Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:13])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7]2.[C:21](O)(=[O:25])[C:22](O)=[O:23]>Cl>[Br:1][C:2]1[C:3]2[CH2:4][CH2:5][N:6]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:7][C:8]=2[C:9]2[NH:13][C:21](=[O:25])[C:22](=[O:23])[NH:12][C:10]=2[CH:11]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Br)c2c(c1N)CN(Cc1ccccc1)CC2
Agent: Cl
Product: O=c1[nH]c2cc(Br)c3c(c2[nH]c1=O)CN(Cc1ccccc1)CC3
Temperature: 25 °C
Yield: 76.5 %

Procedure:
A solution of the product from Example 7 (0.64 g, 1.93 mmol) in 3N HCl (25 mL) was treated with oxalic acid (0.37 g, 2.9 mmol) and refluxed for four hours. When cool to room temperature the precipitate was filtered, suspended in water (70 mL) and basifyed to pH 10. The solids were filtered, and dried to give the title compound (0.57 g, 89%) as a light brown solid, mp=297-302° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][S:8]3)[C:4](=[O:17])[C:3]=1[C:18](=[O:27])[N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[OH:1][C:2]1[C:11]2[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]3[C:10]=2[N:5]([CH2:6][CH2:7][S:8]3=[O:33])[C:4](=[O:17])[C:3]=1[C:18](=[O:27])[N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc2c3c(c1)c(O)c(C(=O)N(C)c1ccccc1)c(=O)n3CCS2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cc2c3c(c1)c(O)c(C(=O)N(C)c1ccccc1)c(=O)n3CCS2=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
A mixture of 2,3-dihydro-7-hydroxy-9-methoxy-6-(N-methyl-N-phenylcarbamoyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzothiazine (1 g) and m-chloroperoxybenzoic acid (0.5 g) in dichloromethane (50 ml) was stirred at 5° C. for 1 hour. The insoluble material was filtered and the filtrate was concentrated in vacuo. The residue (1.5 g) was recrystallized from acetone to give pale yellow crystals of 2,3-dihydro-7-hydroxy-9-methoxy-6-(N-methyl-N-phenylcarbamoyl)-5-oxo-5H-pyrido[1,2,3-de]-1,4- benzothiazine 1-oxide (0.86 g).
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].[N:5]([C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:28])[C:13]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:15]2)=[CH:10][CH:9]=1)=[N+]=[N-]>O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12](=[O:28])[C:11]3[CH:10]=[CH:9][C:8]4[N:5]=[C:1]([CH3:2])[O:3][C:17]=4[C:16]=3[O:15][C:14]=2[CH:18]([CH3:20])[CH3:19])=[CH:22][CH:23]=1
Reactant: CC(C)c1oc2cc(N=[N+]=[N-])ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: CC(=O)O
Solvent: O
Product: Cc1nc2ccc3c(=O)c(-c4ccc(Cl)cc4)c(C(C)C)oc3c2o1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Acetic acid (20 ml) is added to polyphosphoric acid (˜25 g) heated to 80° C. The viscous solution is stirred vigorously for 5 min. 7-azido-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (1.0 g, 2.95 mmol) is added portionwise over a period of 10 min. The reaction mixture is heated at 120° C. for 3 h, cooled to room temperature and poured into water (200 ml), and the product is extracted with CH2Cl2. The organic phase is washed with water and brine, dried (MgSO4) and filtered. Methanol (30 ml) is added, followed by partial evaporation in vacuo to give a precipitate, which is isolated by filtration.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([O:13]C)=[N:11][C:10]2[C:5]1=[N:6][C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:8][C:9]=2[NH2:15].C(N(CC)CC)C.Cl[S:29]([C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>C(#N)C>[NH2:15][C:9]1[N:8]=[C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:6]=[C:5]2[C:10]=1[NH:11][C:12](=[O:13])[N:4]2[CH2:3][CH2:2][NH:1][S:29]([C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCN)c2n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCNS(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1

Procedure:
The compound obtained in Example 2-1 step (vii) (245 mg), triethylamine (0.13 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (217 mg) were dissolved in acetonitrile (5 ml) and the same manner to Example 2-13 step (iii) was conducted to give the titled compound as a white solid. Yield: 40 mg (9%); MS APCI+ve 479 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](O)=O.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([C:6]1[S:17][C:16]([NH2:18])=[N:15][N:14]=1)[CH3:9]
Reactant: NNC(N)=S
Reactant: Cc1ccccc1OC(C)C(=O)O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1OC(C)c1nnc(N)s1
Temperature: 90 °C

Procedure:
A 100 milliliter flask adapted with a paddle stirrer, thermometer, an addition funnel, condenser and drying tube was charged with 7.2 grams (0.040 mole) of 2-(2-methylphenoxy)propanoic acid, 3.6 grams, (0.040 mole) of thiosemicarbazide and 30 milliliters of dioxane. The slurry was heated to 90° C. and the addition funnel was charged with phosphorous oxychloride (POCl3). The POCl3 (6.7 grams; 0.044 mole) was slowly added (for 20 minutes) while maintaining the temperature within 90°-95° C., a gooey white precipitate formed. When the addition was completed the mixture was refluxed for 60 minutes. The flask was evacuated by using a water aspirator to remove volatiles (HCl, POCl3 and some dioxane), and then 50 milliliters of water was added and mixture was made basic by the addition of 50 percent solution of NaOH until the pH of the solution was 10. The white precipitate was filtered off, washed with water and dissolved in the minimum amount of 95 percent ethanol, to which a small amount of a 10 percent sodium hydroxide solution was added to make the ethanol solution basic. Water was added until a precipitate formed and the solution was cooled in the refrigerator, then suctioned filtered. The precipitate was washed with water, and dried in a vacuum oven at 70° C. to white crystals of 5-[1-(2-methylphenoxy)ethyl]-2-amino-1,3,4-thiadiazole (6.8 grams--melting point 176°-179° C.)
Reaction SMILES: [C:1]12[CH2:9][O:8][CH2:7][C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2.[N+]([O-])(O)=[O:11].O>C(O)(=O)C>[CH:7](=[O:11])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]=[O:8]
Reactant: c1ccc2c(c1)COC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccccc1C=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
In a 1000-ml three-neck flask equipped with a thermometer, a reflux condenser and a stirrer were placed 50 g of o-xylylene oxide, 43.8 g of 60% by weight nitric acid, 203.1 g of water, and 220.6 g of acetic acid. The mixture was raised in temperature to 70° C. on an oil bath and was stirred under these conditions for 4 hours. After cooling, the reaction mixture was analyzed by gas chromatography to find that the raw material o-xylylene oxide was completely absent and that phthalaldehyde was formed in a yield of 50%. The obtained reaction mixture was extracted with two portions of toluene, the organic layer was distilled and thereby yielded phthalaldehyde in a yield of 35% on the basis of o-xylylene oxide. Gas chromatographic analysis revealed that phthalaldehyde had a purity of 93.0%. In addition, phthalide was formed in a yield of 9%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[C:17]([NH2:21])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>COCCOC>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:19][CH2:18][C:17](=[O:20])[NH2:21]
Reactant: C=CC(N)=O
Reactant: Brc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: NC(=O)CCN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12

Procedure:
A stirred mixture of 5-bromo-3-(2(R)-pyrrolidinylmethyl)-1H-indole (Preparation 2; 600 mg, 2.1 mmol), acrylamide (168 mg, 2.4 mmol), triethylamine (0.60 ml) and 1,2-dimethoxyethane (11.9 ml), under nitrogen, was heated under reflux for 8 hours, allowed to cool, then partitioned between ethyl acetate (400 ml) and water (400 ml). The organic phase was separated, washed with water (400 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a solvent gradient of 0.880 aqueous ammonia:methanol: dichloromethane (0.1:10:90 to 0.4:10:90), to afford the required product as a foam. Rf 0.26 (SS 7). [α]D25 +59° (c=0.1, CH3OH).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]([CH3:14])[CH2:10][SiH:11]([Cl:13])[Cl:12].[CH2:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:13][Si:11]([Cl:12])([CH2:10][CH:9]([C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:14])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccc(C)c(C(C)C[SiH](Cl)Cl)c1
Reactant: C=Cc1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: Cc1ccc(C)c(C(C)C[Si](Cl)(Cl)CCc2ccccc2)c1
Yield: 78 %

Procedure:
In the same apparatus and procedure as EXAMPLE 1, 6.2 g (0.027 mole) of 3-(2,5-dimethylphenyl)-1,1-dichloro-1-silabutane, 5.4 g (0.05 mole) of styrene, and 90 μl of 1% chloroplatinic acid in isopropanol were placed and refluxed under the dry nitrogen atmosphere for 3 hours. Vacuum distillation of the reaction products gave 7.4 g (bp, 139°-141° C./0.6 mmHg) of 3,3-dichloro-5-(2,5-dimethylphenyl)-1-phenyl-3-silahexane.
Reaction SMILES: [C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=4[CH2:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:39].C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[ClH:39].[C:1]1([N:7]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:8]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH3:29])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:44])[NH2:26])=[CH:21][C:20]=4[CH2:27][CH3:28])=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1CC)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1CC)n2C)c1ccccc1

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyano-2-ethyl-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](O)(=[O:35])[CH3:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:33]([O:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:10]1)(=[O:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(=O)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)N(C(=O)OC(C)(C)C)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred mixture of (2S,4R)-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethy-4-hydroxypyrrolidine (21.7 g, 47.6 mmol), acetic acid (3.0 ml, 52.4 mmol) and PPh3 (12.5 g, 52.4 mmol) in THF (330 ml) was added DIAD (9.4 ml, 47.6 mmol) at room temperature under an atmosphere of nitrogen. After 2 h stirring the same temperature, the mixture was heated at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel [1 Kg, n-hexane/EtOAc(5/1)], to give (2S,4S)-4-acetoxy-1-tert-butoxycarbonyl-2-tert-butyldiphenylsilyloxymethypyrrolidine (23.3 g, 99%) as a colorless oil. 1H-NMR (CDCl3) δ1.06 (s, 9H), 1.35 and 1.43 (s, 9H, amide isomers), 1.92 (br, 3H), 2.20-2.45 (m, 2H), 3.31-4.07 (m, 5H), 5.17-5.30 (m, 1H), 7.36-7.44 (m, 6H), 7.65-7.71 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:55]1[CH2:59][C:58](=[O:60])[NH:57][CH2:56]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:31])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:55]4[CH2:59][C:58](=[O:60])[NH:57][CH2:56]4)=[O:22])=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C1CNCN1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (50 mg, 0.10 mmol, 1.00 equiv), N,N-dimethylformamide (2 mL), EDCI (38 mg, 0.20 mmol, 2.00 equiv), HOBt (27 mg, 0.20 mmol, 2.02 equiv), TEA (50 mg, 0.49 mmol, 5.00 equiv), imidazolidin-4-one (17 mg, 0.20 mmol, 2.00 equiv). The resulting solution was stirred for 30 min at 25° C. The resulting solution was allowed to react, with stirring, for an additional 5 h at 25° C. The reaction was then quenched by the addition of 10 ml of water. The resulting solution was extracted with 2×10 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with PE/EA (1/1). This resulted in 50 mg (79%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]imidazolidin-4-one as yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1cccc(Sc2ccc(Br)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3cccc(Cl)c3)cc2)c1C
Yield: 26.2 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(3-chlorophenylsulfanyl)-benzene (0.159 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(3-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.065 g, 26%) as a solid.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:6]([S:9]CCC(OCC)=O)=[N:7][N:8]=1.Cl>C1COCC1.CO>[Br:3][C:4]1[N:5]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:27]3[CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:6]([SH:9])=[N:7][N:8]=1
Reactant: CCOC(=O)CCSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Sc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
Aqueous lithium hydroxide solution (1M, 437 μL, 0.437 mmol, 3 eq.) was added to a solution of ethyl 3-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)propanoate (65 mg, 0.146 mmol) in THF (1.5 mL) and methanol (1 mL). The mixture was stirred at room temperature for ˜2 hours, and HCl (1N, 584 μL, 0.584 mmol, 4 eq.) added. The mixture was concentrated, a little water added, sonicated and the off-white solids isolated by filtration. The isolated material was placed into small amount of methanol, sonicated again, and then filtered to give 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazole-3-thiol as an off-white solid (39 mg, 78%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:33](Br)([CH3:35])[CH3:34].CN(C)C=O>O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:33]([CH3:35])[CH3:34])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Br
Reactant: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
A mixture of 0.5 g of 1-(3-phenoxyphenyl)-4-(4-hydroxyphenyl)-4-methylpentane, 1.5 g of K2CO3, 3 ml of isopropyl bromide and 20 ml of dimethylformamide was stirred at 130° C. for two hours. The reaction mixture was poured into water and extracted with benzene. The benzene extract was washed with water and dried, and the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: benzene) to give 0.3 g of 1-(3-phenoxyphenyl)-4-(4-isopropoxyphenyl)-4-methylpentane.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.Cl[C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20]>ClCCl.N1C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:1][C:2]1([C:5]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)=[O:20])[CH:23]=[CH2:24]
Reactant: CC(C)(C)OC(=O)c1ccc(C2(N)CC2)cc1
Reactant: C=CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)NC1(c2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 0 °C

Procedure:
3 g of tert-butyl 4-(1-aminocyclopropyl)benzoate was placed in 30 mL of dichloromethane and 1.8 mL of pyridine. The solution was cooled to 0° C. and 1.2 mL of allyl chloroformate (dissolved in 5 mL of dichloromethane) was added dropwise at 0° C.-5° C. The mixture was left to react for 30 minutes at 0° C. and 2 hours at RT. The solution was combined with silica gel and evaporated down to the residue. This was chromatographed with dichloromethane on silica gel 70. Yield: 1.46 g of oil.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:13].[CH2:14](N(CC)CC)[CH3:15]>CCO.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:14]([C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:13])=[CH2:15]
Reactant: CCN(CC)CC
Reactant: Cc1cc2c(c(C)c1Br)COC2=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2c(c1C)COC2=O
Temperature: 140 °C

Procedure:
5-Bromo-4,6-dimethyl-2-benzofuran-1(3H)-one (375 mg, 1.56 mmol), potassium vinyl trifluoroborate (417 mg, 3.11 mmol), Pd(dppf)Cl2 (127 mg, 0.156 mmol), and triethylamine (409 μL, 3.11 mmol) were combined together in EtOH (10 mL) and heated at 140° C. for 30 min. Analysis by LC as well as TLC (hexanes/EtOAc=1/0.3) indicated that reaction had gone to completion. The reaction mixture was then diluted with EtOAc, washed with NaCl, dried over Na2SO4, filtered, and concentrated to dryness. The resulting residue was then re-dissolved in dichloromethane, absorbed to silica gel, concentrated, and loaded onto a silica MPLC column for separation to afford of 5-ethenyl-4,6-dimethyl-2-benzofuran-1(3H)-one.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]#[N:13])[C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([F:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1.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:14][C:9]1[C:10]([C:12]#[N:13])=[N:11][C:2]([C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)c(C#N)nc1Cl
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(Cl)c(C#N)nc1-c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
A solution of methyl 2,5-dichloro-6-cyanonicotinate (2.0 g, 8.6 mmol), (3,5-difluorophenyl)boronic acid (1.5 g, 9.5 mmol) and potassium carbonate (2.6 g, 19 mmol) in water (16 mL) and 1,4-dioxane (41 mL) were bubbled with nitrogen gas (10 minutes). Bis(triphenylphosphine)palladium(II) chloride (0.67 g, 0.95 mmol) was added and the mixture was bubbled with nitrogen gas (10 minutes). The mixture was heated at 80° C. for 1 hour and diluted with ethyl acetate and water. The aqueous layer was separated and extracted again with ethyl acetate. The combined extracts were washed with water, washed with brine, dried over sodium sulfate, filtered and evaporated. Purification on silica gel using ethyl acetate in hexanes (0-50%) gave the desired compound (2.5 g, 94%). LCMS calculated for C14H8ClF2N2O2 (M+H)+: m/z=309.0. found: 308.9.