Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(OC)N(C)C.CC(=O)CC(=O)C.CN([CH:19]=[C:20]([C:24](=O)[CH3:25])[C:21](=[O:23])[CH3:22])C.C[O-].[Na+].[C:30]([CH2:32][C:33]([NH2:35])=[O:34])#[N:31]>C(O)(=O)C.O.CO>[C:21]([C:20]1[CH:19]=[C:32]([C:30]#[N:31])[C:33](=[O:34])[NH:35][C:24]=1[CH3:25])(=[O:23])[CH3:22]
Reactant: CC(=O)C(=CN(C)C)C(C)=O
Reactant: N#CCC(N)=O
Agent: COC(OC)N(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)CC(C)=O
Product: CC(=O)c1cc(C#N)c(=O)[nH]c1C

Procedure:
A solution containing 60 g of dimethylformamide dimethyl acetal and 50 g of 2,4-pentanedione was heated on a steam bath for 2.5 hours and cooled. To the resulting solution containing 3-dimethylaminomethylene-2,4-pentanedione was added 300 ml of methanol, 27 g of sodium methoxide and 47 g of cyanoacetamide. The resulting mixture was heated on a steam bath for 4 hours, the hot solution poured into 700 ml of water, and the aqueous mixture acidified with acetic acid and chilled in an ice bath. The solid that separated was collected, dried, and heated with 400 ml. of methanol. Insoluble material was filtered from the hot methanol mixture and the filtrate cooled. The product that separated was collected and dried at 90° C. to produce 24.6 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinonitrile, m.p. 227°-230° C. [Sunthankar et al., supra, m.p. 231° C.]
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([Cl:13])=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#N)[CH:7]=1.CC(C[AlH]CC(C)C)C.Cl.C1C[O:29]CC1>>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([Cl:13])=[C:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:29])[CH:7]=1
Reactant: C1CCOC1
Reactant: COc1cc(Cl)c(C(C)(C)C#N)cc1Br
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Product: COc1cc(Cl)c(C(C)(C)C=O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(5-bromo-2-chloro-4-methoxy-phenyl)-2-methyl-propionitrile (13 g, 0.045 mol) in dry THF (80 mL) was cooled to −10° C. under argon. DIBALH (1M in THF, 100 mL, 0.10 mol) was added keeping the temperature below 0° C. The mixture was stirred for 30 min/0° C. and then 2 h/25° C. The clear solution was carefully poured into icecold hydrochloric acid (2M, 100 mL). The THF was removed under reduced pressure. The aqueous phase was cooled and the crude product was filtered off and recrystallized from boiling MeOH. Yield: 7.8 g (59%). GCMS: >99%
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27](Cl)=[O:28]>>[F:22][C:23]([F:31])([F:30])[CH2:24][S:25][CH2:26][C:27]([NH:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:13][N:14]=[N:15][N:16]=3)[CH3:10])[CH2:7][S:8][C@H:3]12)=[O:28]
Reactant: O=C(Cl)CSCC(F)(F)F
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Product: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CSCC(F)(F)F)[C@H]2SC1

Procedure:
7-Amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was acylated with trifluoroethylmercaptoacetyl chloride by the procedure of Example 2. The title product was converted into its sodium salt by the procedure described above.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]([C:9]1[CH:18]=[C:17]2[C:13](=[C:14]([CH2:19][CH2:20][OH:21])[CH:15]=[CH:16]2)[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7].[OH-].[Na+].CN([CH:27]=[O:28])C>>[CH:6]([C:9]1[CH:18]=[C:17]2[C:13](=[C:14]([CH2:19][CH2:20][OH:21])[CH:15]=[C:16]2[CH:27]=[O:28])[CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)c1cccc2c(CCO)ccc-2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)c1cccc2c(CCO)cc(C=O)c-2c1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
A POCl3 (0.4 ml ) was added to DMF (5.0 ml ) at 0° C. and stirred for 10 min. To this mixture, 0.5 g of 7-Isopropyl-[3-(2-hydroxyethyl)]-azulene in DMF (2.5 ml) was added and stirred at 0° C. for 30 min. The mixture was poured into icewater and basified with 10% NaOH solution. The solution was extracted with ethyl acetate. The ethyl acetate extracts were washed with H2O and brine, dried (MgSO4), then concentrated to dryness. Purification of the residue by silica gel column chromatography (elution with ether) gave 0.556 g of the desired compound (98.1%)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[C:20]([Cl:23])([Cl:22])=[CH2:21]>C(Cl)Cl>[Cl:22][C:20]([Cl:23])=[CH:21][C:4]([C:3]1[C:2]([Cl:1])=[N:10][C:9]([Cl:11])=[CH:8][C:7]=1[C:12]([F:15])([F:14])[F:13])=[O:5]
Reactant: C=C(Cl)Cl
Reactant: O=C(Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of the 2,6-dichloro-4-(trifluoromethyl)nicotinoyl chloride from the previous reaction in CH2Cl2 (14 mL) was added slowly to a cooled (0° C.) and stirred slurry solution of AlCl3 (4.4 g, 33.0 mmol) in CH2Cl2 (14 mL). After 15 min, vinylidene chloride (2.6 mL, 33.0 mmol) was added to the mixture dropwise. The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was poured over ice and partitioned with CH2Cl2. The organic layer was collected and cooled to 0° C. before TEA (4.6 mL, 33 mmol)was added. After 15 min, the ice bath was removed and the reaction was allowed to warm to room temperature and stirred for an additional 30 min. The solution was washed with 1N HCl, NaHCO3, and water. The organic layer was passed through a pad of silica gel and concentrated in vacuo to afford 3,3-dichloro-1-[2,6-dichloro-4-(trifluoromethyl)-3-pyridinyl]-2-propen-1-one: (4.3 g, 95%) as a brown oil: LCMS RT: 3.59, MH+: 488.1, Rf=0.44 (EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][NH2:29])=[CH:24][CH:23]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:29][O:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:17][CH3:18])[CH:3]=1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOc1ccc(F)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 81 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (386 mg, 1.22 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (200 mg, 1.22 mmol) and anhydrous NaOAc (110 mg, 1.34 mmol) in EtOH (18 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). The residue was purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:4) to afford N-{4-chloro-2-[1-(4-fluorophenoxyimino)propyl]phenyl}trifluoromethanesulfonamide 130 (420 mg, 81%), as a pale yellow solid. M.p. 47-48° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.25, br s, 1H; 7.71, d, J=8.8 Hz, 1H; 7.58, d, J=2.4 Hz, 1H; 7.40, dd, J=2.4 and 8.8 Hz, 1H; 7.18-7.02, m, 4H; 3.02, q, J=7.6 Hz, 2H; 1.31, t, J=7.6 Hz, 3H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:15][C:16]([Br:18])=[O:17].[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[Br:18][C:16](=[O:17])[CH2:15][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: O=C(Br)CBr
Reactant: Clc1cccc(-c2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Br)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
A mixture of 5 g (0.026 mole) of 3-chlorobiphenyl, 50 ml of methylene chloride, 6.95 g (0.034 mole) of bromoacetyl bromide is cooled to 0-5° C. and 4 g (0.030 mole) of aluminum trichloride are added. The mixture is stirred for 1 hour at 5° C., then for 4 hours at room temperature. It is poured onto an ice/water mixture, extracted with methylene chloride, the organic phase is washed with a 1N solution of HCl, dried over sodium sulfate and evaporated under reduced pressure. 4.5 g of the title product is obtained. M.p. 63-65° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:16])[NH:9][CH:10]=[N:11]2.[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[CH3:1][N:2]([CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:16])[NH:9][CH:10]=[N:11]2)[C:17](=[O:19])[CH3:18]
Reactant: CNCCOc1cccc2nc[nH]c(=O)c12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(C)CCOc1cccc2nc[nH]c(=O)c12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
5-[2-(Methylamino)ethoxy]quinazolin-4(3H)-one (823 mg, 3.76 mmol) was dissolved in pyridine (25 ml), and the solution cooled to 0° C. Acetic anhydride (1.20 ml, 12.70 mmol) was added drop wise; the solution was warmed to ambient temperature and stirred for 90 minutes. The mixture was concentrated in vacuo, and the residue purified by chromatography, eluting with 4% to 7% (10:1 methanol/conc. NH3(aq)) in DCM. Evaporation of the appropriate fractions gave N-methyl-N-{2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]ethyl}acetamide as a white foam (970 mg, 99%); NMR Spectrum (DMSO-d6, 400 MHz, 373K) 2.05 (bs, 3H), 2.92 (s, 3H), 3.71 (bt, 2H), 4.20 (bt, 2H), 7.01 (d, 1H), 7.19 (d, 1H), 7.63 (dd, 1H), 7.89 (s, 1H); Mass spectrum M+NH4+284.0 (ES−) M−H+ 260.0.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.Cl[C:26]([O:28][CH2:29][CH2:30][Cl:31])=[O:27]>O>[CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][C:26](=[O:27])[O:28][CH2:29][CH2:30][Cl:31]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NC(=O)OCCCl
Temperature: 90 °C

Procedure:
0.6 mol (100 g) of 2-methyl-4-amino-5-nitroaniline and 0.36 mol (50 g) of potassium carbonate are introduced into 500 ml of dioxane to which 145 ml of water have been added. The mixture is heated to 90° C., whilst stirring, and 0.6 mol (86 g) of chloroethyl chloroformate is then added gradually in the course of 10 minutes. When the addition has ended, the heating is maintained for 10 minutes at 90° C., the reaction medium is cooled to 15° C. and the expected product is then filtered off. After washing with a small amount of dioxane and then with water and alcohol, the product is recrystallised from dioxane and then dried in vacuo. It melts at 192° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]3[CH:13]=[C:12]2[C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ncccn3)cc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncccn1)n2Cc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
To a solution of the compound obtained in Example 6 (3) (3.0 mg) in N,N-dimethylformamide (0.5 ml), 60% sodium hydride (0.7 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 15 minutes. 4-Fluorobenzyl bromide (3.1 mg) was then added thereto at 0° C. and the mixture was stirred at 15 to 30° C. for 1 hour. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with toluene. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (methanol:chloroform=1:20) to obtain 2.4 mg of the desired product as a white crystal.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Br:11][C:12]1[N:17]=[C:16]([CH:18]([OH:20])[CH3:19])[CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[Br:11][C:12]1[N:17]=[C:16]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)c1cccc(Br)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)c1cccc(Br)n1
Temperature: -60 °C
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (2.1 mL, 3.81 mmol) in dry CH2Cl2 was cooled to −70° C. followed by adding DMSO (0.6 mL, 8.39 mmol) dropwise. After stirred for 5 min under −60° C., 1-(6-bromo-pyridin-2-yl)-ethanol (770 mg, 3.81 mmol) in dry CH2CL2 (10 mL) was added dropwise. After stirred for 30 min, TEA (2.7 mL, 19.83 mmol) was added and the resulting mixture was warmed to RT and stirred for 1 h. The reaction mixture was quenched with H2O. The organic layer was washed with H2O, brine, and dried over MgSO4. Solvent was removed and the crude compound was purified by chromatography on silica gel. Elution with hexane:acetone mixture (90:10) gave a white solid. MS m/z: 200.3(M+H). Calc'd. for C7H8BrNO-198.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]1[C:21]([NH2:22])=[N:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[CH3:23][N:24]1[CH:28]=[C:27]([S:29](Cl)(=[O:31])=[O:30])[N:26]=[CH:25]1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[NH:11][C:12]1[C:21]([NH:22][S:29]([C:27]2[N:26]=[CH:25][N:24]([CH3:23])[CH:28]=2)(=[O:31])=[O:30])=[N:20][C:19]2[C:14]([N:13]=1)=[CH:15][CH:16]=[CH:17][CH:18]=2
Reactant: COc1ccc(OC)c(Nc2nc3ccccc3nc2N)c1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: COc1ccc(OC)c(Nc2nc3ccccc3nc2NS(=O)(=O)c2cn(C)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine (50 mg, 0.17 mmol), 1-methylimidazole-4-sulfonylchloride (91.4 mg, 0.51 mmol, commercially available from Acros) are dissolved in pyridine (0.3 ml) and the reaction mixture was stirred at rt, overnight. When TLC confirms the total consumption of N-(2,5-dimethoxyphenyl)quinoxaline-2,3-diamine, the product is extracted with CHCl3. The organic layer is washed with water, 1.5N HCl and brine then dried over Na2SO4. The solvent is removed under reduced pressure and the residue obtained is purified by recrystallization from MeOH to afford 47 mg (64%) of the title compound as a yellow solid. HPLC (max plot) 95%, rt. 3.91 min. LC/MS: (ES+): 441.2.
Reaction SMILES: [OH:1][C@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[K].[CH2:37]([O:39][C:40]([O:42][NH:43][C:44](=[O:48])[O:45][CH2:46][CH3:47])=[O:41])[CH3:38]>CN(C)C=O>[CH2:46]([O:45][C:44]([N:43]([CH2:12][C@@H:2]([OH:1])[CH2:3][P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[O:42][C:40]([O:39][CH2:37][CH3:38])=[O:41])=[O:48])[CH3:47]
Reactant: CCOC(=O)NOC(=O)OCC
Reactant: CCOP(=O)(C[C@H](O)COS(=O)(=O)c1ccc(C)cc1)OCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)ON(C[C@@H](O)CP(=O)(OCC)OCC)C(=O)OCC
Temperature: 70 °C
Reaction time: 10 h
Yield: 95.3 %

Procedure:
Diethyl 2(R)-hydroxy-3-tosyloxypropylphosphonate (7.3 g) was dissolved in N,N-dimethylformamide (100 ml). To the solution was added bis(trimethylsilyl)acetamide (12.2 g) under ice-cooling. After the mixture was stirred for 30 minutes at the same temperature, potassium salt of ethyl N-ethoxycarbonyloxycarbamate (5.16 g) was added thereto. The reaction mixture was stirred for 10 hours at 70° C. To this reaction mixture was added potassium salt of ethyl N-ethoxycarbonyloxycarbamate (0.86 g) and then the reaction mixture was further stirred for 2 hours at 70° C. After the resultant mixture was concentrated under reduced pressure, to the oily residue was added a mixture of ethyl acetate (200 ml) and 2% hydrochloric acid (100 ml). The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2(R)-hydroxypropylphosphonate (7.05 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[NH:11][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)C(Cc2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CC2CN(Cc3ccccc3)CCN2)cc1
Reaction time: 19 h
Yield: 103 %

Procedure:
To a 0° C. suspension of dione 6 (1.38 g, 4.7 mmol) in dry THF (120 mL) was added LiAlH4 (0.713 g, 18.8 mmol) in two portions. The mixture was maintained on ice for 15 min, then the reaction was heated at reflux for 2.5 h. The solution was cooled and stirred for an additional 19 h then the excess LiAlH4 was quenched by the careful, sequential addition of 0.7 mL water, 1.3 mL 4 M NaOH and 0.7 mL water. The solids that formed will filtered (Celite) and the filtrate concentrated to provide 7 as a pale colored solid (1.29 g, 103%, with THF) that slowly formed from an oil. 1H NMR (400 MHz, CDCl3): δ 1.93 (m, triplet shape, 1H), 2.11 (td, J=2.9, 11.0 Hz, 1H, overlapped with bs, NH, 1H), 2.58 (dd, 8.8, 13.2 Hz, 1H), 2.70-2.77 (m, 2H), 2.79-2.87 (m, 2H), 2.92 (dt, J=2.3, 11.7 Hz, 1H), 3.02 (m, 1H), 3.51 (dd, AB pattern, J=12.8 Hz, 2H), 7.18-7.33 (m, 10H); 13C NMR (100 MHz, CDCl3): δ 40.7, 45.6, 53.3, 56.2, 59.6, 63.3, 126.3, 127.0, 128.1, 128.4, 129.2, 137.9, 138.5. HRMS Calcd. for [C18H22N2+H+]: 267.1861. Found 267.1869.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].Cl[CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][C@H:24]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:23]2>CN(C=O)C>[F:7][C:8]([F:16])([F:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][C@H:24]([NH:29][S:30]([CH:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH2:23]2
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(CCl)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(COc3ccccc3C(F)(F)F)cc2C1
Temperature: 120 °C
Yield: 27.8 %

Procedure:
A mixture of potassium carbonate (0.174 mmol, 24.01 mg), 2-(trifluoromethyl)phenol (0.087 mmol, 14.08 mg), and (S)-N-(5-(chloromethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (0.087 mmol, 25 mg) in DMF (2 mL) was heated at 120° C. for 900 s in a Smith Synthesiser microwave. The reaction mixture was concentrated to dryness before DCM (2 mL) and H2O (2 mL) was added and the reaction mixture filtered through a hydrophobic frit washing with further DCM (2 mL). The DCM layer was concentrated to dryness and purified by preparative HPLC to furnish the desired product (10.0 mg, 27.8%). MS (ESI): m/z [M−H]− 412.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][CH3:16])=[C:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O.[OH-].[Li+].C1COCC1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([CH2:15][CH3:16])=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Nc2ccc(CC(=O)OC)cc2)cc(-c2cccc(Cl)c2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1c(Nc2ccc(CC(=O)O)cc2)cc(-c2cccc(Cl)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
An 18-mL vial was charged with methyl 2-[4-[[6-(3-chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetate (8 mg, 0.02 mmol, 1 eq.) and lithium hydroxide monohydrate (13 mg, 0.31 mmol, 15 eq.). To this was added THF (1 ml) and water (0.4 ml). The resulting mixture was stirred at room temperature overnight. Then 2N HCl aq. (0.12 ml) was added. The volatile materials were removed under reduced pressure to give a residue, which was purified by chromatography on silica gel using 2˜4% of MeOH in dichloromethane as eluent to give 2-[4-[[6-(3-Chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetic acid (7 mg, 91% yield). MW=380.87. 1H NMR (Methanol-D4, 360 MHz) δ 7.69 (s, 1H), 7.48-7.58 (m, 3H), 7.44 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz, 2H), 6.89 (s, 1H), 3.67 (s, 2H), 2.85 (q, J=7.5 Hz, 2H), 2.66 (s, 3H), 1.24 (t, J=7.5 Hz, 3H).
Reaction SMILES: CC1N=C(C2C=CC([CH:13]3[O:19][CH2:18][CH2:17][N:16]([C:20]4[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]5[CH:33]=[CH:32][N:31]=[CH:30][N:29]=5)[N:21]=4)[CH2:15][CH2:14]3)=CC=2)ON=1.Cl.[O:35]1[CH:39]=[N:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](C3COCCNC3)=[CH:42][CH:41]=2)=[N:36]1>>[CH3:26][N:25]1[C:24](=[O:27])[CH:23]=[C:22]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)[N:21]=[C:20]1[N:16]1[CH2:15][CH:14]([C:43]2[CH:42]=[CH:41][C:40]([C:37]3[N:38]=[CH:39][O:35][N:36]=3)=[CH:45][CH:44]=2)[CH2:13][O:19][CH2:18][CH2:17]1
Reactant: c1nc(-c2ccc(C3CNCCOC3)cc2)no1
Reactant: Cc1noc(-c2ccc(C3CCN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)n1
Agent: Cl
Product: Cn1c(N2CCOCC(c3ccc(-c4ncon4)cc3)C2)nc(-c2ccncn2)cc1=O

Procedure:
1-Methyl-2-[6-(4-[1,2,4]oxadiazol-3-yl-phenyl)-[1,4]oxazepan-4-yl]-1H-[4,4′]bipyrimidinyl-6-one was prepared the same procedure as that of 2-{7-[4-(3-methyl-[1,2,4]-oxadiazole-5-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one except for utilizing 6-(4-[1,2,4]oxadiazol-3-yl-phenyl)-[1,4]oxazepane hydrochloride instead of 7-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-[1,4]oxazepane hydrochloride. 1-Methyl-2-[6-(4-[1,2,4]oxadiazol-3-yl-phenyl)-[1,4]oxazepan-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (A086) was obtained as white solid (0.05 g, 0.12 mmol, 59%).
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7](=[O:18])[C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([Cl:16])=[CH:10][C:9]=1[Cl:17])([CH3:5])[CH3:4].S(Cl)(Cl)=O>CCOCC>[Cl:17][C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[C:7]1[O:18][CH2:2][C:3]([CH3:4])([CH3:5])[N:6]=1
Reactant: COc1cc(Cl)cc(Cl)c1C(=O)NC(C)(C)CO
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COc1cc(Cl)cc(Cl)c1C1=NC(C)(C)CO1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
N-(2-Hydroxy-1,1-dimethylethyl)-2,4-dichloro-6-methoxybenzamide (5.5 g, 18.8 mmol) was treated dropwise with thionyl chloride (5.5 ml) and stirred magnetically at 20° C. for 30 min. Dry ether (100 ml) was added, the mixture was stirred for an additional one hour and the oxazoline hydrochloride precipitate was collected by filtration. The salt was neutralized with 20% sodium hydroxide to afford an alkaline mixture which was extracted with ether. The ethereal extract was dried (MgSO4) and concentrated to give an oil (3.6 g, 70%), which crystallized on standing, mp 47°-50° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](O)(=[O:27])[CH2:25][CH3:26]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:24](=[O:27])[CH2:25][CH3:26])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCC(=O)O
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CC)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and propionic acid as a pale-yellow solid (23%). MS 374 (MH+).