Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:34]=[CH:33][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:31]=[CH:30][C:17]([C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[C:16]([OH:32])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:31]=[CH:30][C:17]([C:18]([N:20]([CH:27]([CH3:28])[CH3:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:19])=[C:16]([CH:15]=2)[O:32][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:33][CH:34]=1)#[N:2]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(c1ccccc1)C(C)C
Temperature: 70 °C

Procedure:
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N-(1-methylethyl)-N-phenylbenzamide (250 mg, 0.55 mmol) in 2.5 mL of N,N-dimethylformamide is treated with 60% sodium hydride (22 mg, 0.55 mmol), and ethyl bromoacetate (67 μL, 0.60 mmol) and heated at 70° C. for 2.5 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 50-70% ethyl acetate/hexane as the eluent to afford ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N-(1-methylethyl)-N-phenylaminocarbonyl]phenoxyacetate as colorless foam.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)[C:5]=12.[H-].[Na+].Cl[C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]2[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=2[N:21]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:20]4[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:32])[CH3:30])[C:23]5[CH:33]=[CH:34][CH:35]=[CH:36][C:22]=5[N:21]=4)=[CH:12][CH:11]=3)[C:5]=12
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(-c2cccn3ccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Oc2ccc(-c3cccn4ccnc34)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
To a solution of 4-(imidazo[1,2-a]pyridin-8-yl)phenol (0.68 g) in DMF (10 ml) was added sodium hydride (60% in oil, 0.13 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.53 g) obtained in Example 1, step A), and the mixture was stirred under microwave irradiation at 150° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.53 g).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].CN(C=O)C.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:14][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:8])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NCCO1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C1OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A cold (ice-bath) suspension of sodium hydride (0.55 mole, hexane washed) in 100 mL of dry THF was stirred under a nitrogen atmosphere while a solution of 2-oxazolidinone in 500 mL of 10:1 THF:DMF was added dropwise. The resulting gray suspension was warmed to room temperature and stirred for 24 hour. Benzyl bromide (66 mL, 0.056 mole) was added to the resulting white suspension and stirred at ambient temperature 24 hour. The reaction was quenched by careful addition of 26 mL water and the resulting mixture was concentrated and poured into 500 mL of water. After extraction with methylene chloride, the combined extracts were washed with water and brine and dried over magnesium sulfate. Concentration in vacuo afforded 104 g of a yellow oil which was purified by Kugelrohr distillation (bp 100°/0.1 mm) to give 81 g (92% yield) of the product as a colorless liquid which solidified on standing at room temperature to a colorless solid, m.p. 76°-78°.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16][Cl:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1ccc(F)c(Nc2ccccc2)c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(CCl)cc1Nc1ccccc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Two grams of phosphorus oxychloride was added to 470 mg of 3-anilino-4-fluorobenzyl alcohol with ice-cooling, and the mixture was stirred for 1 hour and then for further 12 hours at 15° C. Thereafter, the reaction solution was poured into a 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride liquor and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation to obtain 450 mg of 3-anilino-4-fluorobenzyl chloride.
Reaction SMILES: FC1C(F)=C(F)[C:5]2=[N:6][C:7]3[N:8](C)[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=O)[C:12]=3[CH:13]=[C:4]2C=1.CN1CCNCC1.O.C(O)(=O)C>CS(C)=O>[N:8]1[C:7]2[C:12](=[CH:13][CH:4]=[CH:5][N:6]=2)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=1
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)c(F)c3nc21
Agent: CN1CCNCC1
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cnc2ncccc2c1
Temperature: 80 °C

Procedure:
A suspension of 4 g of 7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 60 cm3 of dimethyl sulphoxide and 3 g of 1-methylpiperazine is heated at 80° C. for 1 hour and a half. After cooling to about 20° C., 150 cm3 of water are added. 18 cm3 of 10% acetic acid are added to the solution obtained. The precipitate formed is drained, washed with 3 times 50 cm3 of water and recrystallized from 50 cm3 of dimethylformamide. 4 g of 7,9-difluoro-1-methyl-8-(4-methyl-1-pip-erazinyl)-4-oxo-1,4-dihydrobenzo[b]1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 316° C..
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](=[O:22])[C:10]([C:23]#[N:24])=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:29][S:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>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.COCCOC.O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH2:13][N:12]1[C:7]([C:5]2[S:6][C:2]([C:34]3[CH:33]=[N:32][C:31]([S:30][CH3:29])=[CH:36][CH:35]=3)=[CH:3][CH:4]=2)=[CH:8][C:9]([C:25]([F:28])([F:27])[F:26])=[C:10]([C:23]#[N:24])[C:11]1=[O:22]
Reactant: CSc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: N#Cc1c(C(F)(F)F)cc(-c2ccc(Br)s2)n(Cc2ccc(F)cc2F)c1=O
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: [K+]
Solvent: COCCOC
Solvent: O
Product: CSc1ccc(-c2ccc(-c3cc(C(F)(F)F)c(C#N)c(=O)n3Cc3ccc(F)cc3F)s2)cn1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
6-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-benzyl)-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile (270 mg, 0.57 mmol), 2-methylsulfanyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) pyridine (214 mg, 0.85 mmol), potassium carbonate (236 mg, 1.71 mmol), and tetrakis(triphenylphosphine)palladium (0) (66 mg, 0.057 mmol) were mixed with 6 ml 9:1 DME/H2O (v/v), then heated at 80° C. overnight. All solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel (10→40% EtOAC/Hexane, 0.25% Et3N in hexane) to give 1-(2,4-difluoro-benzyl)-6-[5-(6-methylsulfanyl-pyridin-3-yl)-thiophen-2-yl]-2-oxo-4-trifluoromethyl-1,2-dihydro-pyridine-3-carbonitrile as an orange solid (276 mg, 93% yield). 1H-NMR (400 MHz, CDCl3): δ 2.61 (s, 3H), 5.45 (s, 2H), 6.66 (s, 1H), 6.82 (m, 1H), 6.88 (m, 1H), 7.09 (m, 1H), 7.12 (d, 1H, J=3.9), 7.27 (m, 2H, mixed with CDCl3), 7.64 (dd, 1H, J=2.4, J=8.4), 8.67 (dd, 1H, J=2.4, J=0.8).
Reaction SMILES: S(OS([O-])=O)([O-])=O.[Na+].[Na+].[Cl:10][C:11]1[S:12][C:13]([CH:16]=O)=[CH:14][CH:15]=1.[NH2:18][C:19]1[CH:20]=[C:21]([S:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[NH2:25].O>CN1CCCC1=O>[Cl:10][C:11]1[S:12][C:13]([C:16]2[NH:25][C:24]3[CH:23]=[CH:22][C:21]([S:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])(=[O:28])=[O:27])=[CH:20][C:19]=3[N:18]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)CS(=O)(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1ccc(Cl)s1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)CS(=O)(=O)c1ccc2[nH]c(-c3ccc(Cl)s3)nc2c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
14.4 747 mg (3.93 mmol) of sodium disulfite are added to a solution of 1.15 g (7.86 mmol) of 2-chlorothiophene-5-carbaldehyde and 1.92 g (7.86 mmol) of methyl (3,4-diaminobenzenesulfonyl)acetate in 25 ml of 1-methylpyrrolidone, and the mixture is stirred at 110° C. for 18 hours. Water is added to the reaction mixture, which is extracted with dichloromethane. The organic phase is dried over sodium sulfate and evaporated. The residue is stirred with water, and the resultant precipitate is filtered off, giving methyl [2-(5-chlorothiophen-2-yl)-1H-benzimidazole-5-sulfonyl]-acetate as a brown solid; ESI 371.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:36])(C)C>CC(CC)=O>[ClH:36].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: CCCC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-butyryl-1,4,8-triazaspiro[4,5]decan-2-one (272 mg, 10.7 mmol) was dissolved in ethyl methyl ketone (2.2 mL), and water (7 μL) and TMSCl (93 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-butyryl-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 281 mg (95%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:34][NH:35][NH2:36]>C(O)C>[NH2:10][C:6]1[NH:36][N:35]([CH2:34][C:33]2[CH:37]=[CH:38][C:39]([CH3:40])=[C:31]([C:30]([F:41])([F:42])[F:29])[CH:32]=2)[C:4](=[O:3])[C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=C(N)OCC)c1ccccc1
Reactant: Cc1ccc(CNN)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)c(-c3ccccc3)c2=O)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 35.3 g α-phenyl-β-amino-β-ethoxyacrylic acid ethyl ester and 1 g p-toluenesulphonic acid in 150 ml ethanol were added dropwise, under nitrogen, 31.5 g 3-trifluoromethyl-4-methylbenzylhydrazine. After stirring overnight, the solvent was distilled off in a vacuum; the residue was recrystallized from dimethyl formamide.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6]([C:8]1[S:12][C:11]([NH2:13])=[N:10][N:9]=1)=[O:7].[C:14](OCC)(=[O:16])C>>[CH3:5][S:6]([C:8]1[S:12][C:11]([N:13]=[C:1]=[O:2])=[N:10][N:9]=1)=[O:7].[CH3:5][S:6]([C:8]1[S:12][C:11]([N:13]=[C:14]=[O:16])=[N:10][N:9]=1)(=[O:2])=[O:7]
Reactant: CCOC(C)=O
Reactant: O=C(Cl)Cl
Reactant: CS(=O)c1nnc(N)s1
Product: CS(=O)(=O)c1nnc(N=C=O)s1
Product: CS(=O)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methylsulfinyl-2-amino-1,3,4-thiadiazole (50 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C([N:18](CC)CC)C.ClC(OC)=O.[Cl:28][C:29]1[CH:35]=[CH:34][C:32](N)=[CH:31][CH:30]=1>C(Cl)(Cl)Cl>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([C:10]2[N:11]=[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]3[C:8](=[O:15])[C:9]=2[C:12]([NH2:18])=[O:14])=[CH:31][CH:30]=1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCN(CC)CC
Reactant: Nc1ccc(Cl)cc1
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cccc2nc(-c3ccc(Cl)cc3)c(C(N)=O)c(=O)n12
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -10° C. and -12° C. during 20 minutes. Alter stirring for 5 minutes, 11.23 g (0.088 mol) of 4-chloroaniline dissolved in 80 ml of chloroform are dropped to the above solution at -10° C. during 35 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 18.5 g (73.7%) of the named compound as yellow crystals alter recrystallization from ethanol, m.p.: 202°-204° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(#N)C>[CH2:18]([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Yield: 103.2 %

Procedure:
To 2-nitro-5-fluorophenol (6.28 g) in acetonitrile (50 ml) was added potassium carbonate (5.6 g) and benzyl bromide (7.2 g). The mixture was stirred at reflux for 2 hrs, added to water and extracted with diethyl ether. The organic layer was washed with brine, dried and evaporated to dryness to give 2-(benzyloxy)-4-fluoro-nitrobenzene (10.2 g) as a solid. nmr (deuterochloroform): 5.2d (s), 2H; 6.7d, (m), 1H; 6.8d (q), 1H; 7.4d (m), 5H; 8.0d, (q), 1H;
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:16]1([S:22][C:4]2[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=2[C:6]#[N:7])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(C(F)(F)F)cc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of 2-nitro-4-trifluoromethylbenzonitrile (8.64 g), thiophenol (4.4 g) and potassium carbonate (6.9 g) in acetonitrile was stirred at room temperature for 1 hour then heated at reflux for 9 hours. Thiophenol (0.3 ml) was added and the mixture was stirred and heated at reflux for 1 hour. Water was added and the mixture was extracted with dichloromethane, dried (MgSO4) and filtered. The flitrate was evaporated to dryness and the residue was recrystallized from n-hexane to give 2-(phenylsulphenyl)-4-trifluoromethylbenzonitrile (9.5 g) as a white solid, m.p. 51° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[OH:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:18]
Reactant: Nc1ccc(F)cc1O
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)Nc1ccc(F)cc1O
Yield: 91 %

Procedure:
N-(2-Hydroxy-4-fluorophenyl)-N′-phenylurea was prepared from 2-amino-5-fluoro phenol (200 mg, 1.57 mmol) and phenyl isocyanate according to the procedure in General Method A. The product was purified by precipitation from toluene and filtering to afford the titled compound (352 mg, 91%). mp: 195.5-195.7° C.; 1H NMR (CD3OD/CDCl3): δ 7.70 (m, 1H), 7.3 (d, 2H, J=8.25 Hz), 7.15 (t, 2H, J=8.25 Hz), 6.89 (t, 1H, J=8.25 Hz), 6.50-6.38 (m, 2H); EI-MS m/z 246 (M+H)+; Anal. (C13H11N2O2F) C, H, N.
Reaction SMILES: BrC[C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:5][CH:4]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[C:28](#N)C>C(OCC)(=O)C>[N:22]1([CH2:28][CH:7]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:10][C:9]2=[O:19])[C:6]2[CH:5]=[CH:4][CH:3]=[CH:21][CH:20]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C1COCCN1
Reactant: O=C1O[C@H](c2ccccc2)CN1Cc1ccc(CBr)cc1
Reactant: CC#N
Solvent: CCOC(C)=O
Product: O=C1O[C@H](c2ccccc2)CN1C(CN1CCOCC1)c1ccccc1
Yield: 69 %

Procedure:
A solution of 3-(4-bromomethyl-benzyl)-5-(R)-phenyl-oxazolidin-2-one (30 mg, 0.086 mmol) and morpholine (0.038 mL, 0.433 mmol) in acetonitrile (2 mL) was heated at 70° C. for 4 hours. The reaction mixture was diluted with ethyl acetate (6 mL), washed with water (4 mL), brine (4 mL), dried over anhydrous sodium sulfate and concentrated to get the product. It was purified by chromatography on silica gel, eluting with 30-60% ethyl acetate in hexanes, to yield the title compound as a white solid (21 mg, 69%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=C[C:10]([O:18][CH3:19])=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1.S(Cl)([Cl:23])(=O)=O.[CH2:25]([Cl:27])Cl>>[Cl:23][C:12]1[C:13]2[C:8](=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:15][CH:14]=2)[C:25]([Cl:27])=[C:10]([O:18][CH3:19])[C:11]=1[O:16][CH3:17]
Reactant: ClCCl
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc2ccc(CCCCCl)cc2cc1OC
Product: COc1c(OC)c(Cl)c2cc(CCCCCl)ccc2c1Cl
Temperature: 24 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
To a stirred solution of 3.0 g (0.011 mole) of 2-(4-chloro-butyl)-6,7-dimethoxynaphthalene in 25 mL of methylene chloride cooled in an ice bath was added 1.8 mL (0.023 mole) of sulfuryl chloride in 10 mL of methylene chloride over 15 minutes. The reaction mixture was stirred at 3° C. for 30 minutes, at 24° C. for 6 hours and then was washed with sodium bicarbonate solution, dried and concentrated under reduced pressure. Purification by HPLC using 2.5% ethyl acetate-hexane gave 3.32 g (79% yield) of 1,4-dichloro-6-(4-Chlorobutyl)-2,3-dimethoxynaphthalene as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:18]([N:20]([CH2:23][CH3:24])[CH2:21]C)[CH3:19].ClC(OC1C=CC=CC=1)=[O:27]>O1CCCC1>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:21]([N:20]3[CH2:23][CH2:24][CH2:19][CH2:18]3)=[O:27])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCCC1
Temperature: 25 °C

Procedure:
4-(4-Nitrophenoxy)pyridin-2-ylamine (100 mg) was dissolved in tetrahydrofuran (5 ml) under a nitrogen atmosphere, triethylamine (0.181 ml) and phenyl chloroformate (0.163 ml) were added while stirring and cooling in an ice water bath. The reaction mixture was allowed to warm up to room temperature and stirred for 30 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (30 ml). The separated organic layer was washed with water (30 ml) and brine (30 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added N,N-dimethylformamide (5 ml), and pyrrolidine (0.181 ml) was added, followed by stirring for 2 hr. The reaction mixture was concentrated under reduced pressure, and the resultant residue was partitioned after addition of ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (30 ml). The separated organic layer was washed with a saturated aqueous solution of ammonium chloride (30 ml), water (30 ml) and brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:3, then ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to provide the roughly-purified titled compound as a pale yellow solid (116.8 mg).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:15]=2)[N:10]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:9]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH:26]([S:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:15]=[C:16]3[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:9][N:10]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:30])=[O:31])[C:11]3=[N:12][CH:13]=2)=[CH:22][CH:21]=1)(=[O:24])=[O:25])([CH3:28])[CH3:27]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(C#C[Si](C)(C)C)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
(Trimethylsilyl)acetylene (168.1 mg, 241.9 μL, 1.711 mmol) was added dropwise to a stirred solution of 7-iodo-2-(4-isopropylsulfonylphenyl)-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine (765 mg, 1.316 mmol), triethylamine (665.8 mg, 917.1 μL, 6.580 mmol), copper(I) iodide (30.07 mg, 0.1579 mmol) and Pd(PPh3)4 (76.04 mg, 0.06580 mmol) in DMF (7 mL) at 0° C. and the resulting solution allowed to warm to ambient temperature over 64 hours. The solution was added dropwise to a mixture of EtOAc/ice water and the layers separated. The organic layer was washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 2 to 20% EtOAc/DCM, loaded in DCM) to give the sub-title product as a beige solid (410.4 mg, 56% Yield). 1H NMR (400.0 MHz, DMSO) δ 0.17 (t, 9H), 1.07 (d, 6H), 2.38 (qn, 3H), 3.45-3.50 (m, 1H), 7.36 (d, 2H), 7.90 (d, 2H), 7.96 (d, 2H), 8.27 (d, 2H), 8.60 (s, 1H) and 9.08 (s, 1H) ppm; MS (ES+) 552.0.