Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:14]=[C:13]([NH2:15])[NH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[N+:17]([CH:20]([CH:23]=O)[CH:21]=O)([O-:19])=[O:18].[Na].C(O)(=O)C>O>[CH2:1]([O:8][CH2:9][C:10]1[C:14]2[C:13](=[N:15][CH:21]=[C:20]([N+:17]([O-:19])=[O:18])[CH:23]=2)[NH:12][N:11]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC(C=O)[N+](=O)[O-]
Reactant: Nc1cc(COCc2ccccc2)n[nH]1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cnc2[nH]nc(COCc3ccccc3)c2c1
Temperature: 100 °C
Yield: 56 %

Procedure:
A round-bottom flask was charged with 3-(benzyloxymethyl)-1H-pyrazol-5-amine (1.74 g, 8.56 mmol, Honma, T. et al. “A Novel Approach for the Development of Selective Cdk4 Inhibitors: Library Design Based on Locations of Cdk4 Specific Amino Acid Residues.” J. Med. Chem. Vol. 44, No. 26 (2001): 4628-4640), sodium nitromalonaldehyde monohydrate (1.46 g, 9.42 mmol) and acetic acid (8.7 mL). The reaction mixture was heated at 100° C. for 24 hours. The reaction mixture was poured into water and then extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography to afford 3-(benzyloxymethyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (1.37 g, 56%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][N:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=2)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CNc1ccccn1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccn1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (75 mg, 0.18 mmol), methyl-pyridin-2-yl-amine (60 mg, 0.54 mmol), BOP (103 mg, 0.234 mmol), DIEA (193 μL, 1.08 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methyl-pyridin-2-yl-amide: MS m/z: (M+H) 505.1.
Reaction SMILES: S(=O)(O)[O-].[Na+].[N+:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])([O-:8])=[O:7].CCOCC.[C-:22]#[N:23].[K+]>O.C1COCC1>[N+:6]([C:9]1[CH:10]=[C:11]([CH:12]([OH:13])[C:22]#[N:23])[CH:14]=[CH:15][CH:16]=1)([O-:8])=[O:7]
Reactant: [C-]#N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: N#CC(O)c1cccc([N+](=O)[O-])c1
Temperature: 10 °C
Yield: 125.4 %

Procedure:
A mixture of a 10% solution of sodium bisulfite (24 g, 230 mmol) and 3-nitrobenzaldehyde (27 g, 178 mmol) was combined in a 1 L flask with 75 mL ether and 100 ml THF. The resulting reaction mixture was cooled in an ice-water bath to 10° C. and a solution of potassium cyanide (15 g, 130 mmol) in 75 mL water was added over a period of a half-hour while stirring. The reaction mixture was stirred at 15° C. for 1 hour. The organic layers were separated and the aqueous phase was extracted with ether (200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford (3-nitrophenyl)(hydroxy)acetonitrile as a yellow oil (29 g, 163 mmol), which was used without further purification in the next step.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:8])[CH2:6][CH3:7])=[O:3].N1C=CC=CC=1.[F:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22]>ClCCl.C(OCC)(=O)C>[F:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[O:22][C:2](=[O:3])[O:4][CH:5]([Cl:8])[CH2:6][CH3:7]
Reactant: CCC(Cl)OC(=O)Cl
Reactant: O[C@@H]1CCCC[C@H]1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(Cl)OC(=O)O[C@@H]1CCCC[C@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Chloropropyl chloroformate [CAS No. 92600-20-9] (2.99 g) and pyridine (1.62 mL) were dissolved in dichloromethane (30 mL), and a solution of trans-2-fluorocyclohexanol [CAS No. 14365-32-3] (2.36 g) in dichloromethane was added dropwise thereto under ice-cooling. After stirring the resulting mixture overnight at room temperature, the reaction mixture was diluted with ethyl acetate, and sequentially washed with 1 N hydrochloric acid, water, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (2.731 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Mg]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(Br)=CC=1)(C)(C)C.[Mg].[Cl:25][CH2:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])Cl.[Cl-].[NH4+]>C1COCC1.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([Si:29]([CH2:28][CH2:27][CH2:26][Cl:25])([CH3:32])[CH3:31])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: C[Si](C)(Cl)CCCCl
Agent: CC(C)(C)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc([Si](C)(C)CCCCl)cc1
Reaction time: 1 h

Procedure:
To a glass reactor fitted with a motor-driven stirrer, a thermometer, water-cooled reflux condenser and dropping funnel was charged 0.5 moles of 4-t-butylphenylmagnesium bromide in THF (prepared in the usual manner from 4-t-butylbromobenzene, magnesium chips and tetrahydrofuran). While maintaining an atmosphere of nitrogen in the reactor, 64.0 g of 3-chloro-n-propyldimethylchlorosilane (prepared in Step A above) was added dropwise to the reactor over a period of 25 minutes, keeping the temperature between 35°-40° C. After the addition was complete, the mixture was stirred for 1 hour while allowing the reation temperature to drop to ~30°. To this mixture was added 400 ml of a 5 percent aqueous ammonium chloride solution. The organic layer was separated and dried over magnesium sulfate. After evaporation of solvent, the residue, weighing 113.6 g, was distilled under vacuum. The fraction boiling at 110°-120° C. at 0.5 mm was collected. It weighed 93.2 g and was a colorless, oily liquid of refractive index 1.5088 at 23° C. Analysis showed the compound to contain 67.4 percent carbon, 9.2 percent hydrogen and 13.0 percent chlorine. Theory for the compound is 67.0 percent carbon, 9.4 percent hydrogen and 13.2 percent chlorine. Gas chromatography showed the compound to be ~90 percent pure.
Reaction SMILES: [CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]([NH:14][CH:15]=[O:16])[CH2:4]1)=[O:2].[N+:17]([O-])([O-:19])=[O:18].[Na+]>FC(F)(F)C(O)=O>[CH:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][C:11]=2[N+:17]([O-:19])=[O:18])[CH2:6][CH:5]([NH:14][CH:15]=[O:16])[CH2:4]1)=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=CNC1Cc2cc(Br)ccc2N(C=O)C1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=CNC1Cc2cc(Br)cc([N+](=O)[O-])c2N(C=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A mixture of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-3-quinolyl)formamide (12.8 g, 45.2 mmol) and sodium nitrate (12.8 g, 150 mmol) in trifluoracetic acid (100 mL) was stirred at room temperature for 18 hours. The bulk of the solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The ethyl acetate was washed with sodium hydroxide and water, and the ethyl acetate was removed to give 14.2 g of N-(1-formyl-6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolyl)formamide (compound XXVIII) as a solid. This was dissolved in ethanolic hydrogen chloride (100 mL of 4.0 N), the mixture was refluxed for 1 hour, ether (200 mL) was added, and the precipitate was filtered off, washed with ether and dried to give 12.8 g (82% of 6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolinamine dihydrochloride, mp >300° C.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[CH2:5].[F-].[Cs+].[F:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24]>CS(C)=O>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:5])[CH2:26][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])=[O:28])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: C=C(O[Si](C)(C)C)c1ccc(Cl)cc1
Reactant: O=C(C=Cc1ccc(F)c(F)c1)c1ccccc1O
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(4-chlorophenyl)ethylene (7.0 mmol; prepared according to J. Chem. Soc., Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-5-(4-chlorophenyl)-1,5-pentanedione on Wang resin.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]/[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][N:20]=1)=[O:9])=O)C.C(=O)([O-])O.[Na+]>CCCCCC.C(OCC)(=O)C>[NH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19](/[CH:18]=[CH:17]/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]2[C:4](=[O:3])[CH2:5][NH:7][C:8]2=[O:9])=[N:20]1
Reactant: CCOC(=O)C(=O)NC(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CNC(=O)N1c1ccccc1/C=C/c1n[nH]c2ccccc12
Yield: 85.3 %

Procedure:
(E)-(3-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}ureido)oxoacetic acid ethyl ester (50 mg, 0.14 mmol) obtained in Step 1 was heated under reflux in a mixed solvent of 6.0 mol/L hydrochloric acid/acetone (1/1, 2.5 mL) under nitrogen atomosphere for 60 hours. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform/methanol=90/10) to obtain Compound 212 (38 mg, 87%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[C:7](=[O:19])[CH:6]3[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.IC.[CH3:26]C([O-])(C)C.[Na+]>CS(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[C:7](=[O:19])[C:6]3([CH3:26])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1
Reactant: Cn1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)n1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CI
Product: Cn1ccc(CN2C(=O)C3(C)COCCN3c3nc(Cl)ncc32)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.299 mmol) and iodomethane (0.037 mL, 0.597 mmol) were mixed in DMSO (2 mL) in a sealed scintillation vial. The mixture was frozen then sodium 2-methylpropan-2-olate (57.4 mg, 0.597 mmol) was added and covered with a layer of DMSO. The mixture was refrozen then allowed to warm to room temperature and stirred overnight. An additional 1 eq of iodomethane was added. After 1 hour the reaction was diluted with water and extracted into EtOAc. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo to give 2-chloro-6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a yellow oil, which was used without further purification. MS [M+H] Found 349
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C(Cl)Cl>[CH2:17]([O:16][C:14](=[O:15])[NH:3][CH2:1][CH3:2])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Ethylamine (1.3 mL, 20.0 mmol) and diisopropylethylamine (7 mL, 40.0 mmol) were combined in CH2Cl2 (200 mL) and cooled to 0° C. Benzyl chloroformate (2.86 mL, 20.0 mmol) was added dropwise, and the reaction was stirred at 0° C. for 30 minutes. Once no starting material was seen by analytical tlc, the mixture was warmed to room temperature and washed with H2O, 0.1N aqueous HCl, and H2O, and then dried and concentrated to give the title compound.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:22])(=[O:21])[CH2:4][CH2:5]CCCCCCCCCCCCCCC.[C:23]([OH:27])(=[O:26])[CH:24]=[CH2:25]>C1(C)C=CC=CC=1>[C:3]([O-:22])(=[O:21])[CH:4]=[CH2:5].[Zn+2:2].[C:23]([O-:27])(=[O:26])[CH:24]=[CH2:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: C=CC(=O)O
Agent: *CCO*
Agent: CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC
Agent: [O-2]
Solvent: Cc1ccccc1
Product: C=CC(=O)[O-]
Temperature: 55 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
To a 4000 liter jacketed stainless steel reactor, at room temperature, were fed successively toluene (1472 kg), zinc oxide (366 kg, 99% purity, 4.41 kmol) and stearic acid (65.1 kg, 0.23 kmol). Then, the temperature was raised to 55±5° C. To the reactor was added dropwise acrylic acid (587 kg, 8.15 kmol) over 2.5 hours, and continued the stirring while keeping at this temperature for additional 2 hours in order to complete the reaction. To this reaction mixture was added Sinopol 1807 (2.0 kg, HLB 10.7, comprising mainly polyoxyethylene octadecyl ether). After stirring for additional 30 minutes, the resulting cream-like mixture was fed into a paddle dryer for distilling off toluene and water under reduced pressure, and pulverizing the powder. A modified zinc acrylate as a white fine powder was thus obtained (910 kg, 96.5% yield). Moisture content<0.5 wt %, acryl content is 55 wt % and ash content is 39 wt %. IR spectrum (KBr): λ 2917, 2848, 1644, 1576, 1522, 1447, 1433, 1373, 1274, 1067, 974 cm−1. After discharging the material, no cluster stuck on the blade in the dryer was observed, and no cake was detected in the powder.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.CCCCCC.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29](=[O:44])[N:30]([CH2:42]O)[CH:31]=[C:32]3[C:37]=2[NH:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[S:33]3)=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:29](=[O:44])[N:30]([CH2:42][O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([CH3:10])([CH3:9])[CH3:1])[CH:31]=[C:32]3[C:37]=2[NH:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[S:33]3)=[CH:26][CH:27]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccccc1N2
Reactant: CC(C)(C)CCCC(=O)O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)CCCC(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1ccccc1S2
Reaction time: 16 h
Yield: 59 %

Procedure:
A mixture of 3.0 g. of 5,5-dimethylhexanoic acid (23.0 mmol.) and 2.5 ml. of thionyl chloride (34.3 mmol.) was allowed to stand at room temperature for 16 hours. Upon addition of 20 ml. of Skellysolve B, the resulting solution was refluxed for 1 hour, then the solvent was removed in vacuo. The remaining residue was azeotroped twice with Skellysolve B to yield a pale yellow liquid which was added dropwise to a suspension of 3.0 g. of 4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (8.4 mmol.) in 30 ml. of cold pyridine. After stirring in an ice-bath for 35 minutes, the reaction mixture was poured onto ice-water resulting in the formation of a solid product which was filtered, washed with water, and purified using flash chromotography on silica gel, using a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing product were combined and triturated with diethyl ether to yield 4 -(4-chlorophenyl)-2-[(5,5-dimethyl-1-oxohexyloxy)methyl]-5H-pyrido[3,4-b][1,4]-benzothiazin-3(2H)-one as a yellow solid (2.4 g; 59% yield) having the structural formula, ##STR15## a melting point in the range of 143°-145° C. and the following elemental analysis:
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][O:13][C@H:14]1[C@@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][NH:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:22][C:21]([NH:20][C@H:19]1[CH2:18][CH2:17][N:16]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH3:11])[CH:3]=2)[CH2:15][C@H:14]1[O:13][CH3:12])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)c1sc(Br)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: COC(=O)c1sc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)cc1C
Yield: 23.6 %

Procedure:
The same operation as in Example (244b) was performed using methyl 5-bromo-3-methylthiophene-2-carboxylate obtained in Example (245a) (218 mg, 0.93 mmol), benzyl cis(±)-(3-methoxypiperidin-4-yl)-carbamate obtained in Example (40b) (270 mg, 1.02 mmol), palladium acetate (42 mg, 0.19 mmol), BINAP (115 mg, 0.19 mmol) and cesium carbonate (423 mg, 1.30 mmol), to obtain 92 mg of the title compound as a yellow oily substance (24%).
Reaction SMILES: [Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:19]([O:21][CH:22](OCC)OCC)[CH3:20].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[C:15]([CH3:16])=[C:14]([F:17])[C:13]([F:18])=[CH:12][C:3]=1[C:4]([C:6](=[CH:22][O:21][CH2:19][CH3:20])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(C)c1Cl
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1Cl
Temperature: 150 °C

Procedure:
To ethyl 2-chloro-4,5-difluoro-3-methylbenzoylacetate (3.9 g) are added triethoxymethane (3.1 g) and acetic anhydride (3.4 g), and the mixture is heated at 150° C. for one hour. The mixture is concentrated to give ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-ethoxyacrylate. To the product is added ethanol (50 ml) and thereto is added cyclopropylamine (1.1 ml) at room temperture, and the mixture is stirred for 30 minutes. Ethanol is distilled off to give ethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-cyclopropylaminoacrylate. To the product is added anhydrous dioxane (30 ml) and thereto is added portionwise 60% sodium hydride (0.6 g). The mixture is stirred at room temperature for 30 minutes and then refluxed for one hour. The reaction mixture is poured into aqueous saturated ammonium chloride and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated to give ethyl 1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (2.2 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][CH2:32][C@@H:33]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:34][O:35][CH2:36][CH3:37]>CN(C=O)C.CCOC(C)=O>[C:41]([O:40][C:39]([NH:38][C@@H:33]([CH2:34][O:35][CH2:36][CH3:37])[CH2:32][NH:31][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:3]=1)=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1cccc(C)c1
Reactant: CCOC[C@@H](CN)NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC[C@@H](CNc1cc(C#N)c(C(=O)OC)c(Nc2cccc(C)c2)n1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-chloro-4-cyano-2-(m-tolylamino)nicotinate (200 mg, 0.663 mmol) in DMF (5 mL) was added DIPEA (0.232 mL, 1.326 mmol) and (R)-tert-butyl 1-amino-3-ethoxypropan-2-ylcarbamate (174 mg, 0.795 mmol). The reaction mixture was stirred at RT overnight. Additional (R)-tert-butyl 1-amino-3-ethoxypropan-2-ylcarbamate (231.25 mg, 1.061 mmol) was added and the mixture was heated at 65° C. for 1 h. After cooling to RT, the reaction mixture was diluted with EtOAc (30 mL) and washed with water (2×20 mL) and brine (20 mL). The combined organic layers were dried over Na2SO4 and concentrated to thick yellow oil. The crude product was used in the next step without further purification (415 mg). [M+H] calc'd for C25H33N5O5, 484. found, 484.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11]O)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.S(Cl)([Cl:26])=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17][CH3:18])=[O:16])[C:5]([CH2:11][Cl:26])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: COC(=O)C[C@H](Cc1cc(C)c2[nH]ncc2c1CO)C(=O)OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C[C@H](Cc1cc(C)c2[nH]ncc2c1CCl)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99 %

Procedure:
(S)-dimethyl 2-((7-methyl-4-(hydroxymethyl)-1H-indazol-5-yl)methyl)succinate (180 mg, 0.56 mmol) was dissolved in dichloromethane (4.0 mL). 2M Thionyl chloride in dichloromethane (4.0 mL, 8.0 mmol) was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Mixture was concentrated. Residue was treated with toluene and then concentrated by roto-vap. Residue was dissolved in dichloromethane and then concentrated to dryness Title compound was obtained as amber solid in 99% yield. MS m/e (M+H)+=339.1.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br.O>C(O)(=O)C.C(O)=O.C(Cl)Cl>[Br:20][C:6]1[C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[N:8][O:9][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Nc1cc(C(C)(C)C)on1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=CO
Solvent: O
Product: COC(=O)Nc1noc(C(C)(C)C)c1Br
Temperature: 70 °C
Yield: 99.1 %

Procedure:
To a solution of methyl 5-t-butyl-3-isoxazolyl-carbamate (2.00 g) and anhydrous sodium acetate (1.1 mol equivalent) in glacial acetic acid (5 ml), bromine (1.0 mol equivalent) is added. The resultant mixture is heated at 50° C. for 53 hours and mixed with glacial acetic acid (5 ml), anhydrous sodium acetate (0.91 g) and bromine (0.81 g). The mixture is heated at 70° C. for 31 hours, mixed with several drops of formic acid, poured onto icy water (50 ml) and shaken with methylene chloride. The organic layer is washed with a saturated aqueous solution of sodium bicarbonate and water in order and evaporated under reduced pressure to remove the solvent, whereby methyl 4-bromo-5-t-butyl-3-isoxazolyl-carbamate (2.77 g) is obtained as an oil. I.R.: 1774, 1203 cm-1 (CCl4).