Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Br[C@H:3]1[C@H:9]([OH:10])[C:8]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:7]=2[O:6][CH2:5][CH2:4]1>CO>[O:10]1[CH:9]2[CH:3]1[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=12
Reactant: O=[N+]([O-])c1ccc2c(c1)[C@@H](O)[C@H](Br)CCO2
Agent: [Na]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C1OC1CCO2

Procedure:
2.65 g (0.115 mole) of metallic sodium are dissolved in 220 ml of methanol and, while stirring, a solution of 31.7 g (0.11 mole) of trans-4-bromo-5-hydroxy-7-nitro-2,3,4,5-tetrahydro-1-benzoxepin in 230 ml of methanol is added dropwise at room temperature. After 2.5 hours the precipitated solid is filtered off with suction and washed with methanol, and the filtrate is evaporated in vacuo. The residue is a solid of melting point 121°-123° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14](=[O:16])[CH3:15])=[N:4][CH:5]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:7]=1.[Br-:17].[Br-].[Br-].C([N+](CC)(CC)C1C=CC=CC=1)C.C([N+](C1C=CC=CC=1)(CC)CC)C.C([N+](C1C=CC=CC=1)(CC)CC)C>O1CCCC1>[Br:17][CH2:15][C:14]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1)=[O:16]
Reactant: [Br-]
Reactant: CC(=O)c1ncc(OCC(F)(F)F)cc1Cl
Agent: CC[N+](CC)(CC)c1ccccc1
Solvent: C1CCOC1
Product: O=C(CBr)c1ncc(OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 189.3 %

Procedure:
To 1.1 g of 1-[3-chloro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethanone in 20 ml of tetrahydrofuran, 1.6 g of triethylphenylammonium tribromide was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the precipitated solid was filtered off through celite, and the solvent was evaporated under reduced pressure to obtain 1.3 g of the desired crude product as a pale yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:12]2[C:7](=[N+:8]([O-])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.S(Cl)(C1C=CC(C)=CC=1)(=O)=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[O:1]=[C:2]1[C:12]2[CH:11]=[CH:10][C:9](=[O:19])[NH:8][C:7]=2[CH:6]=[CH:5][C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1c2ccccc2ccc2c1ccc[n+]2[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1ccc2c(=O)c3ccccc3ccc2[nH]1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 2.23 grams (0.01 mole) of 5-oxo-benzo[4,5]cyclohepta[1,2-b]pyridine N-oxide intermediate and 2.29 grams (0.012 mole) of tosyl chloride in 100 milliliters of chloroform was added a solution of 1.76 grams of potassium carbonate in 25 milliliters of water and the resulting mixture stirred vigorously for 4 days at room temperature. During this period the desired 5-oxo-benzo[4,5]cyclohepta[1,2-b]pyrid-2(1H)one product formed in the reaction mixture as a solid. The solid was recovered by filtration, was washed successively with 10 percent sodium hydroxide solution, water and hot methanol, and was dried. The dried product was a TLC homogeneous 5-oxo-benzo-[4,5]cyclohepta[1,2-b]pyrid-2(1H)one.0.25 methanol solvate, m.p. 320° C. The elemental analyses were as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl.[CH:8]([O:10][CH2:11][CH3:12])=[CH2:9]>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][CH2:8][O:10][CH2:11][CH3:12])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: C=COCC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOCCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.4 %

Procedure:
To a solution of 4-bromopyrazole (70.0 g, 0.476 mol) in CH2Cl2 (600 mL) was added a solution of 3.1 M HCl in dioxane (4 mL) and ethyl vinyl ether (41 g, 0.569 mol, 1.2 equiv) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 3 h. The reaction was quenched with aqueous NaHCO3 and the two layers were separated. The organic layer was washed with water, dried over Na2SO4, and concentrated under reduced pressure to dryness to afford 4-bromo-1-(ethoxyethyl)-1H-pyrazole (113 g, 104.3 g theoretical, 97% yield) as an oil (GC purity: 89%), which was directly used in the subsequent reaction without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:2]1.C(O)=O.[CH3:33][N:34]([C:36]([O:40]N1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:35].[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:35])[C:36]([N:1]1[CH2:2][CH:3]([N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:18]([CH:19]([C:21]5[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=5[Cl:29])[CH3:20])=[CH:17][NH:16][C:13]4=[N:14][CH:15]=3)[CH:7]=[N:6]2)[CH2:4]1)=[O:40]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CNC4)c3)cc12
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O=CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CN(C(=O)N(C)C)C4)c3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(1-azetidin-3-yl-1H-pyrazol-4-yl)-3-[1-(2,6-dichloro-3-fluorophenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine (6.0 mg, 0.014 mmol), formic acid (1.4 μL, 0.037 mmol), TBTU (8.95 mg, 0.0279 mmol), DIPEA (0.02 mL, 0.09 mmol) and DMF (1 mL) was stirred at rt for 30 min. The solution was used directly for HPLC purification. The fractions containing the material were concentrated in vacuo, redissolved in THF and treated with 5M NaOH (0.1 mL) at rt for 10 min. The solution was neutralized with HCl, and loaded into an SCX cartridge. MeOH was used to wash, and the material was ejected with 2M NH3 in MeOH to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=7.1 Hz, 3 H), 2.92 (s, 6 H), 4.33-4.40 (m, 2 H), 4.42-4.50 (m, 2 H), 5.16-5.25 (m, 1 H), 5.25-5.35 (m, 1 H), 7.15-7.22 (m, 1 H), 7.37 (d, J=1.5 Hz, 1 H), 7.38-7.53 (m, 2 H), 7.68 (s, 1 H), 7.94 (s, 1 H), 8.33 (s, 1H). MS (ES+): m/z 501.06 (100) [MH+]. HPLC: tR=3.35 min (ZQ3, polar—5 min).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC(S(O[CH2:31][CH2:32][Cl:33])(=O)=O)=CC=1>O>[Cl:33][CH2:32][CH2:31][O:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=[N+]([O-])c1cc(OCCCl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 3-nitro-5-(trifluoromethyl)phenol (2.10 g, 10.1 mmol) and cesium carbonate (4.00 g, 12.2 mmol) in acetonenitrile (50 ml) was added 2-chloroethyl p-toluenesulfonate (2.9 g, 12 mmol) slowly. The resulting mixture was stirred at RT for 5 hr, poured into water (100 ml) and then extracted with EtOAc (3×80 ml). The combined organic layer was washed with brine (100 ml) and dried over Na2SO4. Solvent was removed under vacuum and the residue was purified by flash column chromatography on the silica gel (hexane/EtOAc=5 to 25%) to afford the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1.[C:17]([NH2:20])(=[S:19])[CH3:18]>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:17]([CH3:18])[S:19][C:5]=1[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[CH:7]=1)=[O:16]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cc(C)cc(C)c1
Product: COC(=O)c1nc(C)sc1-c1cc(C)cc(C)c1

Procedure:
prepared by reaction of 3-Chloro-3-(3,5-dimethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.97 min; [M+H]+=262.3.
Reaction SMILES: Cl[C:2]1[N:3]([C:16]2[CH:21]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[C:19]([Cl:26])=[CH:18][C:17]=2[F:27])[C:4](=[O:15])[CH:5]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[N:7]=1.[Na]>C(O)CC>[Cl:26][C:19]1[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:21][C:16]([N:3]2[C:4](=[O:15])[CH:5]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[N:7]=[C:2]2[O:15][CH2:4][CH2:5][CH3:6])=[C:17]([F:27])[CH:18]=1
Reactant: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: [Na]
Solvent: CCCO
Product: CCCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 2-chloro-1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-pentafluoroethyl-6(1H)-pyrimidinone and sodium propylate in n-propanol there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4 -pentafluoroethyl-2-(n-propoxy)-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.31 ppm (d,1H), 6.82 ppm (d,1H), 6.63 ppm (s,1H), 4.46 ppm (m,1H), 4.36 ppm (m,2H), 1.66 ppm (m,2H), 1.38 ppm (d,3H), 1.37 ppm (d,3H), o.85 ppm (t,3H);
Reaction SMILES: CO[C:3]1([CH3:13])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4]1.CC1C=C2C(=CC=1)OC(OC)(C)CC2>>[CH:13]1[C:3](=[O:4])[CH2:12][CH2:11][CH:10]2[C:5]=1[CH:6]=[CH:7][CH2:8][CH2:9]2
Reactant: COC1(C)CCc2ccccc2O1
Agent: COC1(C)CCc2cc(C)ccc2O1
Product: O=C1C=C2C=CCCC2CC1

Procedure:
This material is prepared according to the procedure for Preparation 3 wherein 2-methoxy-2-methylchroman is substituted for 6-methyl-2-methoxy-2-methylchroman.
Reaction SMILES: [NH2:1][CH:2]1[C:35](=[O:36])[N:4]2[C:5]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:6]([C:9]3[C:12](=[O:13])[C:11](=[O:14])[C:10]=3[O:15][CH:16]([CH3:18])[CH3:17])[CH2:7][S:8][C@H:3]12.[NH2:37][C:38]1[S:39][CH:40]=[C:41](/[C:43](=[N:53]/[O:54][CH3:55])/[C:44](N2C(=S)N(C)N=N2)=[O:45])[N:42]=1>>[NH2:37][C:38]1[S:39][CH:40]=[C:41](/[C:43](=[N:53]/[O:54][CH3:55])/[C:44]([NH:1][CH:2]2[C:35](=[O:36])[N:4]3[C:5]([C:19]([O:21][CH:22]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])=[C:6]([C:9]4[C:12](=[O:13])[C:11](=[O:14])[C:10]=4[O:15][CH:16]([CH3:17])[CH3:18])[CH2:7][S:8][C@H:3]23)=[O:45])[N:42]=1
Reactant: CC(C)Oc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Reactant: CO/N=C(\C(=O)n1nnn(C)c1=S)c1csc(N)n1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OC(C)C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Yield: 95.3 %

Procedure:
Acylation of diphenylmethyl 7-amino-3-[3,4-dioxo-2-(2-propoxy)-1-cyclobutenyl]-3-cephem-4-carboxylate (287 mg, 0.569 mmol) with 1-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetyl]-4-methyltetrazole-5-thione (204 mg, 0.683 mmol), according to Example 13, afforded the title compound (373 mg, 93% yield) as a bright
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1.C(N(CC)CC)C.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18]>C(Cl)(=O)C=C.C(N(CC)CC)C.C1C=CC=CC=1.O1CCOCC1>[C:16]([O:1][CH2:2][CH:3]1[CH2:7][O:6][C:5](=[O:8])[O:4]1)(=[O:19])[CH:17]=[CH2:18]
Reactant: O=C1OCC(CO)O1
Reactant: C=CC(=O)Cl
Solvent: C1COCCO1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OCC1COC(=O)O1
Temperature: 0 °C

Procedure:
Following a similar preparation as described by D'Alelio and Huemmer (J. Poly. Sci., 5, 1967, pp. 307-321), to a two liter, three necked, round bottomed flask equipped with a paddle stirrer and thermometer, was added 87 g (0.74 mol.) of glycerol carbonate, followed by 1000 ml of benzene, 100 ml dioxane and 0.95 g of BHT. A drying tube and a nitrogen line were attached to the flask. Stirring was begun and the heterogeneous mixture was cooled to 0° C. with a brine bath. Two addition funnels were charged as follows: to the first was added 75 g (0.74 mol.) of triethylamine; to the second was added a solution of 100 ml of benzene and 60 g (0.66 mol.) of acryloyl chloride. Two drops of acryloyl chloride solution were added for every one drop of triethylamine. The addition took place over a period of two hours. The reaction contents were filtered through diatomaceous earth filtering media and the solution was washed with cold 5% HCl, followed by four 200 ml portions of water. 0.3 g of tert-butanol was added and the solution was dried over MgSO4. The solution was filtered to remove the drying agent and allowed to stand over a mixture of NaHCO3 and Na2SO4 for two days. The solution was filtered, transferred to a one liter, round bottomed flask and placed on a rotoevaporator. Without heat being applied, a vacuum of approximately 5 mmHg (667 Pa) was applied and the solvent was removed as completely as possible. 52 g (42%) of a light yellow liquid was recovered. 13C NMR identified the liquid to contain 86%, by weight, of the desired compound, the balance being benzene and dioxane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:15][C:16]([F:32])([F:31])[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([C:25]([C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([C:19]4[N:18]=[C:17]([C:16]([F:31])([F:15])[F:32])[O:21][N:20]=4)[CH:23]=3)=[O:26])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)c3cccc(-c4noc(C(F)(F)F)n4)c3)CC2)c1
Yield: 49 %

Procedure:
This compound was synthesized from 1-(3-methoxyphenyl)piperazine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (110 mg, yield 49%). 1H NMR (400 MHz, CDCl3) δ 8.22-8.20 (m, 2H), 7.67-7.60 (m, 2H), 7.23-7.19 (m, 1H), 6.57-6.54 (m, 1H), 6.49-6.48 (m, 2H), 3.98 (m, 2H), 3.80 (s, 3H), 3.61 (m, 2H), 3.30-3.16 (m, 4H). MS (ESI) m/z: Calculated for C21H18F3N4O3: 432.14. found: 433.2 (M+H)+
Reaction SMILES: [OH-].[K+:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O:34]CC)=[O:33].[K+].CN1C2C(=CC(NC(C3C(C4C=CC=CC=4)=CC=C(C(F)(F)F)C=3)=O)=CC=2)C=C1C([O-])=O>O.CC(O)C>[K+:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O-:34])=[O:33]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C
Agent: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3cc(C(F)(F)F)ccc3-c3ccccc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A solution of potassium hydroxide (54.1 g) in water (600 mL) was added over 15 minutes to a suspension of ethyl 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate (300 g), from the previous step, in propan-2-ol (4500 mL) at 60° C. and the resulting mixture was heated to reflux for an hour. The solution was seeded with product (1-methyl-5-[4-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt) and the mixture granulated at 60-70° C. for two hours. The mixture was slowly cooled to 0-5° C. and the product potassium salt collected by filtration, washing with a chilled 90/10 mixture of propan-2-ol and demineralized water (510 mL total volume). The product solids were dried, yielding 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt 2.6 hydrate (287.4 g, 85% correcting for water content of 9.1% by weight). Anhydrous Mol wt of parent acid (calc) 438.41, MS: 439.3 (MH+), 437.3 (M−). 1H NMR (DMSO-d6): δ 3.99 (s, 3H), 6.53 (s, 1H), 7.12-7.76 (complex, 11H), 10.05 (broad), HPLC retention time 9.30 minutes. The preferred solid form of the product is characterized by the pXRD (powder X-ray diffraction) pattern shown in FIG. 7.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]Cl)=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.C(OCC)C>[Br:1][C:2]1[C:11]([CH2:12][NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][CH3:18])=[C:10]2[C:5]([NH:6][C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[N:9]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CCl)c21
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1NCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
7-Bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 2, 1.82 g, 5.73 mmol), 2-methoxyaniline (728 μL, 6.46 mmol), and potassium carbonate (1.19 g, 8.61 mmol) were suspended in anhydrous N,N-dimethylformamide (30 mL) and the mixture was stirred at 80° C. overnight. After cooling down, ethyl acetate (100 mL) and diethylether (100 mL) were added. The organic layer was washed with water (200 mL, 100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.45 g) as a pale yellow amorphous product. (Yield 63%)
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:11])[N:7]=2)[C:3]=1[CH:12]1[CH2:14][CH:13]1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[CH3:11][N:6]1[CH:5]=[C:4]2[C:8]([CH:9]=[CH:10][C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:3]2[CH:12]2[CH2:14][CH:13]2[CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[N:7]1
Reactant: CC(=O)NCC1CC1c1c(Br)ccc2nn(C)cc12
Reactant: OB(O)c1ccccc1
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)NCC1CC1c1c(-c2ccccc2)ccc2nn(C)cc12
Temperature: 80 °C
Yield: 99.9 %

Procedure:
N-{[2-(5-Bromo-2-methyl-2H-indazol-4-yl)cyclopropyl]methyl}acetamide (100 mg, 0.310 mmol) obtained in Example 29, phenylboronic acid (94.6 mg, 0.776 mmol), 2 M aqueous sodium carbonate solution (3 mL) and tetrakis(triphenylphosphine)palladium(0) (35.8 mg, 0.031 mmol) were added to a mixed solution of ethanol (1.5 mL) and toluene (1.5 mL), and the mixture was stirred under nitrogen atmosphere with heating at 80° C. for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (98.9 mg, yield 99%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27].[CH3:37][N:38]([CH3:45])[CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16]([N:42]3[CH2:43][CH2:44][CH:39]([N:38]([CH3:45])[CH3:37])[CH2:40][CH2:41]3)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:27]
Reactant: CN(C)C1CCNCC1
Reactant: Cc1ccccc1-c1cc(Cl)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Product: Cc1ccccc1-c1cc(N2CCC(N(C)C)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCO2
Yield: 41.4 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (47.6 mg) was reacted with 4-(dimethylamino)piperidine (28.8 mg) to obtain 5-[3,5-bis(trifluoromethyl)benzyl]-9-[4-(dimethylamino)piperidine-1-yl]-7-(2-methylphenyl)-6-oxo-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (23.1 mg, 41%).
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:25][C:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)([CH3:26])[C:27]([N:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C(C)(C)C(=O)O)c3)cnc21
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)N1CCOCC1)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.3 %

Procedure:
To a suspension 6-[5-(1-carboxy-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.13 mmol) in DMF (1 mL) is added HATU (57 mg, 0.15 mmol), morpholine (11 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.81 mmol). The mixture is stirred at room temperature for 16 h. The reaction mixture is purified by reverse phase HPLC (mobile phase contains 1% TFA) to afford 53 mg of 2-methyl-1-morpholin-4-yl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-propan-1-one.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C:27](=[O:28])[CH2:26][N:25]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:24]4)=[CH:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CNCC4=O)cc3)CC2)c(C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CN(S(C)(=O)=O)CC4=O)cc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-4-one (48 mg) described in Example 635 and triethylamine (0.12 mL) was dissolved in tetrahydrofuran (1 mL), and methanesulfonyl chloride (15 μL) was added under ice-cooling. After stirring at room temperature for 8 hr, water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (34 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[F:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([N+:15]([O-:17])=[O:16])=[CH:5][C:3]=1[NH2:4]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(F)cc1F
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])c(F)cc1F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 2,4-difluoroaniline (0.394 mL, 3.87 mmol) in concentrated sulfuric acid (5 mL, 94 mmol) at 0° C. was added drop wise nitric acid (0.272 mL, 375 mg, 3.87 mmol) in 20 min. The reaction was stirred under 5° C. for 30 min. The reaction mixture was poured in ice cold water and extracted with ether. Organic layer was washed with saturated NaHCO3 solution, dried and evaporated to give 2,4-difluoro-5-nitroaniline 71 (467 mg, 69.3%). NMR (400 MHz, CDCl3) 3.91 (br s, 2H), 6.98 (t, J=10.2 Hz, 1H), 7.51 (dd, J=8.6 Hz and 7.0 Hz, 1H).