Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:5]1[CH:13]=[C:12]([N:14]([C:22](=[O:24])[CH3:23])[CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(C)(C)C.FC(F)(F)C(O)=O.C(Cl)[Cl:33]>>[ClH:33].[C:22]([N:14]([C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:13]=1)[CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH2:20][CH2:21]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N(CCN1CCCC1)c1ccc(C(=O)O)c(C(C)(C)C)c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(CCN1CCCC1)c1ccc(C(=O)O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 4-[N-acetyl-N-[2-(1-pyrrolidinyl)ethyl]amino]-benzoic acid (37 mg, compound obtained in Reference Example 107) in methylene chloride (0.2 mL) is added trifluoroacetic acid (0.2 mL), and the mixture is shaken at room temperature for one day. The reaction mixture is concentrated and the residue is subjected to azeotropic distillation successively with chloroform, 4N HCl-dioxane and chloroform to give 4-[N-acetyl-N-[2-(1-pyrrolidinyl)ethyl]amino]benzoate hydrochloride. The product and 1 (3-ethoxybenzyl)-4-piperazin-1-yl-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride are treated in the same manner (condensation reaction) as described in Example 3 and then the resultant product is treated in the same manner as described in Example 4(3) to give 1-(3-ethoxybenzyl)-4-[4-[4-[N-acetyl-N-[2-(1-pyrrolidinyl)ethyl]amino]benzoyl]piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (15 mg, yield; 21%) as an amorphous powder. MS (APCI) m/z; 597 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[C:5]([C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:12]=2)=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.1 %

Procedure:
In a flask were placed 2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (20 mg, 0.06 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid (15 mg, 0.12 mmol), pyridine (11 μL, 0.12 mmol) and N,N-dimethylformamide (1 mL), followed by stirring at room temperature for 24 hours. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (8 mg).
Reaction SMILES: COC(C1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1)=O.C1COCC1.C[Mg]Cl.Cl.[C:24]([O:28]C)([CH3:27])([CH3:26])[CH3:25]>O>[F:12][C:11]([F:14])([F:13])[C:7]1[N:6]=[C:25]([C:24]([OH:28])([CH3:27])[CH3:26])[CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1cccc(C(F)(F)F)n1
Reactant: COC(C)(C)C
Agent: C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(O)c1cccc(C(F)(F)F)n1
Temperature: 0 °C
Yield: 90 %

Procedure:
Add 6-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (80.0 g, 390 mmol) to a mixture of THF (240 mL) and tert-butylmethyl ether (400 mL). Add the solution slowly to a 3 M methylmagnesium chloride in THF (390 mL, 1.17 moles) and maintain 8° C. to 16° C. Cool the mixture to 0° C. and add a mixture of 5 M hydrochloric acid (257 mL, 1.29 moles) and water (200 mL). Separate the phases and concentrate the organic phase under reduced pressure. Add heptane (160 mL) and cool the mixture to 5° C. Collect the precipitate by vacuum filtration and rinse the solid with heptane (20 mL) followed by pentane (30 mL). Vacuum dry the solid to afford the title compound as a tan solid (72.3 g, 352 mmol, 90%). 1H NMR (400 MHz, DMSO d6) δ 8.04 (t, J=7.7 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.69 (d, J=7.0 Hz, 1H), 5.40 (s, 1H), 1.43 (s, 6H). HRMS (ESI) m/z (M+H)+ calcd for C9H10F3NO: 206.0787, found 206.0787.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.O[N:12]=[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[NH2:14]>N1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:7][N:12]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[NH:14]2)=[C:4]([CH3:10])[CH:3]=1
Reactant: NC(=NO)c1ccco1
Reactant: Cc1cc(Cl)ccc1C=O
Solvent: C1CCNCC1
Product: Cc1cc(Cl)ccc1C1NC(c2ccco2)=NO1
Temperature: 100 °C
Yield: 24.2 %

Procedure:
A mixture of 4-chloro-2-methylbenzaldehyde (229 mg, 1.49 mmol), N′-hydroxyfuran-2-carboximidamide (263 mg, 2.1 mmol) and one drop of piperidine was heated to 100° C. for 4 h. It was cooled to RT and purified by automated column chromatography on the ISCO-companion (SiO2, gradient heptane/ethyl acetate) to give the 5-(4-chloro-2-methylphenyl)-3-(furan-2-yl)-4,5-dihydro-1,2,4-oxadiazole product (94 mg, 0.36 mmol) as an off-white solid with an HPLC purity 99%. The overall yield was approximately 24%. LC-MS [M+H] 263 (C13H11ClN2O2+H, expected 263.05).
Reaction SMILES: C([O-])(=O)C.[Na+].Cl.[CH2:7]([O:9][NH2:10])[CH3:8].[C:11]([C:15]1[C:16](=[O:36])[CH2:17][CH:18]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:23]=2[CH3:35])[CH2:19][C:20]=1[OH:21])(=O)[CH2:12][CH3:13]>C(O)C.C(Cl)Cl>[CH2:7]([O:9][N:10]=[C:11]([C:15]1[C:16](=[O:36])[CH2:17][CH:18]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[C:23]=2[CH3:35])[CH2:19][C:20]=1[OH:21])[CH2:12][CH3:13])[CH3:8]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)c(NS(C)(=O)=O)c2C)CC1=O
Reaction time: 18 h

Procedure:
Sodium acetate (0.19 g, 2.29 mmol) and ethoxyamine hydrochloride (0.22 g, 2.29 mmol) were added to a solution of 2-propionyl-3-hydroxy-5-(3-methylsulphonamido-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.58 g, 1.53 mmol) in ethanol (25 ml) and methylene chloride (25 ml). Stirring was continued at 20° for 18 hrs. The solvent was removed under reduced pressure and the residue partitioned between chloroform and water. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield2-[1-(ethoxyimino)propyl]-hydroxy-5-[3-(methylsulphonamido)-2,4,6-trimethylphenyl]cyclohex-2-en-1-one as a brown oil (0.27 g, 42%). The compound was characterized by proton magnetic resonance spectroscopy. The spectroscopic data are recorded in Table 2.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14](N)[N:15](C(OC(C)(C)C)=O)[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1.C[N:49](C=O)C>O1CCOCC1>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]([NH2:49])[CH2:16][C@H:17]([OH:39])[C@@H:18]([NH:26][C:27](=[O:38])[C@H:28]([C:34]([CH3:37])([CH3:36])[CH3:35])[NH:29][C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(C(=O)OC(C)(C)C)C(N)c1ccc(-c2ccccn2)cc1)C(C)(C)C
Reactant: CN(C)C=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2ccccn2)cc1)C(C)(C)C
Reaction time: 2.75 h

Procedure:
Analogously to Example 37f), 130 ml of 4 M HCl in dioxane are added to 4.4 g (6.94 mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-2-N-Boc-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane and the mixture is diluted with 7 ml of DMF. After 2.75 hours, the mixture is worked up. The title compound is obtained: TLC: Rf =0.44 (methylene chloride/methanol: 9/1); HPLC20-100 : tRet =8.47; FAB MS (M+H)+ =534.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:20]1[CH:21]=[N:22][CH:23]=[C:18]([F:17])[CH:19]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: CC(N=[N+]=[N-])c1ccc2ccccc2c1Br
Reactant: OB(O)c1cncc(F)c1
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: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1ccc2ccccc2c1-c1cncc(F)c1
Temperature: 100 °C

Procedure:
To a mixture of 2(1-azidoethyl)-1-bromonaphthalene (0.080 g, 0.29 mmol) and (5-fluoropyridin-3-yl)boronic acid (49.0 mg, 0.348 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate in water (0.34 mL) and tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 0.0145 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and then concentrated. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the desired product. LCMS calculated for C17H14FN4(M+H)+: m/z=293.1; found: 293.0.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[N:9][C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:11][C:12]=2[NH2:14])[NH:7][N:6]=1)#[N:4].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C>[CH:21]1([N:7]2[C:8]3=[N:9][C:10]([C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[N:11][C:12]([NH2:14])=[C:13]3[C:5]([C:3]#[N:4])=[N:6]2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: BrC1CCCC1
Reactant: N#Cc1n[nH]c2nc(-c3ccncc3)nc(N)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1nn(C2CCCC2)c2nc(-c3ccncc3)nc(N)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.4 %

Procedure:
To a suspension of 97% NaH (0.64 g, 0.026 mol) in DMF (75 ml) was added 3-cyano-6-(4-pyridyl)-pyrazolo [3,4-d]pyrimidin-4amine (4.7 g, 0.02 mol). The reaction mixture was stirred at room temperature for 30 minutes then cyclopentyl bromide (3.1 g, 0.021 mol) in DMF (25 ml) was added dropwise. The reaction mixture was heated on a steam bath for 3 hours, cooled to room temperature and stirred for 24 hours. Inorganic salts were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica eluting with ethyl acetate (100%) followed by preparative thin layer chromatography on silica eluting with ethyl acetate/hexanes (75/25) to afford 0.45 g (7%) of 1-cyclopentyl-3-cyano-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine, m.p. 219°-221° C. when recrystallized from ether and dried for 16 hours at 90° C. in high vacuum.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].C([Li])CCC.CCCCCC.[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C>C1COCC1.O>[B:23]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([OH:28])[OH:24]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A stirred solution of 4-bromo-3-methylbenzoic acid (5.0 g, 0.02 mole) in dry THF (250 ml) at -78° C. under argon was treated with 1.6M n-butyllithium in hexane (36.3 ml, 0.05 mole). The mixture changed from a clear solution to an orange suspension. This was stirred at -78° C. for 0.25 h, then treated with triisopropyl borate (13.4 ml, 0.05 mole) and stirred at -78° C. for a further 1 h. The mixture was allowed to warm to room temp. and stirred for 19 h, then treated with water (25 ml) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10% methanol/dichloromethane to afford the title compound as a white solid (2.63 g, 67%).
Reaction SMILES: CC(OC)(C)C.O.[CH3:8][CH:9]([CH3:21])[C:10]([O:12][CH:13]([O:17][C:18]([CH3:20])=[S:19])[CH:14]([CH3:16])[CH3:15])=[O:11].FC(F)(F)[C@@H](C1C2C(C=C3C=1C=CC=C3)=CC=CC=2)O>C(O)CO>[CH3:8][CH:9]([CH3:21])[C:10]([O:12][C@@H:13]([O:17][C:18]([CH3:20])=[S:19])[CH:14]([CH3:15])[CH3:16])=[O:11]
Reactant: CC(=S)OC(OC(=O)C(C)C)C(C)C
Agent: O[C@H](c1c2ccccc2cc2ccccc12)C(F)(F)F
Solvent: O
Solvent: OCCO
Solvent: COC(C)(C)C
Product: CC(=S)O[C@H](OC(=O)C(C)C)C(C)C
Reaction time: 5 h
Yield: 70 %

Procedure:
A mixture of MTBE (990 mL) and water (10 mL) was stirred for 5 h until a clear solution was obtained. To this solution was added 2-methyl-1-methylthiocarbonyloxypropyl 2-methylpropanoate (2b) (50 g), prepared as described in Gallop et al., U.S. Pat. No. 7,227,028, and a non-covalent complex of porcine liver esterase (PLE), with methoxypolyethylene glycol (mPEG) (5 wt %, 75 g) prepared according to the method described by Heiss and Gais, Tetrahedron Lett., 1995, 36, 3833-3836; and Rupport and Gais, Tetrahedron Asymmetry, 1997, 8(21), 3657-3664. The resulting suspension was stirred at room temperature and the reaction periodically monitored by 1H-NMR using the chiral solvating agent (R)-(+)-2,2,2-trifluoro-1-(9-anthryl)ethanol. After ca. 48 h, 1H-NMR indicated that only one enantiomer remained in the reaction mixture at which time the reaction was quenched by filtration through a pad of CELITE®. The supernatant was washed with water, aqueous sodium bicarbonate (NaHCO3) then brine, and dried over anhydrous sodium sulfate (Na2SO4). After removing the solvent in vacuo, the title compound (12) was isolated as a single S-enantiomer (as determined by HPLC using a chiral column) in 70% yield. The absolute configuration was established by: (i) conversion to compound (20b) (see Step B); (ii) reaction of (20b) with R-baclofen to afford 4-{[(1S)-isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoic acid; and (iii) correlation with the product formed in Example 18 of Gallop et al., U.S. Pat. No. 7,227,028. 1H NMR (CDCl3, 400 MHz): δ 0.96 (d, J=6.8 Hz, 6H), 1.16 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.98-2.07 (m, 1H), 2.32 (s, 3H), 2.56 (hept, J=7.2 Hz, 1H), 6.67 (d, J=5.6 Hz, 1H). 1H NMR with chiral solvating agent, (R)-(−)-2,2,2-trifluoro-1-(9-anthryl)ethanol: δ 0.98 (d, J=6.8Hz, 3H), 0.99 (d, J=6.8 Hz, 3H), 1.19 (d, J=7.2 Hz, 1.5H), 1.19 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=6.8 Hz, 1.5H), 1.20 (d, J=7.2 Hz, 1.5H), 2.01-2.09 (m, 1H), 2.34 (s, 1.5H), 2.444 (s, 1.5H), 2.591 (hept, J=7.2 Hz, 0.5H), 2.59 (hept, J=6.8 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H), 6.70 (d, J=5.2 Hz, 0.5H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[N:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.Cl>O1CCCC1.O>[N:9]1([C:15]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)N1CCOCC1)C(=O)O
Temperature: 0 °C
Yield: 39.6 %

Procedure:
4 g(50 mmol) of L-alanine and 2 g(50 mmol) of NaOH were added to 30 ml of distilled water. The mixture was cooled to 0° C. and then stirred vigorously. To the mixture was added slowly a solution of 7.1 g(50 mmol) of morpholinecarbonyl-chloride in 30 ml of tetrahydrofuran, while adjusting the whole mixture to pH 8.5-pH 9.5 with the addition of 0.05N NaOH. After the reaction was completed, the reaction mixture was acidified to pH 2 with 6N HCl. The reaction mixture was extracted with a mixed solvent of ethyl acetate and THF(1:1) (30 ml×3) and the organic layer was concentrated under a reduced pressure to give 4 g of the title compound(yield: 40%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH3:21])[CH2:14]3)[CH:11]=2)[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2].[CH2:27]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:22])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:27])[CH:15]([CH2:19][O:20][CH3:21])[CH2:14]3)[CH:11]=2)[C:6](=[O:23])[C:5]([C:24]([OH:26])=[O:25])=[CH:4]1)[CH3:2]
Reactant: C=O
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC)C3)cc21
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(COC)C3)cc21

Procedure:
A 200 mg portion of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-(methoxymethyl)-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid was dissolved in a mixture of 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid, heated on a steam bath for 3 hours and then concentrated in vacuo. The residue was dissolved in 5 ml of water and 1N sodium hydroxide was added to pH 7. The resulting solid was collected, washed with water and dried, giving 180 mg of the desired product, mp 228°-230° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:33])([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[CH:17][C:16]=1[Cl:32])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)Br.[P:39]([O:44]C)([O:42][CH3:43])[O:40][CH3:41].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:33])([CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=2)=[CH:17][C:16]=1[Cl:32])[CH2:10][O:11][P:39]([O:42][CH3:43])([O:40][CH3:41])=[O:44])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COP(OC)OC
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Agent: BrC(Br)(Br)Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: COP(=O)(OC)OC[C@@](C)(CCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl)NC(=O)OC(C)(C)C

Procedure:
To a solution of the compound of Example 16 (456 mg) in pyridine (5 mL) was added under ice cooling carbon tetrabromide (620 mg) and trimethyl phosphite (219 μL), and the resultant solution was then stirred at 0° C. for 1 hour. To the reaction solution was added 10% aqueous citric acid, extracted with ethyl acetate, washed with water and saturated brine in that order, and then dried over anhydrous sodium sulfate. The solvent was evaporated, and the resultant residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain the target product (533 mg) as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][N:65]([C:18](=[O:20])[CH2:17][NH:16][C:14](=[O:15])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:12]=2)[CH2:64][CH2:63]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1ccc(Nc2ccccc2)nc1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a stirred solution of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid (0.035 g, 0.00013 mol) in DMF (1 mL) was added DIPEA (0.05 g, 0.00039 mol), HOBt (0.0209 g, 0.00015 mol) and EDCI.HCl (0.029 g, 0.00015 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.0382 g, 0.00015 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.051 g (85%) of N-{2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-6-phenylamino-nicotinamide. LCMS: 464.18 (M+1)+, 98.3%, 1H NMR (DMSO-d6): δ 9.4 (s, 1H), 8.7 (d, 1H), 8.4 (t, 1H), 8.0 (d, 1H), 7.7 (d, 2H), 7.3 (m, 3H), 7.15 (t, 1H), 7.0 (t, 1H), 6.85 (d, 2H), 6.4 (t, 1H), 4.9 (d, 1H), 4.35 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.6 (s, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (t, 2H), 1.5 (m, 1H), 1.4 (m, 1H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[N+:8]([CH2:11][CH2:12][CH3:13])([O-:10])=[O:9].Cl>C(#N)C.O>[CH3:4][CH:3]([CH:11]([N+:8]([O-:10])=[O:9])[CH2:12][CH3:13])[CH2:2][C:1]([O:6][CH3:7])=[O:5]
Reactant: C/C=C/C(=O)OC
Reactant: CCC[N+](=O)[O-]
Agent: Cl
Solvent: CC#N
Solvent: O
Product: CCC(C(C)CC(=O)OC)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.7 %

Procedure:
A solution of 4 g (40 mmol) of methyl crotonate and 4.72 g (53 mmol) of 1-nitropropane in 20 mL of acetonitrile was treated with 6 mL (40 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene (DBU). After stirring for 22 h at room temperature the reaction mixture was diluted with water and acidified with 2N HCl. The solution was extracted with Et2O and the Et2O layer was washed with brine, dried and concentrated. The residue was chromagraphed on a flash column using 10% Et2O-Hexane to isolate 6.41 g (85%) of the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.O[NH:9][C:10](=[NH:21])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[CH3:6][C:5]1[O:7][N:21]=[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(=N)NO)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nc(-c2ccc(C)c([N+](=O)[O-])c2)no1
Temperature: 25 °C
Yield: 76 %

Procedure:
Acetic anhydride (25 mL, 260 mmol) was added to a solution of compound 1a (11.5 g, 58.8 mmol) in a mixture of pyridine (50 mL, 620 mmol) and toluene (200 mL). The reaction mixture was refluxed for 22 h. After cooling to rt, a solution of concentrated HCl (75 mL) in water (200 mL) was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, and concentrated in vacuo. The residue was recrystallized from absolute ethanol to afford compound 1b as tan needles (9.8 g, 76%). ESI-MS m/e 220.2 (M+1).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)=[N:5]2.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])=[CH:13][CH:12]=1)=[N:5]2
Reactant: Nc1ccc(Oc2ccc3nccn3n2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2ccc3nccn3n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of 4-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (181 mg, 0.80 mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran (10 mL) was added phenyl isocyanate (0.104 mL, 0.96 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and precipitated from ethyl acetate to give the title compound (223 mg, 81%) as a white powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[CH2:6][S:7][C:8]2[CH:14]=[CH:13][CH:12]=[C:11](O)[C:9]=2[CH:10]=1)[CH2:2][CH3:3].CN(C)[CH:21]=[O:22].[CH3:24][OH:25]>>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:10][C:9]2[C:8](=[CH:14][CH:13]=[CH:12][C:11]=2[C:24]([O:22][CH3:21])=[O:25])[S:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CO
Reactant: CCCN(CCC)C1=Cc2c(O)cccc2SC1
Reactant: CN(C)C=O
Product: CCCN(CCC)C1CSc2cccc(C(=O)OC)c2C1

Procedure:
3-Dipropylamino-5-hydroxybenzothiopyran (EP 0222 996; 620 mg, 1.6 mmol) was dissolved in 11 mL of dimethyl-formamide/methanol (6:2) and the solution was degassed (10 mm, 22° C., 15 min). Pd(OAc)2 (11 mg), 1,3-bis-diphenyl-phosphinopropane (19 mg), and triethylamine (0.48 mL, 0.35 g) were added to the reaction mixture.