Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=O)[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:7]#[N:8])[CH3:2].Cl.Cl.[NH2:19][NH2:20]>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:7]([NH2:8])[NH:20][N:19]=1)[CH3:2]
Reactant: CCOCC(=O)C(C#N)c1ccc(C)cc1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: CCOCc1n[nH]c(N)c1-c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
4-Ethoxy-2-(4-methylphenyl)-3-oxobutanenitrile (1.493 g) is dissolved in ethanol (50 mL). After adding hydrazine 2HCl (1.10 g), TEA (0.85 mL) and molecular sieve, the reaction mixture is heated to 80° C. After stirring for 15 hours and cooling to room temperature, the molecular sieve is removed by filtering. The reaction solvent is removed under reduced pressure. After the reaction is terminated by adding saturated aq. NaHCO3, the reaction mixture is extracted 3 times with ethyl acetate. The organic layer is washed with water and dehydrated with MgSO4. After concentration under reduced pressure, the produced solid is recrystallized to obtain the target compound (90%). 1H NMR (CDCl3, 300 MHz): δ 7.26 (m, 2H), 7.02 (m, 2H), 6.80 (br, 2H), 4.20 (s, 2H), 3.38 (m, 2H), 2.24 (s, 3H), 1.06 (t, 3H).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:25][C@H:26]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO.Cl>O>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@H:26]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: N[C@H](CCc1ccccc1)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1nc(C(=O)N[C@H](CCc2ccccc2)CC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 130 °C
Yield: 43 %

Procedure:
1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (75 mg, 0.234 mmol) and 3-(R)-Amino-5-phenyl-pentanoic acid (193 mg, 1.0 mmol) were placed in a CEM 10 mL Microwave vessel and sodium methoxide-methanol solution (0.5 M; 2.0 mL, 1.0 mmol) was added via syringe. The vessel was sealed and heated to 130° C. in a CEM microwave apparatus for 4.5 hours. The reaction mixture was diluted with water and treated with 1N hydrochloric acid and extracted three times with ethyl acetate then dried over sodium sulfate. The crude product was purified by MPLC (methylene chloride-methanol) to provide the title compound as an off-white solid in 43% yield. MS ESI(−) m/e: 480.1305 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])=O.[NH4+:16].C(O)(=O)C>[Ir].CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:16])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [NH4+]
Agent: [Ir]
Agent: O=C[O-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(N)c1ccc([N+](=O)[O-])cc1
Temperature: 60 °C

Procedure:
826 mg (5.0 mmol) of 4′-nitroacetophenone (MW: 165.15), 946 mg (15.0 mmol) of ammonium formate (MW: 63.06) and 5.90 mg (0.01 mmol, S/C=500) of the iridium catalyst Ir-7 (MW: 590.13) were introduced in a 20-mL Schlenk tube, and subjected to argon-gas replacement. To this, 5 mL of dehydrated methanol and 286 μL (5.0 mmol) of acetic acid were added and stirred while heating at 60° C. for 3 hr. After distillation of the solvent, a saturated sodium hydrogen carbonate solution was added, then a product was extracted with methylene chloride, the organic layer was washed with water, and the product was dried with sodium sulfate. The drying agent was removed by filtration and the methylene chloride was distilled away to give a crude product DL-1-(4′-nitrophenyl)ethylamine. Its conversion rate was 100% based on NMR measurement, with 96% of DL-1-(4′-nitrophenyl)ethylamine, 1% of 1-(4′-nitrophenyl)ethanol, and 3% of other by-products. Since no compound in which reduction of nitro groups occurred was generated, we confirmed that reductive amination reaction was carried out in a functional-group-selective manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([C:12](OC)=[O:13])[CH:4]=1.Cl.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12][OH:13])[CH:4]=1
Reactant: COC(=O)c1cc(OC)c2c(c1)OCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(CO)cc2c1OCO2
Temperature: 25 °C
Yield: 88 %

Procedure:
Methyl 7-methoxybenzo[3,4-d]1,3-dioxolane-5-carboxylate(10 g, 47.57 mmol) prepared in Step 3 was dissolved in tetrahydrofuran(200 ml), borane methylsulfide(BMS, 10M) (9.5 ml, 95.0 mmol) was added thereto, and the mixture was stirred under reflux for 1.5 hour. The reaction vessel was cooled down to room temperature and the reaction mixture was neutralized to pH 6-7 using 1N—HCl at 0-5° C., which was then extracted with ethyl acetate. The extract was washed with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2, v/v) to give (7-methoxybenzo[3,4-d]1,3-dioxolan-5-yl)methan-1-ol(7.63 g, Yield 88%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:31])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH2:38](I)[CH3:39]>CC(C)=O>[CH2:38]([N:24]1[C:23](=[O:28])[CH:22]([CH2:21][C:20]2[CH:29]=[CH:30][C:17]([O:16][CH2:15][C:7]3([CH3:14])[CH2:6][CH2:5][C:4]4[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=4[CH3:31])[O:8]3)=[CH:18][CH:19]=2)[S:26][C:25]1=[O:27])[CH3:39]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1C(=O)SC(Cc2ccc(OCC3(C)CCc4c(C)c(O)c(C)c(C)c4O3)cc2)C1=O

Procedure:
Following the procedure described in Example 44, 0.58 g of 5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione [prepared as described in Example 27(b)], 0.27 g of anhydrous potassium carbonate, 0.6 g of ethyl iodide and 5 ml of acetone gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:31][CH2:32][NH2:33]>>[NH2:33][CH2:32][CH2:31][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Reactant: NCCCl
Product: NCCn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12](I)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1.[CH3:21][B-](F)(F)F.[K+]>>[Br:1][C:2]1[C:3]([F:20])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH3:21])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:19]=1
Reactant: NC(=O)c1nc2n(c1I)CCOc1cc(F)c(Br)cc1-2
Reactant: C[B-](F)(F)F
Agent: [K+]
Product: Cc1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2

Procedure:
10-Bromo-9-fluoro-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.2 g) was reacted with potassium methyltrifluoroborate similar to as described in Example 5 to give 20 mg of 10-bromo-9-fluoro-3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide after reverse phase hplc purification. This intermediate was reacted with 2-Methyl-3-butyne-ol similar to as described in Procedure E to afford 17.4 mg of 9-fluoro-3-[(2-fluorophenyl)methyl]-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 344 (M)+. 1H NMR (400 MHz, DMSO) δ 8.55 (dd, J=8.5, 3.5 Hz, 1H), 7.48 (s, 1H), 6.98 (d, J=10.5 Hz, 2H), 5.49 (s, 1H), 4.63-4.36 (m, 2H), 4.35-4.24 (m, 2H), 1.49 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][SH:6].CS(O[C@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([C:33](=[O:35])[CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[C:25](=[CH:26][C:27](=[O:36])[CH:28]=[CH:29]1)[CH2:24][CH2:23]3)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][S:6][C@@H:16]1[CH2:21][CH2:20][C@H:19]2[C@H:22]3[C@H:32]([C:33](=[O:35])[CH2:34][C@:17]12[CH3:18])[C@:30]1([CH3:31])[C:25](=[CH:26][C:27](=[O:36])[CH:28]=[CH:29]1)[CH2:24][CH2:23]3
Reactant: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@@H]2OS(C)(=O)=O
Reactant: SCc1ccc(Cl)c(Cl)c1
Product: C[C@]12CC(=O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2SCc1ccc(Cl)c(Cl)c1

Procedure:
In a manner similar to that described in Example 1A, 3,4-dichlorobenzylmercaptan is reacted with 17β-methanesulfonyloxy-1,4-androstadiene-3,11-dione to obtain the title compound of this example; m.p.=131°-133° C.; [α]D26 +150° (CHCl3); λmaxMeOH 228 nm (ε=26,000).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH2:22])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])C.CC(C)([O-])C.[K+].O.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:10]([O:9][C:7]([N:6]1[CH2:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[NH:22][C:4](=[O:3])[CH2:5]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CN(Cc1cc(Cl)ccc1N)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)Nc2ccc(Cl)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of [(2-amino-5-chloro-benzyl)-tert-butoxycarbonyl-amino]-acetic acid ethyl ester (60 g, 0.18 mol) in tetrahydrofuran (600 ml) was added potassium tert-butoxide (22 g, 0.19 mol) in small portions at 5° C. under cooling on an ice-water batch. After completed addition the cooling bath was removed and reaction mixture was stirred for 3 h at room temperature followed by addition of water (400 ml), saturated aqueous ammonium chloride solution (280 ml) and ethyl acetate (800 ml). After 10 minutes the precipitate was collected by filtration. The layers were separated from the filtrate, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was combined with the precipitate, which had previously been collected by filtration, and crystallized from hot ethyl acetate to give the title compound (46 g, 88%) as white solid. MS m/e: 295 (M−H+).
Reaction SMILES: [OH:1][C:2]([CH3:30])([CH3:29])[CH2:3][C@@:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH:31](OCC)(OCC)OCC>>[OH:1][C:2]([CH3:29])([CH3:30])[CH2:3][C@@:4]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]3[O:18][CH:31]=[N:20][N:19]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CCOC(OCC)OCC
Reactant: C[C@@H](c1ccc(C(=O)NN)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2nnco2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 90 °C
Reaction time: 3 h

Procedure:
4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-benzoic acid hydrazide (300 mg) taken up in triethyl orthoformate (2.5 mL) was stirred at 90° C. for 3 h. After cooling to ambient temperature, the mixture was purified by chromatography on silica gel (CH2Cl2/MeOH 99:1->97:3) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:12]1[CH:13]=[C:14]([CH2:31][NH:32][CH3:33])[CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1>C1COCC1>[F:35][C:2]([F:1])([F:34])[C:3]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:31][N:32]([CH3:33])[C:39](=[O:40])[CH2:38][CH2:37][C:36]([OH:41])=[O:42])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C)C(=O)CCC(=O)O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Compound 14 (114 mg, 184 μmol) was dissolved in freshly distilled THF (3 mL) under nitrogen atmosphere and succinic anhydride (37 mg, 368 μmol) was added. After overnight at 20° C., the solvent was removed under reduced pressure and dissolved in n-hexane. The white precipitate was removed by filtration and the filtrate evaporated to dryness. The residue was purified over silica gel by dichloromethane/methanol (95/5) to give 119 mg (165 μmol, 90% yield) of a colorless oil.
Reaction SMILES: C(OC([O:6][CH2:7][C:8]#[C:9][C:10](=[O:21])/[CH:11]=[CH:12]/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)C)C.Cl>O1CCCC1.O>[OH:6][CH2:7][C:8]#[C:9][C:10](=[O:21])/[CH:11]=[CH:12]/[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: CCOC(C)OCC#CC(=O)/C=C/c1ccc(OC)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(/C=C/C(=O)C#CCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 g (10.4 mmol) of (E)-6-(1-ethoxy-ethoxy)-1-(4-methoxyphenyl)-1-hexen-4-yn-3-one in 50 ml of tetrahydrofuran was treated at room temperature with 3 ml of 1N hydrochloric acid and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and extracted twice with ether. The combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by flash chromatography on 100 g of silica gel (elution agent methylene chloride/ether 4:1) and was subsequently crystallized from methylene chloride/ether/hexane. There was obtained (E)-6-hydroxy-1-(4-methoxyphenyl)-1-hexen-4-yn-3-one of melting point 68°-69°.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])[CH:20]=[CH:21][C:22]=1[Cl:23]>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:18]=[C:19]([CH2:24][CH2:25][C:26]2([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[O:27][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: COC(=O)CC(C)=O
Reactant: O=C(CCc1ccc(Cl)c(Cl)c1)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(CCc2ccc(Cl)c(Cl)c2)(c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 1.7 mL of methyl acetoacetate, 630 mg of NaH 60% dispersion in oil, 9.85 mL of 1.6M n-butyl lithium in hexane, 4.0 g of 3-(3,4-dichlorophenyl)propiophenone and 150 mL of tetrahydrofuran. After addition of the ketone, the reaction was stirred for 15 minutes at 0° C. then allowed to warm to room temperature and stirred for 4 hours. The crude product was triturated from diethyl ether to afford a solid (m.p. 145°-147° C.). 1H NMR (CDCl3) δ2.18-2.35 (m, 2H), 2.39-2.50 (m, 1H), 2.68-2.80 (m, 1H), 2.96 (dd, 2H), 3.36 (dd, 2H), 6.90-7.50 (m, 8H).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[Co:16](Cl)Cl>O>[Co:16].[C:3]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6]
Reactant: Cl[Co]Cl
Agent: CC(=O)CC(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [Co]
Reaction time: 0.17 h

Procedure:
Four grams (0.1 mol) of sodium hydroxide were dissolved in 150 cc of water. To this solution, 17.7 g (0.1 mol) of acetoacetanilide were added while stirring. After the dissolution had been completed, the obtained solution was dripped taking 10 minutes while vigorously stirring into a cobalt (II) chloride aqueous solution which had been prepared in advance by dissolving 11.9 g (0.04 mol) of hexahydrated cobalt (II) chloride in 20 cc of water. Then, the produced precipitate was separated by filtration and washed with 200 cc of water, followed by vacuum drying to obtain 19.0 g of the object: acetoacetanilide cobalt complex.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:5][CH2:4]1.C([BH3-])#N.C([BH3-])#N.[Na+].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][C:33]=1[CH3:40].C[O-].[Na+].CO.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[ClH:1].[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:2][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:7][CH2:8]2)=[CH:34][C:33]=1[CH3:40]
Reactant: Cc1cc(C=O)ccc1F
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4ccc(F)c(C)c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride in 4 mL of methanol, 31 mg of sodium cyanoborohydride cyanoborohydride, 44 μL of 4-fluoro-3-methylbenzaldehyde, 39 mg of a 28% sodium methoxide/methanol solution and 42 μL of acetic acid were added, and the mixture was stirred at room temperature for 1 hour 15 minutes. Thereto were added 44 μL of 4-fluoro-3-methylbenzaldehyde and 31 mg of sodium cyanoborohydride cyanoborohydride, and the mixture was stirred at the same temperature for 45 minutes. Thereto were further added 44 μL of 4-fluoro-3-methylbenzaldehyde and 31 mg of sodium cyanoborohydride, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added thereto, and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=10:1. The resultant residue was dissolved in 2 mL of ethyl acetate, and thereto was added 1 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution at room temperature. The solvent was distilled off under reduced pressure, ethyl acetate was added to the resultant residue and the solid was filtered off to obtain 54 mg of 1-(2-(4-((4-fluoro-3-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[C:22]2[C:17](=[C:18]([Br:23])[CH:19]=[CH:20][CH:21]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:30](ON1C(=O)CCC1=O)([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31]>C1COCC1.CCOCC>[Br:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[C: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)[CH2:3][CH:2]2[NH:1][C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(N)c1cccc(Br)c12
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(NC(=O)OCC[Si](C)(C)C)c1cccc(Br)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.4 %

Procedure:
To a stirred solution of crude (±)-tert-butyl 3-amino-7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (264 mg, 0.69 mmol) in THF (5 mL) was added 10% aq K2CO3 (10 mL), followed by Teoc-OSu (269 mg, 1.04 mmol). The mixture was stirred at rt for 3 d, diluted with ether (80 mL), washed with brine (25 mL) and dried over MgSO4. Removal of the solvent left an oil (240 mg) which was purified chromatography on a 12-g silica cartridge, eluted with a 0-50% EtOAc in hexanes gradient to afford (±)-tert-butyl 7-bromo-3-((2-(trimethylsilyl)ethoxy)carbonylamino)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (85 mg, 31% for 2 steps). LC-MS Method 1 tR=2.35 min, m/z=425, 427, 547, 549.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([F:30])[CH:36]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(F)c1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(F)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-fluorobenzeneboronic acid. The title compound was obtained in 97% yield as yellow foam. MS (m/e): 500.1 (MH+, 100%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:13][C@@H:11]1[CH2:12][NH:8][C@H:9]([CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:10]1
Reactant: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCCCOC[C@@H]1C[C@H](F)CN1
Reaction time: 3.5 h

Procedure:
Methyl 5-((2S,4S)-1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinylmethoxy)pentanoate (1.09 g, 3.27 mmol) was dissolved in methylene chloride (50 ml). At room temperature, trifluoroacetic acid (10 ml) was added to the resulting solution. The mixture was stirred at the same temperature for 3.5 hours. The residue obtained by distilling off the solvent under reduced pressure was diluted with methylene chloride (50 ml). The solution was basified with 1N NaOH, followed by extraction with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (590 mg, 77%) was obtained as a yellow oil (this compound was provided for the subsequent reaction without further purification).