Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].C(N(CC)CC)C>C(Cl)Cl>[C:1]([NH:8][C:7]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:6]=1[CH3:5])(=[O:3])[CH3:2]
Reactant: Cc1c(N)cccc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(F)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
1.98 ml (27.78 mmol) of acetyl chloride were added, with stirring, to a solution of 3.161 g (25.26 mmol of 2-methyl-3-fluoroaniline and 3.87 ml (27.78 mmol) of triethylamine in 50 ml of DCM at 0° C. The solution was allowed to warm up to ambient temperature and was stirred for 1 hour. The solution was washed with water (3 times 50 ml), the product was dried with MgSO4 and the solvent was removed under reduced pressure. After recrystallization from a mixture of mineral oil/ethyl acetate (EtOac), 3.844 g (91%) of the title compound were obtained in the form of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=O)[CH3:16].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([NH2:24])[CH3:16]
Reactant: CC(=O)c1ccccc1-c1cc(F)ccc1F
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccccc1-c1cc(F)ccc1F

Procedure:
The title compound was prepared from 1-(2′,5′-difluoro-1,1′-biphenyl-2-yl)ethanone (2.0 g, 8.6 mmol), anhydrous methanol (100 mL), ammonium acetate (13.3 g, 172 mmol), and sodium cyanoborohydride (1.08 g, 17.2 mmol) according to the procedure and in the same manner as described in Example 105, step b;
Reaction SMILES: Br[CH2:2][C:3](OC(=O)CBr)=[O:4].[NH2:10][C:11]1[CH:12]=[C:13]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:16]2[OH:26].C(N(CC)CC)C>CN(C=O)C>[N:28]1([CH2:27][C:13]2[CH:14]=[C:15]3[C:16](=[O:26])[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][N:19]4[CH2:2][C:3](=[O:4])[NH:10][C:11]([CH:12]=2)=[C:20]34)[CH2:29][CH2:30][O:31][CH2:32][CH2:33]1
Reactant: O=C(CBr)OC(=O)CBr
Reactant: CCOC(=O)c1cnc2c(N)cc(CN3CCOCC3)cc2c1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)NC(=O)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Bromoacetic anhydride (280 mg) is added to ethyl 8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 2, 330 mg) in DMF (4.0 mL). Triethylamine (400 mg) is added and the reaction is heated for 10 min at 60° C. After 1 h, the DMF is removed and the product is chromatographed on silica gel with 10% methanol as the eluant to give 310 mg of the title compound as a mixture with triethylamine hydrobromide. Physical characteristics: 1H NMR (DMSO-d6) δ1.40, 2.45, 3.56, 3.69, 4.39, 4.88, 7.49, 7.97, 8.34.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[C:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][N:35]=1)#[N:33].CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:4]([C:6]1[CH:11]=[C:10]([OH:12])[C:9]([F:13])=[CH:8][C:7]=1[C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]3[NH:24][C:25]4[CH2:30][CH2:29][N:28]([C:38]([C:37]5[CH:41]=[CH:42][C:34]([C:32]#[N:33])=[N:35][CH:36]=5)=[O:39])[CH2:27][C:26]=4[N:31]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: N#Cc1ccc(C(=O)Cl)cn1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3ccc(C#N)nc3)C4)n[nH]c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 17 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 80 μmol) in DMF (1 mL), was added 6-cyano-nicotinoyl chloride (Preparation 46, 17 mg, 96 μmol), and DIPEA (56 μL, 320 μmol). The reaction mixture was stirred at room temperature for 72 hours and then saturated aqueous sodium hydrogen carbonate solution (5 mL) was added. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by reverse phase chromatography (Method C) to afford 6.9 mg of the title compound.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:13]3[N:17]([CH3:18])[N:16]=[N:15][N:14]=3)=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:11]=2)[C:6](=[O:19])[C:7]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][N:14]=2)=[CH:8]1
Reactant: Cn1nnnc1-c1cn(C)c2cc(F)ccc2c1=O
Reactant: C1COCCN1
Product: Cn1nnnc1-c1cn(C)c2cc(N3CCOCC3)ccc2c1=O

Procedure:
In a similar way to that described in Example 30, 7-fluoro-1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-4-quinolone (1 g) was heated with morpholine (25 ml) at 100° for 103 hours to give 1-methyl-3-(1-methyl-1H-tetrazol-5-yl)-7-morpholino-4-quinolone, m.p. 235°-238°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:28])[C:22]#[C:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:20][C:21](=[O:28])/[CH:22]=[CH:23]\[CH2:24][N:25]([CH3:26])[CH3:27])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CO
Product: CN(C)C/C=C\C(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2c1
Reaction time: 8 h
Yield: 36 %

Procedure:
A mixture of 0.05 g (0.118 mmol) N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-6-quinolinyl]-4-dimethylamino-2-butynamide and 6 mg of Lindlar catalyst in 10 mL of methanol was hydrogenated at room temperature overnight. The mixture was filtered through a pad of Celite. After the solvent was removed, the residue was purified by thin-layer chromatography eluted with 30% methanol in ethyl acetate. The product was dried to give 0.018 g (36%) pale yellow solid; HRMS m/z 423.1270 (M.).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:3][CH2:2]1.Cl.[NH2:20][C:21]([CH2:29][CH3:30])([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:20][C:21]([CH2:27][CH3:28])([CH2:29][CH3:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:14])[CH:9]=[CH:8][C:7]=2[C:15]([F:18])([F:17])[F:16])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCC2CC2)n1
Reactant: CCOC(=O)C(N)(CC)CC
Agent: Cl
Product: CCOC(=O)C(CC)(CC)NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Example 113 d) and ethyl 2-amino-2-ethylbutanoate hydrochloride (CAN 1135219-29-2) as starting materials, MS (EI): m/e=403.4 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][CH:11]2[N:8]([C:9](=[O:15])[CH:10]2[NH2:14])[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2].[NH2:19][C:20]([CH:30]([F:32])[F:31])([CH2:24][C:25]1[NH:29][CH:28]=[N:27][CH:26]=1)[C:21](Cl)=[O:22]>C(OCC)(=O)C>[NH2:19][C:20]([CH:30]([F:32])[F:31])([CH2:24][C:25]1[NH:29][CH:28]=[N:27][CH:26]=1)[C:21]([NH:14][CH:10]1[C:9](=[O:15])[N:8]2[CH:11]1[S:12][CH2:13][C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])=[C:7]2[C:16]([OH:18])=[O:17])=[O:22]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: NC(Cc1cnc[nH]1)(C(=O)Cl)C(F)F
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)(Cc3cnc[nH]3)C(F)F)C2SC1

Procedure:
A mixture of 1 g of 3-acetyloxymethyl-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid and 1 g of 2-amino-2-difluoromethyl-3-(5-imidazolyl)propionic acid chloride wherein the free amino groups are protected with tertiary-butoxycarbonyl in 50 ml of ethyl acetate is refluxed for 2 hours after which the solvent is removed leaving a residue which is chromatographed on silica gel using benzene-acetone as the eluant to give 7-[[2-amino-2-difluoromethyl-3-(5-imidazolyl)propionyl]amino]-3-acetoxymethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid wherein the amino groups are protected with tert-butoxycarbonyl. The protected cephalosporin compound is treated with trifluoroacetic acid for 1/2 hour at 25° C. under nitrogen atomosphere then diluted with ether until precipitation stops and filtered to give the di-trifluoroacetic acid salt of the title cephalosporin which can be converted to free base by use of ion exchange resin.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][F:6])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1CCCCC1.C(OCC)(=O)C>[C:3]([C:2]([NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:7])[CH2:5][F:6])#[N:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(N)(C#N)CF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C#N)(CF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1.34 g (11.83 mmol, about 90%) of rac-2-amino-3-fluoro-2-methylpropanonitrile from Example 53A in 29 ml of THF/water (9/1) were admixed with 5.07 g (36.67 mmol) of potassium carbonate. At 0° C., 1.69 ml (11.83 mmol) of benzyl chloroformate were slowly added dropwise and the reaction mixture was stirred at RT overnight. The solvent was decanted off and the aqueous phase was twice extracted by shaking with THF and then decanting off the THF. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was separated by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient) and the product fractions were concentrated by evaporation on a rotary evaporator. 1.89 g of the target compound were obtained (66% of theory, 97% purity).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]=[CH2:24])=[CH:19][CH:18]=4)[N:13]=3)[C:8]=2[CH2:25][CH2:26][CH3:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl>[O:36]1[CH2:24][CH:23]1[C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:13]=[C:12]([C:9]3[C:8]([CH2:25][CH2:26][CH3:27])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)[O:16][N:15]=2)=[CH:22][CH:21]=1
Reactant: C=Cc1ccc(-c2noc(-c3noc(-c4ccccc4)c3CCC)n2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCc1c(-c2nc(-c3ccc(C4CO4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(5-phenyl-4-propylisoxazol-3-yl)-3-(4-vinylphenyl)-1,2,4-oxadiazole (4.64 g, 12.97 mmol) in DCM (500 mL) was added m-CPBA (9 g, 52.2 mmol). The reaction mixture was stirred overnight at room temperature. Next, the reaction mixture was washed with 1N NaOH. The organic layer was dried with MgSO4, filtered, and concentrated to yield Preparation 1B. MS (m+1)=374. HPLC Peak RT=4.36 minutes (Analytical Method A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1.Br[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=1[CH3:38].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[C:32]=2[CH3:38])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Reactant: Cc1nccc(Br)c1C
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: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
Suzuki coupling.: To a mixture of (S)-2-tert-butoxycarbonylamino-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propionic acid methyl ester (8.22 g) in 140 mL toluene and 40 mL water was added 4-bromo-2,3-dimethyl-pyridine (6.77 g), Na2CO3 (7.5 g), and Pd(PPh3)4. The mixture was purged with nitrogen and stirred under nitrogen at 80° C. for 18 h. The mixture was then cooled to rt and poured into water-EtOAc. The organic layer was washed with water and saturated brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-butoxycarbonylamino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (4.5 g). LCMS (m/z) 386.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10][CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].S(Cl)(Cl)(=O)=[O:13].CCO>C(Cl)Cl>[CH3:11][S:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CSc1cccc([N+](=O)[O-])c1
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)c1cccc([N+](=O)[O-])c1
Temperature: -20 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
A solution of 3-nitro thioanisol (96 g, 568 mmol) in DCM (100 mL) is added dropwise to a cooled solution of sulfuryl chloride (96 g, 711 mmol) in DCM (600 mL) at −60° C. The mixture is stirred for 4 h at −20° C., then cooled to −60° C., and 350 mL of EtOH are carefully added. The reaction is then allowed to warm up to rt, subsequently, most of the solvent is evaporated, the residue is poured in sat. aq. NaHCO3, and the solid product is filtered off and carefully washed with hexane on the filter, then air-dried to give the desired sulfoxide (95 g, 90% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:10]=[CH:23][CH:24]=[O:25])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1cccc(-c2ncccn2)c1
Product: O=CC=Cc1cccc(-c2ncccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 3-(2-pyrimidinyl)benzaldehyde (prepared as described in Reference Example 12) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[C:14]([CH3:16])[CH:15]=2)[NH:12][C:11](=[O:17])[CH:10]=[CH:9]3)[CH:5]=[N:4][CH:3]=[N:2]1.C>C(O)C>[CH3:16][C:14]1[CH:15]=[C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:17])[CH2:10][CH2:9]2
Reactant: Cc1cc(-n2cncn2)cc2ccc(=O)[nH]c12
Solvent: CCO
Product: Cc1cc(-n2cncn2)cc2c1NC(=O)CC2

Procedure:
A suspension of 6-(1,2,4-triazol-1-yl)-8-methyl-2-(1H)-quinolone (see Example 9) (1.7 g) in ethanol (450 cm3) was hydrogenated at 60° and 60 p.s.i. (4.13×105Pa) pressure over 10% palladised charcoal (0.35 g) for 72 hours. The cooled mixture was then filtered through "Solkafloc" (Trademark for a cellulose based filtering agent) and evaporated in vacuo to afford a solid. Chromatography on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform:methanol, 49:1, followed by combination and evaporation of the appropriate fractions in vacuo gave a solid which was recrystallised from ethyl acetate/methanol to give 3,4-dihydro-8-methyl-6-(1,2,4-triazol-1-yl)-2-(1H)-quinolone, m.p. 258°-259° (0.266 g).
Reaction SMILES: [N:1]1([NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>ClCCl>[CH2:22]([O:21][C:19](=[O:20])[N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[N:1]1[CH:2]=[CH:3][CH:4]=[CH:5]1)[CH3:23]
Reactant: c1ccn(Nc2ccncc2)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)N(c1ccncc1)n1cccc1

Procedure:
To a solution containing 9 g of N-(1H-pyrrol-1-yl)-4-pyridinamine and 15 g of sodium bicarbonate in 350 ml of dichloromethane was added a solution containing 6.7 g of ethyl chloroformate in 50 ml of dichloromethane.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:20]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CN=[N+]=[N-])C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 10.50 of {(3S)-1-(tert-butoxycarbonyl)-3-piperidyl}methyl methanesulfonate in 100 ml of N,N-dimethylformamide, 4.9 g of sodium azide was added at room temperature, followed by 4 hours' stirring at 80° C. under heating. The reaction liquid was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and resulting residue was purified by means of silica gel column chromatography (eluting solvent: from hexane to hexane/ethyl acetate=15/1) to provide 7.24 g of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CNC(=O)c1cccc(C)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CNC(=O)c1cccc(C)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Temperature: 120 °C
Yield: 29.7 %

Procedure:
3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (76 mg, 0.34 mmol, 1.0 eq), 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (118 mg, 0.38 mmol, 1.1 eq), and 10-camphorsulfonic acid (88 mg, 0.38 mmol, 1.1 eq) were dissolved in IPA (3 mL) and heated at 120° C. in a microwave for 40 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by amine capped silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3,N-dimethyl-benzamide as a pale yellow foam (50 mg, 30%). LCMS (m/e) 495 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.51 (s, 1H), 8.04 (s, 1H), 7.45-7.35 (m, 2H), 7.32-7.22 (m 1H), 7.11 (s, 1H), 6.98 (d, 1H, J=8.1 Hz), 6.85 (d, 1H, J=7.9 Hz), 6.78 (s, 1H), 6.06-5.97 (m, 1H), 3.55 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.89 (d, 3H, J=4.9 Hz), 2.88-2.82 (m, 2H), 2.75 (t, 2H, J=5.7 Hz), 2.73-2.62 (m, 6H), 2.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:28])[C:25]([CH3:27])=[CH2:26]>C1(C)C=CC=CC=1>[C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[CH:15][CH:16]=1)(=[O:28])[C:25]([CH3:27])=[CH2:26]
Reactant: C=C(C)C(=O)Cl
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(CP(=O)(OCC)OCC)cc1
Yield: 92 %

Procedure:
By the same procedure as described in example 1, diethyl 4-(amino)benzylphosphonate (1.94 g; 8 mmoles), triethylamine (0.87 g; 8.6 mmoles), and methacryloyl chloride (0.9 g; 8.6 mmoles) in toluene (9 ml) afford diethyl 4-(methacrylamido)benzylphosphonate as a slight yellow solid (2.3 g; yield 92%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[Br:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: BrCc1cccc(Br)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(Br)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-bromobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([N+:25]([O-])=O)=[C:19]([CH2:20][C:21](OC)=[O:22])[C:12]=2[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.C(O)C>[CH2:1]([NH:8][CH2:9][CH:10]1[O:11][C:12]2=[C:19]3[C:18](=[CH:17][CH:16]=[C:13]2[O:14][CH2:15]1)[NH:25][C:21](=[O:22])[CH2:20]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c([N+](=O)[O-])ccc2c1OC(CNCc1ccccc1)CO2
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccccc2)CO3)N1
Temperature: 70 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
The methyl ester from Example 5 (43 mg) was dissolved in 1:1 ethyl acetate/ethanol (10 mL) and filtered through a syringe filter to remove insoluble material. Platinum oxide (35 weight percent) was added and the mixture placed under 50 psi of hydrogen gas on a Parr shaker overnight. TLC analysis with 95:5 CH2Cl2/MeOH showed consumption of starting material with a more polar product having been formed. The mixture was filtered through a 0.5 μm syringe filter, washing with 1:1 EtOAc/EtOH, and the filtrate concentrated under reduced pressure to a pale red-brown glass. The crude material was redissolved in ethanol (20 mL) and 20 μL of concentrated HCl were added. The solution was warmed to 70° C. and allowed to stir overnight. TLC of the reaction mixture (96:4 CH2Cl2/MeOH) showed the formation of a new product with no remaining starting material. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to a light orange film. This was chromatographed over silica gel eluting with 96:4 CH2Cl2/MeOH. The title product was isolated in 22% yield.