Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[O:7][C:6]2=[O:17].[C:18]1([C:24]2[N:25]=[CH:26][C:27]([NH:30][C:31](=O)[O:32]C3C=CC=CC=3)=[N:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][N:11]([C:31]([NH:30][C:27]3[CH:26]=[N:25][C:24]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:29][N:28]=3)=[O:32])[CH2:10][CH2:9]1)[O:7][C:6]2=[O:17]
Reactant: O=C1OC2(CCNCC2)c2ccc(F)cc21
Reactant: O=C(Nc1cnc(-c2ccccc2)cn1)Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1OC2(CCN(C(=O)Nc3cnc(-c4ccccc4)cn3)CC2)c2ccc(F)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A mixture of 5-fluorospiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (64 mg), phenyl N-(5-phenyl-2-pyrazinyl)carbamate (73 mg) and triethylamine (174 μL) in chloroform (5 mL) was stirred at 80 ° C. for 2 hours. The reaction mixture was poured into water and extracted with chloroform (20 mL). The organic layer was washed with saturated saline solution (20 mL), then dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) and recrystallized from ethyl ether-hexane to give the subject compound (100 mg) as colorless crystals (melting point 236-238° C.).
Reaction SMILES: C(OC(=O)C)(=[O:3])C.[CH2:8]([N:10]1[C:15]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([CH3:20])[C:14]=2[CH:13]=[C:12]([C:23]#[N:24])[C:11]1=N)[CH3:9]>>[CH2:8]([N:10]1[C:15]2[N:16]=[C:17]([S:21][CH3:22])[N:18]=[C:19]([CH3:20])[C:14]=2[CH:13]=[C:12]([C:23]#[N:24])[C:11]1=[O:3])[CH3:9]
Reactant: CCn1c(=N)c(C#N)cc2c(C)nc(SC)nc21
Reactant: CC(=O)OC(C)=O
Product: CCn1c(=O)c(C#N)cc2c(C)nc(SC)nc21
Temperature: 100 °C

Procedure:
Acetic anhydride (10.0 mL) was added to a flask charged with 8-ethyl-7-imino-4-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile (0.506 g, 1.95 mmol) and heated to 100° C. After one h, the reaction was allowed to cool to room temperature and concentrated in vacuo. The acetylated residue was then treated with 6 N HCl (40 mL) and heated to 95° C. for one hour then transferred to a large flask. A saturated solution of NaHCO3 (500 mL) was added slowly at 0° C. until a pH 8.0 was achieved. The aqueous phase was washed thrice with ethyl acetate (100 mL) and the organic layers combined, then washed with brine and dried over Na2SO4. The drying agent was filtered and concentrated in vacuo to afford crude 8-ethyl-4-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile which was used in the subsequent step without further purification.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)=O)[CH:40]=[CH:39][N:38]=1.[CH:65]1([C:71](=[S:73])[NH2:72])[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:73][C:71]([CH:65]3[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]3)=[N:72][C:44]=2[C:46]2[C:47]([F:64])=[C:48]([NH:52][S:53]([C:56]3[C:61]([F:62])=[CH:60][CH:59]=[CH:58][C:57]=3[F:63])(=[O:55])=[O:54])[CH:49]=[CH:50][CH:51]=2)[CH:40]=[CH:39][N:38]=1
Reactant: NC(=S)C1CCCCC1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=S(=O)(Nc1cccc(-c2nc(C3CCCCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Yield: 66 %

Procedure:
Following a procedure analogous to Intermediate 6 using N-{3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (0.45 g, 1.019 mmol) and cyclohexanecarbothioamide (0.18 mg, 1.23 mmol) the title compound of Step B was obtained (0.38 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.92 (s, 1H), 8.54 (d, J=5.3 Hz, 1H), 7.61-7.75 (m, 1H), 7.39-7.50 (m, 2H), 7.32 (t, J=7.9 Hz, 1H), 7.24 (t, J=9.1 Hz, 2H), 6.86 (d, J=5.3 Hz, 1H), 2.96-3.12 (m, 1H), 2.09 (d, J=10.6 Hz, 2H), 1.78 (dd, J=9.7, 3.2 Hz, 2H), 1.68 (d, J=12.5 Hz, 1H), 1.47-1.61 (m, 2H), 1.33-1.45 (m, 2H), 1.21-1.32 (m, 1H). m/z (ES+): 566 [M+H]+.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([N+]([O-])=O)=O>CS(C)=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: F
Agent: O=N[N+](=O)[O-]
Solvent: CS(C)=O
Product: Fc1cc(Cl)cnc1Cl
Yield: 92.1 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 60 ml of dimethyl sulfoxide is added dropwise at a temperature in the range from 0° C. to +10° C. Over 11/2 hours, 24.7 g (0.325 mol) of dinitrogen trioxide are introduced into this solution at a temperature in the range from +°50 C. to 60° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after a total of 3 hours at 50° C. to 60° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate. The solution is separated by distillation, affording 38.2 g (92.1% of theory) of 2,5-dichloro-3-fluoropyridine.
Reaction SMILES: [OH:1][CH:2]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:18])[CH2:3][O:4]CC1C=CC=CC=1.C1(C)C=CC=CC=1.CS(C)=O>C(N(CC)CC)C>[OH:4][CH2:3][C:2]([C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:35])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:18])=[O:1]
Reactant: COc1ccc(OCC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(O)COCc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(OCC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(=O)CO)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.2 %

Procedure:
A sulfur trioxide-pyridine complex (716 mg) was added, under ice-cooling, to a solution of (S)-2-[[(S)-2-(1-hydroxy-2(phenylmethyloxy)ethyl]-1-pyrrolidinyl]carbonyl]-1-[(4methoxyphenyl)oxyacetyl]pyrrolidine (988 mg) in a mixed solvent of toluene (1 ml), DMSO (1.5 ml) and triethylamine (0.7 ml) and the mixture was stirred for 2.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of citric acid, saturated sodium hydrogencarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (673 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1.[Zn]>[CH3:2][CH2:3][CH2:4][CH2:5][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH2:11][C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: BrCCCCBr
Reactant: CCCCC(=O)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCCCC(=O)CCCCC(=O)CCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To the stirring slurry of Zn* in THF was added 1,4-dibromobutane (1.186 g, 5.495 mmol) via disposable syringe. The reaction mixture became slightly warm and stirring was continued for 8 hours. The stirring was then stopped and the excess zinc was allowed to settle for 8 hours. The light brown solution of the bis-organozinc halide reagent was carefully transferred to a solution of CUCN (0.10 g, 1.1 mmol) and dry THF under argon. The resulting solution was stirred for 10 min. and valeroyl chloride (1.40 g, 11.6 mmol) was added by disposable syringe. The reaction was stirred overnight, slowly warming to room temperature. The reaction mixture was then quenched by addition to 30 ml 3M HCl. The organic layer was taken up in 20 ml ether and the aqueous layer was extracted two times, using 20 ml ether each time. The combined organics were washed consecutively with 20 ml each of saturated sodium bicarbonate, water, and brine. The organics were dried over anhydrous magnesium sulfate, filtered, and concentrated. 5,10-tetradecandione (1.11 g, 4.90 mmol) was isolated from silica gel using ethyl acetate/hexanes (1:4) as the eluent system.
Reaction SMILES: BrC1C=CC(C)=C([NH:8][C:9]([C:11]2[N:12]=[CH:13][N:14]3[C:19]=2C(=O)[N:17]2[CH:21]=[N:22][C:23]([C:24]([NH:26][C:27]4[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=4[CH3:34])=[O:25])=[C:16]2[C:15]3=[O:35])=O)C=1.[CH2:37]1COCC1.CC1N=C(N)NC=1C>CN(C=O)C>[Br:33][C:31]1[CH:30]=[CH:29][C:28]([CH3:34])=[C:27]([NH:26][C:24]([C:23]2[N:22]=[CH:21][NH:17][C:16]=2[C:15]([NH:14][C:13]2[NH:8][C:9]([CH3:37])=[C:11]([CH3:19])[N:12]=2)=[O:35])=[O:25])[CH:32]=1
Reactant: Cc1ccc(Br)cc1NC(=O)c1ncn2c(=O)c3c(C(=O)Nc4cc(Br)ccc4C)ncn3c(=O)c12
Reactant: C1CCOC1
Agent: Cc1nc(N)[nH]c1C
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc(C)c(C)[nH]1
Temperature: 53 °C
Reaction time: 16 h

Procedure:
A dry round bottomed flask was charged with N1,N6-bis(5-bromo-2-methylphenyl)-5,10-dioxo-5,10-dihydrodiimidazo[1,5-a:1′,5′-d]pyrazine-1,6-dicarboxamide (490 mg, 0.8 mmol) and anhydrous THF (15 ml). To this suspension was added 4,5-dimethyl-1H-imidazol-2-amine (196 mg, 1.76 mmol) in anhydrous DMF (2 ml). The reaction mixture was then stirred at 53° C. for 16 hours. The reaction mixture was then allowed to cool to room temperature and concentrated at reduced pressure. The crude material was treated with methanol and 1M hydrochloric acid. Saturated potassium carbonate solution was then added to neutralize the mixture. The resulting solid was filtered off, washed with 1M hydrochloric acid, saturated potassium carbonate solution and dichloromethane. Purification by reverse phase HPLC (aqueous ammonium acetate/acetonitrile) gave 32 mg of N4-(5-bromo-2-methylphenyl)-N5-(4,5-dimethyl-1H-imidazol-2-yl)-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): 7.97 (d, 1H), 7.35 (d, 1H), 7.27 (d, 1H), 2.29 (s, 3H), 2.04 (s, 6H); MS (EI): 418.5 (MO.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][C:12]([Cl:19])=[CH:13][C:14]=2[CH3:18])[NH:9]1)=[O:7].[CH3:24]C(C)([O-])C.[K+].IC.C(N(CC)CC)C>C1COCC1>[CH3:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][C:12]([Cl:19])=[CH:13][C:14]=2[CH3:18])[N:9]1[CH3:24])=[O:7]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccccc1CNC(=O)n1[nH]c2nc(Cl)cc(C)c2c1=O
Agent: [K+]
Solvent: CI
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccccc1CNC(=O)n1c(=O)c2c(C)cc(Cl)nc2n1C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
99.89 mg (0.3 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid 2-methylbenzylamide and 37.3 mg (0.33 mmol) of potassium tert-butoxide were stirred in 10 ml of THF at room temperature for 10 minutes. Addition of 20.7 μl of iodomethane was followed by stirring at room temperature for 2 h and at 60° C. for 4 h. Then 30 μl of iodomethane and 50 μl of triethylamine were added, and stirring was continued at 60° C. for 7 h, the mixture was concentrated and mixed with water and ethyl acetate, and the organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 18 mg (17%), M+H+: 345.08.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH2:9][C:10]3[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:11]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:55][N:56](C=O)C.O>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:55]([C:2]1[C:7]2[S:8][CH2:9][C:10]3[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:11]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:56]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1CSc1c(Br)cccc1-2
Reactant: CN(C)C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2ccccc2)c2c1CSc1c(C#N)cccc1-2
Temperature: 120 °C

Procedure:
Ethyl 6-bromo-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate (200 mg, 0.483 mmol) in DMF/water (10:1, 4.4 mL) is taken in a sealed tube and purged with nitrogen for 10 min. Zinc cyanide (64 mg, 0.545 mmol), Pd2 (dba)3 (18 mg, 0.019 mmol) and s-phos (20 mg, 0.483 mmol) are then added and heated to 120° C. for 2 h. After this time, the reaction mixture is diluted with DCM, filtered through acelite pad, washed with water, dried over Na2SO4 and concentrated under reduced pressure to afford 200 mg of the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 7.74-7.72 (m, 1H), 7.60-7.55 (m, 3H), 7.48-7.46 (m, 2H), 7.18-7.14 (m, 1H), 6.91-6.89 (dd, J=1.1, 8.0 Hz, 1H), 4.40 (s, 2H), 4.36-4.31 (m, 2H), 1.33-1.29 (t, J=7.1 Hz, 3H). MS (ESI+): 362.2.
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[C:20]([F:27])[C:21]=3[O:23][CH:24]([F:26])[F:25])[C:16](=[O:29])[C:15]([C:30]([O:32]CC)=[O:31])=[CH:14]2)[CH2:12][CH2:11]1>O>[CH:10]1([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:28])=[C:20]([F:27])[C:21]=3[O:23][CH:24]([F:25])[F:26])[C:16](=[O:29])[C:15]([C:30]([OH:32])=[O:31])=[CH:14]2)[CH2:11][CH2:12]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cn(C2CC2)c2c(OC(F)F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Yield: 84.4 %

Procedure:
9 ml of acetic acid, 1.2 ml of concentrated sulfuric acid and 7 ml of water were added to 1.40 g (0.0039 moles) of ethyl 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate [(XX), R1 =--OCHF2, R3' =H, R17 =C2H5, X=F] (prepared as described in Preparation 6), and the mixture was heated under reflux for 1 hour. At the end of this time, it was cooled to room temperature and poured into ice-water. The precipitated crystals were collected by filtration and washed with water and with diethyl ether, in that order, to give 1.09 g of 1-cyclopropyl-8-difluoromethoxy-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as colorless needles, melting at 202°-207° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1.[I-].[K+].[H-].[Na+].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:4]1[C:5]2=[CH:6][C:7]3[CH:12]=[CH:11][CH:10]=[N:9][C:8]=3[N:13]2[CH2:2][CH2:3]1
Reactant: ClCCCc1cc2cccnc2[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CC#N
Product: c1cnc2c(c1)cc1n2CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Chloro-propyl)-1H-pyrrolo[2,3-b]pyridine (5.6 g) was dissolved in acetonitrile under a stream of argon. Potassium iodide (6 g) was added, and sodium hydride in mineral oil (4.60 g) added in small portions. After stirring 2 h at room temperature, the mixture was poured onto a mixture of ice and saturated sodium hydrogencarbonate solution. The organics were extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to afford 2,3-dihydro-1H-3a,4-diaza-cyclopenta[a]indene as a crude pale brown solid (4.5 g, 99%), which was used without further purification. MS (EI) 159 (M+H)+, 143, 100; 1H NMR (δ, CDCl3) 8.19 (dd,1H, J=1,5 Hz), 7.80 (dd,1H, J=1,8 Hz), 6.99 (dd,1H, J=5,8 Hz), 6.12 (s,1H), 4.22 (t,2H, J=6 Hz), 3.05 (t,2H, J=8 Hz), 2.63 (dt,2H, J=6,8 Hz) ppm.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20](=[O:31])[CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.Cl.Cl[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>>[N:3]1([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:38]5[CH:37]=[CH:36][N:35]=[CH:34][CH:39]=5)[CH2:27][CH2:26]4)[C:20](=[O:31])[CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C1CN(S(=O)(=O)c2ccc(Cn3ccnc3)cc2)CCN1CC1CCNCC1
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2ccc(Cn3ccnc3)cc2)CCN1CC1CCN(c2ccncc2)CC1
Temperature: 130 °C
Reaction time: 15 h
Yield: 48.4 %

Procedure:
A mixture of 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone dihydrochloride (209 mg) and chloropyridine hydrochloride (93 mg) was added to sodium bicarbonate solution, and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (10 ml), and the mixture was stirred at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=7:1) to give colorless solid of 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (102 mg). The obtained 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone was dissolved in ethyl acetate (5 ml), and to the solution was added a solution of 4N hydrochloric acid in ethyl acetate. Precipitates were filtered, washed with ethyl acetate and dried to give colorless solid of the title compound (103 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]1([O:26][CH2:27][CH:28]2[O:30][CH2:29]2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(O)(C)C.Cl>CO.C(OCC)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:29][CH:28]([OH:30])[CH2:27][O:26][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Reactant: COc1cc(O)ccc1N1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Solvent: CCOCC
Product: COc1cc(O)ccc1N1CCN(CC(O)COc2cccc3ccccc23)CC1

Procedure:
A solution of 4.16 g. (0.02 mole) 1-(2-methoxy-4-hydroxyphenyl)-piperazine and 4.2 g. (0.021 mole) 2,3-epoxypropyl naphthyl ether in 50 ml. isopropanol is heated under reflux for 4 hours, while stirring. The solution is evaporated and the tarry residue obtained is dissolved in methanol. It is acidified with isopropanolic hydrochloric acid and diethyl ether carefully added thereto, an oily product precipitating out which is separated by decanting off. The solution is diluted with acetone. After a short time, the compound begins to crystallise out. When crystallisation is complete, the crystals are filtered off with suction and again recrystallised from methanol/diethyl either. Yield 4.8 g. (50% of theory); m.p. 230°-232° C.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[CH:8]=[C:9]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22](Cl)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]2)[C:10]([F:14])=[CH:11][C:12]=1[F:13].[OH:31][CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.[CH:37]([O:40][CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38]>C(N(CC)CC)C>[CH:37]([O:40][CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38].[NH2:6][C:7]1[CH:8]=[C:9]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22]([N:34]4[CH2:35][CH2:36][CH:32]([OH:31])[CH2:33]4)[N:23]=3)[C:18](=[O:27])[C:17]([C:28]([OH:30])=[O:29])=[CH:16]2)[C:10]([F:14])=[CH:11][C:12]=1[F:13]
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Reactant: OC1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCC(O)C4)nc32)c(F)cc1F
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To 550 mg of N,N-dimethylformamide were added 150 mg of 1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, 100 mg of 3-hydroxypyrrolidine, and 100 mg of triethylamine. The solution was stirred at 70° C. for 30 minutes. The reaction solution was combined with 8 ml of diisopropyl ether, stirred, and allowed to stand. The supernatant was removed by decantation. To the remainder was added 2 ml of ethanol. The precipitate was collected by filtration and washed with ethanol and then with diisopropyl ether to give 156 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:8]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][C:11]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:13])[CH:8]=1)([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: O=C(O)CCn1cc([N+](=O)[O-])cn1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCn1cc([N+](=O)[O-])cn1)N1CCCCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propanoic acid (4.4 mmol) in 5 mL DMF were added diisopropylethylamine (1.2 mL, 1.5 eq), piperidine (0.66 mL, 1.5 eq), 1-hydroxybenzotriazole (0.90 g, 1.5 eq) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (1.27 g, 1.5 eq). After stirring at rt for 17 h, saturated sodium bicarbonate was added and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and evaporated to afford 3-(4-nitro-1H-pyrazol-1-yl)-1-(piperidin-1-yl)propan-1-one in quantitative yield.
Reaction SMILES: C(OC([N:11]1[C@@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13][C:12]1=[O:19])=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[O:19]=[C:12]1[NH:11][C@@H:15]([C:16]([OH:18])=[O:17])[CH2:14][NH:13]1
Reactant: [H][H]
Reactant: O=C(O)[C@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1NC[C@H](C(=O)O)N1
Yield: 71.3 %

Procedure:
Under nitrogen atmosphere, to a solution of (R)-2-oxoimidazolidine-1,5-dicarboxylic acid 1-benzyl ester (1.61 g) in methanol/tetrahydrofuran (4/1, 20 ml) was added 10 wt % palladium on carbon (161 mg) at room temperature, and the mixture was stirred for 24 hours under one atmosphere of hydrogen. Under nitrogen atmosphere, palladium on carbon in this reaction solution was filtered off through Celite, and the filtrate was concentrated under reduced pressure. To the resulting residue were added diisopropyl ether and n-hexane, and the mixture was stirred. A solid was collected from this suspension by filtration, and dried under reduced pressure to give the titled compound (565 mg).