Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C@H:14]2[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C:7]1=[O:15])C.[NH3:17]>CO>[O:15]=[C:7]1[N:6]([CH2:5][C:4]([NH2:17])=[O:3])[C@@H:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:8]1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCC[C@H]21
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCCC[C@H]21
Reaction time: 24 h

Procedure:
A solution of trans-octahydro-2-oxo-1H-indole-1-acetic acid ethyl ester; (7.7 g, 0.032 mole) in methanol (200 ml) in methanol (200 ml) is saturated with ammonia and stirred at ambient temperatures 24 hours. The solution is concentrated at reduced pressure to yield a solid, trans-hexahydro-2-oxocyclohexa[b]pyrrol-1-(2H)-acetamide.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2O[C:9](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:34]>C(O)(=O)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[NH:34][C:9](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:16]([O:26][CH3:27])[CH:15]=3)=[N:10][N:11]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: COc1cc(/C=C/c2nnc(Cc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(Cc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
A solution of 2-(4-fluorobenzyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (65 mg) and ammonium acetate (256 mg) in acetic acid (1 mL) was stirred at 150° C. for four hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1). The resulting solid was suspended in diethyl ether and collected by filtration to obtain 40 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25].C(=O)([O-])[O-].[K+].[K+].[Br:32][CH2:33][CH2:34][CH2:35]Br>CN(C)C=O>[Br:32][CH2:33][CH2:34][CH2:35][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=1)=[N:7][CH:6]=[C:5]2[CH:24]=[O:25]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(O)c(OC)cc23)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCCBr)c(OC)cc23)c1
Temperature: 85 °C
Yield: 63.6 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (86 g, 0.24 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (337 mg, 2.40 mmol) and 1,3-dibromopropane (0.124 mL, 1.22 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 6-(3-bromo-propoxy)-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde as a colorless oil (70 mg, 62% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:18][S:19]([O:1][CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=1)(=[O:21])=[O:20]
Reactant: OCc1cn(-c2cccnc2)c2ccccc12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CS(=O)(=O)OCc1cn(-c2cccnc2)c2ccccc12
Temperature: 0 °C

Procedure:
A solution of 3.3 g of 3-hydroxymethyl-N-(3-pyridyl)indole in 25 ml of pyridine is cooled to +5° and 1.36 ml of methanesulfonyl chloride is added dropwise. After 3 hours the reaction is diluted with 75 ml of ice water and 1.5 g of sodium bicarbonate is added. Extraction with methylene chloride (3×25 ml) and drying of the extracts with sodium sulfate yields 3-(methanesulfonyloxymethyl)-N-(3-pyridyl)indole which is used directly in the next step.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].[C:15]([OH:20])(=[O:19])[CH:16]([CH3:18])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH:16]([C:15]([OH:20])=[O:19])[CH3:18])=[O:13])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3]
Reactant: CC(O)C(=O)O
Reactant: C=CCNc1cccc(CC(=O)O)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: C=CCNc1cccc(CC(=O)OC(C)C(=O)O)c1

Procedure:
A flask containing 10.0 g. 3-(allylamino)phenylacetic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene equipped with a Soxhlet extractor charged with activated 4 Å Linde molecular sieves. The solution is refluxed for 24 hours during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon 1-carboxyethyl 3-(allylamino)phenylacetate separates as off-white crystals.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH2:14])=[N:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:29][C:26]2[CH:25]=[CH:24][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:28][CH:27]=2)=[N:2]1
Reactant: NCCCNc1nsc2ncccc12
Reactant: COc1ccc(-c2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(CNCCCNc3nsc4ncccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N1-(isothiazolo[5,4-b]pyridin-3-yl)propane-1,3-diamine (1.20 g, 5.77 mmol), 4′-methoxybiphenyl-4-carbaldehyde (1.22 g, 5.77 mmol), sodium triacetoxyborohydride (2.50 g, 11.8 mmol) and acetic acid (one drop) was taken up in methylene chloride (25 mL) and stirred overnight at room temperature under argon. The crude reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and washed successively with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 95:5 methylene chloride:methanol yielded N1-(isothiazolo[5,4-b]pyridin-3-yl)-N3-((4′-methoxybiphenyl-4-yl)methyl)propane-1,3-diamine. 1H NMR (300 MHz, CD3OD): 8.66-8.68 (d, 1H), 8.40-8.45 (d, 1H), 7.33-7.45 (m, 7H), 6.96 (s, 1H), 6.93 (s, 3.83 (s, 2H), 3.80 (s, 3H), 3.58-3.63 (t, 2H), 2.78-2.83 (t, 2H), 1.96-2.00 ppm (t, 2H). MW=405 confirmed by LC-MS, tr=9.08 min (Method Y) MH+=406.
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[CH:15]=O)=[CH:6][CH:5]=1.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][NH2:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1.CCO>O>[F:1][CH:2]([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14](/[CH:15]=[N:32]/[NH:31][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)(=[O:29])=[O:30])[CH:17]=[CH:18][CH:19]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N/N=C/c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)cc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A mixture of 3-{[4-(difluoromethoxy)phenyl]ethynyl}benzaldehyde (3.69 g, 13.57 mmol), 4-methylbenzenesulfonohydrazide (2.9 g, 15.6 mmol) and EtOH (11 mL) was refluxed for 30 minutes. cooled to room temperature, poured into water and extracted with ethyl ether. The organic extracts were combined dried over MgSO4 and concentrated in vacuo. The resultant residue was purified on silica gel (Biotage) using hexanes/EtOAc (2/1) as the eluting solvents to give N′-[(1E)-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzenesulfonohydrazide as a tan solid (5.4 g, 90% yield), MS m/e (M+H)+ 441; 1H NMR (400 MHz, DMSO-d6) 2.32 (s, 3H), 7.2 (d, J=8.66 Hz, 2H), 7.3-7.6 (m, 8H), 7.72 (d, J=8.3 Hz, 2H), 7.88 (s, 1H), 11.54 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14](N)=[O:15]>>[CH2:1]([N:8]1[CH2:9][C:10](=[O:12])[NH:13][C:14]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: NC(N)=O
Product: O=C1CN(Cc2ccccc2)C(=O)N1
Yield: 42.7 %

Procedure:
The starting material for the abovementioned synthetic route a), viz. N-benzyl-aminoacetonitrile, is prepared by reaction of benzylamine and formaldehyde with the extremely toxic hydrocyanic acid (see also Tetrahedron Letters [23], 27 (1982), 2741-4). The starting material for the synthetic route b), viz. N-benzylglycine, also firstly has to be prepared by reaction of glycine with benzyl chloride or of chloroacetic acid with benzylamine. The reaction of N-benzylaminoacetonitrile or N-benzylglycine as per a) or b) is carried out either by fusion with urea for a long time or by reaction with the toxic cyanic acid. Both methods give 1-benzyl-hydantoin in only low yields: thus, according to Huaxue Shiji 1993, 15(1) 15-16, the reaction of N-benzylglycine (obtained by reaction of benzylarnine with chloroacetic acid) with cyanic acid gives 1-benzylhydantoin in a yield of only 39.5% and the reaction of N-benzylglycine with urea gives 1-benzylhydantoin in a yield of only 45.6%. The subsequent bromination of the 1-benzylhydantoin and treatment with ethanol again proceeds in only a low yield of 42.7%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([Cl:15])[CH:17]=2)[N:3]=1
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCc3cccc(Cl)c3)nc(Cl)nc21

Procedure:
2-Chloro-6-[(3-chloro)benzylamino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine, 3-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[C:32]([Sn](CCCC)(CCCC)CCCC)=[CH:31][N:30]=[CH:29]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cn1cncc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 89.8 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.0 g, 2.46 mmol), 1-methyl-5-(tributylstannyl)imidazole (prepared according to Gaare, K., et al. Acta Chem. Scand. (1993), 47(1), 57-62) (1.25 g, 3.37 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic amount) were reacted according to Procedure B in dioxane (50 ml) for 3 hours. The solvent was removed in vacuo, and the solid was washed with i-hexane. The resulting dark solid was suspended in IMS, and undissolved material removed by filtration. The resulting filtrate was concentrated in vacuo to give the product as a pale baige solid (0.90 g, 2.21 mmol, 90%);_δH [2H6]-DMSO 9.69 (1H, b, NH), 8.60 (1H, s, 5-H), 8.55 (1H, s, 2-H), 8.00 (1H, d, 7-H), 7.83 (2H, m, 8-H, imidazole-H), 7.69 (2H, d, 2′-H, 6′-H), 7.52-7.33 (5H, m, 5×Ph-H), 7.22 (1H, s, imidazole-H), 7.09 (2H, d, 3′-H, 5′-H), 5.14 (2H, s, CH2), 3.80 (3H, s, CH3); m/z 408 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1

Procedure:
Prepared according to Procedure N using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and ethyl chloroformate to give ethyl 4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazine-1-carboxylate. 1H NMR (DMSO-d6) δ ppm 1.09 (t, J=7.2 Hz, 3H), 2.13 (s, 3H), 3.04-3.06 (m, 4H), 3.27 (s, 4H), 3.55 (s, 4H), 3.68-3.70 (m, 4H), 4.08 (q, J=6.8 Hz, 2H,), 6.49 (m, 1H), 7.14-7.20 (m, 1H), 7.29 (dd, J=9.8 Hz, J=2 Hz, 1H), 7.52 (d, J=1.6 Hz, 1H), 7.78 (d, J=2 Hz, 1H), 8.38 (s, 1H). Mass Spectrum (ESI) m/e=513.1 (M+1).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=1>>[C:1]1([S:7](/[CH:10]=[CH:11]/[C:18]2[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)c1ccccc1
Yield: 78 %

Procedure:
A solution of phenyl sulfonylacetic acid (0.01 mol) and 4-chlorobenzaldehyde (0.01 mol) was subjected to Procedure 1, Part B. The title compound was obtained in 78-80% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]O)=[CH:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: OCCc1ccsc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCCc2ccsc2)c(I)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution 6-chloro-2-iodopyridin-3-ol (6.75 g, 26.4 mmol), 2-(3-thienyl) ethanol (3.79 mL, 34.4 mmol), and triphenylphosphine (9.01 g, 34.4 mmol) in tetrahydrofuran (140 mL) was added diisopropyl azodicarboxylate (6.76 mL, 34.4 mmol) dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by column on silica gel (eluted at EtOAc/Hexanes=1:20) to give 5.5 g of 6-chloro-2-iodo-3-(2-(thiophen-3-yl)ethoxy)pyridine. Yield: 58%. 1H NMR (DMSO, 400 MHz): δ7.50-7.43 (m, 3H), 7.34 (d, J=1.6 Hz, 1H), 7.17 (d, J=4.8 Hz, 1H), 4.29 (t, J=6.4 Hz, 2H), 3.10 (t, J=6.4 Hz, 2H). LC-MS (ESI): m/z=366 [M+H]+
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([CH2:20][C:21]([O-:23])=[O:22])[C:17](=[O:24])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].O>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][N:18]([CH2:20][C:21]([OH:23])=[O:22])[C:17](=[O:24])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2CC(=O)N(CC(=O)[O-])C2)cc1OC1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(C2CC(=O)N(CC(=O)O)C2)cc1OC1CCCC1
Reaction time: 10 h
Yield: 100.8 %

Procedure:
4-(3-Cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone-1-acetate (250 mg, 0.72 mmol) was treated with 8 ml of a 1M solution of potassium hydroxide in 95% methanol. After 10 hours, the reaction solution was acidified with 2NHCl to pH 3 and 30 ml of water was added and the resulting mixture was extracted with 60 ml of ethyl acetate twice. The organic layer was concentrated and chromatographed (methanol/dichloromethane 5:100) to give 242 mg (quantitative yield) of 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone-1-acetic acid: 1H NMR (300 MHz, CDCl3) δ 6.85-73 (m, 3H), 4.84-4.74 (m, 1H), 4.20 (d, J=12.0 Hz, 1H), 4.12 (d, J=12.0, 1H), 3.82 (s, 4H), 3.66-3.46 (m, 2H), 2.89 (dd, J=16.8, 8.7 Hz, 1H), 2.58 (dd, J=16.8, 8.4 Hz, 1H), 2.00-1.72 (b, 6H), 1.70-1.50 (b, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[CH:7].I[C:10]1[C:18]([N+]([O-])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>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.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[C:7][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Reactant: C#CCNC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (71.3 mg, 0.63 mmol) (see below) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.3 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (11 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 25 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[N:11]=[N:12][NH:13][N:10]=2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(Cc2nn[nH]n2)cc1
Yield: 46.7 %

Procedure:
4-Bromophenylacetonitrile (30.0 g, 0.15 mol), sodium azide (10.9 g, 0.17 mol) and ammonium chloride (8.9 g, 0.17 mol) were heated in DMF (300 mL) at 90° C. for 2 days. After concentration, water (200 mL) was added to the residue, the mixture was basified with 1M NaOH (170 mL) and washed with ether (2×100 mL). Acidification of the aqueous layer with 1N HCl and collection of the precipitate by suction filtration produced the crude product. This was purified by recrystallization from ethanol to provide 5-[(4-bromophenyl)methyl]-2H-tetrazole (17.2 g, 0.07 mol) in 44% yield, mp. 173°-175° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:18](OC)(OC)([O:20][CH3:21])[CH3:19].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[OH:1][CH2:2][CH:3]1[CH2:5][O:6][C:18]([O:20][CH3:21])([CH3:19])[O:4]1
Reactant: COC(C)(OC)OC
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC1(C)OCC(CO)O1
Reaction time: 18 h
Yield: 97 %

Procedure:
Example: A 1-liter round-bottomed flask was equipped with a pressure equalizing addition funnel was flushed with nitrogen and charged with 41.5 grams (451 mmol.) of glycerol, 750 ml. of methylene chloride and 100 mg. of p-toluenesulfonic acid. Trimethyl orthoacetate, 56.9 grams (473 mmol), was added over 5 minutes at room temperature, with stirring. The stirring was continued for 18 hours followed by addition of 1 gram of anhydrous sodium carbonate. The mixture was stirred for one additional hour and filtered. The solvent was stripped under vacuum to yield 65 grams (97% of theoretical) of 4-hydroxymethyl-2-methoxy-2-methyl-1,3-dioxolane as a clear oil. Its molecular structure was confirmed by proton and carbon-13 nuclear magnetic resonance spectroscopy. A 3-necked 2 liter round-bottomed flask was equipped with a mechanical stirrer, condenser, thermometer, and addition funnel. The flask was charged with 0.5 g methyltrialkylammonium chloride, 100 mL chloroform, 30 mL distilled water, and 32 g of 50 percent aqueous sodium hydroxide. The flask was immersed in a ice-water bath and cooled to approximately 10° C. while stirring rapidly followed by addition of 30 g (0.2 mol) 4-hydroxymethyl-2-methoxy-2-methyl-1,3-dioxolane. A solution of 20.2 g terephthaloyl chloride (0.1 mol) in chloroform was added to the flask through the addition funnel over a 60 minute period maintaining the reaction temperature at approximately 10° C. or lower. After the addition of the acid chloride was complete, the reaction was stirred for additional 60 minutes. The layers were separated and the chloroform layer was washed twice with 500 mL distilled water, dried over anhydrous sodium sulfate and vacuum stripped to yield the product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[S:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Sn](Cl)(Cl)(Cl)Cl.O>C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(Cl)CCCCCBr
Reactant: c1ccsc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: O=C(CCCCCBr)c1cccs1
Reaction time: 1 h
Yield: 120.7 %

Procedure:
6-Bromohexanoyl chloride (2.1 g) and thiophene (0.84 g) were dissolved in benzene (20 ml) and tin chloride (1.3 ml) was added under ice-cooling, which was followed by stirring for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 3.1 g of 6-bromo-1-(2-thienyl)-1-hexanone.
Reaction SMILES: I[CH2:2][Si:3]([CH3:33])([CH3:32])[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12.C([O-])([O-])=O.[K+].[K+].CC(O)(C)C.[NH:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1>O>[CH3:32][Si:3]([CH3:33])([CH2:2][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)[CH2:4][CH2:5][C:6]1[C:18]2[CH2:17][N:16]3[C:11](=[CH:12][C:13]4[C@:23]([CH2:25][CH3:26])([OH:24])[C:22](=[O:27])[O:21][CH2:20][C:14]=4[C:15]3=[O:19])[C:10]=2[N:9]=[C:8]2[CH:28]=[CH:29][CH:30]=[CH:31][C:7]=12
Reactant: C1CCNC1
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CN1CCCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A slurry of Compound 4 (60 mg) and K2CO3 (43 mg) in deionized water (1 mL) was stirred at room temperature for 30 min. To the resulting reaction mixture, t-BuOH (1 mL) and pyrrolidine (52 μL) were added and heated at 70° C. for 5 hours. The reaction mixture was then concentrated under reduced pressure and the residue was dissolved in acetic acid (10 mL) and stirred at room temperature for 2 hours. The acetic acid solution was concentrated again under vacuum. Finally, the residue was partitioned between chloroform (2×15 mL) and 7% aqueous NaHCO3 solution (5 mL). The collective organic layers were dried, concentrated and purified on a silica gel using 10% ethanol in dichloromethane to afford the required product in 83% yield (45 mg).