Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:4]([CH3:9])=[CH:5][C:6]=1[CH:7]=O.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:1][C:2]1[N:3]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:11]=2)[C:4]([CH3:9])=[CH:5][C:6]=1[CH2:7][N:34]1[CH2:35][CH2:36][CH:31]([C:27]2[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:37])[CH3:20])[CH:30]=[CH:29][CH:28]=2)[CH2:32][CH2:33]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1cc(C=O)c(C)n1-c1cccc(C(F)(F)F)c1
Product: Cc1cc(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c(C)n1-c1cccc(C(F)(F)F)c1

Procedure:
Prepared by Procedure F and Scheme R using 2,5-dimethyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 498.2 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1>CO>[CH3:1][O:2][C:5]1[N:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][CH3:13])=[CH:7][CH:6]=1
Reactant: CCC(=O)c1ccc(Cl)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC(=O)c1ccc(OC)nc1
Yield: 77 %

Procedure:
Sodium methoxide (2.8 g, 50 mmol) was added to a solution of 1-(6-chloro-pyridin-3-yl)-propan-1-one (2.8 g, 16.5 mmol) in methanol (70 mL) and the reaction mixture was heated under reflux for eighteen hours. The solution was concentrated to fifty percent, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated to give product as a colorless oil (2.1 g, 77 percent yield), which was used without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10](Cl)(=[O:21])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>C(#N)C.CN(C1C=CN=CC=1)C.O>[CH3:8][C:2]([O:1][C:10]([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)=[O:21])([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.5 %

Procedure:
To a solution of ethyl 2-hydroxy-2-methylpropanoate (1.2 g) and 4-nitrophenyl chlorocarbonate (1.2 g) in acetonitrile (20 mL) was added DMAP (0.77 g) at 0° C., and the mixture was stirred at room temperature for 3 days. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→25% ethyl acetate/hexane) to give ethyl 2-methyl-2-{[(4-nitrophenoxy)carbonyl]oxy}propanoate (1.3 g, 74%) as a pale-yellow oil.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][C:13]1[S:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[N+:17]=1[CH2:18][CH3:19].C(N(CC)CC)C.[Cl:31][C:32]([Cl:37])([Cl:36])[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[Cl:31][C:32]([Cl:37])([Cl:36])[C:33]([CH:12]=[C:13]1[N:17]([CH2:18][CH3:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1)=[O:34]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC[n+]1c(C)sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN1C(=CC(=O)C(Cl)(Cl)Cl)Sc2ccccc21
Reaction time: 3 h

Procedure:
10 g (28.6 mmol) of 2-methyl-3-ethyl-benzothiazolium p-toluenesulfonate are suspended in 150 ml of toluene, 6.8 g (67.2 mmol) of triethylamine are added and, at 5°-10° C. 6 g (33 mmol) of trichloroacetyl chloride, dissolved in a minor amount of toluene, are added dropwise. After three hours at room temperature, the ammonium salts are filtered off with suction, and the reaction solution is washed with water, dried over sodium sulfate and concentrated in vacuo. The product is caused to crystallize from the diisopropyl ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C

Procedure:
A mixture of 30.0 g 3-(1,1-dimethylethyl)-4-hydroxybenzoic acid methyl ester, 42.9 ml of 1-bromotetradecane, 47.8 g of potassium carbonate and 700 ml of acetone is refluxed for 48 hours. The cooled reaction is filtered, concentrated in vacuo and purified by column chromatography (silica gel:0-3% ethyl acetate/hexane) to give 38.8 g of the desired product as colorless prisms.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: FC(F)(F)c1cccc(I)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4cccc(C(F)(F)F)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 1-iodo-3-trifluoromethyl-benzene.
Reaction SMILES: [CH3:1]I.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[O:22][CH3:23])=[CH:16][CH:15]=1.[H-].[Na+].O>CN(C)C=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:1])[C:21](=[O:24])[O:22][CH3:23])=[CH:16][CH:15]=1
Reactant: CI
Reactant: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N(C)c1ccc(OCc2nc3ccccc3s2)cc1
Reaction time: 0.17 h
Yield: 87 %

Procedure:
0.27 ml of methyl iodide were added to a solution of 138.6 mg of methyl N-[4-(benzothiazol-2-ylmethoxy)phenyl]carbamate (prepared as described in Example 11) in 5 ml of dimethylformamide cooled in an ice-water bath and then 19.4 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to the resulting mixture. The reaction mixture was stirred at the same temperature for 10 minutes, the temperature of the mixture was then elevated to room temperature and the mixture was stirred for a further 30 minutes. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and was then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 2:1 by volume mixture of hexane and ethyl acetate to give 126.7 mg (yield 87%) of the title compound as a solid having a melting point of 85°-87° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:27]1([CH2:30]O)[CH2:29][CH2:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:30][CH:27]2[CH2:29][CH2:28]2)=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC1CC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCC2CC2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and cyclopropyl-methanol in analogy to Example 9c): MS (ISP): 450.2 and 452.0 (M+H)+, 350.2 and 352.2 ((M-Boc)+H)+ (100%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].C(=O)([O-])[O-].[K+].[K+].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][NH:6][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[CH3:7]
Reactant: CN(C)CCCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCCNc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 109.7 %

Procedure:
N,N-Dimethylpropane-1,3-diamine (4.90 ml, 39 mmol) and potassium carbonate (6.37 g, 46 mmol) were added to 1-fluoro-4-nitrobenzene (5.0 g, 35 mmol) and the mixture was heated at 70° C. for 3 hours. Insoluble material was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate (100 ml) and the solution was washed with water (3×100 ml) and saturated sodium chloride (100 ml) and dried. The solvent was removed by evaporation to give the product as a yellow oil (8.57 g). MS (MH+): 248.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1ccccc1Cl
Product: C[C@@H](CCl)COc1ccccc1Cl

Procedure:
Prepared by Procedure U and Scheme AK using 2-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[N+:9]([C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:15]=2[O:14][CH:13]=1)([O-])=O>O.C(O)C>[NH2:9][C:12]1[C:17](=[O:18])[C:16]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:15]=2[O:14][CH:13]=1
Reactant: O=c1c([N+](=O)[O-])coc2ccc(Cl)cc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1coc2ccc(Cl)cc2c1=O
Yield: 75.2 %

Procedure:
Sodium dithionite (20 g, 0.115 mole) was added to a suspension of 3-nitro-6-chloro-4H-1-benzopyran-4-one (7.0 g, 0.037 mole) in water (80 ml) and absolute ethanol (30 ml). The reaction mixture was refluxed under nitrogen for 3 hrs., concentrated at reduced pressure and filtered. The solids were washed with water and recrystallized from acetone to give yellow crystals (5.44 g, 90%), m.p. 184°-186°.
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.I[CH:10]([CH3:12])[CH3:11].[OH-].[K+].[OH-].[Na+]>C(O)C.O>[CH3:11][CH:10]([O:7][C:3]1[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][CH:4]=1)[CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)I
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cccc(O)c1
Yield: 19.5 %

Procedure:
To a solution of 1,3-benzenediol (8 g, 72.7 mmol) and 2-iodopropane (12 g, 70.6 mmol) in ethanol (100 mL preheated at reflux) was added a solution of KOH (83%, 5.3 g, 77.6 mmol) in water (20 mL) over a period of 30 minutes. The mixture was refluxed for 3 hours and poured into NaOH (1 N, 100 mL). The resulting mixture was extracted with ethyl acetate (3 times 50 mL) and the aqueous layer was acidified with 10% HCl to adjust the pH=5 and extracted with ethyl acetate (3 times 50 mL). The combined extracts were washed with brine (50 mL), dried and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE:EtOAc=5:1) to afford the title compound as a colourless oil (2.1 g).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=O)[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>O1CCOCC1>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[S:36])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=S)c2nc1NC(C)(C)C
Temperature: 75 °C
Yield: 38.4 %

Procedure:
A mixture of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.02 g, 0.057 mmol), Lawesson's reagent (Sigma-Aldrich) (0.028 g, 0.069 mmol), Dioxane (0.88 mL) was heated to 75° C. overnight. Reaction mixture was directly loaded onto prep-plate TLC. Purification (3% MeOH/DCM) provided 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridine-4(5H)-thione (292) (8 mg, 36% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.54-1.60 (m, 4H), 1.66 (s, 9H), 2.56 (s, 3H), 2.95-3.08 (m, 2H), 3.62-3.76 (m, 2H), 4.78-4.93 (m, 1H), 7.28-7.31 (m, 1H), 7.34-7.45 (m, 1H), 7.62-7.72 (m, 1H), 7.95-8.04 (m, 1H), 12.69-12.74 (m, 1H). m/z (ES, +ve) 366.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([F:33])=[CH:25][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[C:6]1=[O:24].Cl.CC(O)C>CO>[F:1][C:2]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[C:26]([F:33])=[CH:25][C:3]=1[O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Oc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: CS(=O)(=O)c1cc(F)c(O[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Yield: 95.9 %

Procedure:
To a stirred solution of (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (370 mg, 0.757 mmol) in methanol (5 mL) was added, 5 M HCl in IPA (1.51 mL, 7.57 mmol) and the mixture was stirred at ambient temperature for 6 hours and concentrated in vacuo. The residue was stirred in 1M NaOH (20 mL) and DCM (25 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo to give (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-[1,4′-bipiperidin]-2-one as light brown foam (282 mg, 0.726 mmol, 96% yield). Mass spectrum (apci) m/z=389.1 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:15])([F:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1>>[N+:1]([C:10]1[CH:11]=[CH:12][C:7]([C:6]([F:15])([F:14])[F:5])=[CH:8][C:9]=1[OH:13])([O-:4])=[O:2]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Yield: 27 %

Procedure:
2-Nitro-5-trifluoromethylphenol was prepared by adding concentrated HNO3 (6 mL) drop-wise to α,α,α-trifluoro-m-cresol (5 g, 30.8 mmol) at room temperature. After the addition was complete. the reaction was quenched with saturated ammonium acetate and extracted with EtOAc. The organic was separated, dried over sodium sulfate and filtered. Concentration of the solution in vacuo afforded an oil which was purified by column chromatography (gradient 100% hexane to 50% EtOAc/hexanes) to afford the titled compound as an oil(1.7 g, 27%). 1H NMR (CDCl3): 10.6 (s, 1H, OH), 8.26(d, 1H, J=7.8 Hz), 7.45(s, 1H, arom), 7.26(d, 1H, J=7.8 Hz).
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])=O.[NH4+].C(O)=O>>[CH:8](=[C:7]1[NH:1][C:2](=[O:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccccc1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A mixture of 100 grams (1.0 mole) of hydantoin, 106 grams (1.0 mole) of benzaldehyde, 63 grams (1.0 mole) of ammonium formate, and 230 grams (5.0 moles) of formic acid were held for 3 hours at reflux temperature. After the cooling off, there were obtained 173 grams of 5-benzylidene hydantoin, corresponding to 92% of theory based on hydantoin.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=3[CH:3]=2)=[O:31])=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1nc2ccc(OC(=O)Cc3ccc(Cl)cc3)cc2s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (1.15 g., 0.005 mole) triethylamine (0.7 ml, 0.005 mole) and 4-dimethylaminopyridine (5 mg, catalyst) in dimethylformamide (10 ml) is added 2-(4-chlorophenyl)acetyl chloride (0.8 ml). The reaction mixture is stirred for 2 hours, poured into ice water, acidified with hydrochloric acid and extracted with ether. The organic extract is washed with water and dried over magnesium sulfate. The ether is distilled at reduced pressure and the residue chromatographed on silica gel as eluant (130 g, 70-230 mesh) using ethylacetatehexane (1:1) to give 2-sulfamoyl-6-benzothiazolyl 2-(4-chlorophenyl)acetate which melts at 206°-208° C. after recrystallization from benzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CC(C)([O-])C.[K+]>CC(N(C)C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCc2ccccc2OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 87.2 %

Procedure:
Following a procedure similar to that described in Example 40(a), 1.20 g of 2-[2-(3-methoxyphenyl) ethyl]phenol (prepared as described in Preparation 20), 2.00 g of 1-t-butoxycarbonyl-4-[2-(p-toluenesulfonyloxy)ethyl]piperidine and 0.590 g of potassium t-butoxide were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 2.00 g (yield 86%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=1>>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C(C)=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (329 mg, 0.83 mmol) is coupled to 4′-bromoacetophenone (200 mg, 1.00 mmol) using Method B to give the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][O:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
A mixture of 27.4 g (0.2 mole) of p-isopropylphenol, 63 g (0.4 mole) of 1-bromo-3-chloropropane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 24 hr. The reaction mixture was cooled, filtered and filtrate concentrated. The residue was dissolved in 200 ml of benzene and treated with potassium hydroxide pellets to remove excess starting phenol. The mixture was stirred in ambient temperature for 0.5 hr, filtered through Celite® and the filtrate concentrated to give 36.4 g (87% yield) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:18][NH2:19])[C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
A mixture of 50 g of 4,4'-difluorobenzophenone, 35.5 ml of hydrazine hydrate and 200 ml of ethanol is refluxed for 8 h. It is concentrated to dryness, taken up with water and extracted with ether. The organic phase is washed with water, dried over MgSO4 and then concentrated. The yellow oil obtained crystallizes slowly to give 50.6 g of 4,4'-difluorobenzophenone hydrazone.
Reaction SMILES: [K+].[N+:2]([C:5]1[CH:6]=[C:7]([S:15]([O-:18])(=O)=[O:16])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[Cl:11])([O-:4])=[O:3].P(Cl)(Cl)([Cl:21])=O>C(#N)C.C1S(=O)(=O)CCC1>[N+:2]([C:5]1[CH:6]=[C:7]([S:15]([Cl:21])(=[O:18])=[O:16])[CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[Cl:11])([O-:4])=[O:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)[O-])cc([N+](=O)[O-])c1Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)cc([N+](=O)[O-])c1Cl

Procedure:
760 g (2 moles) 3,5-dinitro-4-chlorobenzenesulfonic acid potassium salt (approx. 85%) and 614 g (4 moles) phosphorus oxychloride were reacted as in Example 1(a) in 800 ml acetonitrile and 800 ml tetramethylenesulfone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:10][C:9]2=[O:25])=[C:4]([CH3:26])[CH:3]=1.[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC>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>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:11]1[CH:12]=[C:13]([CH3:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:27]=[CH2:28])=[CH:3][C:4]=2[CH3:26])[C:9](=[O:25])[CH:10]=1
Reactant: Cc1cc(Br)ccc1-n1c(C)cc(OCc2ccc(F)cc2F)cc1=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c(C)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a 50 ml round bottom flask previously evacuated and filled with nitrogen, 1-(4-bromo-2-methylphenyl)-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (0.420 g, 1.0 mmol) was dissolved in dry THF (10 mL). To this mixture was added Pd (PPh3)4 (0.173 g, 0.15 mmol). The reaction flask was sealed with a rubber septum, evacuated and filled with nitrogen. Under a nitrogen atmosphere, tributyl(vinyl)tin (0.35 ml, 1.2 mmol) was added to the sealed reaction mixture and stirred overnight at 50° C.