Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21]([OH:23])=O)=[O:15])[CH2:7][CH2:6]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([CH:16]1[S:20][CH2:19][NH:18][C@@H:17]1[C:21]([N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])=[O:15])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(CC(=O)C1SCN[C@@H]1C(=O)O)C2
Reactant: C1CCNC1
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: COc1ccc2c(c1)CCC(CC(=O)C1SCN[C@@H]1C(=O)N1CCCC1)C2
Yield: 52 %

Procedure:
A colorless oil of 1-[3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]pyrrolidine was prepared in the same manner as in Example 1, except that 3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline prepared in Reference Example 23 and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 52%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]([OH:28])=O)=[CH:23][C:22]=4[CH:29]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[CH2:33]([NH:36][C:37](=[O:46])[C@H:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH2:39])[CH2:34][CH3:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:46]=[C:37]([NH:36][CH2:33][CH2:34][CH3:35])[CH:38]([NH:39][C:26]([C:24]1[O:25][C:21]2[CH:22]=[CH:29][C:18]([NH:17][C:15]([C:10]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:30])([F:31])[F:1])=[CH:8][CH:7]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])=[CH:19][C:20]=2[CH:23]=1)=[O:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCCNC(=O)[C@@H](N)c1ccccc1
Reactant: O=C(O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCNC(=O)C(NC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2o1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product from step (d) (100 mg, 0.235 mmol), (S)-N-propyl-2-phenylglycinamide hydrochloride salt (1 eq.) and PyBrop (1.1 eq.) were dissolved in CH2Cl2 (2 mL), followed by the addition of diisopropylethylamine (3 eq.), and the reaction mixture was stirred at room temperature between 2 hours. The solvent was then evaporated, and the product was purified by prep-TLC using 2:1 EtOAc/hexane as eluting solvent, and the yield was 79 mg.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12](Cl)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([O:33][C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cnn(Cc3ccccc3)c(=O)c2Oc2ccc(Cl)cc2)cc1
Temperature: 50 °C
Yield: 85.7 %

Procedure:
A mixture of 2-benzyl-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (187 mg, 0.5 mmol), prepared in Example 78, p-chlorophenol (129 mg, 0.5 mmol) and NaH (60% oil suspension) (40 mg, 1 mmol) in THF (25 mL) was refluxed at 50° C. for 3 hours and then concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The acetate layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed (silica gel, 1:1 hexanes-ethyl acetate) to provide 2-benzyl-4-(4-chlorophenoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 200 mg, 82%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH3:9][C@H:10]([O:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[N:30]([CH3:33])[CH2:31][O:32][C:27]=3[CH:26]=2)[CH:23]=1)[C:18]([OH:20])=O)[CH2:11][O:12][CH3:13].[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][C@H:10]([O:14][C:15]1[CH:16]=[C:17]([C:18]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:20])[CH:21]=[C:22]([O:24][C:25]2[CH:36]=[CH:35][C:28]3[C:29](=[O:34])[N:30]([CH3:33])[CH2:31][O:32][C:27]=3[CH:26]=2)[CH:23]=1)[CH2:11][O:12][CH3:13]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC[C@H](C)Oc1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 1 h
Yield: 52.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.13 mL, 0.97 mmol) was added to a solution of 3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(3-methyl-4-oxo-3,4-dihydro-2H-1,3-benzoxazin-7-yl)oxy]benzoic acid (0.25 g, 0.65 mmol) in DCM (10 mL) and stirred for 1 hour. 1,1-Dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (0.18 g, 0.97 mmol) then pyridine (0.11 mL, 1.29 mmol) were added and the reaction stirred for a further 45 mins then reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound as a golden oil (0.19 g). 1H NMR δ (CDCl3): 1.32 (d, 3H), 1.63 (s, 9H), 3.10 (s, 3H), 3.40 (s, 3H), 3.48-3.60 (m, 2H), 4.56-4.60 (m, 1H), 5.18 (s, 2H), 6.54 (d, 1H), 6.73-6.76 (m, 1H), 6.83 (t, 1H), 7.07-7.08 (m, 2H), 7.25-7.26 (m, 1H), 7.95 (d, 1H), 8.00 (d, 1H), 8.65 (s, 1H); m/z 551 (M−H)−
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])(=O)=O.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([NH:16][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: C#CCCCCOS(C)(=O)=O
Product: C#CCCCCNC(C)(C)C

Procedure:
A solution of 3.5 g of 17b in 30 ml of tert-butyl amine was stirred at ambient temperature for 24 hrs. The reaction mixture was concentrated and the residues were partitioned between ethyl acetate and 5% NaHCO3. The organic layer was dried and concentrated, to provide 3.0 g of 17c as a colorles oil, which was used without further purification in next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([Cl:30])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:28])[CH3:29]
Reactant: O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Yield: 89.4 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(3-fluorophenyl)methyl]-1-indanol (98% trans, 2% cis) and 0.93 g (0.004 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.55 g of trans-3-[(3-fluorophenyl)methyl]-1-indanyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:3]1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H-].[Na+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N+:39]([O-:41])=[O:40])=[O:32].O>CN(C)C=O>[N+:39]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:31](=[O:32])[CH2:30][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][CH:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:2]1=[O:1])([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2NC1=O
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CN(C(=O)C(C)(C)C)c2ccccc2N(CC(=O)c2ccccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.4 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (100 mg) was added to a suspension of 60% sodium hydride (22 mg) in N,N-dimethylformamide (5 ml), the mixture was stirred at room temperature for 15 minutes. Subsequently, 2-bromo-2′-nitroacetophenone (102 mg) was added thereto, and stirred at room temperature for one hour. Water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue for trituration and collected by filtration, to thereby to obtain 76 mg of the title compound as a light yellow solid (Yield: 52%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[CH2:9]([CH2:13][C:14](=O)[CH3:15])[C:10]([CH3:12])=O.O>C1(C)C=CC=CC=1>[CH3:15][C:14]1[N:7]([C:6]2[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=2)[C:10]([CH3:12])=[CH:9][CH:13]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(O)cc1

Procedure:
A mixture of 4.0 g of p-aminophenol and 4.0 g of acetonylacetone is heated under reflux in toluene for 3 hours using a Dean Stark water separator to yield 4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenol. Condensation with ethyl alpha-bromoisobutyrate in ethyl alcohol in the presence of potassium carbonate gives ethyl 2-[4-(2,5-di-methyl-1H-pyrrol-1-yl)-phenoxy]-2-methylpropanoate. Hydrolysis with 1.5 N sodium hydroxide solution yields 2-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenoxy]-2-methyl-propanoic acid, m.p. 178°-180°.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([S:13][C:14]1[C:23]([NH:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>>[CH2:6]([S:13][C:14]1[C:23]([NH:24][CH2:25][C:2]([O:4][CH3:5])=[O:3])=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)Cl
Reactant: CNc1cccc(C(=O)OC)c1SCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CNc1cccc(C(=O)OC)c1SCc1ccccc1

Procedure:
4.6 ml of methyl chloroformate are added dropwise to a suspension of 15.0 g (0.052 mol) of methyl 2-benzylmercapto-3-methylaminobenzoate and 5.88 g (0.07 mol) of sodium hydrogen carbonate in 100 ml of CH2CN. After 5 h volatile components are removed by distillation (15 torr, 40° C.). The residue is taken up in ethyl acetate and washed in succession with 1 N hydrochloric acid and water. The organic phase is dried over MgSO4 and then the solvent is removed by distillation. Methyl 2-benzylmercapto-3-(N-methoxycarbonylmethylamino)benzoate is obtained in the form of a yellowish oil )14.8 g); 1H NMR (CDCl3, 80 MHz): δ=3.0 (s, 3H, N-CH3), 3.6 (s, 3H, O-CH3), 3.9 (s, 5H, OCH3 and SCH2Ph), 7.1-7.6 (m, 8H, Harom.).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH3:7][C:8]([CH3:10])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(NCC)C>ClCCl>[CH3:7][C:8]1([CH3:10])[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1
Reactant: CC(O)CCS
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCNCC
Solvent: ClCCl
Product: CC1CCSC(C)(C)O1

Procedure:
75 ml of dichloromethane is placed into a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 3.2 grams (0.055 moles) of acetone is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with diethyl amine to a pH of about 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 7.2 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 3 fractions:
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C)=[O:8])[CH2:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:3]1=[O:17].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:3]1=[O:17]
Reactant: COC(=O)C1CN(c2cccnc2)C(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)N(c2cccnc2)CC1C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-bromopyridine (316 mg, 2. mmol) and methyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (316 mg, 2 mmol) (prepared as described in step (ii) of Example 8) in 1,4-dioxane (10 ml) was treated with cesium carbonate (977 mg, 3 mmol), Xantphos™ (87 mg, 0.15 mmol) (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, e.g. available from Aldrich, CAS no. 161265-03-8) and tris(dibenzylideneacetone)dipalladium(0) (45.8 mg, 0.05 mmol) and the mixture was heated under reflux under argon for 22 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate (273 mg, 58%). LC/MS [M+H]+=236. (ii) A solution of methyl 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylate (0.27 g, 1.15 mmol) in tetrahydrofuran (3 ml) at 0° C. was treated with a solution of lithium hydroxide (0.030 g, 1.26 mmol) in water (2 ml) and the mixture was stirred at 0° C. for 90 minutes. Hydrochloric acid (2M) was added to adjust the pH of the reaction mixture to pH 2 and the solvent was evaporated. The residue was dried over phosphorus pentoxide to give crude 3-methyl-2-oxo-1-(3-pyridinyl)-4-imidazolidinecarboxylic acid which was used in the next step. LC/MS [M+H]+=222.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:10]([C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])=[CH:9]2.[N:33]([Si](C)(C)C)=[N+:34]=[N-:35].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:2]([Cl:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][CH2:16][CH2:17][C:18]1[NH:35][N:34]=[N:33][N:19]=1)[C:10]([C:20]([N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:21])=[CH:9]2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCn1c(C(=O)N2CCOCC2)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCc1nnn[nH]1)N1CCOCC1
Yield: 79.8 %

Procedure:
To a solution of 4-[5-(2,6-dichlorobenzyloxy)-2-(1-morpholin-4-yl-methanoyl)indol-1-yl]butyronitrile (0.085 g, 0.18 mmol) in toluene (10 mL) was added azidotrimethylsilane (0.071 mL, 0.54 mmol) and dibutyltin oxide (0.014 g, 0.054 mmol). The reaction mixture was heated to reflux and stirred under argon at reflux temperature for 40 h. The solution was then cooled and the toluene removed under reduced pressure. Methanol was then added and removed under reduced pressure. Ethyl acetate was added and the reaction mixture was washed with water and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 10% methanol/dichloromethane) yielded a white solid (0.074 g, 79%). MS(ES) m/e 515.2 [M+H]+.
Reaction SMILES: COC(=O)C.[CH2:6]([O:8][C:9](=[O:24])[CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19](Cl)(=O)=O)=[CH:14][C:13]=1[CH3:23])[CH3:7].S(=O)(=O)(O)O>C(O)C>[CH2:6]([O:8][C:9](=[O:24])[CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([SH:19])=[CH:14][C:13]=1[CH3:23])[CH3:7]
Reactant: CCOC(=O)COc1cc(C)c(S(=O)(=O)Cl)cc1C
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: COC(C)=O
Product: CCOC(=O)COc1cc(C)c(S)cc1C

Procedure:
(4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester was prepared as described for 2,6-difluoro-4-mercapto-phenoxy)acetic acid methyl ester (compound 21) in Eur. J. Med. Chem., 1995, 30, 403 (Kawashima, M. S.) except that (4-chlorosulfonyl-2,5-dimethylphenoxy)-acetic acid ethyl ester was reduced with 4 eq. of zn (dust) in a mixture of konc. sulfuric acid and ethanol at 80° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].[C:7]([NH:10][C:11](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:9])[CH3:8].Cl>CO.O>[C:7]([NH:10][C:11](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[C:12]([O:14][CH3:1])=[O:13])(=[O:9])[CH3:8]
Reactant: COc1ccc(C=C(NC(C)=O)C(=O)O)cc1OC
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(=Cc1ccc(OC)c(OC)c1)NC(C)=O

Procedure:
This compound was prepared from the product of Example 2 by treatment with sodium carbonate in methanol by a modification of the procedure of Saxena et al (supra). Alternatively, it could be made by esterification of α-acetylamino-3,4-dimethoxycinnamic acid. Thus, 9.62 g of the acid was heated under reflux for 19 hours in 100 mL of methanol containing 1 mL of concentrated hydrochloric acid. After diluting with 500 mL of water, the solution was basified with a 10% aqueous solution of sodium carbonate to a pH of 8-9. The resultant solids were collected by filtration, washed with 3×50 mL of water and dried at the pump. The crude product was further purified by column chromatography on silica gel, eluting with a gradient of methylene chloride/methanol (99:1 thru 96:2). After stripping the solvent from the appropriate fractions, and drying at the pump 2.07 g (21%) of the title compound were obtained; 1HNMR (CDCL3) 7.42 (s, 1H), 7.10 (d, J= 8.5 Hz, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 2.17 (s, 3H); MP 198°-200° C. Anal. calcd for C14H17NO5 : C, 60.2; H, 6.14; N, 5.02. Found: C, 60.42; H, 5.78; N, 4.53.
Reaction SMILES: C([C:3]1(C#C)[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[C:7]([Si](C)(C)C)[CH:8]=[C:9]([C:15]([O-:17])=[O:16])[CH:10]=2)[O:5][C:4]1([CH3:23])[CH3:22])C.[OH-].[Na+].Cl.[CH2:29](O)[CH3:30]>>[C:29]([C:7]1[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[CH:10]=[C:11]2[C:6]=1[O:5][C:4]([CH3:22])([CH3:23])[CH2:3][C:12]2([CH3:13])[CH3:14])#[CH:30]
Reactant: CCO
Reactant: C#CC1(CC)C(C)(C)Oc2c(cc(C(=O)[O-])cc2[Si](C)(C)C)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#Cc1cc(C(=O)O)cc2c1OC(C)(C)CC2(C)C
Yield: 84 %

Procedure:
A solution of ethyl-8-trimethylsilanyl-ethynyl-2,2,4,4-tetramethylchroman-6-carboxylate (Compound 25, 0.525 g, 1.47 mmol) in ethanol (5 mL) was treated with 2N aqueous sodium hydroxide solution (5 mL, 10 mmol) and the resulting solution was adjusted to pH˜5 with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a brown solid (0.316 g, 84%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)co2)cc1
Yield: 57.1 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-4-methyl-benzenesulfonamide (7-06) (20.0 g, 57.08%) was synthesized as a light brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (21.0 g, 90.90 mmol) and 4-methyl-benzenesulfonyl chloride (6-06) (20.7 g, 109.09 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]([NH:6][NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=1)=O.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:3]=1[C:4]1[N:38]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:7][N:6]=1
Reactant: COc1ccc(N)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Cl)ccc2Cl)cc1
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Cl)ccc3Cl)n2-c2ccc(OC)cc2)cc1
Temperature: 180 °C
Yield: 33.9 %

Procedure:
Into a 1 L round-bottomed flask fitted with a mechanical stirrer, reflux condenser and nitrogen inlet were introduced 2,5-dichloro-N′-[4-(octyloxy)benzoyl]benzohydrazide (40 g, 0.09146 mole, 1 equivalent), p-anisidine (67.60 g, 0.5487 mole, 6 equivalents) and 300 mL 1,2-dichlorobenzene. Mechanical stirring resulted in partial solvation of the solids. Phosphorus trichloride (12.56 g, 0.0146 mole, 1 equivalent) was added and the contents of the flask heated at 180° C. for 12 hrs. The solvent was distilled off under a light vacuum and the residue transferred to a 2 L flask with 1 L of a 1:1 acetone/heptane mixture. The solid material was filtered off and dissolved in acetone. Enough heptane was added to precipitate a purple-colored oily sludge. Heptane dilution of a test sample of the acetone/heptane layer ensured that the oily sludge had been completely precipitated. The acetone/heptane layer was decanted off and diluted further with a large excess of heptane to precipitate a white solid. This was filtered off, dissolved in acetone and re-precipitated with heptane. Filtration and drying gave 3-(2,5-dichlorophenyl)-4-(4-methoxyphenyl)-5-[4-(octyloxy)phenyl]-4H-1,2,4-triazole (16.25 g, 34% yield).