Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18](=[O:30])[N:17]([CH3:31])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.N1C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C:21]3[C:20](=[O:23])[N:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18](=[O:30])[N:17]([CH3:31])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Reactant: COc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2OC)n(C)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-[1-(Ethoxycarbonylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester, 2-methoxyphenyl boronic acid (60 mg), and copper (II) acetate (200 mg) were dissolved in anhydrous tetrahydrofuran (5 ml), and pyridine (0.2 ml) was added thereto. The reaction mixture was stirred at room temperature for 3 days, filtered through a short column packed with NH-silica gel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 18 mg of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@H:11]([C:12]2([CH3:17])[CH3:16])[C@@H:10]1[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>C(Cl)Cl>[S:27]([NH:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@H:11]([C:12]2([CH3:17])[CH3:16])[C@@H:10]1[CH2:18][CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([CH3:30])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)[C@H]2C[C@H](N)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@H]2C[C@H](NS(C)(=O)=O)[C@@H](CCOC3CCCCO3)[C@@H]1C2
Reaction time: 1 h

Procedure:
Triethylamine (1.9 ml) was added to a solution of (1S,2S,3S,5R)-3-amino-2-[2-(2-tetrahydropyranyloxy)ethyl]-6,6-dimethylbicyclo[3.1.1]heptane (3.25 g) in methylene chloride (30 ml). The reaction solution was cooled. To the above solution, mesyl chloride (1.0 ml) was dropped slowly. The reaction solution was allowed to stand for 1 hour. The reaction solution was extracted with methylene chloride. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give the title compound (3.05 g) having the following physical data.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([O-:3])=[O:2].[C:17]1([S:27](Cl)(=[O:29])=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][S:27]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)(=[O:29])=[O:28])([O-:3])=[O:2]
Reactant: NCCCCCOc1cccc([N+](=O)[O-])c1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(OCCCCCNS(=O)(=O)c2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
To a stirred solution of 5-(3-nitro-phenoxy)-pentylamine (336 mg, 1.5 mmol) and naphthalene-1-sulfonyl chloride (340 mg, 1.5 mmol) in dichloromethane (10 mL) was added triethylamine (182 mg, 1.8 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride (30 mL) followed by extraction with ethyl acetate (10 mL×3). The organic layers were combined, washed with brine, and then concentrated under vacuum. The residue was subjected to column chromatography on silica gel to give naphthalene-1-sulfonic acid [5-(3-nitro-phenoxy)-pentyl]-amide (600 mg, 1.45 mmol, 97%) as a yellow liquid.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1.[Li+].[OH-].Cl>O1CCCC1>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([S:38]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)(=[O:40])=[O:39])[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(S(=O)(=O)c3ccc(F)cc3)c2c1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
An ice cold solution of methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (20 mg, 0.043 mmol) in Tetrahydrofuran (THF) (0.5 mL) was treated with NaH (9.93 mg, 0.248 mmol) and allowed to stir at 0° C. for 10 minutes. The mixture was then treated with 4-fluorobenzenesulfonyl chloride (39.4 mg, 0.199 mmol) in one portion. The mixture was stirred for 10 minutes, quenched with water and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resultant was dissolved in Tetrahydrofuran (THF) (0.500 mL), treated with 2M LiOH (0.4 mL, 0.800 mmol) (2 M) and then stirred at ambient temperature overnight. The mixture was cooled to 0° C., treated with HCl (1M) until pH<2 and then extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) to afford the title compound. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.16-8.29 (m, 2H) 7.81-7.92 (m, 1H) 7.51-7.58 (m, 1H) 7.45-7.51 (m, 2H) 7.28-7.35 (m, 1H) 7.17-7.25 (m, 2H) 6.09-6.18 (m, 1H) 5.21-5.32 (m, 1H) 3.54-3.65 (s, 3H) 0.99 (s, 9H); LCMS (m/z) ES+=547 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[C:25]([F:26])=[CH:24][C:23]([Br:27])=[CH:22][C:21]=3[F:28])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:29][CH3:30])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[Br:27][C:23]1[CH:22]=[C:21]([F:28])[C:20]([NH:19][C:13]2[C:12]3[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:29][CH3:30])[CH:11]=3)[N:16]=[CH:15][N:14]=2)=[C:25]([F:26])[CH:24]=1
Reactant: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3c(F)cc(Br)cc3F)ncnc2cc1O
Yield: 97.6 %

Procedure:
Using an analogous procedure to that described for the synthesis of the starting material in Example 8, 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline (1.9 g, 4.02 mmol) was reacted with TFA (20 ml) to give 4-(4-bromo-2,6-difluoroanilino)-7-hydroxy-6-methoxyquinazoline (1.5 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([C:26]([O:28]C)=[O:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>CO>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([C:26]([OH:28])=[O:27])=[CH:21][CH:22]=3)[N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2cnc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2ncc3ccc(C(=O)O)cc3n2)CC1
Temperature: 50 °C

Procedure:
The methyl 2-({trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)quinazoline-7-carboxylate (1.0 g, 4.0 mmol) was dissolved in MeOH (20 ml). To this solution LiOH (538.0 mg, 22.5 mmol) was added and then heated to 50° C. for 16 hours. Evaporation of the solvent and partition with EtAc/H2O, followed by separation of the organic layers and evaporation provided the crude product. Purification using a silica gel column with 40% EA in heptane to give 780.0 mg of the desired product (yield 81.3%). 1H NMR (400 MHz, DMSO-d6) ppm 1.23-1.36 (m, 4H), 1.38 (s, 9H), 1.82 (s, 2H), 1.93-2.05 (m, 2H), 3.18-3.27 (m, 1H), 3.77 (s, 1H), 6.76 (d, J=8.06 Hz, 1H), 7.27 (d, J=8.06 Hz, 1H), 7.63-7.71 (m, 1H), 7.71-7.78 (m, 1H), 7.93 (s, 1H), 9.10 (s, 1H). (APCI); 387.5 ([M+H]+).
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]#[C:19][CH3:20].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C:19]([CH3:20])=[C:18]([C:17]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#CC(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1=C(C)CN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 26.7 %

Procedure:
Benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (10.78 mL, 42.12 mmol) and ethyl but-2-ynoate (5.89 mL, 50.54 mmol) were stirred in DCM (500 mL) at 0° C. under nitrogen, then trifluoroacetic acid (161 μL, 2.11 mmol) was added dropwise. The reaction mixture stirred at 0° C. for 20 minutes, then the ice bath was removed and the solution was allowed to warm to room temperature. The solution was stirred at room temperature overnight. The mixture was concentrated and purified by FCC, eluting with 0-70% EtOAc in heptane, to afford the title compound (2.76 g, 27%). δH (500 MHz, DMSO-d6) 7.38-7.32 (m, 4H), 7.30-7.23 (m, 1H), 4.13 (q, J 7.1 Hz, 2H), 3.75 (s, 2H), 3.60-3.51 (m, 4H), 2.05 (s, 3H), 1.22 (t, J 7.1 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)=[CH:5][C:4]=1OS(C(F)(F)F)(=O)=O.[CH:28]([O:30]CCCC)=[CH2:29].C1(C(C2C=CC=CC=2)(P)CC)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:30])[CH3:29]
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(OS(=O)(=O)C(F)(F)F)c2)c1
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCC(P)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(C(C)=O)c2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
357 mg of Methyl (4′-methoxy-3′-trifluoromethanesulfonyloxybiphenyl-3-yl)acetate was dissolved in 3 ml of N,N-dimethylformamide, then 0.45 ml of butyl vinyl ether, 10 mg of palladium acetate, 20 mg of diphenyl phosphinopropane and 1 ml of triethylamine were added thereto, and the mixture was stirred at 80° C. overnight in a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography, to give 184 mg of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=[O:12])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19]>CO>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][C:3](=[O:12])[C:2]([F:13])([F:14])[F:1])[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(C#Cc1ccccc1)C(F)(F)F
Reactant: Nc1cccc(Cl)c1
Solvent: CO
Product: O=C(C=C(Nc1cccc(Cl)c1)c1ccccc1)C(F)(F)F

Procedure:
Into a 1-Neck round-bottom flask was added 1,1,1-trifluoro-4-phenyl-but-3-yn-2-one (2.0 g, 0.01 mole), methanol (5 mL) and m-chloroaniline (0.961 mL, 0.0091 mol). The reaction was stirred. TLC (SiO2, hexanes/methylene chloride 1:1) indicated near reaction completion after 1 h. After 1.5 h the product was concentrated in vacuo to afford an orange oil, which was placed on high vacuum overnight, affording a yellow gum. The crude product was chromatographed on Silica gel with hexanes, Methylene Chloride 2:1, and place on high vacuum for 2 h to afford the title compound as a yellow gum; 1H NMR (CDCl3, 400 MHz) δ 5.74 (s, 1H), 6.67-6.69 (m, 1H), 6.85 (m, 1H), 7.08-7.10 (m, 1H), 7.31-7.39 (m, 4H), 7.43-7.47 (ft, 1H), 12.39 (bs, 1H)
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](O)=[O:14])[CH:9]=[CH:10][CH:11]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:28][OH:29].C(N(CC)CC)C>C(Cl)Cl.C1COCC1.O>[OH:29][NH:28][C:13](=[O:14])[CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:2]([CH3:1])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:20])[CH:7]=1
Reactant: NO
Reactant: Cc1cccc(C)c1COc1cccc(CC(=O)O)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1COc1cccc(CC(=O)NO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(2,6-Dimethylbenzyloxy)phenylacetic acid (Step C, 2.06 g, 7.6 mmol) in methylene chloride (20 ml) at 0° C., oxalyl chloride (1.49 g, 11.9 mmol) was added in a dropwise manner. The reaction mixture was stirred at room temperature for 2 hours. Simultaneously, in a separate flask, a mixture of hydroxylamine hydrochloride (2.98 g, 43 mmol) and triethylamine (10 ml) was stirred in THF/water (5:1, 45 ml) at 0° C. for 1-2 hours. At the end of 2 hours, the oxalyl chloride reaction mixture was concentrated and the yellow residue was dissolved in methylene chloride (10 ml). The mixture was added slowly to the hydroxylamine mixture at 0° C. The reaction mixture was stirred for 24 hours, and concentrated. The residue was taken into chloroform and washed with water, dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (chloroform:methanol, 92.5:7.5 spiked with acetic acid) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([C:11]#[N:12])([CH3:10])[CH2:6][CH2:7][CH2:8]Cl)[CH3:2].Cl.C(N(CC)CC)C>CCO>[CH2:1]([O:3][C:4]([C:5]1([CH3:10])[CH2:6][CH2:7][CH2:8][NH:12][CH2:11]1)=[O:13])[CH3:2]
Reactant: CCOC(=O)C(C)(C#N)CCCCl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C)CCCNC1
Temperature: 40 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
Ethyl-5-chloro-2-cyano-2-methylpentanoate (DE 31 39 301 A1) (10.43 g, 51.2 mmol), PtO2 hydrate (1.16 g) and concentrated HCl (12.5 ml) in absolute EtOH (125 ml) were stirred and heated at 40° C. under hydrogen at normal pressure for 2 h. The cooled solution was filtered. After evaporation of the solvent, the residue was dissolved in absolute EtOH (125 ml). The solution was cooled with an ice-water bath and triethylamine (9.8 g, 96.8 mmol) was added. After the addition the mixture was stirred at RT for 16 h under nitrogen atmosphere. The solvent and triethylamine were evaporated, and the residue was dissolved in DCM (100 ml) and extracted with 1 M HCl (3×100 ml). After separating the layers, ice (150 g) and 5 M NaOH (100 ml) were added to the aqueous layer, which was then extracted with DCM (3×60 ml). The combined extracts were dried, filtered and evaporated to dryness followed by vacuum distillation (bp. 62-65° C./2 mbar) to give 6.0 g of the title compound as a colorless liquid.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH2:18]([OH:20])[CH3:19]>C(O)(=O)C>[O:20]=[C:18]1[C:19]2[C:8](=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:9][N:1]1[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCO
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2Cc3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Yield: 62 %

Procedure:
A stirred mixture of phthalic dicarboxaldehyde (2.68 g, 20.0 mmol) and 3-amino-3-(3-ethoxy4-methoxyphenyl)propionic acid (4.78 g, 20.0 mmol) in glacial acetic acid (50 mL) under nitrogen was heated to reflux for 5 minutes. The reaction mixture was then allowed to cool to room temperature and was concentrated in vacuo to afford a yellow solid. The crude product was recryslallized twice from refluxing ethanol (150 mL). The resulting solid was then dried in vacuo (60° C., <1 mm) to afford 4.4 g (62%) of 3-(1-oxoisoindolin-2-yl)-3-(3-ethoxy-4-methoxyphenyl)propionic acid as a white solid: mp 193.5°-194° C.; 1H NMR (DMSO-d6) δ 12.40 (br s, 1 H), 7.75-7.40 (m, 4 H), 7.05-6.85 (m, 3 H), 5.71 (m, 1 H), 4.51 (d, J=17.7 Hz, 1 H), 4.11 (d, J=17.7 Hz, 1 H), 3.99 (m, 2 H), 3.73 (s, 3 H), 3.25-3.02 (m, 2 H), 1.30 (t, J=6.9 Hz, 3 H); 13C NMR (DMSO-d6) δ 171.9, 166.9, 148.5, 147.9, 141.7, 132.2, 131.6, 131.4, 127.9, 123.5, 122.9, 119.3, 111.8, 63.7, 55.4, 51.2, 46.3, 36.8, 14.7; Anal. Calcd. for C20H21NO5. Theoretical: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.64; H, 5.97; N, 3.92.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[S-:10][C:11]#[N:12].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][S:10][C:11]#[N:12]
Reactant: N#C[S-]
Reactant: ClCc1cccc(Cl)c1
Agent: [K+]
Solvent: CCO
Product: N#CSCc1cccc(Cl)c1

Procedure:
The mixture of 250 g of m-chlorobenzyl chloride, 16.6 g of potassium thiocyanate and 150 ml of 95% aqueous ethanol is refluxed for 3 hours and evaporated. The residue is taken up in methylene chloride and water, the organic solution separated; washed with water dried and evaporated to yield the m-chlorobenzyl-thiocyanate.
Reaction SMILES: C(OC(=O)COC1C=CC(Cl)=CC=1C#C)(C)(C)C.C[Si](C)(C)[C:21]#[C:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:24]=1>>[C:22]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:30])=[O:31])[CH:24]=1)#[CH:21]
Reactant: CCCS(=O)(=O)c1cccc(C#C[Si](C)(C)C)c1
Agent: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: C#Cc1cccc(S(=O)(=O)CCC)c1
Yield: 70 %

Procedure:
Following the general method as outlined in Intermediate 3, starting from 1-(2-trimethylsilyl-1-ethynyl)-3-(propylsulfonyl)benzene (Intermediate 41), the title compound was obtained as a brown liquid in 70% yield after purification by column chromatography (silica) eluting with petroleum ether and ethyl acetate.
Reaction SMILES: [OH:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[F:22][C:23]([CH2:26][C:27](O)=[S:28])([F:25])[F:24]>>[F:22][C:23]([CH2:26][C:27]([O:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[S:28])([F:25])[F:24]
Reactant: OC(=S)CC(F)(F)F
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](O)[C@H]3SC2)s1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](OC(=S)CC(F)(F)F)[C@H]3SC2)s1

Procedure:
Reaction of 7β-hydroxy-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid and trifluoromethylthioacetic acid according to the procedure of Preparation 3 gives the title compound.
Reaction SMILES: Cl.C([N:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)(=O)C.FC(F)(F)S(O[CH2:25][C:26]([F:29])([F:28])[F:27])(=O)=O.C(N(CC)CC)C>CC(C)=O>[F:27][C:26]([F:29])([F:28])[CH2:25][N:10]1[CH2:9][CH2:8][C:7]2([C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:5][CH2:6]2)[CH2:12][CH2:11]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: FC(F)(F)CN1CCC2(CC1)CNc1ccccc12

Procedure:
A mixture of 1-acetyl-1,2-dihydrospiro[indole-3,4′-piperidine] hydrochloride, [Chen et al. Tetrahedron Lett. 1996, 37(30), 5233-5234] (200 mg, 0.750 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.128 mL, 0.900 mmol), and triethylamine (0.522 mL, 3.75 mmol) in acetone (2 mL) was heated at reflux for 15 h. The mixture was allowed to cool, and the solvent removed under reduced pressure. The residue was taken up in CH2Cl2 (10 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous layer was further extracted with CH2Cl2 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, to provide the title compound. MS: m/z=271 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Product: Cc1cc(C(=O)N2CCOCC2)ccc1[N+](=O)[O-]

Procedure:
Prepared from 3-methyl-4-nitrobenzoic acid and morpholine following the method used to prepare Intermediate 29. δH (DMSO-d6) 8.03 (d, J=8.3 Hz, 1H), 7.60-7.52 (m, 1H), 7.47 (dd, J8.4, 1.9 Hz, 1H), 3.50-3.70 (m, 6H), 3.28 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]([Cl:24])=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:25](Cl)=[O:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:1]([O:11][C:25]([C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[C:18]([C:22]([Cl:24])=[O:23])[CH:17]=2)[CH:12]=1)=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCO
Reactant: O=C(Cl)c1ccc2cc(C(=O)Cl)ccc2c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOC(=O)c1ccc2cc(C(=O)Cl)ccc2c1
Yield: 56.3 %

Procedure:
After a solution of n-decyl alcohol (0.5 g), naphthalene-2,6-dicarboxylic acid dichloride (0.6 g), and triethylamine (0.27 g) and a very small amount of dimethylaminopyridine in methylene chloride (50 ml) was stirred at room temperature overnight, the solution was distilled to remove the solvent, until the titled compound (about 0.5 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1)#[N:2].S(C1C=CC(C)=CC=1)(O[CH:14]1[CH2:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[CH2:15]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:20][C:16]1([CH3:21])[CH2:17][CH2:18][CH2:19][CH:14]([S:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC(C)(C)C2)cc1
Reactant: N#Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CCCC(Sc2ccc(C#N)cc2)C1
Temperature: 60 °C

Procedure:
To a solution of 4-cyanothiophenol (1 g, 7.4 mmol) in DMF (15 mL) add 3,3-dimethylcyclohexyl tosylate (2.06 g, 7.4 mmol) and potassium carbonate (3.06 g, 22.2 mmol), and warm to 60° C. for 18 h. Dilute the mixture with EtOAc (50 mL) and wash sequentially with water (3×50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL). Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to obtain the desired intermediate as a clear oil that solidifies on standing (0.35 g, 20%).