Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[C:10](=[O:13])([O-])[O-:11].[Na+].[Na+].[OH-].[Li+].[C:18](#[N:20])[CH3:19]>CO.O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:20]2[CH2:4][CH2:3][CH:2]([CH2:9][C:10]([OH:11])=[O:13])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC#N
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC1CCN(Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
Ethyl-4-pyridylacetate (5 g) is dissolved in ethanol (30 mL), treated with platinum oxide catalyst (30 mg) and hydrogenated on a Parr apparatus for 4 hr. The catalyst is filtered off and the ethyl-4-piperidinylacetate is isolated by removal of the solvent under vacuum. This material is then dissolved in acetonitrile (50 mL) and treated with 4-chlorobenzyl chloride (4.9 g) and sodium carbonate (10 g). The resulting mixture is heated in methanol (30 mL) and treated with a solution of lithium hydroxide (2 g) in water (10 mL). The mixture is allowed to stand overnight. Addition of 47.6 mL of 1 N HCI solution followed by concentration and extraction of the residue with chloroform provides the desired 1-(4-chlorobenzyl)-4-piperidylacetic acid. A portion of this material (1 g) is dissolved in methylene chloride and treated with 1,1′-carbonyldiimidazole (0.65 g) and allowed to stand overnight. This solution is then treated with 2-methylindoline (0.5 g). After 2 h the resulting mixture is washed 3 times with water dried and concentrated. Purification by column chromatography on silica gel provides 1.2 g of the desired 2-(1-[4-chlorobenzyl]piperidin-4-yl)-1-(2-methylindolin-1-yl)-1-ethanone (Compound 1). The 5 dihydrochloride salt is subsequently prepared (Compound 1a).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([C:13]([C@@H:15]3[C@@H:20]([C:21]([O:23]C)=O)[CH2:19][C@H:18]([S:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:17][N:16]3[C:32]([O:34][CH3:35])=[O:33])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH:41][NH2:42].C[O-].[Na+].Cl>CO>[OH:41][NH:42][C:21]([C@H:20]1[CH2:19][C@H:18]([S:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][N:16]([C:32]([O:34][CH3:35])=[O:33])[C@@H:15]1[C:13]([N:10]1[CH2:9][CH2:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)=[O:14])=[O:23]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](Sc2ccccc2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1C[C@@H](Sc2ccccc2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To the reaction mixture of dimethyl(2S,3S,5S)-2-[(4-phenylpiperazin-1-yl)carbonyl]-5-(phenylthio)piperidine-1,3-dicarboxylate (51 mg, 0.00010 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) was added 1.640 M of N-hydroxyamine in methanol (1.25 mL) made from the corresponding salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (39 mg, 63%). MS (ESI): (M+H)+=499.1.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:8]=[C:9]([NH: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)[C:10]([CH2:13][CH2:14][C:15]([O:17]CC)=O)=[N:11][CH:12]=1.CC(C)([O-])C.[K+]>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:10]([CH2:13][CH2:14][C:15](=[O:17])[N:20]2[CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:25][CH2:26]2)=[N:11][CH:12]=1
Reactant: CCOC(=O)CCc1ncc(Cl)cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3ncc(Cl)cc32)CC1
Yield: 64.2 %

Procedure:
Under ice cooling, to a tetrahydrofuran solution (500 ml) of tert-butyl 4-{[5-chloro-2-(3-ethoxy-3-oxopropyl)pyridin-3-yl]amino}piperidine-1-carboxylate (54.7 g) was added dropwise a tetrahydrofuran solution (1 M, 159 ml) of potassium tert-butoxide over 15 minutes. After stirring for 15 minutes at the same temperature, water was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (31.2 g).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:6][C@H:5]1[NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[N+]=[N-].O.CP(C)C>C1COCC1>[NH2:1][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[N:17]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:6][C@H:5]1[NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Temperature: 50 °C
Reaction time: 15 h
Yield: 104.9 %

Procedure:
To a solution of di-tert-butyl (4-{(3R,4S,5S)-4-azido-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)imidodicarbonate (1.337 g, 2.441 mmol) in THF (20 mL), water (1.00 mL, 55.5 mmol) was added, followed by trimethylphosphine (383 mg, 5.03 mmol). The mixture was stirred at 50° C. for 15 h. The mixture was then concentrated under reduced pressure. The residue was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the sub-title compound as a white foamy solid (1.336 g, 105%). LCMS calc. for C26H44N5O6 (M+H)+: m/z=522.3. Found: 522.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([OH:12])[C:6]3[C:13](=O)[O:14][CH:15](O)[C:5]=3[C:4]=2[C:3]=1[Cl:18].O.[NH2:20][NH2:21].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([OH:12])[C:6]3[C:13](=[O:14])[NH:20][N:21]=[CH:15][C:5]=3[C:4]=2[C:3]=1[Cl:18]
Reactant: O=C1OC(O)c2c1c(O)nc1ccc(Cl)c(Cl)c21
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]ncc2c1c(O)nc1ccc(Cl)c(Cl)c12
Temperature: 25 °C
Reaction time: 50 h

Procedure:
2.9 g (0.010 mol) of (RS)-8,9-dichloro-1,4-dihydroxy-1,3-dihydro-furo[3,4-c]quinolin-3-one were dissolved in 60 ml of dimethyl sulphoxide while gassing with argon. 0.51 g (0.010 mol) of hydrazine hydrate was added thereto and the mixture was stirred at room temperature for 50 hrs. An orange coloured solution was obtained and this was treated with 300 ml of ethyl acetate. The precipitated product was filtered off under suction, rinsed with ethyl acetate and recrystallized from dimethylformamide/ethyl acetate. Yield: 0.70 g (25%) of 9,10-dichloro-5-hydroxy-3,4-dihydro-pyridazino[4,5-c]quinolin-4-one as yellow-orange coloured crystals; m.p. ~270° C.
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])(=[O:6])[CH3:5].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>CO>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[O:6])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)c1cccc(C#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
Part A. Sodium methoxide (25% in MeOH, 1.5 mL, 6.8 mmol) was added dropwise to a solution of 3-acetylbenzonitrile (987 gm, 6.8 mmol) and 4-nitrobenzaldehyde (1 gm, 6.8 mmol) in dry methanol. Within 5 minutes, a precipitate begins to appear. The mixture was stirred at room temperature for 4 hours and diluted with methanol. The solids were filtered off, washed with cold methanol and dried to give 3-[3-(4-nitrophenyl)-1-oxo-2-propenyl]benzonitrile as a white solid 1.7 gm (97%) MS: 279(M+H)+ ; 1H NMR (CDCl3): 7.60 (d, 1H), 7.70 (t, 1H), 7.85 (m, 4H), 8.25 (m, 4H)
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[CH:29]([N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH3:34])([CH3:31])[CH3:30]>C(O)C>[CH:29]([NH+:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH3:34])([CH3:31])[CH3:30].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([O-:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC[NH+](C(C)C)C(C)C
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g (2R,4S)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) is added to ethanol (10 ml). Diisopropylethylamine (0.454 ml) is then added and the mixture is stirred at room temperature for 30 minutes. The mixture is then concentrated in vacuo to afford (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid diisopropylethylammonium salt (1-a, R1=Boc, R2=H, R3=CO2−[NHiPr2Et]+). 1H NMR (DMSO-d6): 0.95-0.98 (15H), 1.04 (3H), 1.32 (9H), 1.36 (1H), 1.74 (1H), 2.38-2.49 (3H), 2.67 (2H), 2.99 (2H), 3.66 (1H), 6.29 and 6.70 (1H), 7.23-7.25 (2H), 7.33-7.37 (1H), 7.42-7.46 (2H), 7.55-7.57 (2H), 7.62-7.64 (2H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)=[CH:16][S:17][CH:18]=1.CN([CH:30]=[O:31])C>C1COCC1>[Br:13][C:14]1[C:15]([C:19]2[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=2)=[CH:16][S:17][C:18]=1[CH:30]=[O:31]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(-c2cscc2Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#Cc1ccc(-c2csc(C=O)c2Br)cc1
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of diisopropylamine (1.2 g, 11.4 mmol) in 20 mL of anhydrous THF was added n-BuLi (3.7 mL, 2.5 M in hexane) at −78° C. After the mixture was stirred at this temperature for 0.5 h, a solution of 4-(4-bromothiophen-3-yl)benzonitrile (prepared in Step 1 of Compound 2) (2.0 g, 7.6 mmol) in anhydrous THF (20 mL) was added dropwise. The mixture was stirred at −78° C. for 15 min., a solution of DMF (611 mg, 8.4 mmol) in THF (5 mL) was added. The reaction mixture was stirred at −78° C. for 0.5 h, and at room temperature for 2 h. The mixture was quenched with saturated NH4Cl aqueous solution, extracted with EtOAc, concentrated, and purified by column chromatography on silica gel to give 4-(4-bromo-5-formylthiophen-3-yl)benzonitrile (600 mg, yield 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][OH:5].Cl[C:12]([N:14]1[C@H:19]([CH3:20])[CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C@@H:15]1[CH3:28])=[O:13]>>[ClH:1].[CH3:28][C@H:15]1[CH2:16][NH:17][CH2:18][C@@H:19]([CH3:20])[N:14]1[C:12]([O:5][CH2:4][C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:13]
Reactant: OCc1c(F)cccc1Cl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1c(F)cccc1Cl
Product: Cl

Procedure:
2-Chloro-6-fluorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from 2-chloro-6-fluorobenzyl alcohol and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 52 and 54 to give the product as a white solid (0.2713 g, 80% overall); (Found: C, 49.8; H, 5.7; N, 8.0%. C14H18ClN2O2.HCl requires C, 49.9; H, 5.7; N, 8.3%); δH (400 MHz, DMSO-d6) 10.01 (1H, br), 9.27 (1H, br), 7.49 (1H, m, J 8.0 Hz), 7.40 (1H, d, J 8.0 Hz), 7.30 (1H, t, J 9 Hz), 5.22 (2H, d, J 1.6 Hz), 4.24 (2H, m, J 6.5 Hz), 3.17–3.06 (4H, m), and 1.28 (6H, d, J 7.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].CN(C)C=O.C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([Cl:21])=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To the suspension of 2-nitrobenzoic acid (200 g) and a catalytic amount of dimethylformamide (DMF; 5 mL) in DCM (2.5 L) was added oxalyl dichloride (304 g) dropwise at room temperature over a 30 minute interval. After the addition, the reaction was continued stirring for approximately 1 hour at room temperature and the suspension turned into a clear solution. The completion of the reaction was monitored by TLC (generally ˜1 hour). The reaction mixture was then concentrated at 35° C. to dryness to give 225 g of the crude product (13) as light yellow oil or solid (mp: 17° C., lit), which was directly used for the next step without further purification.
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.CC1(C)C(C)(C)OB([C:22]2[CH:23]=[N:24][N:25](C(OC(C)(C)C)=O)[CH:26]=2)O1.C(#N)C.C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH:11]([C:3]1[C:2]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)c1nn2ccccc2c1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)c1nn2ccccc2c1-c1cn[nH]c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To two 20 ml microwave reaction vials were each added 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine (486 mg, 1.69 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-pyrazolecarboxylate (500 mg, 1.69 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (139 mg, 0.17 mmol), acetonitrile (8 ml), and 1 M aqueous NaHCO3 solution (5 ml). The mixture was placed in a microwave reactor for 2 hours at 140° C. The reaction mixture from the two vials were combined and concentrated in vacuo, and the crude material was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel flash chromatography (0 to 50% ethyl acetate in hexanes) to give the protected-analog. The protected analog was dissolved in 20% trifluoroacetic acid in dichloromethane (50 ml) and stirred at room temperature. The reaction was monitored by HPLC for completion (2 hours). The mixture was concentrated in vacuo, and the concentrated material was dissolved in 4N hydrochloric acid in dioxane. Ether was added to the acidic solution to precipitate out the desired material. The material was filtered and dried in vacuo under high vacuum to give 235 mg (31%) of 2-isopropyl-3-(1H-pyrazol-4-yl)-pyrazolo[1,5-a]pyridine as the hydrochloric acid salt. 1H-NMR (250 MHz, DMSO-d6) δ 8.70 (broad s, 1H), 8.64 (d, J=7.0 Hz, 2H), 8.07 (s, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.19 (dd, J=7.8, 6.8 Hz, 1H), 6.85 (t, J=6.8 Hz, 1H), 3.30 (sept, J=7.0 Hz, 1H), 1.29 (d, J=6.8 Hz, 6H); LC/MS 227.1 m/z (M+H+). Compound 1104.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:23]([F:24])=[CH:22][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])[N:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH3:34]OC(OC)N(C)C>C1C=CC=CC=1>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[C:12]3[C:13]([C:14](=[O:15])[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:34][N:25]3[C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=3[F:33])=[CH:22][C:23]=2[F:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 88.1 %

Procedure:
In 2 ml of benzene was suspended 200 mg of ethyl 2-[6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinoyl]acetate, and 100 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 7 hours. Subsequently, the crystals thus deposited were collected by filtration and washed with 2 ml of dithyl ether to obtain 180 mg (yield 88.1%) of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 233°-236° C.
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[C:35]1([CH3:42])[C:36](Cl)=[CH:37][CH:38]=[CH:39][CH:40]=1>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:11]([O:23][C:40]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:42])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2O)cc1
Reactant: Cc1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)(C)C)cc2Oc2ccccc2C)cc1

Procedure:
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with o-toluyl chloride there is obtained 3-(o-toluyloxy)-4-(p-toluyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(o-toluyloxy)-4-(p-toluyloxy)-alpha-(tert-butylaminomethyl)-benzyl alcohol hydrochloride.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[O:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[O:16][CH:17]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:22][CH2:21]4)[N:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCNCC4)co3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3nc(C4CCN(CCCCO)CC4)co3)ccc21

Procedure:
The preparation was carried out as already described starting from 200 mg (0.32 mmol) of 4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)oxazol-4-yl]piperidine hydrochloride and 94 μl (0.64 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 2N NaOH solution in methanol. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[O:21]=[C:22]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:30][CH2:29]1)[CH2:23][CH2:24][C:25](O)=[O:26].CN(C)C=O.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:18][O:17][C:15]([CH2:14][C@@H:10]1[N:11]([C:25](=[O:26])[CH2:24][CH2:23][C:22](=[O:21])[N:28]2[CH2:29][CH2:30][N:31]([C:34]3[N:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:32][CH2:33]2)[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9]1=[O:19])=[O:16]
Reactant: O=C(O)CCC(=O)N1CCN(c2ncccn2)CC1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CCC(=O)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.1 %

Procedure:
To a suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.45 g) and 4-oxo-4-(4-pyrimidin-2-ylpiperazin-1-yl)butanoic acid (0.46 g) produced in Reference Example 4 in acetonitrile (20 ml) and dimethylformamide (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g) and the suspension was stirred for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the solution was added saturated brine and the solution was extracted with ethyl acetate. The extract was dried over Na2SO4 and was concentrated under reduced pressure. To the produced ester derivative was added trifluoroacetic acid (10 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by CHP-20 column chromatography (H2O→30% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.45 g) as a white amorphous powdery product.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>C1COCC1>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
In THF (250 ml) was dissolved 4-nitrobenzyl bromide (25.0 g), and to the mixture was added pyrrolidine (24.1 ml) at 0° C. The reaction mixture was stirred at room temperature for 60 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate) to give 1-(4-nitrobenzyl)pyrrolidine (23.5 g) as orange oil.
Reaction SMILES: [F:1][C:2]([F:13])=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:21](Cl)(Cl)=[O:22].[NH:25]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[CH2:26]1>C1(C)C=CC=CC=1.ClCCl>[F:13][C:2]([F:1])=[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:21]([N:25]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=3)[CH2:26]2)=[O:22])[CH2:5][CH2:4]1
Reactant: O=C(Cl)Cl
Reactant: FC(F)=C1CCNc2ccccc21
Reactant: c1cncc(C2CCNC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(N1CCC(c2cccnc2)C1)N1CCC(=C(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.07 g of 4-difluoromethylene-1,2,3,4-tetrahydroquinoline and 5 ml of dichloromethane are introduced into a three-necked flask equipped with a magnetic stirrer and placed under an inert atmosphere. After cooling to +4° C., 0.11 ml of triethylamine and 0.39 ml of a 20% solution of phosgene in toluene are successively added. The reaction medium is stirred at ambient temperature for 2 h. The reaction medium is cooled in an ice bath and 0.08 g of 3-(pyrrolidin-3-yl)pyridine in 2 ml of dichloromethane is then introduced. The mixture is stirred at ambient temperature for 18 h. The reaction medium is washed with a 1N sodium hydroxide solution; the organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluted with a dichloromethane/methanol 98/2 mixture. 0.05 g of (4-difluoromethylene-3,4-dihydro-2H-quinolin-1-yl)(3-(pyridin-3-yl)pyrrolidin-1-yl)methanone is obtained and is treated with fumaric acid in an ethanol/diisopropyl ether mixture to give the fumarate.