Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[CH:15]=[CH:16][CH:17]=[C:7]2[C:6]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]4[CH:15]=[CH:16][CH:17]=[C:7]4[C:6]3=[O:18])[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: O=c1c2cccn2c2ccccc2n1CCCCl
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1c2cccn2c2ccccc2n1CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 140 °C
Yield: 28.9 %

Procedure:
5-(3-chloropropyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (100 mg; 0.38 mmol) was added to a 5 mL microwave vessel containing a magnetic stir bar. 4-(4-Chlorophenyl)piperidin-4-ol (89.3 mg; 0.42 mmol), potassium carbonate (78.77 mg; 0.57 mmol), and 2 mL of acetonitrile were added to the vessel. The vessel was sealed and heated to 140° C. for 1 hour, after which the solvent was evaporated and the reaction mixture was purified by flash chromatography to yield 5-(3-(4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl)propyl)pyrrolo[1,2-a]quinoxalin-4(5H)-one (48.5 mg; 0.11 mmol; 29%). [M+1]+=436.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.C(Cl)Cl.B(Cl)(Cl)Cl>CO>[F:34][C:31]([F:32])([F:33])[C:30]([C:27]1[CH:28]=[CH:29][C:24]([N:11]2[CH2:12][CH2:13][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH2:15][CH:10]2[CH2:9][OH:8])=[CH:25][CH:26]=1)([OH:36])[CH3:35]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2ccccc2)cc1)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2CO)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-(4-(2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (2.93 g, 5.43 mmol) and CH2Cl2 (50 mL) and cooled to −78° C. A 1.0 M solution of BCl3 (1M in CH2Cl2, 7.31 mL, 7.31 mmol, Sigma-Aldrich, St. Louis, Mo.) was added slowly to the mixture and the reaction was stirred for 1 h at −78° C. After this time, MeOH (25 mL) was added and the mixture was warmed to room temperature. After the MeOH was removed in vacuo, diethyl ether (100 mL) was added. The resulting precipitate was collected by filtration, dried under reduced pressure to yield 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (2.17 g) as a mixture of four isomers.
Reaction SMILES: [CH3:1][C:2]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1ncc(-c2ccccc2)o1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1ncc(-c2ccccc2)o1
Yield: 10 %

Procedure:
This compound was synthesized from 2-methyl-2-(5-phenyloxazol-2-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (18 mg, yield 10%) as a yellow viscous liquid. 1H NMR (400 MHz, MeOD) δ 8.50-8.49 (t, J=1.8 Hz, 1H), 8.28-8.25 (dt, J=7.8 Hz, 1.4 Hz, 1H), 8.00-7.98 (dt, J=7.8 Hz, 1.5 Hz, 1H), 7.68-7.64 (m, 3H), 7.39-7.36 (m, 3H), 7.32-7.27 (m, 1H), 4.58 (s, 2H), 1.54 (s, 6H). MS (ESI) m/z: Calculated for C23H19F3N4O3: 456.14. found: 457.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[OH:8][CH:9]([CH3:16])[CH2:10][C:11]([O:14][OH:15])([CH3:13])[CH3:12].S(=O)(=O)(O)O>>[CH3:6][C:5]([O:15][O:14][C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([OH:8])[CH3:16])([CH2:4][C:2](=[O:1])[CH3:3])[CH3:7]
Reactant: CC(O)CC(C)(C)OO
Reactant: CC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Product: CC(=O)CC(C)(C)OOC(C)(C)CC(C)O

Procedure:
A mixture of 19.60 g. (0.20 mole) of mesityl oxide, 36.90 g. (0.25 mole) of 3-hydroxy-1,1-dimethylbutyl hydroperoxide (90%) and 10 g. of Amberlyst 15® sulfuric acid type ion exchange resin was stirred for 16 hours at 30° C. The resin was separated by filtration and the filtrate subjected to steam distillation at 20 torr in the presence of sodium bicarbonate to maintain a slightly alkaline pH during the distillation. The distillation was ended when the removal of unreacted mesityl oxide was complete.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][CH2:21][CH:22]1[O:24][CH2:23]1>C(O)C>[OH:24][CH:22]([CH2:21][O:20][CH3:19])[CH2:23][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:12]
Reactant: COCC1CO1
Reactant: O=C1NCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCC(O)COc1cccc2c1CCNC2=O
Yield: 43.8 %

Procedure:
A mixture of 1 g (6 mmol) of 3,4-dihydro-5-hydroxy-1(2H)-isoquinolinone and 2.1 g (15 mmol) of potassium carbonate in 50 ml of ethanol was refluxed for one hour. To this was added 0.65 ml (18 mmol) of glycidyl methyl ether and the mixture was refluxed overnight. The reaction was concentrated, the residue dissolved in chloroform, filtered and concentrated to an oil which solidified. The solid was recrystallized twice from water to give 0.66 g (44%) of the desired product; mp 119°-123°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[CH:33]1[CH2:36][N:35]([C:37]2[S:38][CH2:39][CH2:40][N:41]=2)[CH2:34]1.[C:42]([OH:45])(=[S:44])[CH3:43]>O1CCCC1>[C:42]([S:44][CH:33]1[CH2:36][N:35]([C:37]2[S:38][CH2:39][CH2:40][N:41]=2)[CH2:34]1)(=[O:45])[CH3:43]
Reactant: CC(O)=S
Reactant: OC1CN(C2=NCCS2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC1CN(C2=NCCS2)C1
Reaction time: 1 h
Yield: 65 %

Procedure:
To a mixture solution of triphenylphosphine and diethyl azodicarboxylate in 10 ml of tetrahydrofuran was added a mixture of 119 mg of Compound (3) and thioacetic acid under ice-cooling, and the reaction mixture was stirred for 1 hour at the same condition, then for 1 hour at room temperature. After the reaction solvent was removed under reduced pressure, the resulting residue was purified by silica gel column chromatography (chloroform:ethanol=1:1) to give 107 mg (65%) of 3-acetylthio-1-(thiazolin-2-yl)azetidine [Compound (4)].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][Br:14].[Cl:15][CH:16]([Cl:20])[C:17]([OH:19])=[O:18]>>[Br:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:16]([Cl:20])([Cl:15])[C:17]([OH:19])=[O:18]
Reactant: O=C(O)C(Cl)Cl
Reactant: BrCCCCCCCCCCCCBr
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCBr

Procedure:
Analogously to example 1 from 50.0 g (152 mmol) 1, 12-dibromododecane and 39.3 g (305 mmol) dichloroacetic acid. Yield 11.9 g (21%), melting point 59-60° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[CH:19]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:26])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Reactant: O=C(Cl)C1CCCCC1
Product: Cc1noc(-c2sc(NC(=O)C3CCCCC3)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and cyclohexanecarbonyl chloride.
Reaction SMILES: Cl[Sb-](Cl)(Cl)(Cl)(Cl)Cl.ClOC(N(C)C)=[N+](C)C.[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:36])[C:23]=1[S:24][C:25]1[S:29][C:28]([C:30]([OH:32])=O)=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34].[CH:37]([NH2:40])([CH3:39])[CH3:38].C(N(CC)CC)C>ClCCl>[Cl:36][C:22]1[CH:21]=[N:20][CH:19]=[C:18]([Cl:17])[C:23]=1[S:24][C:25]1[S:29][C:28]([C:30]([NH:40][CH:37]([CH3:39])[CH3:38])=[O:32])=[CH:27][C:26]=1[N+:33]([O-:35])=[O:34]
Reactant: CC(C)N
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: CN(C)C(OCl)=[N+](C)C
Agent: Cl[Sb-](Cl)(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
Chloro-1,1,3,3-tetramethyluronium hexachloroantimonate (47 mg, 0.1 mmol) was added to a suspension of 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (39 mg, 0.11 mmol) in dichloromethane (1 mL) and the mixture was stirred at ambient temperature for 10 min. A solution of isopropylamine (9 mg, 0.12 mmol) and triethylamine (12 mg, 0.12 mmol) in dichloromethane (0.5 mL) was added to the above mixture and was stirred at ambient temperature for over night. After passing through a ISOLUTE™ PE-AX cartridge to remove excess amines, the resulting mixture was concentrated and the residue was purified by reverse-phase HPLC to afford the title product as a white solid (25 mg, 49% yield). 1H NMR (300 MHz, d6-DMSO) δ: 9.0 (2H, s), 8.65 (1H, d), 8.50 (1H, s), 4.0 (1H, m), 1.25 (6H, d). MS m/z: 391.70, 393.80 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(NC(C)C)(C)C.[Li].[CH3:21][CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1>O1CCCC1>[CH3:21][C:22]1([F:43])[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC1CCc2ccccc2C1=O
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC1(F)CCc2ccccc2C1=O
Reaction time: 1.67 h
Yield: 50 %

Procedure:
0.16 milliliter diisopropylamine in 10 milliliters tetrahydrofuran were allowed to stand with 1.15 equivalents butyllithium at -25° C. The resulting solution of lithium diisopropylamine was cooled to -78° C. and 1 equivalent 2-methyl-1-tetralone in 5 milliliters tetrahydrofuran solution was dropped in. The mixture was allowed to stand at -70° C. for 100 minutes. 1.5 equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 11 milliliters tetrahydrofuran were mixed rapidly with the mixture at -95° C. The mixture was quenched with 30 milliliters ammonium chloride solution and extracted with dichloromethane. The organic phase was dried with magnesium sulfate, filtered, and evaporated. 2-methyl-2-fluoro-tetralone was obtained in 50% yield.
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[CH2:5]([OH:15])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].N1C=CC=CC=1>C(OCC)C>[CH3:1][S:2]([O:15][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:3]
Reactant: CS(=O)Cl
Reactant: CCCCCCCCCCO
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCCCCCCCCOS(C)=O
Temperature: 50 °C

Procedure:
Into a 50 ml three-necked flask equipped with a magnetic stirrer, thermometer, nitrogen purge and dropping funnel is added 9.9 gms (0.10 moles) of methanesulfinyl chloride. The methane sulfinyl chloride is cooled to -10°C and 17.4 gms (0.11 moles) of decanol is added dropwise while maintaining the temperature of -5° to -10°C. When the addition of the decanol is complete, the reaction mass is warmed to 50°C under 20 mm of vacuum. The resulting product is then cooled and dissolved in 100 ml of diethyl ether admixed with 2 gms. of pyridine. The reaction mass is then extracted with two 10 ml portions of water. A drop of pyridine is added to the ether layer in order to remove additional chloride. In the event that no precipitation occurs the ether layer is then extracted with two 10 ml portions of 3% aqueous hydrochloric acid. The ether layer is then dried over anhydrous sodium sulfate and is then evaporated by means of rotary evaporation yielding an oil which is then subjected to a distillation operation. The resulting product is distilled at 98°C at 0.50-0.65 mm Hg pressure. (Yield 16 gms). GLC, mass spectral and infrared analysis yield the information that the structure of this material is as follows: ##EQU13##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl.[Cl-].[Na+].O>[C:15]([O:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:9][CH2:10]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CCN(c2ccc(Br)cn2)CC1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)OC1CCN(c2ccc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)piperidin-4-ol (200 mg, 0.78 mmol), acetic anhydride (0.16 mL, 1.7 mmol), DMAP (10 mg, 0.08 mmol), and Et3N (0.24 mL, 1.7 mmol) in CH2Cl2 (4 mL) was stirred at rt for 17 h. Brine was added and extracted with CH2Cl2, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with water and the title compound was collected by vacuum filtration (203 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=2.2 Hz, 1H), 7.52 (dd, J=9.0 Hz, 2.5 Hz, 1H), 6.57 (d, 9.0 Hz, 1H), 5.01-4.95 (m, 1H), 3.9-3.85 (m, 2H), 3.35-3.28 (m, 2H), 2.07 (s, 3H), 1.99-1.92 (m, 2H), 1.74-1.65 (m, 2H); MS ESI 300.9 [M+H]+, calcd for [C12H15BrN2O2+H]+ 299.03.
Reaction SMILES: [C:1]([O:6]CCO)(=[O:5])[C:2](C)=[CH2:3].CC1C=C(O)C=CC=1O.CC1C(N=C=O)=CC=CC=1N=C=O.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[NH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71]>C(O)CO>[C:1]([OH:6])(=[O:5])[CH:2]=[CH2:3].[NH2:69][C:70]([O:72][CH2:73][CH3:74])=[O:71]
Reactant: C=C(C)C(=O)OCCO
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: CCOC(N)=O
Solvent: OCCO
Product: C=CC(=O)O
Temperature: 77.5 °C

Procedure:
In a reactor, 163 g of 2-hydroxyethyl methacrylate, and 0.2 g of monomethyl hydroquinone were put, and 218.3 g of 2,6-toluene diisocyanate was dropped at room temperature over 1 hour so as to be reacted, while the internal temperature was kept at 50 to 55° C. After the dropping was completed, the reaction was continued at 50 to 55° C. until the content of NCO groups became 14 to 15 mass %. Subsequently 0.5 g of dibutyltin dilaurate was added thereto, and while the temperature was kept at 50 to 55° C., 600 g of the EO adduct of polypropylene glycol of Example 12 and 50 g of ethylene glycol was dropped over 1 hour. After the dropping was completed, it was heated to 75 to 80° C., so as to be reacted until the absorption of NCO groups at 2270 cm−1 in the infrared absorption spectrum disappeared. As a result, a urethane acrylate compound was obtained. The obtained compound was adjusted with styrene so as to have a non-volatile portion of 74 mass %, and 0.01 part by mass of 6% cobalt naphthenate and 0.1 part by mass of methylethylketone peroxide with respect to 100 parts of the foregoing resin were mixed therein as a curing accelerator. The mixture was cured over 1 hour at 120 to 130° C., whereby an acryl urethane resin was obtained.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=2)[CH:11]=[CH:10][N:9]=1>>[Cl:20][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:13]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1cc(-c2ccnc(Cl)n2)ccn1
Reactant: NC1CCCC1
Product: Clc1cc(-c2ccnc(NC3CCCC3)n2)ccn1

Procedure:
Cyclopentylamine (3 mL) was combined with 2-chloro-4-(2-chloro-4-pyridinyl)pyrimidine (i.e., the product of Example 6, Step A) (300 mg, 1.3 mmol) and stirred at 55° C. for 2 hours. The resulting suspension was filtered, and the collected solid was oven dried at 50° C. in vacuo to give 340 mg of the title compound as a brown solid.
Reaction SMILES: [CH3:1][C@H:2]1[C:6](=[O:7])[O:5][C@@H:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[I:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C[Si](C)(C)N[Si](C)(C)C.[Li].C(=O)(O)[O-].[Na+]>C1COCC1>[I:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][C@:2]1([CH3:1])[C:6](=[O:7])[O:5][C@@H:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:3]1[C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15]
Reactant: BrCc1cccc(I)c1
Reactant: C[C@H]1C(=O)O[C@@H](c2ccccc2)N1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@@]1(Cc2cccc(I)c2)C(=O)O[C@@H](c2ccccc2)N1C(=O)OCc1ccccc1
Temperature: 20 °C
Yield: 72.8 %

Procedure:
A solution of benzyl (2S,4S)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate (J. Org. Chem. 2001, 66, 1903) (1.2 g) and 3-iodobenzyl bromide (1.15 g) in THF (8 ml) was added dropwise to a solution of lithium hexamethyldisilazane in THF (1M, 4.1 ml) diluted in THF (32 ml) at −30° C. The mixture was stirred at this temperature and then allowed to warm to 20° C. over 4 h. Aqueous sodium bicarbonate solution was then added and the mixture was extracted with Et2O. The organic phase was separated and dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on a Biotage cartridge (40 g) eluting with EtOAc-petroleum ether (1:9, 1:4) to give the title compound (1.48 g) HPLC RT=9.33 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:31]([O-])=O)=[C:6]([NH:8][C:9]2[N:17]=[C:16]3[C:12]([NH:13][C:14](=[O:24])[N:15]3[CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:11]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[N:10]=2)[CH:7]=1.C(O)(=O)C.O.[OH-].[NH4+]>[Fe].C(O)C>[NH2:31][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][C:14](=[O:24])[N:15]2[CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:11]([C:25]2[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=2)[N:10]=1
Reactant: O=c1[nH]c2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3[N+](=O)[O-])nc2n1C1CCOCC1
Agent: [Fe]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cl)cc1Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Temperature: 90 °C
Reaction time: 0.17 h

Procedure:
To a vial containing 2-(5-chloro-2-nitrophenylamino)-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (7 mg, 0.015 mmol) was added glacial acetic acid (0.5 mL), water (1.25 mL) and ethanol (2.5 mL), followed by iron powder (8.4 mg, 0.15 mmol, 10 equiv.) and the resulting mixture heated at 90° C. for 15 min (HPLC monitoring). The reaction mixture was left to cool down to room temperature, concentrated ammonium hydroxide solution was added to bring the pH to basic, and the mixture was stirred for 10 min. The aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with brine, dried (anhydrous Na2SO4), and the solvent removed in vacuo to give the desired product as a pale yellow solid (yield quantitative). This material was used in the next step without further purification. MS (EI) m/z 438.3 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=[O:31])[CH:26]=[CH:27][CH:28]=1>CN(C=O)C>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[C:3]=1[C:30](=[O:31])[CH2:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:33])([F:21])[F:34])[CH:24]=1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cc1cccc(C(F)(F)F)c1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 352 mg, 8.8 mmol, 2.2 eq.), and the mixture was stirred at a room temperature for 35 minutes. Then, 3-trifluoromethylphenylacetyl chloride (4.8 mmol, 1.2 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 1.5 hours. Thereafter, the resulting mixture was purified by a flash column chromatography to give 4-hydroxy-1-phenyl-3-(3-trifluoromethylphenylacetyl)-1,8-naphthyridin-2(1H)-one as a form of crystal (1.04 g, yield 61%).
Reaction SMILES: C[O-].[Na+].C1COCC1.C1(C)C(S([CH2:18][N+:19]#[C-:20])(=O)=O)=CC=CC=1.[NH2:22][C:23]1[C:28]2=[C:29]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH:43][C:44]4[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][N:45]=4)=[O:42])=[C:36]([F:54])[CH:35]=3)[CH:30]=[C:31]([CH:32]=[O:33])[N:27]2[N:26]=[CH:25][N:24]=1>CO.CCOC(C)=O>[NH2:22][C:23]1[C:28]2=[C:29]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41]([NH:43][C:44]4[CH:49]=[C:48]([C:50]([F:52])([F:51])[F:53])[CH:47]=[CH:46][N:45]=4)=[O:42])=[C:36]([F:54])[CH:35]=3)[CH:30]=[C:31]([C:32]3[O:33][CH:20]=[N:19][CH:18]=3)[N:27]2[N:26]=[CH:25][N:24]=1
Reactant: Nc1ncnn2c(C=O)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncnn2c(-c3cnco3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.7 %

Procedure:
A solution of sodium methoxide in MeOH (25% by wt, 211 mg, 0.98 mmol) was taken up in MeOH (2 mL) and THF (8 mL) and the solution cooled to 0° C. Toluenesulfonylmethylisocyanide (96.6 mg, 0.49 mmol) and N-[4-(4-amino-7-formylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-N′-[4-(trifluoromethyl)pyridin-2-yl]urea (150 mg, 0.33 mmol) were added in succession to the solution. The reaction was stirred at 0° C. for 5 min, then heated at 60° C. for 1 h. The reaction was cooled to rt and diluted with EtOAc (100 mL). The organic layer was wash with water (2×) and dried with sodium sulfate. The suspension was filtered and the filtrate concentrated in vacuo. The resulting solid was triturated with ether, and subsequently with THF to provide the title compound (67 mg, 41%) as a tan solid. 1H-NMR (DMSO-d6) δ 9.43 (s, 1H), 9.30 (s, 1H), 8.65 (dd, 1H), 8.31 (t, 1H), 8.17 (s, 1H), 7.52 (t, 1H), 7.37-7.46 (m, 2H), 7.26-7.32 (m, 1H), 7.23 (m, 1H); MS [M+H]+=499.1; LCMS RT=3.00 min.