Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[N:12]=2)=[CH:8][C:7]([CH3:34])=[N:6]1)(C)(C)C>C(O)=O.ClCCl>[CH3:34][C:7]1[CH:8]=[C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)[N:12]=2)[NH:5][N:6]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(N4CCCCC4)cc3)c(=O)c3ccccc23)n(C(C)(C)C)n1
Solvent: ClCCl
Solvent: O=CO
Product: Cc1cc(Nc2nn(-c3ccc(N4CCCCC4)cc3)c(=O)c3ccccc23)[nH]n1
Temperature: 95 °C
Yield: 57.6 %

Procedure:
4-(2-tert-Butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-piperidin-1-yl-phenyl)-2H-phthalazin-1-one (0.012 g, 0.026 mmol) was dissolved in formic acid (1 ml) and heated at 95° C. for 4 h. The resulting raw product was dissolved in dichloromethane, after evaporation of formic acid. Extraction with a saturated aqueous NaHCO3 solution, combining of the organic phases, evaporation of the solvent in vacuum and purification by chromatography over silica gel with dichloromethane:MeOH (20:1) yielded the title compound (0.006 g, 57%). 1H-NMR: (400 MHz, D6-DMSO) 11.81 (1H, s), 9.21 (1H, s), 8.48 (1H, d), 8.35 (1H, d), 7.87–7.96 (2H, m), 7.50 (2H, d), 7.01 (2H, d), 6.25 (1H, s), 3.21 (4H, m), 2.19 (3H, s), 1.64 (4H, m), 1.60 (2H, m); MS (ESI+)=401.29 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5]([N+:27]([O-])=O)=[CH:4][CH:3]=1.[NH2:30][C:31]1[N:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CS(C)=O.CO>[NH2:30][C:31]1[C:32]([C:33]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[C:6]3=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=[C:5]3[N:27]=2)=[CH:35][CH:36]=[CH:37][N:38]=1
Reactant: Nc1ncccc1C=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Nc3nc(Cl)ccc3[N+](=O)[O-])cc2)CCC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(Cl)nc43)cc2)CCC1
Temperature: 100 °C
Yield: 21.2 %

Procedure:
To a suspension of tert-butyl (1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}cyclobutyl)carbamate (10 g, 24 mmol) in DMSO/MeOH (4:1, 200 mL), were added 2-aminonicotinaldehyde (3.5 g, 29 mmol) and sodium dithionite (16 g, 93 mmol) and the mixture was heated for 48 h at 100° C. The mixture was poured into water and the solid was collected by filtration. The solid was purified by silica gel column chromatography (dichloromethane/ethyl acetate, 10:0 to 0:10) to give the titled compound as a white solid (2.5 g, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.[CH3:21][O:22][C:23]([C:25]1[O:26][C:27](Br)=[CH:28][CH:29]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:22][C:23]([C:25]1[O:26][C:27]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:3]=2[O:2][CH3:1])=[CH:28][CH:29]=1)=[O:24]
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cccc1[N+](=O)[O-]
Reactant: COC(=O)c1ccc(Br)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2OC)o1
Yield: 18 %

Procedure:
2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 6a (3.6 g, 12 mmol), 5-bromofuran-2-carboxylic acid methyl ester (2.05 g, 10 mmol), tetrakis(triphenylphosphine)palladium (1.55 g, 0.5 mmol) and sodium carbonate (2.12 g, 20 mmol) were dissolved in 1,4-dioxane. The reaction mixture was heated to reflux for 3 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 30 mL of water and 50 mL of ethyl acetate. The separated organic layer was concentrated under reduced pressure and recrystallized from a solvent mixture of ethyl acetate and n-hexane to obtain the title compound 5-(2-methoxy-3-nitro-phenyl)-furan-2-carboxylic acid methyl ester 54a (500 mg, yield 18%) as a yellow solid.
Reaction SMILES: C(OC(N1CCN([C:12]2[N:21]=[C:20]3[C:15]([C:16](=[O:27])[C:17]([C:24]([OH:26])=[O:25])=[CH:18][N:19]3[CH:22]=[CH2:23])=[CH:14][C:13]=2[F:28])CC1)=O)C.[OH-:29].[Na+]>>[F:28][C:13]1[CH:14]=[C:15]2[C:20](=[N:21][C:12]=1[OH:29])[N:19]([CH:22]=[CH2:23])[CH:18]=[C:17]([C:24]([OH:26])=[O:25])[C:16]2=[O:27]
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=O)OCC)CC3)nc21
Reactant: [OH-]
Agent: [Na+]
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(O)nc21
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A mixture of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid (78 g) and aqueous 20% sodium hydroxide (1,100 ml) was refluxed with stirring for 24 hours. After cooling, the resulting crystals were collected by filtration and washed with aqueous 10% sodium hydroxide (50 ml). The crystals were added to water (600 ml) and the mixture was heated at 90° C. and the acetic acid (50 ml) was added. After treatment with charcoal, the solution was acidified with concentrated hydrochloric acid (100 ml), and cooled in an ice-bath. The resulting crystals were collected by filtration, washed with water, and recrystallized from ethanol-chloroform to give 42.5 g of 6-fluoro-1,4-dihydro-7-hydroxy-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid, m.p. 256°-259° C.
Reaction SMILES: BrC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:38][CH:39]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:42][C:43]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:16]3[C:15]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=4)[N:19]=[CH:18][N:17]=3)=[CH:27][CH:28]=2)=[S:44])=[O:41])=[CH:36][CH:35]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(N=C=S)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
4-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (53 mg, yield 58%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:10])[CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.ClCCl>O>[CH2:6]([O:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (15.45 g, 0.13 mol) was added to a mixture of n-butanol (10 g, 0.13 mol), triethylamine (26.3 g, 0.26 mol) and dichloromethane (150 g) at 10° C. After being stirred at room temperature overnight, water (100 g) was added to the reaction mixture and the layers were separated. The organic layer was concentrated in vacuo at room temperature. This gave 18 g (90%) of the title mesylate as an oil. 1H NMR analysis supports the stated structure. *Previously described in J. Am. Chem. Soc. 1933, 55, 345-349.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[N:10]([CH2:17][CH:18]=C)[CH:11](C)[CH2:12][CH2:13][CH:14]=[CH2:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl>[CH2:1]([O:8][C:9]([N:10]1[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15][CH:17]1[CH3:18])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(C)N(CC=C)C(=O)OCc1ccccc1
Agent: Cl[Ru]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CC1CCC=CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
Allyl-(1-methyl-pent-4-enyl)-carbamic acid benzyl ester (0.872 g, 3.19 mmol) was dissolved in CH2Cl2 (10 ml) and a stream of argon gas was bubbled into the reaction mixture for 10 minutes. Then bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (Strem Chemicals, Grubbs' catalyst, 19 mg, 0.0227 mmol) was added and the reaction mixture was refluxed for 2 h. Additional bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride ( mg, 0.0108 mmol) was added and the reaction mixture was refluxed for an additional 1.5 hours. The reaction was cooled to RT under argon overnight, then was concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 5% EtOAc/hexanes) to give the title compound (0.72 g, 92%): 1H NMR: 7.35–7.20 (m, 5H), 5.65 (1H, m), 5.13 (2H, AB), 4.45–4.05 (m, 2H), 3.56 (1H, d), 2.25–2.10 (m, 2H), 1.90–1.60 (m, 2H), 1.12 (3H, d); Liquid Chromatgraphy/Electrospray mass spec: M+H+=246.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][CH3:36])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Cl:37]CC1C(NCC)=NC2C(C=1)=CC(OC)=CC=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:20].[ClH:37].[CH2:35]([NH:34][C:23]1[C:22]([CH2:21][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]=2[OH:18])=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:32][CH3:33])[CH:29]=2)[N:24]=1)[CH3:36]
Reactant: CCNc1nc2ccc(OC)cc2cc1CCl
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.01 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine hydrochloride SLA 28166 (290 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 92:8) provided, after evaporation and drying, 25 mg of 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.45 mL). The reaction mixture was stirred for 5 min at RT, concentrated at 40° C. under vacuum, to afford 4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-6,7-dimethoxy-1-propylisoquinolin-3-ol dihydrochloride 50 as a yellow solid (30 mg, 6% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[N+:18]([C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:1]=1)([O-:20])=[O:19]
Reactant: c1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
Following the procedure of Block et al. (J. Med. Chem. 2002, 45, 3509), 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline (1 g, 4.4 mmol) was stirred in concentrated sulfuric acid (12 mL) at 0° C. for 30 min and then KNO3 (0.45 g, 4.4 mmol) was introduced in portions. The reaction mixture was stirred for 2 hours at 0° C. and was then poured into ice water and extracted with ethyl acetate. The combined organic extracts were dried over MgSO4 and concentrated to give 0.95 g of 2-nitro-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline as a brown solid. MS (ESI) m/z 271
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH3:19][O:20][C@:21]1([C:39]2[CH:40]=[C:41]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]=[CH2:52])[CH:46]=3)[CH:42]=[CH:43][CH:44]=2)[CH2:25][N:24](C(OCC[Si](C)(C)C)=O)[C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1>C1COCC1.CCOC(C)=O>[CH3:19][O:20][C@:21]1([C:39]2[CH:40]=[C:41]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([CH:51]=[CH2:52])[CH:46]=3)[CH:42]=[CH:43][CH:44]=2)[CH2:25][NH:24][C@H:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1
Reactant: C=Cc1cccc(-c2cccc([C@]3(OC)C[C@@H](C(=O)OC)N(C(=O)OCC[Si](C)(C)C)C3)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=Cc1cccc(-c2cccc([C@@]3(OC)CN[C@H](C(=O)OC)C3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.6 %

Procedure:
TBAF (1.0M in THF, 19 mL, 19 mmol) was added to a solution of (2S,4R)-2-methyl 1-(2-(trimethylsilyl)ethyl) 4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-1,2-dicarboxylate (2.3 g, 4.78 mmol) in THF (30 mL) and stirred at r.t. overnight. The reaction was diluted with EtOAc and washed with water and then brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give (2S,4R)-methyl 4-methoxy-4-(3′-vinylbiphenyl-3-yl)pyrrolidine-2-carboxylate (1.75 g, 5.19 mmol, 100% yield) as a yellow oil. LCMS: rt=1.42 min. [M-OMe]+=306; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[CH:20]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[CH:20]1([NH:25][C:10]2[N:11]=[C:6]([CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[CH:3]=3)[NH:7][C:8](=[O:16])[C:9]=2[C:14]#[N:15])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CSc1nc(Cc2cccc(C)c2)[nH]c(=O)c1C#N
Reactant: NC1CCCC1
Solvent: CC#N
Product: Cc1cccc(Cc2nc(NC3CCCC3)c(C#N)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(3-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.31 g (3.65 mmol) of cyclopentylamine in 3 ml of acetonitrile at 90° C. under argon overnight. After cooling to room temperature, the crude product is purified by preparative HPLC. 0.03 g (26% of theory) of the title compound is obtained as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:15][CH2:16][CH2:17]O)[C:7]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.S(Cl)([Cl:23])=O>ClC(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:15][CH2:16][CH2:17][Cl:23])[C:7]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCn1c(C2CCCCC2)nc2cc(Cl)ccc21
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCCCn1c(C2CCCCC2)nc2cc(Cl)ccc21
Reaction time: 2 h

Procedure:
To a stirred mixture of 21 parts of 5-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol in 225 parts of trichloromethane are added dropwise 40 parts of sulfinyl chloride (exothermic reaction). Upon completion, stirring is continued for 2 hours at reflux temperature. The reaction mixture is evaporated and the residue is dissolved in boiling water. The solution is treated with activated charcoal. The latter is filtered off till a clear filtrate is obtained. After cooling in an ice-bath, the precipitated product is filtered off and dried, yielding 5-chloro-1-(3-chloropropyl)-2-cyclohexyl-1H-benzimidazole hydrochloride; mp. 211.7° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].Br[C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15].Cl>C(OCC)C.O.C(C(C)=O)C>[CH3:3][C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15]
Reactant: CC(C)(Br)C(=O)O
Reactant: Cc1cccc(O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CCC(C)=O
Product: Cc1cccc(OC(C)(C)C(=O)O)c1C
Temperature: 50 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
Sodium hydroxide (82.0 g, 2.05 mol) was added to a solution of methyl ethyl ketone (400 mL) containing 2,3-dimethylphenol (50.0 g, 410 mmol), and the mixture was stirred at 50° C. for 1 hour. After that, a solution of methyl ethyl ketone (200 mL) containing 2-bromo-2-methylpropionic acid (103 g, 615 mmol) was added thereto, and the mixture was stirred at 50° C. for 4 hours. After cooled to room temperature, the reaction solution was distributed by adding water and diethyl ether. 6N hydrochloric acid was added to the aqueous layer to be acidic, and then extraction was performed using ethyl acetate. The extract was washed with saturated saline, and then dried using anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 50/50) to give 38.3 g of the title compound (yield: 45%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C.[C:33](Cl)(=[O:35])[CH3:34].N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([N:26]3[CH2:27][CH2:28][N:29]([C:33](=[O:35])[CH3:34])[CH2:30][CH2:31]3)=[CH:24][N:25]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2ncc(N3CCNCC3)n2cc1-c1ccc(Cl)cc1Cl
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCN(c2cnc3cc(CN)c(-c4ccc(Cl)cc4Cl)cn23)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 56.7 %

Procedure:
To a solution of [6-(2,4-dichloro-phenyl)-3-piperazin-1-yl-imidazo[1,2-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (30 mg, 0.06 mmol) in DCM (0.5 mL) were added successively acetyl chloride (6 mg, 0.07 mmol), pyridine (0.015 mL, 0.19 mmol) and DMAP (1 mg, 0.006 mmol). The reaction mixture was stirred at RT for 14 h then evaporated to dryness. The resulting residue was dissolved in DCM (2 mL) then TFA (1 mL) was added and the mixture was stirred at RT for 30 min. The reaction mixture was concentrated to dryness and the remaining residue purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 22 mg, 0.034 mmol, 57% for 2 steps) as a white solid. MS: 419 [M+1]+; HPLC: AtRet=1.00.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>CO>[CH3:13][O:12][C:8](=[O:11])[CH2:9][CH2:10][NH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN1CCCCC1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
To a solution of 1-aminopiperidine (100 g, 1.00 mol) in dry methanol at 0° C., methyl acrylate (99.0 ml, 1.10 mol) was added dropwise. The resulting mixture was stirred at room temperature overnight. After evaporation of the solvent, heptane was added to the residue, and the white solid (impurity) removed by filtration. The filtrate was concentrated to dryness to afford 80.0 g (43%) of the title compound as a yellow oil.
Reaction SMILES: [C:1](=[O:6])([O:4]C)[O:2][CH3:3].[CH2:7]([N:9]1[CH2:13][CH2:12][N:11]=[C:10]1[CH3:14])[CH3:8]>>[CH3:3][O:2][C:1](=[O:4])[O-:6].[CH2:7]([NH+:9]1[CH2:13][CH2:12][N:11]([CH3:1])[CH:10]1[CH3:14])[CH3:8]
Reactant: COC(=O)OC
Reactant: CCN1CCN=C1C
Product: CC[NH+]1CCN(C)C1C
Product: COC(=O)[O-]
Yield: 98 %

Procedure:
Furthermore, from JP-A-10 17,553 (Chem. Abstracts 128: 167423p) and from JP-A-10 17,554 (Chem. Abstracts 128: 167424q), it is known that N-alkylimidazolines are methylated by reaction with dimethyl carbonate on the nitrogen atom in the 3-position. Thus, the reaction of 1-ethyl-2-methylimidazoline with (MeO)2CO gives the product 1-ethyl-2,3-dimethylimidazolinium methyl carbonate in 98% yield.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:11][CH:10]=1.[CH3:20][N:21]1[C:26]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][C:24](=[O:33])[N:23]([CH3:34])[C:22]1=[O:35]>C(O)C>[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:30]2[CH2:31][CH2:32][N:27]([C:26]3[N:21]([CH3:20])[C:22](=[O:35])[N:23]([CH3:34])[C:24](=[O:33])[CH:25]=3)[CH2:28][CH2:29]2)=[CH:11][CH:10]=1
Reactant: Clc1ccc(OCCCBr)cc1
Reactant: Cn1c(N2CCNCC2)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cn1c(N2CCN(CCCOc3ccc(Cl)cc3)CC2)cc(=O)n(C)c1=O
Yield: 86.1 %

Procedure:
3 ml of triethylamine was added to 10 ml of an ethanol solution containing 2.5 g of 3-(4-chlorophenoxy)propyl bromide and 1.3 g of 1,3-dimethyl-6-(1-piperazinyl)-2,4(1H,3H)-pyrimidinedione, and the solution was then heated under reflux for 3 hours. Afterward, the reaction solution was concentrated to dryness, and the resultant residue was dissolved in chloroform and then washed with water. The thus obtained chloroform solution was dried and then concentrated, and the residue was recrystallized from ethanol/hexane, thereby preparing 1.96 g (yield: 86%) of 6-[4-(3-[4-chlorophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:35]1[CH:40]=[C:39]([Cl:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[ClH:41].[ClH:41].[ClH:41].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:35]5[CH:36]=[C:37]([Cl:43])[C:38]([OH:42])=[C:39]([Cl:41])[CH:40]=5)[N:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC[C@@H](N)C2)nc1
Product: Cl
Yield: 233.9 %

Procedure:
Following general procedure IV-2, (R)-tert-butyl 1-(5-(3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (60 mg, 0.10 mmol) was reacted with TFA (1.5 mL) to afford the desired product (37 mg, 74%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 9.28 (s, 1H), 8.49-8.31 (m, 2H), 8.16 (d, J=2.7 Hz, 1H), 7.63 (dd, J=9.1, 2.8 Hz, 1H), 7.51 (s, 2H), 6.98 (d, J=9.1 Hz, 1H), 4.40 (dd, J=12.7, 3.6 Hz, 1H), 3.93 (d, J=13.4 Hz, 1H), 3.41-3.19 (m, 3H), 2.80 (s, 3H), 2.16 (m, 1H), 1.97-1.89 (m, 1H), 1.78-1.65 (m, 2H); ESI MS m/z 523 [M+H]+; HPLC 98.1% (AUC), tR=9.87 min.