Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[N:3]=1.[CH3:18][N:19]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:38]3[CH:39]=[N:40][N:41]([CH3:43])[CH:42]=3)[CH:25]=2)[C:20]1=[O:44]>>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:38]5[CH:39]=[N:40][N:41]([CH3:43])[CH:42]=5)[CH:25]=4)[C:20](=[O:44])[N:19]([CH3:18])[CH:28]=3)=[N:3][C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: CS(=O)(=O)Cc1ncc(OCC2CC2)c(Cl)n1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(B4OC(C)(C)C(C)(C)O4)c3c2)cn1
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4nc(CS(C)(=O)=O)ncc4OCC4CC4)c3c2)cn1

Procedure:
The title compound of Example 143, step 2 was reacted with the title compound of Example 46, step 2 in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (d, J=8.4 Hz, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.5 (d, J=8.4 Hz, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 3.87 (s, 3H), 3.85-3.80 (m, 4H), 3.57 (s, 3H), 3.28 (s, 3H), 0.88-0.87 (m, 1H), 0.30-0.25 (m, 2H), 0.07-0.04 (m, 2H). LCMS: 480.2 (M+1)+
Reaction SMILES: [H-].[Na+].[CH2:3]([O:11][N:12]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH:15]([O:20][CH2:21][CH:22]2[O:24][CH2:23]2)[CH2:14][C:13]1([CH3:26])[CH3:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:27][CH:28]1[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:30]([CH3:46])([CH3:45])[CH2:29]1>O1CCOCC1.C(OCC)C>[CH2:37]([O:36][N:31]1[C:32]([CH3:34])([CH3:35])[CH2:33][CH:28]([O:27][CH2:23][CH:22]([OH:24])[CH2:21][O:20][CH:15]2[CH2:14][C:13]([CH3:25])([CH3:26])[N:12]([O:11][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:17]([CH3:18])([CH3:19])[CH2:16]2)[CH2:29][C:30]1([CH3:45])[CH3:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCCCCCCON1C(C)(C)CC(OCC(O)COC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C
Yield: 45.7 %

Procedure:
Sodium hydride (0.7 g. 5.9 mmol) is added to a solution of 17.0 g (59.5 mmol) of 1-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yloxy)-2,3-epoxypropane (prepared in Example 11) in 75 ml of dioxane. The reaction mixture is heated at reflux for 10 minutes and then cooled to 60° C., whereupon a solution of 10.0 g (29.3 mmol) of 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 5) in 25 ml of dioxane is rapidly added. The reaction mixture is heated at reflux for 4 hours, treated with an additional 0.6 g of sodium hydride, and heated at reflux for 7 hours. The reaction mixture is diluted with diethyl ether (500 ml), and the organic solution is washed with 1N hydrochloric acid (2×100 ml) and saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated to an oil. Purification by flash chromatography on silica gel (9:1 heptane: ethyl acetate) affords 8.4 g (46% yield) of the title compound, a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:21][CH2:22][CH3:23])(=[O:20])[CH3:19].CCCCCC>CN(C=O)C>[CH2:22]([O:21][C:18]([C:19]1[O:10][C:7]2[CH:8]=[CH:9][C:2]([Br:1])=[C:3]([CH3:11])[C:4]=2[CH:5]=1)=[O:20])[CH3:23]
Reactant: CCOC(C)=O
Reactant: Cc1c(Br)ccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)c1cc2c(C)c(Br)ccc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
To a solution of 3-Bromo-6-hydroxy-2-methyl-benzaldehyde (6.8 g, 0.032 mol)) in anhydrous DMF (50 ml) was added potassium carbonate (13.1 g, 0.095 mol) and cooled to 0° C. Bromo ethyl acetate (7.1 ml, 0.063 mol) was added slowly. The reaction mixture was stirred for one hour at 0° C. The completion of the reaction was confirmed by TLC. The reaction mixture was then heated to 100° C. and maintained for 2 hours. After cooling to room temperature, ice water (250 ml) was added and the mixture was stirred for 20 minutes. The solid separated was filtered, washed with water (100 ml) and dried under vacuum, to get crude product. Column chromatography using 2/5 ethyl acetate/hexane yielded 5-Bromo-4-methyl-benzofuran-2-carboxylic acid ethyl ester (6.2 g, 69.6%)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][O:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:29](=[O:31])[CH3:30]>O1CCCC1>[CH2:13]([O:20][C:21]([C:23]1([CH:29]([OH:31])[CH3:30])[CH2:28][CH2:27][CH2:26][O:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC=O
Reactant: O=C(OCc1ccccc1)C1CCCOC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)C1(C(=O)OCc2ccccc2)CCCOC1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 40.2 %

Procedure:
A cooled (−78° C.) solution of N,N-diisopropylamine (4.7 mL, 33.316 mmol, dried over calcium hydride) in anhydrous tetrahydrofuran (60 mL) was treated with a solution of n-butyllithium in hexanes (12.5 mL, 31.234 mmol, 2.5 M). After stirring at −78° C. for 25 minutes, the mixture was treated with a solution of tetrahydro-pyran-3-carboxylic acid benzyl ester (4.587 g, 20.823 mmol) in anhydrous tetrahydrofuran (20 mL). After stirring at −78° C. for 15 minutes, the mixture was treated with acetaldehyde (3.5 mL, 62.469 mmol). After stirring at room temperature for 45 minutes, the reaction was quenched at 0° C. with hydrochloric acid (2 M, 50 mL). The aqueous layer was saturated with sodium chloride, extracted with dichloromethane (2 x). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 3:2 to afford the title compound (2.212 g, 40%) as a yellow oil and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 287.0 [M+Na], Tr=2.00 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]([CH:20](OC)[O:21][CH3:22])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.C(OC(=O)C)(=O)C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: COC(=O)C(c1ccccc1Oc1cc(Cl)ncn1)C(OC)OC
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cc(Cl)ncn1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 98.5 %

Procedure:
A mixture of methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-dimethoxypropanoate (17.98 g), acetic anhydride (5.16 g) and toluene (73 ml) was stirred at 90° C. for 20 minutes. Methane sulphonic acid (0.49 g) was added to the mixture and the mixture was heated at 90° C. for 1 hour. The mixture was cooled to room temperature, washed with cold water (25 ml) and with hot (50° C.) water (2×25 ml). The organic layer was evaporated at 75° C. (initially on a rotary evaporator, then at circa 15 mm Hg) to leave (E)-methyl 2-[-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxypropenoate as a solid (16.1 g).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])O1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[C:17]2[NH2:23]>O1CCOCC1>[F:25][C:13]([F:12])([F:24])[C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][N:18]=[C:17]2[N:23]1[C:3](=[O:10])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:11]
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1c1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
Isobenzofuran-1,3-dione (4.24 g, 28.6 mmol) and 5-trifluoromethyl-1H-indazol-3-ylamine (5.76 g, 28.6 mmol) in dioxane (10 mL) in a sealed tube were heated at 100° C. overnight. The solvent was removed to give the crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:40][C:23]2=[CH:24][C:25]3[C:26](=[O:39])[N:27]([CH:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[C:28](=O)[C:29]=3[CH:30]=[C:22]2[N:21]=1)[CH3:11]>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[C:14]=1[C:20]1[NH:21][C:22]2=[CH:30][C:29]3[CH2:28][N:27]([CH:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[C:26](=[O:39])[C:25]=3[CH:24]=[C:23]2[N:40]=1)[CH3:11]
Reactant: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(C1CCN(C)CC1)C3=O
Yield: 13.8 %

Procedure:
To a solution of 2-(4-(1-(2,5-difluorophenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.30 g, 0.53 mmol) in 50 mL of acetic acid was added zinc powder (0.64 g, 9.78 mmol). The mixture was heated to reflux for 16 h and filtered through Celite. Acetic acid was removed under vacuum and the residue was taken up with 10 mL of MeOH. Reverse phase chromatography purification yielded the title compound as a white solid (39 mg, 13.8%). 1H NMR δ (500 MHz, DMSO-d6) 13.05 (d, J=3.5 Hz, 1H), 11.23 (t, J=6.5 Hz, 1H), 11.10 (d, J=7.5 Hz, 1H), 7.96 (s, 0.5H, conformational isomer), 7.85 (s, 0.5H), 7.81 (s, 0.5H), 7.68 (s, 0.5H), 7.44-7.30 (m, 2H), 7.22-7.14 (m, 1H), 7.11-7.02 (m, 1H), 6.17 (d, J=8.0 Hz, 1H), 4.48 (s, 2H), 4.18-4.08 (m, 1H), 4.08-3.98 (m, 1H), 3.08-3.02 (m, 1H), 3.02-2.94 (m, 1H), 2.91 (d, J=10.5 Hz, 2H), 2.23 (s, 3H), 2.11-2.02 (m, 2H), 1.90-1.78 (m, 2H), 1.74-1.66 (m, 2H), 1.34-1.29 (m, 3H). ESI MS: m/z 533.02 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[C:11]#[C:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)([O-])=O>C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[C:11]#[C:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C#Cc2cc(Cl)ccc2[N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C#Cc2cc(Cl)ccc2N)cc1
Yield: 88.4 %

Procedure:
To a solution of methyl 4-[2-(2-nitro-5-chlorophenyl)ethynyl]benzoate (180 mg; prepared in Reference Example 15.) in acetic acid (3.6 ml), reduced iron powder (160 mg) was added. The mixture was refluxed for 30 minutes and filtered. The filtrate was concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (144 mg) having the following physical data.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])O[C:2]1=[O:11].[CH2:12]1[C@@H:15](C(O)=O)[NH:14][CH2:13]1>CN(C)C=O.C(O)(=O)C>[S:9]1[C:5]2[C:4](=[O:10])[N:14]3[CH2:15][CH2:12][C@H:13]3[C:2](=[O:11])[NH:1][C:6]=2[CH:7]=[CH:8]1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1Nc2ccsc2C(=O)N2CC[C@@H]12
Yield: 42.7 %

Procedure:
A solution of 26.9 g (0.171 mol) of 2H-thieno-[3,2-d][1,3]-oxazine-2,4(1H)-dione and 16.1 g (0.171 mol) of L-azetidine-2-carboxylic acid in 200 ml of dimethylformamide and 40 ml of acetic acid was stirred at 120° for 3 hrs. The brown solution was evaporated and the brown residue obtained was crystallised from ethanol. There were obtained 15.2 g (43%) of (S)-6,7-dihydroazeto[1,2-a]thieno[3,2-e][1,4]diazepine-5,9(4H,5aH)-dione as colorless crystals; m.p. 274°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[C:14](=[CH:7]/[C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)/[C:15]#[N:16])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccncc1
Product: COc1ccc(/C(C#N)=C/c2ccncc2)cc1OC
Yield: 63.2 %

Procedure:
4-Pyridinecarboxaldehyde (2.14 g) was condensed with 3,4-dimethoxybenzyl cyanide (3.54 g) through Method A (production step 2), to thereby yield the target product (yield: 3.36 g, 63%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:21][C:12]3[N:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][NH2:20])=[O:18])[C:11]=3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:29](=[S:31])=S.C(=O)([O-])[O-].[K+].[K+].[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42]Cl>C(O)C.C(OCC)(=O)C>[F:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][S:31][C:29]1[O:18][C:17]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:21][C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:10][C:11]=23)=[N:19][N:20]=1
Reactant: Fc1cccc(CCl)c1
Reactant: NNC(=O)c1ccnc2[nH]c(CCc3ccccc3)cc12
Reactant: S=C=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1cccc(CSc2nnc(-c3ccnc4[nH]c(CCc5ccccc5)cc34)o2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.8 %

Procedure:
A solution of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine-4-carbohydrazide (126 mg, 0.449 mmol), triethylamine (0.156 mL, 1.122 mmol) and carbon disulfide (0.136 mL, 2.246 mmol) in ethanol (10 mL) was stirred at 90° C. for 20 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (5 mL). To this solution were added potassium carbonate (93 mg, 0.674 mmol) and 3-fluorobenzyl chloride (0.065 mL, 0.539 mmol), and the resulting mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) and basic silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (44 mg, yield 23%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I:13][CH2:14][C:15](O)=[O:16]>>[I:13][CH2:14][C:15]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:16]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(O)CI
Product: CCOC(=O)C(NC(=O)CI)C(=O)OCC

Procedure:
Diethyl 2-aminomalonate and iodoacetic acid are treated in the same manner as described in Reference Example 1 to give diethyl 2-[(iodoacetyl)amino]malonate, m.p. 96°-98° C.
Reaction SMILES: [CH3:1][N:2]([C:11](SC)=[N:12][C:13](=O)[CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:3]=CC1C=CC=CC=1.[CH3:22][N:23]([CH3:30])[CH2:24][C:25]1[O:26][CH:27]=[CH:28][CH:29]=1>C(#N)C>[CH3:22][N:23]([CH2:24][C:25]1[O:26][C:27]([CH2:18][S:15][CH2:14][CH2:13][NH:12][C:11]2[N:2]([CH3:1])[N:3]=[C:13]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:12]=2)=[CH:28][CH:29]=1)[CH3:30]
Reactant: CN(C)Cc1ccco1
Reactant: CSC(=NC(=O)CS(C)(=O)=O)N(C)N=Cc1ccccc1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNc2nc(CS(C)(=O)=O)nn2C)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 135.2 %

Procedure:
Methyl 1-methyl-N-[(methylsulphonyl)acetyl]-2-(phenylmethylene)hydrazinecarboximidothioate (1.05 g) and 5-[[2-aminoethyl)thio]methyl]-N,N-dimethylfuranmethanamine (0.85 g)in acetonitrile (3 ml) were heated on a steam bath at atmospheric pressure for 5 minutes then under water vacuum for 10 minutes. The oily residue was dissolved in acetonitrile (3 ml) and the solution re-evaporated under water vacuum. The oily residue was dissolved in 2N hydrochloric acid (3 ml) and 5N hydrochloric acid (4 ml) added to the solution. The solution was heated on a steam bath for 15 minutes and after cooling to room temperature, water (10 ml) was added and the oily suspension extracted with ethyl acetate. The aqueous phase was basified with sodium carbonate and the oily suspension extracted with ethyl acetate to yield an oil (0.84 g). This was chromatographed (using solvent system D) to give the title compound (0.78 g) as an oil. T.l.c. System D, Rf 0.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[C:16]([O:18]C(=O)C(C)(C)C)[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH:27]1[CH2:29][CH2:28]1)([CH3:4])([CH3:3])[CH3:2].CC([O-])(C)C.[Na+]>CO>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[C:12]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:13]=1[O:25][CH2:26][CH:27]1[CH2:29][CH2:28]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1c1cc(OC(=O)C(C)(C)C)ccc1OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1c1cc(O)ccc1OCC1CC1
Reaction time: 4 h
Yield: 93.7 %

Procedure:
A solution of compound 16 (127 mg, 0.304 mmol) in MeOH (1 mL) was treated with NaOtBu (146 mg, 1.52 mmol) at 0° C. After stirring at it for 4 h, the reaction was quenched adding sat. NH4Cl (2 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using gradient elution from 0% EtOAc-hexane to 30% EtOAc-hexane to afford the title compound as a thick oil (95 mg, 94% yield). 1H NMR (400 MHz, CDCl3) δ 6.68-6.60 (m, 2H), 6.48-6.44 (m, 2H), 5.48 (bs, 1H), 3.94-3.90 (m, 1H), 3.70-3.65 (m, 2H), 2.64-2.60 (m, 1H), 1.84-1.81 (m, 1H), 1.45-1.39 (m, 10H), 0.98-0.95 (m, 2H), 0.76-0.73 (m, 1H), 6.64-6.62 (m, 2H), 0.35-0.34 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:26][C:27](O)=[O:28])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:27](=[O:28])[CH2:26][C:18]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: COc1ccc(CCN)cc1OC
Product: COc1ccc(CCNC(=O)Cc2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 3,4,5-trimethoxyphenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1([C:17]([O-:19])=[O:18])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1([C:17]([O:19][CH3:20])=[O:18])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1(C(=O)[O-])CCN(C(=O)OCc2ccccc2)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C1(C)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.9 %

Procedure:
To 1-benzyl 3-methylpyrrolidine-1,3-dicarboxylate (3.45 g, 13.1 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (16.4 mL, 16.4 mmol) in THF at −78° C., and the reaction was stirred at this temperature for 20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and the reaction was warmed to room temperature. After 2 hours at room temperature, the mixture was poured onto saturated ammonium chloride (20 mL) and extracted with ether, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexane:ethyl acetate 4:1) to give 1-benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]1=[O:12].[OH:13]O>C(O)(=O)C>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:13])[C:3]1=[O:12]
Reactant: OO
Reactant: Cn1c(=O)cnc2ccccc21
Solvent: CC(=O)O
Product: Cn1c(=O)c(=O)[nH]c2ccccc21
Reaction time: 72 h

Procedure:
1-Methyl-2(1H)-quinoxalinone (5.3 grams) was allowed to stand at room temperature for 72 hours in a mixture of 60 ml. of acetic acid and 35 ml. of 30 percent hydrogen peroxide. The product separated out as needles after 48 hours. After 72 hours, no starting material was detectable in thesupernatant liquid by TLC (ethyl acetate). The product was separated and washed sequentially with water and with ethanol, m.p. 287°-289° C. It was then recrystallized from water, 287°-290° C. (literature: 286°-287° C., G. W. H. Cheeseman, J. Chem. Soc. 1804 (1955); 285°-286° C., G. W.H. Cheeseman, J. Chem. Soc. 1246 (1961)). NMR also confirmed the identity of the product.
Reaction SMILES: [N:1]([CH2:4][C:5](Cl)=[O:6])=C=O.[CH3:8][NH:9][C:10]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>O>[CH3:8][N:9]1[C:10]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:1][CH2:4][C:5]1=[O:6]
Reactant: O=C=NCC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Solvent: O
Product: CN1C(=O)CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Temperature: 95 °C

Procedure:
2-Milliliters of 2-isocyanatoacetyl chloride was cooled, and 0.20 g. of powdered 2-methylamino-5-nitrobenzophenone was added thereto with stirring. After stirring the resulting mixture at room temperature for one hour, excess 2-isocyanatoacetyl chloride was removed by reduced pressure distillation. To the residue was added 4 ml. of pyridine, whereby a reaction took place with generation of heat. The reaction liquid was heated at 95° C, for 1.5 hours, diluted with water and then extracted with chloroform. The chloroform layer was washed with a 5% aqueous hydrochloric acid solution and then with an aqueous sodium chloride solution in this order, dried over Glauber's salt, and evaporated by reduced pressure distillation. Subsequently, the residue was chromatographically purified (solvent: chloroform→ethyl acetate) by use of a column packed with 10 g. of silica gel to obtain 1-methyl-5-phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2-one having a melting point of 154° to 156° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:8])[CH3:7].Cl[O-:10].[Na+].ClCl>O1CCCC1.O>[CH3:7][C:6]1[O:8][CH:5]=[CH:4][C:3](=[O:10])[C:2]=1[OH:1]
Reactant: [O-]Cl
Reactant: CC(O)c1ccco1
Agent: ClCl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1occc(=O)c1O

Procedure:
To a solution of 1(2-furyl)-1-ethanol (0.05 mole) in 15 ml of tetrahydrofuran and 15 ml of water at 5° C. is added 21.7 ml of 2.8 M sodium hypochlorite solution. Chlorine (0.05 mole) is added to the reaction flask via a gas inlet tube maintaining the reaction temperature below 5° C. The reaction mixture is then heated to reflux and the tetrahydrofuran removed by distillation. Heating is continued for an additional hour. The reaction mixture is cooled and maltol is isolated by the procedure described in Example 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1)(=O)C.Cl>CO.O>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[C:18]#[C:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[OH:10]
Reactant: CC(=O)Oc1ccccc1C#Cc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Oc1ccccc1C#Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Potassium carbonate (0.48 g, 3.48 mmol, 2.0 eq.) was added to a stirred solution of 2-(quinolin-2-ylethynyl)phenyl acetate (0.50 g, 1.74 mmol, 1.0 eq.) in a 1:1 mixture of methanol-water (10 mL). The resulting mixture was stirred at r.t. for 3 h. The reaction was poured onto water (50 mL) and the pH was adjusted to 7.0 by careful addition of aqueous hydrochloric acid (10%). The mixture was extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate and were concentrated under reduced pressure yielding the product (0.42 g, 95%) as a pale yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 6.87 (t, J=7.5 Hz, 1H, Ar), 6.97 (d, J=8.0 Hz, 1H, Ar), 7.30 (t, J=8.0 Hz, 1H, Ar), 7.50 (d, J=7.5 Hz, 1H, Ar), 7.63 (t, J=7.5 Hz, 1H, Ar), 7.69 (d, J=8.5 Hz, 1H, Ar), 7.81 (t, J=7.0 Hz, 1H, Ar), 8.00 (d, J=7.0 Hz, 1H, Ar), 8.01 (d, J=7.0 Hz, 1H, Ar), 8.40 (d, J=8.5 Hz, 1H, Ar), 10.23 (s, 1H, OH).