Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH:16]([O:20]C(C)(C)C)[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1.C(N(CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[O:6][C:7]3[CH:28]=[CH:27][CH:26]=[CH:25][C:8]=3[C:9]([N:11]3[CH2:19][C@H:18]4[N:14]([CH2:15][CH:16]([OH:20])[CH2:17]4)[CH2:13][CH2:12]3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: OC1C[C@H]2CN(C3=Nc4cc(Cl)ccc4Oc4ccccc43)CCN2C1
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
8-chloro-11-[(6S)-8-t-butoxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenzo[b,f]-1,4-oxazepine (0.211 g, 0.495 mmol), prepared as described above, was dissolved in trifluoroacetic acid (10 mL) and stirred for 15 minutes. The solvent was removed and the resulting residue was redissolved in methylene chloride (20 mL). Triethylamine (0.100 g, 0.991 mmol) was then added via syringe and the resulting solution was stirred for 1 hour. Washing with water (50 mL), drying over MgSO4 and concentrating resulted in a white solid (0.180 g, 99%); mp 94°-96° C.; Rf(35% acetone/hexanes): 0.15; HRMS (FAB) MH+ of C20H20N3O2Cl, calculated 370.1322, found 370.1 318.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][C@H:20]1[CH2:21]O)=[O:18])([CH3:15])([CH3:14])[CH3:13].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:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:20]1[CH2:21][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1ccc(O)nc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)OC(C)(C)C)nc1
Temperature: 70 °C
Reaction time: 13 h
Yield: 32.4 %

Procedure:
To a stirred solution of methyl 2-hydroxypyridine-5-carboxylate (1.00 g, 6.529 mmol), N-tert-butoxycarbonylprolinol (1.31 g, 6.529 mmol), and Ph3P (2.06 g, 7.836 mmol) in THF (10 mL) was added DIAD (1.54 mL, 7.836 mmol) at room temp, and the resulting mixture was stirred for 13 hr at 70° C. The mixture was concentrated and the residue was chromatographed on silica-gel with n-hexane:EtOAc (3:1, v/v) as eluent to give 712.3 mg (32%) methyl 2-[[1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy]pyridine-5-carboxylate as a pale yellow oil. 1H-NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 1.85–1.98 (m, 4H), 3.37 (br s, 2H), 3.92 (s, 3H), 4.12–4.33 (br m, 2H), 4.48 (br s, 1H), 6.75 (m, 1H), 8.15 (m, 1H), 8.79 (m, 1H); MS (FAB) m/z 337 (M++1).
Reaction SMILES: [K].[C:2]([C:5]1[O:6][C:7]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)(=[O:4])[CH3:3].[CH:15]([NH2:18])([CH3:17])[CH3:16].[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl>C(O)C>[C:2]([C:5]1[O:6][C:7]2[C:13]([O:14][CH2:19][CH:21]([OH:23])[CH2:22][NH:18][CH:15]([CH3:17])[CH3:16])=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)(=[O:4])[CH3:3]
Reactant: ClCC1CO1
Reactant: CC(C)N
Reactant: CC(=O)c1cc2cccc(O)c2o1
Agent: [K]
Solvent: CCO
Product: CC(=O)c1cc2cccc(OCC(O)CNC(C)C)c2o1
Temperature: 100 °C

Procedure:
A mixture of 214 mg. of potassium salt of 2-acetyl-7-hydroxybenzofuran, 70 mg. of isopropylamine and 0.8 ml. of epichlorohydrin was suspended into 5 ml. of ethanol. After heating the suspension in a sealed tube at 100° C. for 20 hours, the reaction mixture was filtered and then the solvent was evaporated under a reduced pressure. The residue was subjected to thin layer chromatography (solid support: Kieselgel PF254 made by E. Merck, developer: benzene-chloroform-methanol-28 % aqueous ammonia (17:4:3:0.4), eluant: chloroform) for the purification to give 2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran having a melting point of 115° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2.N1C2C(=C[CH:28]=[C:29]([C:32]([O:34]C)=[O:33])C=2)C=C1.BrCCC(O)=O>CN(C=O)C>[Br:3][C:4]1[N:5]([CH2:28][CH2:29][C:32]([OH:34])=[O:33])[C:6]2[C:11]([C:12]=1[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[CH:10][CH:9]=[C:8]([C:19]([O:21][CH3:22])=[O:20])[CH:7]=2
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: O=C(O)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaH (3.5 eq, 60% dispersion in mineral oil) was added to a solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in WO 2004065367, from commercially available methyl indole-6-carboxylate) in DMF (0.2 M) and the solution allowed to stir at RT for 1 h. Then 3-bromopropanoic acid (1.1 eq) was added and the mixture stirred at RT for 2 h. DMF was concentrated in vacuo and the residue taken up in EtOAc. The organic phase was washed with 1 N HCl and then brine before being dried (Na2SO4), filtered and the solvent evaporated in vacuo. The title compound was used crude in the next step; MS (ES+) m/z 408 (M+H)+, m/z 410 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1.Cl.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:14])(=[O:13])[NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:26][CH2:27][C:28](=[O:31])[CH2:29][CH2:30]3)=[CH:21][CH:20]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: COC(=O)COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1

Procedure:
The title compound was prepared from (4-chlorosulfonyl-phenoxy)-acetic acid methyl ester (Chem. Pharm. Bull. 1995, 43, 1132) and 1-(4-amino-phenyl)-piperidin-4-one hydrochloride (which was obtained in Example 224) according to the procedure B of Example 225 as a grey solid; MS (ES) m/z: 418.9 (MH+); HRMS Calcd. for C20H23N2O6S (MH+): 419.1271. Found: 419.1271.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.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>[S:10]1[C:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][N:12]=[CH:11]1
Reactant: c1cscn1
Reactant: O=Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(-c2cncs2)cc1

Procedure:
In a bomb tube, a mixture of 3.7 g (20 mmol) of 4-bromo-benzaldehyde, 6.64 ml (93 mmol) of thiazole, 2.94 g of potassium acetate and 1.16 g (1 mmol) of Pd(PPh3)4 is stirred in 50 ml of dimethylacetamide at 150° C. for 12 hours. The reaction mixture is concentrated by evaporation; water is added to the residue and the mixture is extracted three times with methylene chloride. The organic phases are filtered through cotton wadding, concentrated by evaporation and chromatographed (SiO2; hexane/ethyl acetate=1:2): 4-(Thiazol-5-yl)-benzaldehyde is obtained; HPLC:tRet(grad20-100/20)=11.4.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:43]=[N:44][C:39]([S:38][CH3:37])=[CH:40][CH:41]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(B(O)O)cn1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Yield: 87.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.5 g, 0.96 mmol), 6-methylsulfanyl-pyridine-3-boronic acid (370 mg, 2.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (67.4 mg, 0.096 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 0.96 mL, 1.92 mmol). The resulting mixture was subjected to microwave irradiation for 3 h at 100° C. The mixture was diluted with ethyl acetate (80 mL), washed with a saturated aqueous sodium bicarbonate solution (2×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (400 mg, 88%) as a light yellow solid: LC/MS m/e calcd for C26H25N3O2S2 [M+H]+ 476.64, observed 476.0.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.Cl.[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>C(O)C>[CH2:16]([N:20]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[CH2:17][CH2:18][CH3:19]
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Reactant: CCCCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCN1CCc2c(C)nc3ncnn3c21

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 0.95g of n-butylamine hydrochloride, 4 ml of triethylamine and 20 ml of ethanol was stirred under reflux for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in chloroform and purified by an column chromatography of alumina. The crystals thus obtained were recrystallized from isopropyl ether affording 1.35g of pale yellow needles of m.p. 72° - 75° C.
Reaction SMILES: [C:1]1(=[O:22])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:17])[C@H:3]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:2]12.C(N1C=CN=C1)([N:25]1C=CN=C1)=O.[OH-].[NH4+]>O1CCCC1>[C:1]1(=[O:22])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:8]([NH2:25])=[O:9])[C:4](=[O:17])[C@H:3]2[CH2:18][CH2:19][CH2:20][CH2:21][C@@H:2]12
Reactant: O=C(O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)CC(c1ccccc1)N1C(=O)[C@H]2CCCC[C@H]2C1=O
Reaction time: 1 h
Yield: 23.3 %

Procedure:
A mixture of 3-(cis-hexahydrophthalimido)-3-phenylpropionic acid (0.903 g, 3.00 mmol) and carbonyldiimidazole (0.525 g, 3.75 mmol) in 13 mL of anhydrous tetrahydrofuran under nitrogen was stirred for 1 hour, then 0.25 mL of concentrated ammonium hydroxide was added to the reaction solution. After 20 minutes, the reaction mixture was concentrated in vacuo to an oil. The oil was diluted with 20 mL of water and the mixture extracted with ethyl acetate (20 mL). The organic layer was dried (sodium sulfate) and concentrated to afford an oil. The oil was then purified by flash chromatography (silica gel, 5/95 methanol/methylene chloride, Rf0.3) to afford 210 mg of 3-(cis-hexahydrophthalimido)-3-phenylpropionamide as an oil which slowly crystallized to an ivory solid: 1H NMR (DMSO-d6) d7.49 (s. 1H, NH), 7.4–7.2 (m, 5H, Ar). 6.90 (s, 1H, NH), 5.54 (t, 1H, J 7.8 Hz, CH), 3.09 (d, 2H, J=7.8 Hz, CH2), 2.95–2.80 (m, 2 H, CH2), 1.8–1.1 (m, 8H); 13C NMR (DMSO-d6) δ179.6, 179.5, 171.5, 139.5, 128.6, 127.7, 127.2, 55.2, 50.6, 38.8, 36.5, 23.4, 23.3, 21.5
Reaction SMILES: [CH:1]([CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7])=O.[C:27]1([NH2:34])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33].C(O)(=O)C>CO>[N:33]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:34][C:1]=1[CH:3]([NH:8][C:9](=[O:26])[C@H:10]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(C=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: Nc1ccccc1N
Solvent: CC(=O)O
Solvent: CO
Product: CCCCC(NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)c1nc2ccccc2[nH]1
Yield: 24.1 %

Procedure:
In 20 ml of methanol was dissolved 1.1 g of N-benzyloxycarbonyl-L-leucine-(1-formyl)pentylamide obtained in the same manner as in Example 4-(b), and 356 mg of o-phenylenediamine and 0.2 ml of a 50% aqueous solution of acetic acid were added thereto. The mixture was allowed to react at room temperature for 40 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was purifled by medium-pressure column chromatography on silica gel to obtain 330 mg of the titled compound as a colorless crystal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:8]([O:14]C)(=O)[CH2:9][C:10]([CH3:12])=O.[C:16](O)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[C:16]([NH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:14])[CH2:9][C:10]([CH3:12])=[N:7][CH2:6][CH2:5]1)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: NCCNCCN
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 103.1 g (1 mole) of diethylenetriamine and 116.1 g (1 mole) of methyl acetoacetate. At 110° to 120° C. and under a reduced pressure of 70 mmHg, 18 g of water and 32 g of methanol were distilled off. Then, with the addition of 282.5 g (1 mole) of oleic acid, the amide formation was effected at 210° to 215° C. to distil off 18 g of water and to obtain 4-oleamidoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]Cl.Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cc(C(=O)N2Cc3ccc(OCCN(C)C)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A mixture of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (100 mg, 0.2 mmol), 2-dimethylaminoethylchloride.HCl (72 mg,0.5 mmol) and K2CO3 (173 mg, 1.25 mmol) in DMF (5 ml) was heated at 90° C. for 16 hours. Dilute reaction mixture with EtOAc and filtered. The reaction mixture was diluted with EtOAc and filtered. The filtrate was reduced in vacuo and purified by flash column chromatography, eluting 100% DCM then 90% DMAW 90 to give the title compound as an off white gel (79 mg). MS: [M+H]+ 565.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([OH:14])=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH3:16])[CH2:5]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:15])[C:9]([O:14][C:23](=[O:25])[CH3:24])=[C:10]([CH3:13])[CH:11]=2)[CH:6]([CH3:16])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N1CC(C)c2c1cc(C)c(O)c2C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc2c(c1C)C(C)CN2C(C)=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 87.3 %

Procedure:
To an ice-cold solution of indoline 11a (219 mg, 1 mmol) dissolved in methylene chloride (5 mL) were added sequentially pyridine (1 mL) and acetic anhydride (0.12 mL, 1.1 mmol), and the resulting mixture was stirred over a range of 0° C. to room temperature for 18 h. The reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were washed with 5% aq. hydrochloric acid and brine then dried (MgSO4). Removal of solvents and chromatographic purification of the residue using 3:7 ethyl acetate:hexanes as eluent gave the acetate 12a (228 mg, 87% yield) as a pale yellow solid. This was recrystallized from hexanes-methylene chloride to afford a colorless solid, mp 128°-130° C. Spectral data: 1H NMR: δ 1.23 (d, 3H, J=7 Hz), 2.04 (s, 3H), 2.10 (s, 3H), 2.17 (s, 3H), 2.31 (s, 3H), 3.61 (dd, 1H, J=10.2, 2.3 Hz), 4.13 (t, 1H, J=9.53 Hz), 7.96 (s, 1H); 13C NMR: δ 12.3, 16.7, 20.4, 20.7, 24.8, 33.9, 57.4, 116.4, 125.7, 129.3, 133.7, 139.5, 144.2, 168.5, 169.1; HRMS: calcd. for C15H20NO3 (M+H+) 262.1443, fnd. 262.1446.
Reaction SMILES: O1C2C=CC(C(Cl)=O)=CC=2OC1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[F:35].[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1>C1(C)C=CC=CC=1.C(O)C>[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1.[O:36]1[C:40]2[CH:41]=[CH:42][C:43]([C:45]([NH:47][C:48]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([O:27][C:18]4[C:17]5[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=5)[N:21]=[CH:20][CH:19]=4)=[C:29]([F:35])[CH:30]=3)=[S:49])=[O:46])=[CH:44][C:39]=2[O:38][CH2:37]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Agent: O=C(N=C=S)c1ccc2c(c1)OCO2
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc5c(c4)OCO5)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
1,3-Benzodioxole-5-carbonyl isothiocyanate was prepared using commercially available 1,3-benzodioxole-5-carbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 1,3-benzodioxole-5-carbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (62 mg, yield 75%).
Reaction SMILES: [CH2:1]([S:3](C1C=CC(F)=C(F)C=1)(=[O:5])=[O:4])C.N[C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH:22]=1)[C:20]#[N:21].CSSC>>[Cl:23][C:18]1[CH:17]=[CH:16][C:15]([S:3]([CH3:1])(=[O:5])=[O:4])=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: N#Cc1cc(N)ccc1Cl
Reactant: CCS(=O)(=O)c1ccc(F)c(F)c1
Solvent: CSSC
Product: CS(=O)(=O)c1ccc(Cl)c(C#N)c1

Procedure:
The subtitle compound was prepared by the methods of example 2 steps (i) and (ii) using 5-amino-2-chlorobenzonitrile and dimethyldisulfide.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[CH3:18][CH:17]([C:14]1[CH:15]=[CH:16][C:8]([O:7][CH2:10][C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:8]=2)=[C:9]([CH:13]=1)[C:10]([O:12][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:11])[CH3:19]
Reactant: BrCc1ccccc1
Reactant: CC(C)c1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
K2CO3 (3.83 g, 27.7 mmol) was added to a stirred solution of 2-hydroxy-5-(1-methylethyl)benzoic acid (may be prepared as described in Description 1; 2.0 g, 11.10 mmol) in acetone (80 ml), followed by the addition of (bromomethyl)benzene (4.75 g, 27.7 mmol). The mixture was refluxed for 12 h and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid. Flash chromatography over silica gel, using 1:10 ethyl acetate-petroleum ether yielded the title compound as a yellow oil. 1.0 g.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[CH3:12][NH:13][CH:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[CH3:12][N:13]([CH:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)[C:9](=[O:10])[O:8][CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC1CCNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)OCc1ccccc1)C1CCNC(=O)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 27 %

Procedure:
Cbz-Cl (7.2 ml, 21.259 mol, 1.5 eq., 50% solution in toluene) was added at 0° C. to a mixture of 4-(methylamino)piperidin-2-one (1.814 g, 14.173 mmol, 1.0 eq.) and K2CO3 (3.91 g, 28.346 mmol, 2.0 eq.) in THF (50 ml) and the mixture was stirred for 14 hours at RT. After monitoring by TLC, the reaction mixture was diluted with DCM (300 ml), washed with water and saturated NaCl solution (in each case 150 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (Alox, 1% MeOH in DCM). Yield: 27% (1.0 g, 3.82 mmol)
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:18]([NH2:20])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([C:11]([NH:13][C@H:14]([C:18]([NH2:20])=[O:19])[CH:15]([CH3:16])[CH3:17])=[O:12])[CH3:10]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)[C@H](C)N)C(N)=O
Yield: 23 %

Procedure:
N-(tert-butoxycarbonyl)-L-alanyl-L-valinamide (0.5 g, 1.74 mmol) is stirred with 3 mL of TFA in 6 mL of dichloromethane for 1 h. It is then concentrated, neutralized with 3.5 mL of 1N NaHCO3 and 3.5 mL of 1N Na2CO3, and extracted into 60 mL of ethyl ether containing several mL of methanol. The aqueous phase is extracted with 100 mL of dichloromethane and 10 mL of methanol. The aqueous layer is evaporated and the solids are extracted with methanol. This is concentrated to 180 mg (0.96 mmol, 55%) of an 85:15 mixture of the title compound and a minor diastereomer. The combined organic phases are concentrated to afford 74 mg (0.4 mmol, 23%) of the title compound as a white solid. HRMS (ESI) calcd for C8H17N3O2+H1 188.1399, found 188.1408.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15].CO[C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O>C(Cl)Cl>[CH3:20][C:19]1([CH3:21])[N:11]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[C@H:3]2[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[CH2:10][C@H:2]2[O:1]1
Reactant: C=C(C)OC
Reactant: CCCC(=O)N[C@H]1c2ccccc2C[C@H]1O
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCC(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C
Reaction time: 0.33 h

Procedure:
N-(1S,2R)-(2-Hydroxyindan-1-yl)-butyramide (XV, 2.2 g) and 2-methoxypropene (5 mL) were combined with CH2Cl2 (70 mL) at rt, and methanesulfonic acid (0.05 mL) was added. After 20 min at rt, the reaction mixture was partitioned between half-saturated NaHCO3 (30 mL) and CH2Cl2 (2×30 mL). The combined organic layers were dried dried (MgSO4), filtered, and concentrated under reduced pressure to give an oil as product: MH+260.1.