gave its azido derivative (3) in quantitative yield. Reduction of azido derivative with tin chloride in the presence of thiophenol and triethylamine in THF for 2 h at 25° C. afforded the title compound, 9-aminonoscapine (4) in 83% yield.
Reaction SMILES: [CH:1]1([C@@:6]([OH:30])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH:14]3[N:16]([C:17](OC(C)(C)C)=O)[C@@H:11]2[CH2:12][CH2:13]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCOCC1.ClC(Cl)C.O>[CH:1]1([C@@:6]([OH:30])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]([O:9][C@H:10]2[CH2:15][CH:14]3[N:16]([CH3:17])[C@@H:11]2[CH2:12][CH2:13]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C2CC[C@@H]1[C@@H](OC(=O)[C@](O)(c1ccccc1)C1CCCC1)C2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CC(Cl)Cl
Product: CN1C2CC[C@@H]1[C@@H](OC(=O)[C@](O)(c1ccccc1)C1CCCC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
To (1R,2S)-2-((R)-2′-cyclopentyl-2′-hydroxy 2′-phenylacetoxy)-7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]heptane (76 mg, 0.182 mmol) was added 1 mL of 4N hydrochloric acid in dioxane and the mixture was stirred at room temperature for 0.5 hr. The dioxane was removed under vacuum and the residue was basified with ammonium hydroxide to pH 10 and extracted with 3×30 mL of methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated to yield the crude amine. To this amine, dissolved in 5 mL of dichloroethane, was added 0.1 mL of formaldehyde solution (37% w/v in water) followed by sodium triacetoxyborohydride (76 mg, 0.364 mmol) and the mixture stirred at room temperature overnight. Water was added and the mixture was extracted with 3×50 mL of methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated to yield the crude tertiary amine which was further purified on silica gel using methylene chloride/methanol/ammonia (90:9:1) as the eluent to yield 46 mg of (1R,2S)-2-((R)-2′-cyclopentyl-2′-hydroxy 2′-phenylacetoxy)-7-methyl-7-azabicyclo[2,2,1]heptane as an oil.
Reaction SMILES: C([O-])=O.[NH4+].Cl[C:6]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]([N:16]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH2:17][CH2:18][CH3:19])[N:7]=1>[Pd].O>[CH:21]1([CH2:20][N:16]([CH2:17][CH2:18][CH3:19])[C:8]2[N:7]=[CH:6][N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=2)[CH2:22][CH2:23]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)OC)nc(Cl)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)OC)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A suspension of palladium on charcoal (1.2 g) in IPrOH (219 ml) was treated with a solution of (ammonium formate (12.16 g; 193 mmol) in 35 mL of water) followed by methyl 2-chloro-6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxylate (7.30 g; 25.7 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was filtered through a pad of celite and rinsed with MeOH. Solvents were concentrated under vacuum. The crude was dissolved in DCM and washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under vacuum to afford the title compound as a yellow oil (5.24 g, 81.7%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.CCO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][O:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc2cc(Br)cnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1ccc2cc(-c3ccc(C(=O)O)cc3)cnc2c1
Temperature: 120 °C
Yield: 29.1 %

Procedure:
To a mixture of 3-bromo-7-methoxyquinoline (Intermediate 13, 380 mg, 1.6 mmol), 4-boronobenzoic acid (266 mg, 1.6 mmol) and Na2CO3 (848 mg, 8.0 mmol) in DME/H2O/EtOH (5 mL, V/V/V=1/1/0.5) was added Pd(dppf)Cl2 (585 mg, 0.8 mmol). The mixture was heated to 120° C. by microwave for 1 h. The mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The aqueous phase was separated and acidified to pH=3 with 1 N HCl. The precipitate was filtered and dried in vacuo to afford product as a powder (130 mg, 29.1%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH:5]=[C:6]([CH3:8])[CH3:7])[C@@H:3]1[C:9]([Cl:11])=[O:10]>B(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[CH:4]([CH:5]=[C:6]([CH3:7])[CH3:8])[CH:3]1[C:9]([Cl:11])=[O:10]
Reactant: CC(C)=C[C@H]1[C@H](C(=O)Cl)C1(C)C
Agent: ClB(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)=CC1C(C(=O)Cl)C1(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
In a 200 ml flask, there were charged (-)-trans-2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride (30.0 g) and toluene (70 g). Thereafter, boron trichloride (0.94 g) was added thereto at 0° C. with stirring under a nitrogen atmosphere, and the reaction was carried out for 10 minutes. After removal of the catalyst, the toluene was recovered by distillation, and the residue was distilled to obtain racemized 2,2-dimethyl-3-isobutenylcyclopropane-1-carboxylic acid chloride (27.0 g) having a boiling point of 72°-78° C./2 mmHg. The proportion of the optical isomers in this product was determined by gas chromatography. The result was as follows: (+)-trans, 46.8%; (-)-trans, 46.7%; (+)-cis, 3.3%; (-)-cis, 3.2%.
Reaction SMILES: NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.[CH2:44]([NH:48][C:49]1[N:57]=[C:56]2[C:52]([N:53]=[C:54]([O:58][CH3:59])[NH:55]2)=[C:51]([NH2:60])[N:50]=1)[CH2:45][CH2:46][CH3:47].Br[CH2:62][CH2:63][CH2:64][CH2:65][CH:66]1[CH2:71][CH2:70][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1>>[NH2:60][C:51]1[N:50]=[C:49]([NH:48][CH2:44][CH2:45][CH2:46][CH3:47])[N:57]=[C:56]2[C:52]=1[N:53]=[C:54]([O:58][CH3:59])[N:55]2[CH2:62][CH2:63][CH2:64][CH2:65][CH:66]1[CH2:67][CH2:68][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)=[O:73])[CH2:70][CH2:71]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCBr)CC1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from N2-butyl-8-methoxy-9H-purine-2,6-diamine trifluoroacetic acid salt and phenylmethyl 4-(4-bromobutyl)-1-piperidinecarboxylate. LCMS (System B): tRET=2.64 min; MH+ 510
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:4][CH:3]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[C:28]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:6][CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(C)=O)cc3)ccn2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
50 mg of ethyl 8-(4-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 2) was dissolved in 2 ml of pyridine. 17 mg of acetic anhydride was added to the obtained solution, and they were stirred at room temperature for 16 hours. Water was added to the reaction mixture. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduce pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: chloroform/ethyl acetate=4/1) to obtain 55 mg of ethyl 8-(4-acetylaminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13](B3OC(C)(C)C(C)(C)O3)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:32]1[CH:33]=[C:34]([C:38]2[CH:43]=[C:42]([NH:44][CH3:45])[N:41]=[C:40]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH:39]=2)[CH:35]=[N:36][CH:37]=1>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:45][NH:44][C:42]1[N:41]=[C:40]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)[CH:39]=[C:38]([C:34]2[CH:35]=[N:36][CH:37]=[C:32]([C:13]3[CH:12]=[CH:11][C:10]([C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[O:9])=[CH:15][CH:14]=3)[CH:33]=2)[CH:43]=1
Reactant: CN1CCN(C(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CNc1cc(-c2cncc(Br)c2)cc(-c2ccccn2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CNc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C)CC4)cc3)c2)cc(-c2ccccn2)n1

Procedure:
To a solution of (4-Methyl-piperazin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.2 eq, 1.55 mmol, 0.511 g) and 2M Na2CO3 (2.0 eq, 2.58 mmol, 1.3 ml) in DME (10 ml) is added (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-methyl-amine (1 eq, 1.29 mmol, 0.44 g) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.128 mmol, 0.094 g). The reaction mixture is heated using microwave radiation at 90° C. for 90 mins. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 465.