Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:11]3[C:23]=2I)[CH:5]=[CH:6][CH:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Li+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[O:16])[NH:14][CH2:13][CH:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:11]3[C:23]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(Cl)c3)c(I)n21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CC1CNC(=O)c2cc(-c3cccc(Cl)c3)c(-c3ccccc3)n21
Yield: 90 %

Procedure:
To a solution of ethyl [7-(3-chlorophenyl)-6-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl]acetate (123 mg, 0.269 mmol) in 9 ml of 1,4-dioxane and 1 ml of water, under argon atmosphere, phenylboronic acid (130 mg, 1.07 mmol), bis(triphenylphosphine)palladium(II) dichloride (9:4 mg, 0.013 mmol), sodium carbonate (85.0 mg, 0.80 mmol) and lithium chloride (34 mg, 0.81 mmol) were successively added. The mixture was heated at 100° for 4 hour in a sealed vial. The reaction was filtered through a celite pad and the solvent evaporated to dryness. The crude was then portioned between ethyl acetate and water, the organic layer dried over sodium sulphate and the solvent removed in vacuo. Purification by flash chromatography on silica gel column (EtOAc/Hex 3/2) led to the wanted compound in 90% yield.
Reaction SMILES: P(=O)([O-])O[C:3](CC)(CC)[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[Li]CCCC.[Si:23]([O:30][C@H:31]([CH3:34])[CH:32]=O)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>O1CCCC1>[Si:23]([O:30][C@H:31]([CH3:34])/[CH:32]=[CH:3]/[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: C[C@H](C=O)O[Si](C)(C)C(C)(C)C
Reactant: CCC(CC)(O[PH](=O)[O-])Sc1ccc(C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(S/C=C/[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Under the nitrogen atmosphere, 3.02 g (11 mmole) of diethyl-p-methylphenylthiomethyl phosphonate was dissolved in 50 ml of anhydrous tetrahydrofuran and after lowering the reaction temperature to -78° C., 6.25 ml (10 mmole) of 1.6M n-BuLi was added to the reaction mixture for ten minutes, and the resultant mixture was agitated at the temperature of -78° C. for 30 minutes. At the same temperature, 1.87 g (10 mmole) of (2R)-2-(t-butyldimethylsilyloxy)propanal diluted with 10 ml of anhydrous tetrahydrofuran was added to the said mixture and the reaction temperature was slowly raised from -78° C. to 0° C., and then the the mixture agitated at 0° C. for another one hour. Once the reaction was completed, the reaction was quenched by adding saturated ammonium chloride solution. After the work-up treatment in the same manner as did in method A of EXAMPLE 32, 2.8 g of crude product was obtained. The crude product was purified by a column chromatography (using n-hexane containing 1% diethyl ether as an eluent), thereby obtaining 2.5 g of desired compound having E/Z ratio of over 100/1 (yield: 81%) stereoselectively.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[F:12][C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=1)[CH2:16][C:17]1[CH:36]=[CH:35][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]#[C:27][Si:28]([CH2:33][CH3:34])([CH2:31][CH3:32])[CH2:29][CH3:30])=[O:22])=[CH:19][CH:18]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][CH:39]=1)[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]2[C:3]3[C:4](=[CH:6][C:7]([F:10])=[C:8]([F:9])[C:2]=3[F:1])[NH:5][C:27]=2[Si:28]([CH2:29][CH3:30])([CH2:31][CH3:32])[CH2:33][CH3:34])=[O:22])=[CH:35][CH:36]=1
Reactant: Nc1cc(F)c(F)c(F)c1I
Reactant: CC[Si](C#CCCNC(=O)c1ccc(Cc2cccc(F)c2)cc1)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(F)c(F)c(F)c2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 28.8 %

Procedure:
3,4,5-Trifluoro-2-iodoaniline (0.100 g; 0.366 mmol), 4-(3-fluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)benzamide (0.145 g; 0.366 mmol), bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g; 0.018 mmol), lithium chloride (0.015 mg; 0.366 mmol) and sodium carbonate (0.078 g; 0.732 mmol) were suspended in DMF (5 mL) and the mixture was stirred at 100° C. for 72 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 60% ethyl acetate in heptane) to afford 0.057 g (29%) of the title compound.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]([O:17][C:18]([NH:20][C@H:21]([C:23]([OH:25])=O)[CH3:22])=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.[CH3:27][O:28][NH:29][CH3:30]>ClCCl.C(N(CC)CC)C>[CH3:27][O:28][N:29]([CH3:30])[C:23](=[O:25])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH3:22]
Reactant: CNOC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
CDI (185.6 g) was added to a dichloromethane (2000 ml) solution containing N-(tert-butoxycarbonyl)-L-alanine (200 g) at 5° C. or less, followed by stirring for 1 hour. Subsequently, triethylamine (115.8 g) and N-methoxy-N-methylamine hydrochloride (111.7 g) were added to the solution, followed by stirring at 15° C. or less for 1.5 hours. Dichloromethane (230 ml) was added to the reaction solution. The organic layers were washed with a 20% sodium hydroxide aqueous solution and the solvent was distilled away under reduced pressure. Heptane was added to the obtained residue for suspension and a solid was collected by filtration. A white solid of (S)-tert-butyl (1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (237.8 g) was thus obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8]N.N[C@H:11]1CN2C3C(C(CC(OCCC)=O)=C2C[CH2:12]1)=CC=CC=3>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:12]=[CH:11]2
Reactant: NNc1ccccc1F
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Product: Fc1cccc2cc[nH]c12

Procedure:
This compound was prepared from 2-fluoro-phenylhydrazine according to the procedure outlined for propyl ([7R]-7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[CH3:13][C:14]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH3:25])=[O:17]>O1CCCC1>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:16]([C:15]1[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:14]=1[CH3:13])([OH:17])[CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1
Reactant: Cc1nnnn1C
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2C)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(Cc2nnnn2C)c2ccc(C)cc2C)c(C)c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of 1,5-dimethyltetrazol (8.9 g, 91.0 mmoles) in 100 mL of dry tetrahydrofuran at -60° C. was treated with n-butyl lithium (48 mL of 1.89M solution, 91.0 mmoles). After stirring for 20 minutes, 2,2',4,4'-tetramethylbenzophenone (18 g, 76 mmoles) [prepared by the procedure described in J. Am. Chem. Soc., 81, 4858 (1959)] in 50 mL dry tetrahydrofuran was added and the solution was stirred for 1 hour during which time it was allowed to warm to -20° C. The reaction was quenched with 1N HCl, then extracted with chloroform. The combined organic extracts were dried (MgSO4) and evaporated to give 22 g of the title compound; m.p.=175°-177° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:3]=1.[NH:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1.C1(O)C=CC=CC=1>O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:20]1[CH2:28][CH2:27][CH:23]([C:24]([NH2:26])=[O:25])[CH2:22][CH2:21]1
Reactant: NC(=O)C1CCNCC1
Reactant: Clc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Solvent: Oc1ccccc1
Solvent: O
Product: NC(=O)C1CCN(c2cc(-c3ccc(Cl)cc3)nc3ccc(Cl)cc23)CC1

Procedure:
A mixture of 3.1 g of 4,6-dichloro-2-(4-chlorophenyl)quinoline, 2.56 g (20 mmol) of isonipecotamide, and 10 g of phenol was stirred and heated in an oil bath at 160°-170° for 4 hr. It was then cooled and diluted with water. It was made alkaline with 3N sodium hydroxide, and crystallization was induced by the addition of ether and scratching. The solid was collected and washed with ether to give 2.45 g of crude product. Recrystallization from ethanol gave the above-named compound as off-white prisms, mp 272°-275°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[CH:2].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na]>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])#[CH:2]
Reactant: C#Cc1cccc(C(=O)Cl)c1
Reactant: Sc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: C#Cc1cccc(C(=O)Sc2ccccc2)c1

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added 7 ml of THF and the resultant mixture was ice-cooled. Then, 971 mg (7.35 mmol) of sodium benzenethiol was added to the mixture and the resultant mixture was stirred at room temperature for 2 hours. After completion of the stirring, THF was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (Hexane/AcOEt=20/1) using silica gel to obtain 0.51 g of S-phenyl 3-ethynyl-thiobenzoate which is a desired product as yellow solid. (Yield: 31%)
Reaction SMILES: Cl.CO[CH:4](OC)[CH2:5][NH:6][CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9].S(=O)(=O)(O)O>>[CH2:5]1[CH:4]2[C:18]3[C:13]([CH2:12][CH2:11][N:10]2[C:8](=[O:9])[CH2:7][NH:6]1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: COC(CNCC(=O)NCCc1ccccc1)OC
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C1CNCC2c3ccccc3CCN12
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 74.7 %

Procedure:
2-(2,2-Dimethoxy-ethylamino)-N-phenethyl-acetamide hydrochloride (8.77 g, 29.0 mmol) was added to the ice-cooled sulfuric acid (8.8 ml) and the mixture was stirred for 3.5 hours at room temperature. Ice-water was added to the solution after cooling by ice and the resulting solution was extracted with dichloromethane after adjusted to pH 12 with 20% aqueous sodium hydroxide. The organic layer was washed with brine and dried with magnesium sulfate, and then the solvents were removed under reduced pressure. Recrystallization of the residue with hexane-ethyl acetate afforded 1,2,3,6,7,11b-hexahydro-pyrazino[2,1-a]isoquinolin-4-one (4.38 g, 75%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:4][CH:5]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CN)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CNC(=O)Cc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to the procedure described under (d), from tert-butyl (3RS,4RS)-4-(4-aminomethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate by acylation with phenylacetyl chloride there was obtained crude tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(phenylacetylamino-methyl)-phenyl]-piperidine-1-carboxylate, which was used in the following step without further purification and characterization.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1C(CCO)=CC=[CH:23][N:22]=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[C:4]([CH2:1][CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)=[CH:3][CH:2]=[CH:23][N:22]=1
Reactant: COc1ncccc1CCO
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1ncccc1CCOc1cccc2[nH]c(C(=O)O)cc12

Procedure:
4-[2-(2-Methoxy-pyridin-3-yl)-ethoxy]-1H-indole-2-carboxylic acid (16m) is synthesized analogous to 16a from 4-[2-(2-methoxy-pyridin-3-yl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:11]2[CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:11]2[CH:10]=1
Reactant: CCOC(=O)c1nc2cc(NC(=O)OC(C)(C)C)ccn2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1nc2cc(N)ccn2n1
Yield: 75.5 %

Procedure:
A solution of ethyl 7-(tert-butoxycarbonylamino)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.07 g, 3.49 mmol) in dichloromethane (5 ml) and trifluoroacetic acid (5.38 ml, 69.9 mmol) is stirred for 3 hours at 25° C. The mixture is made basic using sat. aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer is washed with water and brine, dried with magnesium sulfate and the solvent is removed in vacuo affording ethyl 7-amino-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (543 mg, 75.4%) as a light yellow solid. mp.: 150-171° C. MS: m/z=207.0 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[N:11][C:5]=2[N:4]2[CH:16]=[CH:17][CH:18]=[C:3]12.[H-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CO.O>[OH:13][CH2:12][C:9]1[CH:10]=[N:11][C:5]2[N:4]3[CH:16]=[CH:17][CH:18]=[C:3]3[C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1cnc2c(c1)[nH]c(=O)c1cccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(CO)cnc2n2cccc12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.3 %

Procedure:
Methyl 6-oxo-5,6-dihydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (2.0 g, 8.22 mmol) was suspended in THF (Volume: 27.4 ml) under nitrogen atmosphere and cooled to 0° C. Sodium hydride (0.658 g, 16.45 mmol) was added in several portions over 7 min. The reaction mixture was stirred at 0° C. for 10 min, at room temperature for 20 min and cooled to below −50° C. Lithium aluminum hydride (7.40 ml, 14.80 mmol) was added over the period of 5 min and the reaction was kept at a temperature between −30 and −20° C. for 1 h. The mixture was cooled to below −40° C. and MeOH (6 mL) was added. Water (5 mL) was added and then more MeOH (50 mL). The reaction mixture was stirred at rt for 10 min. The resulting precipitate was filtered, suspended in MeOH (100 mL) and filtered again. The solid was suspended with heating overnight in MeOH:DCM (1:1, 200 mL) and filtered hot. This solid was dissolved in MeOH/DCM (100 mL, 3:1) and loaded onto silica gel (12 g) then purified by flash column chromatography on silica gel (220 g SiO2, gradient DCM:MeOH 100:1-85:15) to give 3-(hydroxymethyl)pyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (854 mg, 3.97 mmol, 48.3% yield) as a white solid. 1H NMR (DMSO-d6) δ 11.36 (br. s., 1H), 8.14 (d, J=1.8 Hz, 1H), 8.10 (dd, J=2.8, 1.5 Hz, 1H), 7.61-7.66 (m, 1H), 7.09 (dd, J=3.8, 1.5 Hz, 1H), 6.71 (dd, J=3.7, 2.9 Hz, 1H), 5.42 (br. s., 1H), 4.53-4.64 (m, 2H). [M+H] calc'd for C11H9N3O2, 216; found, 216.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](N(CC)CC)C.COC(ON=C(C#N)C(OCC)=O)=O>CO>[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)C(C#N)=NOC(=O)OC
Solvent: CO
Product: COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzoic acid (1.22 g) and triethylamine (1.4 ml) are dissolved in methanol (15 ml), and ethyl 2-methoxycarbonyloxyimino-2-cyanoacetate (2.0 g) is added thereto. The resulting mixture is stirred at room temperature for 2 hours and then extracted with ethyl acetate. The extract is treated as in Example A to give methyl benzoate (0.9 g) as an oil.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1Cl.FC1C=CC(C=O)=C([C:23]([F:26])([F:25])[F:24])C=1>>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Product: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
The titled compound is prepared analogously to 1-bromomethyl-2-chloro-4-methanesulfonyl-benzene by replacing 2-chloro-4-fluorobenzaldehyde (step 90a) with 4-fluoro-2-trifluoromethylbenzaldehyde.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](O)=[O:13]>>[CH:12]([NH:10][NH:9][C:8]([NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])=[O:13]
Reactant: NNC(=O)Nc1ccccc1
Reactant: O=CO
Product: O=CNNC(=O)Nc1ccccc1

Procedure:
Other known methods for the preparation of 4-aryl-1,2,4-triazol-3-ones involve the use of hydrazine as a raw material. In one such method, phenylurea is reacted with hydrazine to give a 4-phenylsemicarbazide. The semicarbazide is then condensed with ethyl formate to give the 4-phenyltriazolone. The overall yield from this method is about 20%. In another method, a 4-phenylsemicarbazide is reacted with formic acid to form the 1-formyl-4-phenylsemicarbazide intermediate, followed by intramolecular condensation to the 4-phenyltriazolone. The yield obtained by this method is about 40%. In yet another method, a substituted aniline is converted to the phenylcarbamate derivative. The phenylcarbamate is treated with hydrazine to give the phenylsemicarbazide derivative, followed by condensation with formamidine acetate to give the 4-phenyltriazolone. Each of these methods requires the use of the toxic compound hydrazine. In addition, the methods suffer from low overall yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:12]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:11][C:10](=[O:19])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[CH:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]1([C:20]#[C:21][C:2]2[CH:3]=[C:4]([C@H:8]3[C@H:12]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[O:11][C:10](=[O:19])[NH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#Cc1ccccc1
Reactant: O=C1N[C@@H](c2cccc(Br)c2)[C@H](c2cccnc2)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](c2cccc(C#Cc3ccccc3)c2)[C@H](c2cccnc2)O1
Temperature: -78 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
To trans-4-(3-bromophenyl)-5-(pyridin-3-yl)oxazolidin-2-one (46 mg, 0.144 mmol) slurried in triethylamine (3 mL) was added ethynylbenzene (0.021 mL, 0.187 mmol), copper(I) iodide (2.74 mg, 0.014 mmol), and triphenylphosphine (26.5 mg, 0.101 mmol). The reaction mixture was cooled to −78° C. under nitrogen and subjected to three rounds of pump/nitrogen purge. The mixture was then warmed to ambient temperature and (Ph3P)2PdCl2 (10.12 mg, 0.014 mmol) was added. The vessel was fitted with a reflux condensor and placed in an oil bath at 93° C. for 18 h at which time the vessel was removed from the heat and the residue was solubilized in 1:1 dimethylformamide/methanol and purified via preparative HPLC method 4. Pooling and concentration of the fractions containing the peak eluting at 7.37 min provided 14.3 mg trans-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one as an indeterminate enantiomeric mixture. 1H NMR (500 MHz, MeOD) δ ppm 8.44 (1H, d, J=7.32 Hz), 8.16 (1H, br. s.), 7.57-7.63 (2H, m), 7.47-7.57 (4H, m), 7.44 (1H, d, J=7.63 Hz), 7.36-7.42 (4H, m), 5.68 (1H, d, J=6.41 Hz), 4.98 (1H, d, J=6.71 Hz). LC/MS (Analytical HPLC Method 6) 1.97 min, Anal. Calcd. for [M+H]+ C22H16N2O2: 341.12. found 341.29. HPLC retention time (Analytical HPLC method 3): 7.30 min. Further purification via preparative SFC method 5 provided 2.2 mg (4%) (4R,5R)-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one (5.8 min retention time) as a colorless oil and 2.0 mg (4%) (4S,5S)-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one as a colorless oil. HPLC retention time for (4R,5R)-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one (Analytical HPLC method 3): 7.12 min. HPLC retention time for (4S,5S)-4-(3-(phenylethynyl)phenyl)-5-(pyridin-3-yl)oxazolidin-2-one (Analytical HPLC method 3): 7.10 min.
Reaction SMILES: [C:1]([N:3]=[C:4]1[N:8]([CH3:9])[CH2:7][CH2:6][N:5]1[C@@H:10]1[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]([CH3:23])([CH3:22])[C@H:11]1[OH:24])#[N:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.C(OCC)(=O)C>[C:25]([O:24][C@H:11]1[C@H:10]([N:5]2[CH2:6][CH2:7][N:8]([CH3:9])[C:4]2=[N:3][C:1]#[N:2])[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][C:12]1([CH3:22])[CH3:23])(=[O:27])[CH3:26]
Reactant: CN1CCN([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1=NC#N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1[C@H](N2CCN(C)C2=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of trans-4-(2-cyanoimino-3-methylimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.95 g) in dry pyridine (9.5 ml) was added acetic anhydride (0.68 ml) at ambient temperature. The reaction mixture was stirred for 21 hours and 20 minutes at ambient temperature and then diluted with ethyl acetate (90 ml). The resultant solution was washed successively with 10% hydrochloric acid (50 ml, 30 ml), water (50 ml), saturated aqueous sodium bicarbonate (50 ml), dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether, and recrystallized from ethanol to give trans-3-acetoxy-4-(2-cyanoimino-3-methylimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.57 g).