Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH2:9][C:10](=[O:12])[O-:11])([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])O.CCN(C(C)C)C(C)C.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:10]([O-:12])(=[O:11])[CH3:9].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:38])[NH:1][C@@H:2]([CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6])[CH2:9][C:10]([OH:11])=[O:12])=[CH:32][CH:31]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C[N+](C)(C)CC(N)(O)CC(=O)[O-]
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)[O-]
Product: C[N+](C)(C)C[C@@H](CC(=O)O)NC(=O)Nc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of aminocarnitine (35 mg) in anhydrous MeOH (2 mL) was treated with DIPEA (2.5 equiv) and 1-(benzyloxy)-4-isocyanatobenzene (2 equiv) at rt. The reaction was sealed and stirred at rt overnight. The reaction mixture were concentrated under reduced pressure and purified on silica gel using MeOH/DCM (0->80%) and/or 55% DCM:22% MeOH:23% AcOH. The purified material was then taken into 10% MeOH/DCM, filtered through a plug of Celite, concentrated under reduced pressure and optionally triturated with Et2O and/or hexanes to provide the title compound as a white solid (1.8 mg). 1H NMR (400 MHz, CD3OD): δ=7.42 (d, J=8.0 Hz, 2H), 7.36 (t, J=7.6, 2H), 7.30 (d, J=7.60 Hz, 1H), 7.28-7.20 (m, 2H), 6.92 (d, J=8.80 Hz, 2H), 5.04 (s, 2H), 5.59 (br s, 1H), 3.80-3.45 (m, 2H), 3.21 (s, 9H), 2.60-2.45 (br, 2H), 1.96 (s, 3H); MS ESI [M+H]+, calcd for [C21H26N3O4+H]+ 386.5 found m/z 386.2 (100).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].[OH-].[Na+]>CO>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2c(c1)CC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1Cc2cc(C(=O)O)ccc2N1
Yield: 75.5 %

Procedure:
5-Methoxycarbonyl-2-oxindole (1 g) and 1 g of sodium hydroxide in 20 mL of methanol was refluxed for 3 hours. The reaction mixture was cooled and concentrated to dryness. The residue was dissolved in water and extracted twice with ethyl acetate. The aqueous layer was acidified with 6 N hydrochloric acid and the precipitated solid collected, washed with water, and dried to give 0.7 g (78%) of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:5]=1
Reactant: C1CNCCN1
Reactant: Clc1cc(Cl)nc(N2CCCC2)n1
Solvent: CCO
Product: Clc1cc(N2CCNCC2)nc(N2CCCC2)n1

Procedure:
A solution of 2.0 g (9.17 mmoles) of 4,6-dichloro-2-pyrrolidinopyrimidine and 3.95 g (45.9 mmoles) of piperazine in ethanol is boiled under reflux for 1 hour and then evaporated. The evaporation residue is distributed between 100 ml of chloroform and 100 ml of 1% sodium hydroxide solution. After separation the organic phase is twice washed with 50 ml of water each, then dried and evaporated. After recrystallizing the residue from hexane, the title product is obtained in a yield of 2.25 g (91.6%), m.p. 89°-100° C.
Reaction SMILES: [CH2:1]=[CH:2]Cl.[CH3:4][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH2:6]>>[C:7]([O:9][CH2:10][CH:2]=[CH2:1])(=[O:8])[C:6]1[C:5](=[CH:4][CH:6]=[CH:5][CH:4]=1)[C:7]([O:9][CH2:10][CH:2]=[CH2:1])=[O:8]
Reactant: C=C(C)C(=O)OC
Reactant: C=CCl
Product: C=CCOC(=O)c1ccccc1C(=O)OCC=C

Procedure:
Polyvinyl chloride resin of 54 mass % and carbon nanofibers of 1.4 mass % having an average grain diameter of 0.1 μm and a length of 5 μm as single-layer molded amorphous carbon source having a porosity of 50% and PMMA as a pore opening member to form pores were mixed together to form a composition and diallyl phthalate monomer as a plasticizer was added to this composition, the composition was then dispersed using a Henschel mixer, kneaded repeatedly a sufficient number of times using a pressure kneader to obtain a kneaded composition, which was then pelletized using a pelletizer to obtain a composition for molding. This pellet was used to perform extrusion molding for a film-like molded product having a thickness of 400 μm through extrusion molding. This film was processed in an air oven heated to 200° C. for five hours to be a carbon precursor. The film was then heated in a nitrogen gas at a temperature rising rate of 20° C./h and left for three hours at 1000° C. The film was naturally cooled and then kept under a vacuum at 1500° C. for three hours, naturally cooled, carbonization completed and a composite carbon vibration plate was thus obtained.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]=2[OH:14])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].S(OC)(O[CH3:26])(=O)=O>O1CCCC1.CN(C)C=O>[CH:1]1([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:12]=3[C:13]=2[O:14][CH3:26])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COS(=O)(=O)OC
Reactant: O=C(c1oc2ccc(F)cc2c1O)C1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c(C(=O)C2CCCCC2)oc2ccc(F)cc12
Reaction time: 0.25 h
Yield: 63 %

Procedure:
Cyclohexyl(5-fluoro-3-hydroxy-1-benzofuran-2-yl)methanone (3.0 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (15 mL) and N,N-dimethylformamide (15 mL). The reaction mixture was ice-cooled, sodium hydride (0.69 mg) was added to the solution, and the mixture was stirred for 15 min. Dimethyl sulfate (1.6 mL) was added to the mixture, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the precipitate was recrystallized from diisopropyl ether-hexane to give the title object compound (2.0 g, 63%) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][C:14]([NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:20]3=[N:21][CH:22]=2)=[O:15])[CH2:8]1)(=[O:6])=[O:5].O.C(N)CN>Cl.C(O)(=O)C>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][S:4]([N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13][C:14]([NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][NH:23][C:20]3=[N:21][CH:22]=2)=[O:15])[CH2:8]1)(=[O:5])=[O:6]
Reactant: CC(C)(C)CS(=O)(=O)N1CCC[C@H](NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Solvent: NCCN
Product: CC(C)(C)CS(=O)(=O)N1CCC[C@H](NC(=O)Nc2cnc3[nH]ccc3n2)C1
Temperature: 60 °C
Yield: 73.7 %

Procedure:
1-[(S)-1-(2,2-Dimethyl-propane-1-sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (0.045 g, 0.086 mmol) was dissolved in 1M HCl in acetic acid (0.9 mL) and stirred at 60° C. After 1.5 hours the solvent was evaporated and the residue was dried under high vacuum. The remaining oil was taken up in MeOH:H2O:EtN 8:1:1 (0.9 mL) and ethylenediamine (0.029 mL, 0.429 mmol) was added. The yellow solution stirred at RT overnight. The solvent was evaporated and the residue was purified by SiO2 chromatography (8 g SiO2, DCM:MeOH 0 to 5% MeOH) to give 0.025 g of 1-[(S)-1-(2,2-dimethyl-propane-1-sulfonyl)-piperidin-3-yl]-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-urea as an off-white solid (74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Reactant: OB(O)c1ccc(F)cc1
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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1-c1ccc(F)cc1
Yield: 83.9 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.058 g (84%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-fluorobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].CCOCC.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1.C(=O)([O-])[O-].[Ca+2]>O>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]=[C:1]=[S:2])=[N:15][CH:16]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCOCC
Solvent: O
Product: S=C=Nc1ccc(Cl)cn1

Procedure:
A solution of 16.3 ml. of thiophosgene in 600 ml. of ether is added with rapid stirring to a suspension of 25.6 g. of 5-chloro-2-aminopyridine and 42 g. of calcium carbonate in 600 ml. of water. The reaction mixture is stirred for 11/2 hours and the ether layer separated and the water layer extracted with a 400 ml. portion of ether. The combined ether extracts are washed with water, dried over magnesium sulfate and evaporated to dryness in vacuo affording 29.9 g. of a dark red oil. The oil is distilled at 0.75 mm. of Hg. at a temperature 96° C. affording 5-chloro-2-pyridylisothiocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:20]=1[CH3:28])=[O:18].[NH4+].[Cl-]>CO.[Zn]>[NH2:25][C:23]1[CH:22]=[CH:21][C:20]([CH3:28])=[C:19]([C:17]([C:3]2[CH:4]=[CH:5][C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=3[F:16])=[CH:7][C:2]=2[Cl:1])=[O:18])[CH:24]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
Compound 493 (6.0 g, 14.9 mmol) was dissolved in MeOH (350 mL). Zinc-dust (12.69 g, 194 mmol) and NH4Cl (5.59 g, 104 mmol) were added. The reaction mixture was heated at reflux temperature for 1 h. The mixture was filtered and washed with MeOH. The filtrate was concentrated and the solid was dissolved in EtOAc (150 mL) and saturated aqueous Na2CO3 (100 mL). The water phase was extracted with EtOAc and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:2 as the eluent to afford the title compound as a slightly coloured crystalline compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]([CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1)[C:7](=[O:12])[C:8]([F:11])([F:10])[F:9]
Reactant: [H][H]
Reactant: O=C(N(CCc1ccc([N+](=O)[O-])cc1)Cc1cccc(Cl)c1)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(CCN(Cc2cccc(Cl)c2)C(=O)C(F)(F)F)cc1
Yield: 65 %

Procedure:
To a solution of the product of step (b) (3.89 g, 10.05 mmol) in ethyl acetate (100 ml) was added 5% Pd/C. The mixture was hydrogenated at 50 psig for 1.4 hours, until the theoretical amount of hydrogen was taken up. The catalyst was filtered and the filtrate concentrated to an oil. This was purified by chromatography (silica gel, methylene chloride: n-hexane (1:1)) to yield 2.33 g of pure N-(3-chlorobenzyl)-N-(2-(4-aminophenyl)ethyl)trifluoroacetamide as a thick oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=2)=[C:11]([CH3:24])[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:25]1([C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH:35][C:34]3[CH:36]=[CH:37][C:31]([N:25]4[CH2:26][CH2:27][O:28][CH2:29][CH2:30]4)=[CH:32][CH:33]=3)[CH:16]=2)=[C:11]([CH3:24])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)ccc1-c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)OC(C)(C)C)ccc1-c1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2)c1
Reaction time: 18 h

Procedure:
A mixture of 4′-tert-butoxycarbonylamino-2′-methyl-biphenyl-3-carboxylic acid (436 mg), 4-morpholin-4-yl aniline (238 mg), triethylamine (0.55 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (757 mg) in dry DMF (1 ml) was stirred at 20 C for 18 h. Water (50 ml) was then added and the resulting colourless precipitate was collected by filtration and dried (680 mg)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.CN(C=O)C.P(Br)(Br)([Br:19])=O.O>C1(C)C=CC=CC=1>[Br:19][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cnc1Br
Temperature: 90 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
To a suspension 5-bromo-3-nitro-pyridin-2-ol (20 g, 91.32 mmol) in toluene (100 ml) was added DMF (0.7 ml, 9.13 mmol) and the mixture was heated to 90° C. (the reaction mixture was protected from light). A solution of POBr3 (31.41 g, 109.51 mmol) in toluene (40 ml) was added dropwise at 90° C. and the reaction mixture was stirred at that temperature for 16 h. The mixture was allowed to cool to room temperature and toluene (50 ml) and water (50 ml) were added. The organic layer was separated, washed successively with aqueous 1N NaOH (60 ml), water (60 ml) and brine (30 ml), dried with Na2SO4 and evaporated obtain the title compound as yellow solid (25.2 g, 97%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][CH2:14][N:15]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:34]4[C:35]5[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=5[N:37]=[C:33]4[N:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=O)=O)=CC=1.[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[N:42]([CH2:12][CH2:13][CH2:14][N:15]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:34]3[C:35]4[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=4[N:37]=[C:33]3[N:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:43]=[N-:44]
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C(=O)OC(C)(C)C)c2ccc(-c3ccnc4nc5ccccc5n34)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCN=[N+]=[N-])c1ccc(-c2ccnc3nc4ccccc4n23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-((4-(benzo[4,5]imidazo[1,2-a]pyrimidin-4-yl)phenyl)(tert-butoxycarbonyl)amino)propyl 4-methylbenzenesulfonate (130 mg, 0.23 mmol) in DMF (2 mL) was added NaN3 (83 mg, 1.3 mmol). The mixture as stirred at rt for 2 h and concentrated under reduced pressure to remove volatiles. The residue was taken up to DCM (50 mL) and washed with water (2×50 mL) and dried over MgSO4 and concentrated to afford the title compound as a yellow solid. The product was used directly for the next reaction without further purification. MS (ESI) m/z [M+H]+444.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].Cl.Cl.[CH3:18][N:19]([CH3:29])[CH2:20][CH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([CH2:21][CH2:20][N:19]([CH3:18])[CH3:29])[CH2:23][CH2:24]1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)CC[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CCN(C)C)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (250 mg, 1.0 mmol) was reacted with trans-4-[2-(dimethylamino)ethyl]cyclohexanamine dihydrochloride (300 mg, 1.2 mmol) to afford the desired product (140 mg, 36%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.88 (br s, 1H), 8.93 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 5.04-4.96 (m, 1H), 2.67 (s, 3H), 2.36-2.22 (m, 4H), 2.24 (s, 6H), 1.93-1.83 (dd, J=13.9, 3.5 Hz, 2H), 1.49-1.31 (m, 5H), 1.27-1.15 (m, 2H); ESI MS m/z 375 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][C@@H:11]([CH3:15])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C@@H:11]([CH3:15])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a solution of (3S)-1-[(3-Bromophenyl)methyl]-3-methylpiperazine (250 mg, 0.5 mmol), TEA (0.5 ml, 3.5 mmol), and DMAP (12 mg, 0.1 mmol) in 1 mL of dry DMSO was added dropwise benzyl chloroformate (0.34 mL, 2.25 mmol) at 10° C. while stirring. The mixture was then heated and stirred at 50° C. for 1.5 h. After cooling to room temperature, 15 mL of ethyl acetate and 5 mL of saturated NaHCO3 were added. The organic layer was separated, concentrated under vacuum and purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (180 mg, 70%). LC/MS: m/z, 403 (M+H), 1.74 min.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C>[CH2:17]([O:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)c(OC)cc1[N+](=O)[O-]
Temperature: 92.5 °C
Yield: 77.1 %

Procedure:
To solution of methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (13.0 g, 0.0572 mol) in DMF (120 mL) and benzyl chloride (7.23 ml, 0.0629 mol), K2CO3 (8.69 g, 0.0629 mol) and potassium iodide (0.949 g, 0.0057 mol) were added. The reaction mixture was heated at 90-95° C. overnight. The solvent was evaporated under vacuum and the residue was taken in ethyl acetate and washed with water and brine. After drying over MgSO4, the solution was concentrated ad purified on silica gel column to yield methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (13.99 g, 77% yield). 1HNMR (DMSO-d6): δ 7.66 (1H, s), 7.40 (6H, m), 5.27 (2H, s), 3.83 (3H, s), 3.80 (3H, s). LC-MS (ESI) m/z 318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:4]=2[N:3]=1.Br[CH:22]([CH3:24])[CH3:23]>>[Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH:22]([CH3:24])[CH3:23])=[CH:19][C:4]=2[N:3]=1
Reactant: CC(C)Br
Reactant: O=C1c2cnccc2-c2c1c(Cl)nc1cc(O)ccc21
Product: CC(C)Oc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cnccc1-3

Procedure:
This compound was prepared from 6-chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34a) and 2-bromopropane in a similar manner to Example 34b. The desired product was obtained as a yellow powder. ESI−MS: m/z 325 (MH+); 1H-NMR (CDCl3): δ1.47 (6H, d, J=6 Hz), 4.80 (1H, quintet like, J=ca 6 Hz), 7.36 (1H, dd, J=9 Hz, 2.5 Hz), 7.43 (1H, d, J=2.5 Hz), 8.01 (1H, dd, J=5.5 Hz, J=1 Hz), 8.34 (1H, d, J=9 Hz), 8.95 (1H, d, J=5.5 Hz), 9.03 (1H, d, J=1 Hz).
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([CH3:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17](F)[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1>N1C=CC=CC=1>[NH2:3][C:4]1[C:5]([F:28])=[CH:6][C:7]([CH3:27])=[C:8]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:22])=[C:17]([NH:2][CH3:1])[C:18]=3[Cl:20])[C:13](=[O:23])[C:12]([C:24]([OH:26])=[O:25])=[CH:11]2)[CH:9]=1
Reactant: CN
Reactant: Cc1cc(F)c(N)cc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3C)c2c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 40% aqueous solution (100 mg) of methylamine and 1-(5-amino-4-fluoro-2-methylphenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) were added to pyridine (2 ml), and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, a mixed liquid of ethanol and diethyl ether was added to the residue, and the mixture was left to stand overnight. Solids deposited were collected by filtration to obtain the title compound (63 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([F:19])[F:18])[C:10]2[CH2:14][O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1.[C:20]([Li])(C)(C)C.CI>O1CCCC1.CCCCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH:17]([F:19])[F:18])[C:10]2[CH:14]([CH3:20])[O:13][C:12](=[O:15])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: [Li]C(C)(C)C
Reactant: O=C1C=C(N(Cc2ccc(Cl)nc2)CC(F)F)CO1
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1OC(=O)C=C1N(Cc1ccc(Cl)nc1)CC(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
300 mg (1.04 mmol) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]furan-2(5H)-one (1) are dissolved in 10 ml of tetrahydrofuran, the solution is cooled to −78° C. and 611 μl (1.04 mmol) of a 1.7 M solution of tert.-butyllithium in pentane are added. After 30 min of stirring at −78° C., 65 μl (1.04 mmol) of methyl iodide are added, stirring is continued at −78° C. for a further 30 min and the mixture is warmed to room temperature. Concentration under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (2:1) gives 152 mg (47% of theory) of 4-[[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino]-5-methylfuran-2(5H)-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3Cl)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:27](N)[CH2:28]C1C=CC=CC=1.Cl[C:37]1C=CC=CC=1N>>[C:2]1([CH3:37])[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:28][CH:27]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Cl
Reactant: NCCc1ccccc1
Reactant: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(Nc3ccccc3Cl)c12
Product: Cc1ccc(-c2c[nH]c3ccnc(NCCc4ccccc4)c3c2=O)cc1

Procedure:
3-(4-Chlorophenyl)-1,4-dihydro-4-oxo-5-(2-chlorophenylamino)-1,6-naphthyridine The title compound was prepared as described in Example 1 above except that phenethylamine was replaced with 2-chloroaniline. MS 382 (M+1)+.