Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][O:2][S:3]([OH:6])(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O>[S:3]([O-:6])([O-:5])(=[O:4])=[O:2].[NH2:1][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[NH2:1][N+:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: c1ccnnc1
Reactant: NOS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N[n+]1ccccn1
Product: O=S(=O)([O-])[O-]
Temperature: 40 °C

Procedure:
A solution of hydroxylamine-O-sulfonic acid (73.4 g) in water (80 mL) and a separate solution of potassium carbonate (65.5 g) in water (80 mL) were added concurrently dropwise to a solution of pyridazine (40.0 g) in water (120 mL) at 50° C., maintaining a reaction mixture pH of 3.5-4.0. The reaction mixture was then heated at 40° C. for 2 hours to give a solution of N-aminopyridazinium sulfate, which was subsequently cooled to 20° C. and filtered. The filtrate was added dropwise to a solution of potassium hexafluorophosphate (91.9 g) in water (460 mL) at 50° C. The resulting suspension was slowly cooled to 5° C. over a 2 hour period, stirred for 30 minutes and the product isolated by filtration. The filtercake was washed portionwise with water (320 mL) and the product dried in vacuo at 40° C. to give the title compound as a white crystalline solid (69.9 g, 58%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:26]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:26])[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCNC(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCCO[Si](C)(C)C(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To the solution of benzyl 3-(tert-butyldimethylsilyloxy)propylcarbamate obtained in step 2 (5 g, 15.5 mmol) in tetrahydrofuran (20 ml), sodium hydride (1.24 g, 31 mmol, 60% in mineral oil) and iodomethane (3.86 ml, 62 mmol) were added slowly. The reaction temperature was warmed up to room temperature, and stirred for overnight. The reaction was completed quenched by water and organic material was extracted with ether. After evaporation of volatile material under reduced pressure, the residue was purified with silica gel column chromatography (EtOAC:Hx=1:10) to give the title compound (4.9 g, 94%) as light yellow oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]([OH:24])=O)=[CH:16][CH:15]=1)=[O:12].C(Cl)Cl.Cl.[NH2:29][OH:30]>CN(C)C=O.O1CCCC1>[OH:30][NH:29][C:22]([CH:21]=[CH:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])=[CH:15][CH:16]=1)=[O:24]
Reactant: NO
Reactant: O=C(O)C=Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(C=Cc1ccc(NC(=O)c2ccc3ccccc3c2)cc1)NO
Temperature: 40 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
(Method H8) To a suspension of 3-{4-[(naphthalene-2-carbonyl)-amino]-phenyl}-acrylic acid (5c) (0.740 g, 1.75 mmol) in methylene chloride (8 ml) oxalyl chloride (0.54 ml, 6.14 mmol) and one drop of dimethylformamide were added. The mixture was stirred for 30 min. at room temperature and for 1 hour at 40° C. Then the mixture was concentrated under reduced pressure and the residue was diluted with tetrahydrofuran (8.0 ml). In an another vessel, to a suspension of hydroxylamine hydrochloride (0.695 g, 10.0 mmol) in tetrahydrofuran (12 ml) saturated NaHCO3 solution (8.0 ml) was added and the mixture was stirred at room temperature for 5 min. The both mixtures were combined and vigorously stirred at room temperature for 30 min. The solvents were evaporated and the residue was acidified with 3% HCl to pH 5. The resulting precipitate was filtered off and washed with water (3×10 ml). The crystallization from methanol/water provided the title compound as a white solid (0.262 g, 45%). M.p. 231-233° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.41 (d, 1H, J=15.8 Hz); 7.45 (d, 1H, J=15.8 Hz); 7.52-7.70 (m, 4H); 7.82-8.16 (m, 6H); 8.59 (s, 1H); 9.02 (s, 1H); 10.58 (s, 1H); 10.73 (s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities <1% (column size 4.6×150 mm; mobile phase methanol×-0.1% H3PO4, gradient from 50:50 to 90:10; sample concentration 0.05 mg/ml; flow rate 1.5 ml/min.; detector UV 220 nm). Anal. Calcd for C20H16N2O3 containing 1% of inorganic impurities, %: C, 71.55; H, 4.80; N, 8.34. Found, %: C, 71.60; H, 4.78; N, 8.39.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1>CO.CCOCC>[CH3:1][O:2][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1
Reactant: Cc1cc(CCl)no1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COCc1cc(C)on1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
Sodium methoxide (30% in methanol, 7.46 mmol) was added to 3-chloromethyl-5-methyisoxazole (491 mg, 3.73 mmol) in methanol (4 mL) at room temperature under nitrogen. The reaction mixture was stirred for 15 h at room temperature then heated to reflux for 3 h. After cooling to room temperature the reaction was diluted with ether (75 mL) and washed with saturated aqueous ammonium chloride (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated to provide 362 mg (76% yield) of 3-methoxymethyl-5-methyl isoxazole as a clear liquid which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ ppm 6.02 (s, 1H), 4.48 (s, 2H), 3.38 (s, 3H), 2.42 (d, J=0.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Cl)=[N:6][CH:5]=1.CS(C)=O.[N-:17]=[N+:18]=[N-:19].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:17]=[N+:18]=[N-:19])=[N:6][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CCl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
Add 6-chloromethyl-nicotinic acid methyl ester (9.1 g, 40.98 mmol) and dimethylsulfoxide (100 mL) into a flask and cool to 0° C. Add sodium azide (4 g, 61.47 mmol) and sodium carbonate (13 g, 122.9 mmol) to the reaction mixture. Let the mixture slowly warm to room temperature. Stir for 1 hr at room temperature. Add water (100 mL) to the mixture. Extract with diethyl ether (100 mL×3). Wash the organic layer with water and brine. Dry with sodium sulfate. Remove solvent under reduced pressure to give the product (6.8 g, 86% yield) as light yellow oil. MS (m/z): 193.3 (M+1).
Reaction SMILES: FC1C=CC([CH2:6][N:7]2CCN3C=C(C(OCC)=O)C(O)=C3C2=O)=CC=1.[Cl:25][C:26]1[CH:48]=[CH:47][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]3[CH:37]=[C:38]([C:41]([O:43]CC)=O)[C:39]([OH:40])=[C:33]3[C:32]2=[O:46])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:48]=[CH:47][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][N:34]3[CH:37]=[C:38]([C:41]([NH:7][CH3:6])=[O:43])[C:39]([OH:40])=[C:33]3[C:32]2=[O:46])=[CH:28][CH:27]=1
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(Cl)cc1)CC2
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(F)cc1)CC2
Product: CNC(=O)c1cn2c(c1O)C(=O)N(Cc1ccc(Cl)cc1)CC2

Procedure:
The title compound was prepared using a procedure similar to that described in Example 5, except that ethyl 2-(4-fluorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate was substituted with ethyl 2-(4-chlorobenzyl)-8-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-7-carboxylate (Example 13).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH2:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH2:28][O:29][CH3:30]>CC#N>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][NH:11][C:32]([NH:31][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:20]([F:19])[CH:21]=2)=[O:33])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc(NC(=O)Oc2ccccc2)cc1F
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Solvent: CC#N
Product: COCCOc1ccc(NC(=O)NCc2cc(C(C)(C)C)nn2-c2cccc(Cl)c2)cc1F

Procedure:
To a stirred solution of (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine (synthesis described for example A18) (81 mg, 0.31 mmol, 1.0 eq.) in MeCN (7 mL) was added TEA (0.17 mL, 1.2 mmol, 4.0 eq.) followed by phenyl 3-fluoro-4-(2-methoxyethoxy)phenylcarbamate (95 mg, 0.31 mmol, 1.0 eq.) at RT and stirred at reflux for 16 h. The solvent was evaporated under vacuum. The crude product obtained was purified by column chromatography (eluent EtOAc/n-hexane 1:1) to yield example A17 (121 mg; 83%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([CH3:16])[CH:7]=1>>[F:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:10][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[C:8]([CH3:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)ccc1CC(=O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1CC(=O)O
Yield: 96.9 %

Procedure:
To stirring fuming HNO3 (90.00 wt %, 30.0 ml, 45 g, 643 mmol, 7.21 eq) at −15° C. was added 4-fluoro-2-methylphenylacetic acid (15.00 g, 89.2 mmol, 1.00 eq) in portions such that the internal temperature remained below −10° C. After completing the addition the reaction was stirred with warming to +5° C. over 15 min. The mixture was poured onto ice (400 g). Product separated as a slightly sticky solid which on manipulation with a spatula became powdery. The suspension was stirred vigorously until the ice had completely melted. While still very cold, the solids were collected by filtration, rinsed very well with H2O and dried on the filter to afford crude 2-(4-fluoro-2-methyl-5-nitrophenyl)acetic acid (18.43 g, 97% yield) as a pale yellow solid which was used as is in the next reaction. 1H NMR (400 MHz, acetone-d6): δ 8.06 (d, J=7.6 Hz, 1H), 7.36 (d, J=12.0 Hz), 3.84 (s, 2H), 2.44 (s, 3H)
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][C:21]4([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:18])=[C:12]([Cl:29])[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1.[CH3:30][C:31]([Si:34]([CH3:40])([CH3:39])[O:35][CH2:36][CH:37]=O)([CH3:33])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[Si:34]([O:35][CH2:36][CH2:37][NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:13]([C:17]([NH:19][CH2:20][C:21]4([OH:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)=[O:18])=[C:12]([Cl:29])[CH:11]=[CH:10][C:9]=3[N:8]=2)[CH2:3]1)([C:31]([CH3:33])([CH3:32])[CH3:30])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: N[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCN[C@H]1CCN(c2ccc3c(C(=O)NCC4(O)CCCCCC4)c(Cl)ccc3n2)C1
Reaction time: 0.08 h

Procedure:
2-[(3S)-3-Aminopyrrolidin-1-yl]-6-chloro-N-[(1-hydroxycycloheptyl)methyl]-quinoline-5-carboxamide (17.6 g) was suspended in dichloromethane (300 ml) and molecular sieves (17.6 g) were added under a nitrogen atmosphere. [[(1,1-dimethylethyl)-dimethylsilyl]-oxy]acetaldehyde (7.2 ml) was added dropwise with stirring over 5 minutes and the mixture was stirred at room temperature for 6 hours. Sodium triacetoxyborohydride (17.9 g) was added in one portion and the mixture was stirred at room temperature for a further 17 hours before water (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, concentrated onto silica in vacuo and purified by flash column chromatography (SiO2, 1:2:97-1:8:91 7M NH3 in methanol:methanol:dichloromethane as gradient elution) to afford the subtitle product as a colourless solid (16.0 g). Impure fractions (4.1 g) were repurified by flash column chromatography (SiO2, 1:2:97-1:8:91 7M NH3 in methanol:methanol:dichloromethane as gradient elution) to afford a second crop of the subtitle product (2.8 g).
Reaction SMILES: CO.C1COCC1.O.[NH2:9][NH2:10].[CH3:11][C:12]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:27][O:28][CH3:29])[C:23](OC)=[O:24]>O>[CH3:11][C:12]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](=[N:27][O:28][CH3:29])[C:23]([NH:9][NH2:10])=[O:24]
Reactant: NN
Reactant: CON=C(C(=O)OC)c1ccccc1COc1cc(C)ccc1C
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CON=C(C(=O)NN)c1ccccc1COc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
Methanol (10 ml), THF (10 ml) and hydrazine monohydrate (1.68 g, 0.03 mol) were added to methyl 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetate (3.27 g, 0.01 mol), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, water (200 ml) was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give 2-(2,5-dimethylphenoxymethyl)-α-methoxyiminophenylacetohydrazide (2.93 g, 89.6%) as colorless crystals.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[N:11]([CH2:2][C:3]1[C:4]([I:10])=[CH:5][C:6]([F:9])=[N:7][CH:8]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: Fc1cc(I)c(CBr)cn1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: [N-]=[N+]=NCc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
Combine 5-bromomethyl-2-fluoro-4-iodo-pyridine (0.45 g, 1.4 mmol), sodium azide (370 mg, 5.7 mmol), and 18-crown ether (45 mg, 0.17 mml) in dimethylformamide (10 mL) in a round bottom flask. Stir the mixture for 4 hours at room temperature. Dilute the reaction mixture with chloroform, and wash with water and saturated aqueous sodium chloride. Separate the organic layer from the aqueous layer and dry over MgSO4. After filtration, evaporate the organic solvent in vacuo to give a crude product. Purify the crude with flash column chromatography (eluted with 20% methyl acetate in hexane) to give the title compound (colorless oil, 0.0.32 g, 82%). MS (ES) m/z 279 [M+1]+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](O)=[C:6]([F:14])[CH:5]=1)([O-:3])=[O:2].P(Br)(Br)[Br:16]>CN(C=O)C.C1(C)C=CC=CC=1>[Br:16][C:7]1[C:6]([F:14])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11]
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(F)c(O)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Br)c([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 98.2 %

Procedure:
To a solution of 4,6-dinitro-2-fluorophenol (8 g, 39.60 mmol, 1 equiv) in DMF (24 mL) and toluene (160 mL), PBr3 (5.6 mL, 59.40 mmol, 1.5 equiv) was added at room temperature. Then the reaction mixture was heated at 110° C. for 1 hour. After allowing to cool to room temperature, the upper colorless layer was poured into a separate funnel and diluted with hexanes. The organic layer was washed with water, dried over MgSO4 and evaporated to dryness to give the product (10.3 g, 98%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[N+:11]([O-])[C:10]([CH3:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:17])=O.CCN(CC)CC>C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:14][Cl:17])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2ccccc2)c[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1ccc(-c2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 75 g 5-phenyl-2-picoline N-oxide from Step 1 in 375 mL of CH2Cl2 were added simultaneously a solution of 41.5 mL phosphoryl chloride in 150 mL of CH2Cl2 and a solution of 62 mL Et3N in 150 mL of CH2Cl2. The rate of addition was adjusted so that the reaction reached reflux temperature. The addition completed, the reaction was poured into a solution of NH4OAc (25%), stirred 30 minutes and extracted with EtOAc. The organic layer was dried over MgSO4, filtered on a silica gel bed and evaporated to dryness. The resulting solid was recrystallised from petroleum ether (30°-60° C.) to afford pure title product, m.p.: 73° C. The filtrate was chromatographed on silica gel (hexane/EtOAc 9:1) to give the title product along with 4-chloro-5-phenyl-2-picoline and 6-chloro-5-phenyl-2-picoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:20])=[C:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].C(O)(=[O:23])C.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:20]=[O:23])=[C:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)c2ccccc2)c1C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1[nH]c(C=O)c(C(=O)c2ccccc2)c1C
Yield: 75 %

Procedure:
A mixture of 4-benzoyl-3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (4.13 g, 15.2 mmol) and ceric ammonium nitrate (33 g, 4 equiv.) in 50 mL of tetrahydrofuran (THF):acetic acid (HOAc):H2O 1:1:1 was refluxed overnight. The reaction mixture was then cooled, extracted with EtOAc and then basified to pH 9 with sodium carbonate. The organic layer was then washed with brine, dried (MgSO4) and concentrated followed by column chromatography to give 3.25 g (75%) of 4-benzoyl-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester as a yellow solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[F:9][C:10]([F:20])([F:19])[C:11](=O)[CH2:12][C:13](OCC)=[O:14].O.Cl>C(O)C.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:3]1[CH:2]=[C:1]2[C:6]([C:11]([C:10]([F:20])([F:19])[F:9])=[CH:12][C:13](=[O:14])[NH:8]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: Nc1cccc(N)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(C(F)(F)F)cc(=O)[nH]c2c1
Yield: 31.4 %

Procedure:
m-Phenylenediamine (28.84 g, 0.26 mole), ethyl trifluoroacetoacetate (49.12 g, 0.26 mole), and ZnCl2 (44 g) were refluxed in 280 ml ethanol containing 10 ml isopropanol for 18 hours. The reaction mixture was poured into 1600 ml iced water containing 10 ml. conc. HCl and let stand at room temperature 2 hours. The solid was filtered, washed with water and air dried. The product was recrystallized from 800 ml boiling ethanol to give 18.63 g (31%) 7-amino-4-trifluoromethylquinolone (AFQ).
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[F:13][C:14]1[CH:31]=[CH:30][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]O)[CH2:22][CH2:21]2)=[O:19])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][N:5]3[C:4](=[O:8])[N:3]4[CH2:9][CH2:10][CH2:11][CH2:12][C:2]4=[N:1][C:6]3=[O:7])[CH2:22][CH2:21]2)=[O:19])=[CH:30][CH:31]=1
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCCn2c(=O)nc3n(c2=O)CCCC3)CC1

Procedure:
In the manner described in Example 1-2), 6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione prepared in Example 1-1) and 4-(4-fluorobenzoyl)-1-(3-hydroxypropyl)piperidine were condensed in N,N-dimethylformamide in the presence of triphenylphosphine and diethyl azodicarboxylate to obtain the entitled compound as an oily substance.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1COCC1.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>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:19]=[CH:18][C:17]([C:16]3[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=3)=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: COc1cccc(I)c1
Reactant: Nc1ncccc1-c1ccc(B(O)O)cc1
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: COCCOC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2ccc(-c3cccnc3N)cc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (8.49 mg) was added to a suspension of 1-iodo-3-methoxybenzene (68.8 mg), 4-(2-aminopyridin-3-yl)phenylboronic acid (52.4 mg) and sodium carbonate decahydrate (210 mg) in DME (5 mL), water (1 mL) and THF (dry) (5 mL). The mixture was stirred at 80° C. under nitrogen overnight. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (49.1 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[OH:5][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:19]=[C:20]([NH:24][C:25]([CH:27]3[CH2:28][CH2:29]3)=[O:26])[CH:21]=[CH:22][CH:23]=2)[CH2:14][CH2:13]1
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1)C1CC1

Procedure:
Prepared by Procedure G and Scheme B1 using (1R)-3-chloro-1-phenyl-1-propanol and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 379.2 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][PH:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:12][C:13]#[N:14].[Na+]>C(#N)C>[C:1]1([CH:7]=[CH:8][PH:9]([N:14]=[C:13]=[O:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[O-]
Reactant: O=[PH](Cl)C=Cc1ccccc1
Agent: [Na+]
Solvent: CC#N
Product: O=C=N[PH](=O)C=Cc1ccccc1
Reaction time: 23 h
Yield: 76.3 %

Procedure:
106 g (0.57 mol) of phenylvinylphosphinic acid chloride were dissolved in 150 ml of acetonitrile and stirred with 38 g (0.59 mol) of sodium cyanate at a temperature of 30° C. After 23 hours, the precipitate was filtered off by suction and washed with acetonitrile; the filtrate was concentrated and the residue distilled at a temperature of 107°-110° C. and at a pressure of 33 Pa. 84 g of phenylvinylphosphinic acid isocyanate (77% of theory) were obtained.