Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15]C(C)C)=[CH:9][C:8]=2[C:19](=[O:21])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH:1]1([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([OH:15])=[CH:9][C:8]=2[C:19](=[O:21])[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C2CCCCC2)c(C(C)=O)cc1OC(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(C2CCCCC2)c(C(C)=O)cc1O
Temperature: 18 °C
Reaction time: 2.5 h
Yield: 72.6 %

Procedure:
A solution of ketone 52 (50 mg, 0.172 mmol) in dry CH2Cl2 (1.5 mL) was treated with AlCl3 (0.069 mg, 0.517 mmol) and the resulting mixture stirred magnetically at 18° C. under a nitrogen atmosphere for 2.5 h then partitioned between H2O (10 mL) and CH2Cl2 (10 mL). The separated aqueous phase was extracted with CH2Cl2 (1×10 mL) and the combined organic fractions dried (MgSO4), filtered and concentrated, under reduced pressure, onto TLC-grade silica (ca. 80 mg). The resulting free-flowing solid was subjected to flash chromatography (1:19→15:85 v/v ethyl acetate/hexane gradient elution) to afford the title compound 53 (31 mg, 72%) as a colourless oil, Rf 0.6 in 1:1 v/v ethyl acetate/hexane.
Reaction SMILES: C1C2C(=CC=CC=2)C=[N:3][N:2]=1.[Br:11][C:12]1[CH:13]=[C:14]2[C:19](=O)[O:18][C:16](=[O:17])[C:15]2=[CH:21][CH:22]=1.NN>C(O)(C)C>[Br:11][C:12]1[CH:13]=[C:14]2[C:15](=[CH:21][CH:22]=1)[C:16]([OH:17])=[N:3][N:2]=[C:19]2[OH:18]
Reactant: c1ccc2cnncc2c1
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: NN
Solvent: CC(C)O
Product: Oc1nnc(O)c2cc(Br)ccc12

Procedure:
The synthesis of phthalazine derivatives of general formulas 25-26 may be achieved as outlined in Scheme III. In general, a mixture of 4-bromophthalic anhydride and hydrazine may be refluxed in a suitable solvent, e.g., isopropyl alcohol, to provide 6-bromo-phthalazine-1,4-diol 21 in almost quantitative yield. Compound 21 may then be treated with phosphorus oxychloride to form 1,4-dichloro-6-bromo phthalazine 22. Treatment of compound 22 with a suitable nucleophile (where, for example, Y is NR1R2 or NaOR) affords two isomers of general formulas 23 and 24. Displacement of the bromine atom with a suitable amino or alcohol derivative A-B-X (where, for example, A is alkyl, aryl, arylalkyl, arylheteroalkyl, B is absent, CO, and X is OH, NH2), using a suitable Pd complex derivative in the presence of a base like sodium tert-butoxide in a suitable solvent, affords the desired 6-amino or 6-alkoxy phthalazine derivatives of general formula 25-26.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.C1(=O)O[CH2:17][CH2:16][O:15]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:17][CH2:16][OH:15]
Reactant: OCC(F)(F)F
Reactant: O=C1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Product: OCCOCC(F)(F)F
Yield: 61 %

Procedure:
2,2,2-Trifluoroethanol (10.0 g, 0.10 mol), triethylamine (10.1g, 0.10 mol), ethylene carbonate (13.2 g, 0.15 mol) and tetrabutyl ammonium iodide (0.74 g) were heated in a flask fitted with a reflux condenser under nitrogen in an oil bath at 100° C. for 1 day. The triethylamine and unreacted alcohol were removed by distillation. The product 2-(2,2,2-trifluoroethoxy)ethanol, b.p. 138° C., was obtained in 61% yield (8.6 g) of 97% pure material.
Reaction SMILES: [N:1]([C@H:4]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C@:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[F:15])([OH:7])[CH3:6])=[N+]=[N-].CP(C)C>O1CCCC1.CCOCC>[NH2:1][C@H:4]([C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[C@:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[F:15])([OH:7])[CH3:6]
Reactant: C[C@](O)(c1cc(F)ccc1F)[C@H](N=[N+]=[N-])c1cncc(Br)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@](O)(c1cc(F)ccc1F)[C@H](N)c1cncc(Br)c1
Reaction time: 18 h
Yield: 93.3 %

Procedure:
To a solution of (1R,2S)-1-azido-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol (44 mg, 0.119 mmol) in tetrahydrofuran (2 mL) at 0° C. was added trimethylphosphine (0.179 mL, 0.179 mmol) drop wise. Ice bath was removed once no more nitrogen gas come out. One hour later, water (0.1000 mL) was added and continuously stirred for 18 hours. The reaction mixture was concentrated to afford a yellow oil that was redissolved in 5 mL ether then washed with 10 mL water. The ether layer was dried by magnesium sulfate, filtered, and concentrated to provide a light yellow of (1R,2S)-1-amino-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)propan-2-ol (42.2 mg, 0.111 mmol, 93% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.36 (d, J=2.1 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.73 (t, J=2.0 Hz, 1H), 7.15 (ddd, J=11.1, 8.9, 4.7 Hz, 1H), 7.06-6.98 (m, 1H), 6.90 (ddd, J=9.9, 6.3, 3.4 Hz, 1H), 5.70 (s, 1H), 4.13 (s, 1H), 3.33 (s, 2H), 1.65 (d, J=1.5 Hz, 3H), Mass spec.: 345.1 (MH)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].[C:18]([C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH:26]([C:31](O)=[O:32])[CH2:25][CH2:24][C:23]=2[N:22]=1)(=[O:20])[CH3:19].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCCC1=O.C(N(CC)C(C)C)(C)C>CCOC(C)=O>[C:18]([C:21]1[CH:30]=[CH:29][C:28]2[CH2:27][CH:26]([C:31]([NH:2][C@@H:3]([C:5]3[CH:6]=[C:7]([CH3:17])[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:10]=3[F:11])[CH3:4])=[O:32])[CH2:25][CH2:24][C:23]=2[N:22]=1)(=[O:20])[CH3:19]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: CC(=O)c1ccc2c(n1)CCC(C(=O)O)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc2c(n1)CCC(C(=O)N[C@H](C)c1cc(C)c(NS(C)(=O)=O)cc1F)C2
Temperature: 60 °C
Yield: 91.7 %

Procedure:
To a mixture of N-[4-((R)-1-Aminoethyl)-5-fluoro-2-methylphenyl]methanesulfonamide hydrochloride (55.3 mg, 0.195 mmol), 2-acetyl-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (45 mg, 0.20 mmol) and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (110 mg, 0.29 mmol) in N-Methylpyrrolidinone (192 uL, 1.99 mmol), N,N-Diisopropylethylamine (0.10 mL, 0.59 mmol) was added and the reaction was heated at 60° C. 4 h. The crude was diluted with EtOAc and washed with 1N HCl, 1M NaHCO3 and brine. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford the title product (80 mg, 90%) as a brown oil that was used without further purification into the next step. m/z=448.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:23])C(=O)C1>>[Br:23][C:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:10]=[CH:11][C:12]=1[NH2:15]
Reactant: COc1ccc(-c2ccc(N)cc2)cn1
Reactant: O=C1CCC(=O)N1Br
Product: COc1ccc(-c2ccc(N)c(Br)c2)cn1

Procedure:
The title compound was prepared from 4-(6-methoxy-pyridin-3-yl)-phenylamine (as prepared in the previous step, 73 mg, 0.36 mmol) and NBS (65 mg, 0.36 mmol) according to the procedure in Example 16, step (b) (20 mg, 20%). Mass spectrum (ESI, m/z): Calcd. for Cl2H11BrN2O, 279.0 (M+H), found 279.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[S:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=1)(=[O:14])=[O:13].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cn1cc(S(=O)(=O)c2ccc(F)cc2)c2cc(Br)ccc21
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(S(=O)(=O)c2ccc(N3CCNCC3)cc2)c2cc(Br)ccc21
Temperature: 120 °C
Yield: 81.8 %

Procedure:
The 5-Bromo-3-(4-fluoro-benzenesulfonyl)-1-methyl-1H-indole (0.30 g, 0.85 mmol) was mixed with piperazine (0.34 g, 4 mmole) and methyl sulfoxide (3 mL). The mixture was heated at 120° C. in a sealed tube for 3 hours. The mixture was diluted with 10 mL water and the resultant precipitate was collected by filtration, washed with water, and recrystallized from chloroform/benzene to provide 5-Bromo-1-methyl-3-(4-piperazin-1yl-benzenesulfonyl)-1H-indole (0.302 g, 0.695 mmol), M+H 436.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[CH:6]=1.[H][H]>CCO.[Pd]>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([CH3:1])[CH:3]=[N:4]2)=[CH:8][C:9]=1[NH2:14]
Reactant: Cc1cnn(-c2ccc(C)c([N+](=O)[O-])c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cnn(-c2ccc(C)c(N)c2)c1
Reaction time: 20 h

Procedure:
4-Methyl-1-(4-methyl-3-nitro-phenyl)-1H-pyrazole from step 1 was dissolved in EtOH and hydrogenated at room temperature using a hydrogen balloon in the presence of 5% palladium on charcoal. After 20 hours, TLC (EtOAC/Hexanes 1:2) indicated complete reaction. The reaction mixture was filtered through celite and the filtrate was evaporated under reduced pressure to give 2-methyl-5-(4-methyl-pyrazol-1-yl)-phenylamine, MS (M+H)=188.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.ClC1C2OCCOC=2C(C(Cl)=O)=CC=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:12]([C:5]2[C:6]3[O:11][CH2:10][CH2:9][O:8][C:7]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:14])[CH2:36][CH2:35]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(Cl)c2c1OCCO2
Agent: O=C(Cl)c1ccc(Cl)c2c1OCCO2
Solvent: O=S(Cl)Cl
Product: CN1CCN(C(=O)c2ccc(Cl)c3c2OCCO3)CC1
Yield: 50.6 %

Procedure:
According to the method described in Example 33, 20 g of 8-chloro-1,4-benzodioxane-5-carboxylic acid were treated with thionyl chloride and the resulting 8-chloro-1,4-benzodioxane-5-carbonyl chloride (M.P.: 83° C.) was treated with 10.5 g of methylpiperazine. 14 g of 5-[(4-methyl-1-piperazinyl)-carbonyl]-8-chloro-1,4-benzodioxane were obtained (M.P.: 260° C. with decomposition; yield: 50.5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl.[O:18]([NH2:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][O:18][N:20]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CON
Reactant: O=C(Cc1ccccc1)c1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(Cc1ccccc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
1-(4-hydroxy-phenyl)-2-phenyl-ethanone (10.00 g, 47.12 mmol) was dissolved in pyridine (60 mL) and methoxylamine hydrochloride (5.90 g, 70.64 mmol) was added. The resulting reaction mixture was stirred at room temperature for 14 hours, and then concentrated. The solids were washed with ether, and the ether layers were combined and concentrated to afford the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 4.06 (s, 2 H) 6.73 (d, J=8.21 Hz, 1 H) 7.18 (dt, J=15.46, 7.66 Hz, 2 H) 7.38-7.44 (m, 1H) 7.50 (d, J=7.92 Hz, 1 H) 7.81 (s, 2 H) 8.55-8.64 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([O:10]CC)=[O:9])[N:6]=1.CO.[OH-].[Na+]>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: CCCCON=C(C(=O)OCC)c1csc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCON=C(C(=O)O)c1csc(N)n1
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
A solution of ethyl 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetate (syn isomer, 36 g.), methanol (133 ml.), tetrahydrofuran (133 ml.) and 2N aqueous solution of sodium hydroxide (133 ml.) was stirred at 30° C. for 5 hours. After the resultant solution was concentrated in vacuo, the residue was dissolved in water. The solution was adjusted to pH 7 with 10% hydrochloric acid and treated with activated charcoal. The solution was adjusted to pH 2.0 with 10% hydrochloric acid and stirred for 20 minutes under ice cooling. The precipitates were collected by filtration, washed with water and acetone in turn, and dried to give 2-(2-aminothiazol-4-yl)-2-n-butoxyiminoacetic acid (syn isomer, 25.4 g.).
Reaction SMILES: N(C1C=C(N2CCOCC2)N=C(OCCN2CCOCC2)N=1)N.C[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=O>C(O)(=O)C.C(O)C>[NH:30]1[C:31]2[C:27](=[CH:26][CH:25]=[CH:33][CH:32]=2)[CH2:28][C:29]1=[O:34]
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: NNc1cc(N2CCOCC2)nc(OCCN2CCOCC2)n1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1Cc2ccccc2N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Hydrazino-6-(morpholin-4-yl)-pyrimidin-2-yloxy)-ethyl]-morpholine (80 mg; ¼ mmol) was added to a flask along with 5-methylisatin (53 mg; ⅓ mmol) and ethanol (4 mL). One drop of acetic acid was added, and the reaction was stirred overnight at 60° C. The mixture was then filtered and the precipitate was washed with ethanol (1 mL) and dried to give 5-methyl-3-{[6-morpholin-4-yl-2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yl]-hydrazono)}-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14]C)=[O:13])=[CH:5][CH:4]=1.[OH-].[Na+].CO>C1COCC1>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COC(=O)CC(C)C(=O)c1ccc(SC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)C(C)CC(=O)O)cc1

Procedure:
The ester from Step B (1.07 g) was saponified with 1N NaOH (5 ml) and methanol (5 ml) and THF (5 ml) to provide after acidification, extraction into CH and evaporation to dryness the title compound, mp 69°-71° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([NH:31][CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]>C(#N)C.ClCCl>[CH2:28]([N:31]([CH2:2][C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[N:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)[CH2:32][CH2:33][CH3:34])[CH2:29][CH3:30]
Reactant: Cc1cc(C)c(Nc2nc3cccc(CBr)c3s2)c(C)c1
Reactant: CCCNCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CCCN(CCC)Cc1cccc2nc(Nc3c(C)cc(C)cc3C)sc12
Reaction time: 0.67 h
Yield: 59 %

Procedure:
To 0.045 g (0.12 mmol) of 7-(bromomethyl)-N-mesityl-1,3-benzothiazol-2-amine in 0.5 mL of acetonitrile and 2 mL of dichloromethane was added 0.086 g (0.62 mmol) of potassium carbonate and 85 μl, (0.62 mmol) of dipropylamine. The reaction was stirred for 40 min, diluted with dichloromethane and filtered. The filtrate was concentrated and purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 0.027 g (57%) of the title compound as a light yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[O:26]1[CH2:30][CH:29]=[N:28][C:27]1=[O:31]>>[C:7]([C:6]1[CH:9]=[C:2]([N:28]2[CH2:29][CH2:30][O:26][C:27]2=[O:31])[CH:3]=[CH:4][C:5]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11])#[N:8]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)c(C)c1
Reactant: O=C1N=CCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3C#N)CC2)c(C)c1
Yield: 80.7 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using 5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (399 mg) described in Preparation Example 193 and oxazolin-2-one (104 mg), the title compound (327 mg) was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>CCCCCC.[Cl-].[NH4+].O1CCCC1>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]([C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)Cc1ccco1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C(=O)C(C)C)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 327 %

Procedure:
To 60 mL of tetrahydrofuran and 9.3 mL (66 mmol) of diisopropylamine, 38 mL (60 mmol) of 1.57 M n-butyllithium in n-hexane was added dropwise under a nitrogen atmosphere under cooling with ice, and the reaction mixture was warmed to room temperature and stirred for 30 minutes. After the stirring, the reaction mixture was cooled to −78° C., and after dropwise addition of 4.62 g (30.0 mmol) of ethyl 2-(furan-2-yl)acetate, stirred at the same temperature for 1 hour. After the stirring, 3.8 mL (36 mmol) of isobutyryl chloride was added at −78° C., and the reaction mixture was gradually warmed and then stirred at room temperature for 15 hours. After completion of the reaction, the reaction mixture was diluted with saturated aqueous ammonium chloride under cooling with ice and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by intermediate pressure silica gel column chromatography (silica gel 30 g, ethyl acetate:hexane=1:10) to give 22 g of the desired product as an orange liquid.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][N+:11]([CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=2)=[O:16])=[CH:10][CH:9]=1)=[O:6])[CH3:3].[C:28]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:32])/[CH:29]=[CH:30]/[CH3:31]>[O-2].[Mn+2]>[CH2:2]([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][N:11]2[C:10]([CH:9]=1)=[C:29]([C:28]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C:30]([CH3:31])=[C:14]2[C:15](=[O:16])[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)Nc1cc[n+](CC(=O)c2ccc([N+](=O)[O-])c(OC)c2)cc1
Reactant: C/C=C/C(=O)OCc1ccccc1
Agent: [Mn+2]
Agent: [Br-]
Agent: [O-2]
Product: CCOC(=O)Nc1ccn2c(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)c(C)c(C(=O)OCc3ccccc3)c2c1
Yield: 26 %

Procedure:
This compound is prepared according to the same method as that described in Example 47 Step B from 1.8 g (4.1 mmol) of 4-[N-(ethoxycarbonyl)amino]-1-[2-(3-methoxy-4-nitrophenyl)-2-oxoethyl]pyridinium bromide with benzyl crotonate in the presence of manganese oxide as oxidizing agent. 573 mg of a yellow powder are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:13]([C:12]3[CH:15]=[CH:16][C:17]([OH:19])=[CH:18][C:11]=3[Cl:10])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=Cc1ccc(O)cc1Cl
Product: Oc1ccc(-c2nc3cc(Br)cnc3[nH]2)c(Cl)c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 2-chloro-4-hydroxybenzaldehyde.
Reaction SMILES: [F:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C@:13]2([CH2:18][CH2:17][NH:16][C@@H:15]([CH3:19])[CH2:14]2)[N:12]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)[C:11](=[O:27])[N:10]=1.F[C@H]1CCCC[C@@H]1NC1[C@]2(CCN[C@@H](C)C2)N([C:47]2[CH:52]=[CH:51][CH:50]=[C:49](F)C=2)C(=O)N=1.C([O-])([O-])=O.[K+].[K+].BrCC1CCC1>CN(C=O)C.O>[CH:50]1([CH2:49][N:16]2[CH2:17][CH2:18][C@@:13]3([N:12]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[C:11](=[O:27])[N:10]=[C:9]3[NH:8][C@@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]3[F:1])[CH2:14][C@@H:15]2[CH3:19])[CH2:51][CH2:52][CH2:47]1
Reactant: C[C@H]1C[C@]2(CCN1)C(N[C@H]1CCCC[C@@H]1F)=NC(=O)N2c1cccc(F)c1
Reactant: C[C@H]1C[C@]2(CCN1)C(N[C@@H]1CCCC[C@H]1F)=NC(=O)N2c1cccc(F)c1
Agent: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1C[C@]2(CCN1CC1CCC1)C(N[C@@H]1CCCC[C@H]1F)=NC(=O)N2c1cccc(F)c1
Temperature: 60 °C

Procedure:
To a solution containing 55 mg (0.15 mmol) of (5R,7S)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one and (5R,7S)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one in DMF (1.5 mL) was added powdered K2CO3 (81 mg, 0.58 mmol) and bromomethylcyclobutane (22 mg (0.15 mmol). The solution was heated to 60° C. overnight. The reaction was diluted with water (1.5 mL) and extracted three times with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated then chromatographed using 100% EtOAc to give the desired product which was further purified on a Waters automated system affixed with a Chiralpak AD 5 cm×50 cm cartridge eluting at 80 mL/min with isocratic 20% ethyl alcohol in hexanes with no modifier. The second peak was the product. The salt could be formed as described for the examples in Table 5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH:19]=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(Br)c1
Product: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)OCC
Temperature: 110 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromoaniline (10.0 g, 58.1 mmol) and diethyl(ethoxymethylidene)propanedioate (13.9 mL, 63.9 mmol) were heated to 110° C. for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The obtained solid was filtered and dried to afford 16.0 g 78% of diethyl {[(3-bromophenyl)amino]methylidene}propanedioate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]([CH3:17])=[N:10]1.[H-].[Na+].I[CH3:21].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:21])[C:12](=[O:16])[C:11]([CH3:17])=[N:10]1
Reactant: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)n(C)c1=O
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of 1.1 g (0.0040 mole) of 2-(2,4-dichlorophenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione in 5 mL of N,N-dimethylformamide was added to a stirred mixture of 0.11 g (0.0045 mole) of sodium hydride in 10 mL of N,N-dimethylformamide. After 0.5 hour, 0.63 g (0.0045 mole) of iodomethane in 5 mL of N,N-dimethylformamide was added, and the resultant mixture was stirred for approximately 18 hours. The mixture was poured into water and the resulting precipitate was collected and dissolved in ethyl acetate. The organic solution was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to leave a solid. The solid was purified by recrystallization from heptane to yield 0.52 g of 2-(2,4-dichlorophenyl)-4,6-dimethyl-1,2,4-triazine-3,5(2H,4H)-dione (mp 109°-110° C.), Compound 5 in the tables.