Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].[C:5]1([C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]#[C:20][C:21]3[N:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=3)[CH2:15][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:5]1([C:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]#[C:20][C:21]3[N:26]=[CH:25][C:24]([NH:27][CH2:1][CH2:2][CH3:3])=[CH:23][CH:22]=3)[CH2:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCC=O
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCCNc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of propionaldehyde (0.18 mL, 2.5 mmol), 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 20) (0.83 g , 2.7 mmon) and glacial acetic acid (0.14 mL, 2.5 mmol) in 20 mL of dichloroethane is treated with sodium triacetoxyborohydride (0.79 g, 3.7 mmol) under nitrogen and is stirred at room temperature for 18 hours. The reaction is quenched with saturated aqueous sodium bicarbonate, diluted with dichloromethane, and the organic layer is dried (sodium sulfate) and concentrated under reduced pressure. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.20 mol of water; mp 138°-139° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]([F:19])(S(F)(=O)=O)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C>[Br:1][C:2]1[C:3]([O:9][CH:11]([F:19])[F:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(O)c(Br)c1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(OC(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 3-bromo-5-methylpyridin-2-ol (25.0 g, 0.13 mol) in ACN (100 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (23.7 g, 0.13 mol) and sodium carbonate (28.2 g, 0.270 mol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-10%, EtOAc/hexanes) afforded the title compound as an off-white solid (22 g, 70%). M+H]=238.09/240.09.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]2[NH:19][CH:18]=[N:17][N:16]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.O1CCCC1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C([O-])(O)=O.[Na+]>[Br:1][C:2]1[S:3][C:4]([C:15]2[N:19]=[CH:18][N:17]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)[N:16]=2)=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1
Reactant: Clc1ccc(Cc2nc(Br)sc2-c2nnc[nH]2)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(Cc2nc(Br)sc2-c2ncn(C3CCCCO3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
In a 250 mL round bottomed flask were placed 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-4H-1,2,4-triazole (0.7 g, 2 mmol) and tetrahydrofuran (50 mL, 600 mmol). To the mixture were added dihydropyran (2 mL, 20 mmol) and p-toluenesulfonic acid monohydrate (911.3 mg, 4.791 mmol). The mixture was refluxed for 2 h then was allowed to cool to rt and then a saturated aqueous solution of NaHCO3 (50 mL) was added. The resulting biphasic mixture was vigorously stirred for 30 min at rt. The aqueous phase was separated then was extracted with EtOAc (50 mL×2). The combined organic phases were dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica, elution with a 10%-80% mixture of EtOAc in hexane (linear gradient, 30 min) to afford 3-[2-bromo-4-(4-chlorobenzyl)-1,3-thiazol-5-yl]-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (778 mg; 67% six steps) as a yellow syrup which spontaneously solidified on standing at rt for 2 days. LC/MS (FA) ES+ 441. 1H NMR (d6-DMSO, 400 MHz): δ: 8.89 (1H, s), 7.28-7.34 (4H, m), 5.62 (1H, dd, J=2.8 and 9.6 Hz), 4.52 (2H, s), 3.92-3.96 (1H, m), 3.63-3.70 (1H, m), 1.91-2.14 (3H, m), 1.52-1.72 (3H, m)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)(=[O:18])[CH3:17]
Reactant: O=C(O)c1csc(-c2ccccc2O)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1-c1nc(C(=O)O)cs1
Temperature: 25 °C

Procedure:
To a solution of 2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (900 mg) dissolved in dry pyridine (15 ml) was added dropwise acetic anhydride (0.461 ml) under ice-cooling. The mixture was allowed to warm up to room temperature and to react for additional 1.5 hours. Then the solvent was removed and the residue was treated with water, acidified with 2N--HCl and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give the desired compound,
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11](I)[N:10]=[C:9]2[CH3:14])=[CH:4][N:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[N:10]=[C:9]2[CH3:14])=[CH:4][N:3]=1
Reactant: Cc1nc(I)cn1-c1ccc(Cl)nc1
Reactant: C#C[Si](C)(C)C
Product: Cc1nc(C#C[Si](C)(C)C)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=290.6 (M+H+), was prepared in accordance with the general method of example B, step 1, from 2-chloro-5-(4-iodo-2-methyl-imidazol-1-yl)-pyridine and trimethylsilylacetylen.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].C(Cl)Cl.[C:20]([O:24][C:25](=[O:53])[NH:26][C:27]([C:29]1[S:30][C:31]([S:51][CH3:52])=[C:32]([S:34]([C:37]2[CH:38]=[C:39]([C:43]3[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][C:44]=3[CH3:50])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:33]=1)=[NH:28])([CH3:23])([CH3:22])[CH3:21].NC(N)=S>>[C:20]([O:24][C:25](=[O:53])[NH:26][C:27](=[NH:28])[C:29]1[S:30][C:31]([S:51][CH3:52])=[C:32]([S:34]([C:37]2[CH:38]=[C:39]([C:43]3[CH:48]=[CH:47][C:46]([N:49]=[C:1]=[S:2])=[CH:45][C:44]=3[CH3:50])[CH:40]=[CH:41][CH:42]=2)(=[O:36])=[O:35])[CH:33]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N)cc2C)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: NC(N)=S
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ccc(N=C=S)cc2C)c1

Procedure:
A solution of 1,1′-thiocarbonyldi-2(1H)-pyridone in DCM (0.25 M, 300 μL, 0.075 mmol) was added to {[4-(4′-amino-2′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 220: step b) 26 mg, 0.05 mmol) at rt. The orange color of the thiourea dissipated as the reagent was added, and a new higher spot appeared on TLC. The solvent was removed in vacuo and the residue was purified by preparative TLC to yield 23 mg of product. 1H-NMR (CDCl3): δ 8.01 (br s, 1H), 7.96 (d, 1H, J=7.4 Hz), 7.87 (s, 1H), 7.53 (m, 2H), 7.10 (d, 1H, J=7.9 Hz), 6.93 (br s, 1H), 6.87 (d, 1H, J=7.9 Hz), 2.51 (s, 3H), 2.17 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:23])[C:10]([CH3:22])([CH3:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45]Cl)[N:44]=2)[CH:41]=1>O>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]2[N:40]([CH:42]=[C:43]([CH2:45][O:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[C:9](=[O:23])[C:10]([CH3:21])([CH3:22])[O:11][C:12]=4[C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[CH:6][CH:7]=3)[N:44]=2)[CH:41]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: COc1ccc(C2=C(c3ccc(O)cc3)C(=O)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4cn5cc(Cl)ccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 80 °C
Yield: 39.5 %

Procedure:
4-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (300 mg, 0.96 mmol) was added to a mixture of cesium carbonate (1.05 g, 3.8 mmol) and DMF (20 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 minutes, upon which 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (201 mg, 1.4 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). Upon completion of the reaction as judged by TLC, the reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 20% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(4-((6-chloroimidazo[1,2-a]pyridin-2-yl)methoxy)phenyl)-5-(4-methoxy phenyl)-2,2-dimethylfuran-3(2H)-one (180 mg, 39.3%) as a white solid. 1H NMR, 500 MHz, DMSO-d6: δ 8.85 (s, 1H), 8.0 (s, 1H), 7.6 (d, 3H), 7.3 (d, 1H), 7.15 (d, 2H), 7.1 (d, 2H), 7.0 (d, 2H), 5.15 (s, 2H), 3.8 (s, 3H), 1.4 (s, 6H). MS: [M+H]+: m/z=475. HPLC: (98.0%, Condition-A).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:13])[CH:11]=[CH2:12])=[CH:2]1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([CH2:12][CH2:11][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:13])[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: c1c[nH]cn1
Reactant: C=CC(=O)c1c[nH]c2ccccc12
Product: O=C(CCn1ccnc1)c1c[nH]c2ccccc12
Yield: 56.2 %

Procedure:
By a similar procedure to that described in Example 1, 1-(1H-indol-3-yl)-1-prop-2-enone (0.4 g) was reacted with imidazole (0.8 g) to give the title compound (0.314 g), m.p. 194°-197°; λmax (EtOH) 242.5 nm (ε12,900) λinf 259 nm (ε9,090) λmax 299.5 nm (ε12,390).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[O-]CC.[Na+].[Br-].Br[CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>C(O)C>[C:6]([CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:15][CH2:16][CH2:17][S:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1)#[N:7]
Reactant: CCOC(=O)c1ccc(SCCCBr)cc1
Reactant: CCOC(=O)CC#N
Agent: CC[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1ccc(SCCCC(C#N)C(=O)OCC)cc1
Yield: 71.4 %

Procedure:
Ethylcyanoacetate (6.30 g, 55.7 mmoles) was added to a solution of sodium ethoxide (50 mmoles) in ethanol (25 mL) and refluxed 15 minutes. After cooling, the mixture was treated with bromide, 1A, (7.68 g, 25.3 mmoles) as a solution in ethanol (25 mL) and refluxed for 6 hours. The mixture was filtered, and the filtrate was treated with acetic acid to pH 7.0 and was evaporated to a viscous residue. The residue was partitioned between water (50 mL) and ether (50 mL), and the ether phase collected. The aqueous phase was washed with 4 volumes (50 mL) of ether, and the combined ether fractions were dried (CaSO4) and filtered. The filtrate was evaporated in vacuo, and the residue chromatographed (400 g silica, 3:1 hexane/ethyl acetate) to yield 6.06 g (70%) of the title compound, 1B, as a pale yellow oil. NMR (DMSO-d6) δ1.17 (t, 3H, CH3 of benzoate ether), 1.7 (m, 2H, CH2CH2 --CH2), 1.95 (m, 2H, CH2 --CH2CH2 --S), 1.28 (t, 3H, CH3 of acetate ester), 3.1 (m, 2H, CH2 --S), 4.15 (m, 1H, CH), 4.15 (q, 2H, CH2 of benzoate ester), 4.28 (q, 2H, CH2 of acetate ester), 7.4 (d, 2H, benzoate H's ortho to S), 7.85 (d, 2H, benzoate H's ortho to carbonyl). Compound 1B was used in the next reaction without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(OCC)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:2][CH2:3][CH:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCC(CN)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(CNS(=O)(=O)c1ccc(Cl)cc1)c1cccnc1
Reaction time: 2 h

Procedure:
Methyl 7-amino-6-(3-pyridyl)-heptanoate hydrochloride (8.0 g) is suspended in 200 mL of ethyl acetate, 15 mL of triethylamine is added, and then a solution of 10 g of 4-chlorophenylsulfonyl chloride in 100 mL of ethyl acetate is added dropwise over a period of 0.5 hour. The reaction is then stirred for 2 hours and is extracted with 1N aqueous sodium hydroxide, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated. The residue is chromatographed over activated magnesium silicate (Florisil) and eluted with ethyl acetate to yield methyl 7-(p-chlorophenylsulfonamido)-6-(3-pyridyl)-heptanoate as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].C(O[CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])C>CCO>[NH2:14][C:13]1[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[CH:9][C:10]=1[C:11]#[N:12]
Reactant: CCOC=C(C#N)C#N
Reactant: NNCCO
Solvent: CCO
Product: N#Cc1cnn(CCO)c1N
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 2-hydroxyethylhydrazine (38.9 g.) in EtOH (425 ml.) was heated to 50° while a solution of ethoxymethylenemalononitrile (52 g.) in warm EtOH (250 ml.) was added over a period of ten minutes. The last of this material was washed into the reaction flask with EtOH (50 ml.), and the mixture was heated under reflux for 2.5 hours. The resulting solution was allowed to cool to room temperature overnight. The golden-brown crystals which formed were collected by filtration, washed with ether, and dried in vacuo at room temperature to give 5-amino-4-cyano-1-(2-hydroxyethyl)pyrazole (45.57 g.): m.p. 158°-160 °.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:5]([CH3:7])[CH:6]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:7][N:5]1[CH:6]=[C:2]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)[N:3]=[C:4]1[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: OB(O)c1ccsc1
Reactant: Cn1cc(Br)nc1CCc1ccc2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccsc2)nc1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
A suspension of 2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)ethyl)quinoline (0.31 g, 0.980 mmol), thiophen-3-ylboronic acid (0.25 g, 1.960 mmol), and Pd(PPh3)4 (0.022 g, 0.441 mmol) in 1,4-dioxane (6 mL) under N2 was stirred at room temperature for 0.5 h and then Na2CO3 (0.3105 g, 2.94 mmol) in water (1 mL) was added. The mixture was refluxed overnight. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate (EtOAc). The separated organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 55.6 mg of the desired compound. LC-MS: m/z 320 (M+H+).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH3:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33].C(N(CC)CC)C.Cl>C(#N)C>[CH3:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33]
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.00 mmol) and 3,4-dimethylphenylisocyanate (0.15 g, 1.00 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.00 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(3,4-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.30 g, 71% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.02 min (97.86%); mp: 254-256° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H), 2.12 (s, 3H), 2.15 (s, 3H), 2.30-2.47 (m, 1H), 2.60 (d, J=17.2 Hz, 1H), 2.82-3.00 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.36-4.50 (m, 3H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 6.66 (t, J=5.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 7.11 (dd, J=1.7, 8.1 Hz, 1H), 7.18 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 8.41 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 18.60, 19.62, 22.49, 31.20, 42.77, 47.10, 51.56, 115.35, 119.15, 121.86, 122.91, 126.89, 128.67, 129.49, 130.26, 136.08, 138.03, 142.36, 144.96, 155.26, 167.95, 170.98, 172.85; Anal Calcd for C23H24N4O4: C, 65.70; H, 5.75; N, 13.33. Found: C, 65.48; H, 5.62; N, 13.20.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][O:17][N:18]=[C:19]([C:23]1[N:24]=[C:25]([NH:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:26][CH:27]=1)[C:20]([OH:22])=O.[CH3:48][O:49][CH:50]([O:61][CH3:62])[CH2:51][N:52]1[C:57](=[O:58])[C:56](=[O:59])[NH:55][NH:54][C:53]1=[S:60]>CN(C)C=O>[CH3:62][O:61][CH:50]([O:49][CH3:48])[CH2:51][N:52]1[C:57](=[O:58])[C:56](=[O:59])[NH:55][N:54]=[C:53]1[S:60][C:20](=[O:22])[C:19](=[N:18][O:17][CH3:16])[C:23]1[N:24]=[C:25]([NH:28][C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[S:26][CH:27]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COC(Cn1c(=S)[nH][nH]c(=O)c1=O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CON=C(C(=O)Sc1n[nH]c(=O)c(=O)n1CC(OC)OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 4 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
N,N'-Dicyclohexylcarbodiimide (0.50 g) is added all at once to a solution, cooled to 4° C., of the syn isomer of 2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (0.89 g) and 4-(2,2-dimethoxyethyl)-5,6-dioxo-3-thioxo-perhydro-1,2,4-triazine (0.47 g) in dimethylformamide (20 cc); the mixture is stirred for 1 hour at 4° C. and then for 3 hours at 20° C. The reaction suspension is filtered, the filtrate is diluted with ethyl acetate (100 cc), the mixture is washed with water (2×50 cc), a 1% strength solution of sodium bicarbonate (2×50 cc) and a semi-saturated solution of sodium chloride (2×50 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The residue is triturated in isopropyl ether (10 cc) and, after filtration and drying, the syn isomer of 4-(2,2-dimethoxyethyl)-5,6-dioxo-3-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetylthio]-1,4,5,6-tetrahydro-1,2,4-triazine (0.91 g) is obtained in the form of a yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@@H:12]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][CH2:14][CH:15]=[CH2:16].C([C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([CH3:40])[CH:31]=1)=C>CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru-4](Cl)(Cl)=CC1C=C(S(N(C)C)(=O)=O)C=CC=1OCCC.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C@H:12]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:13][CH2:14]/[CH:15]=[CH:16]/[C:30]1[CH:35]=[C:34]([C:36]([F:37])([F:39])[F:38])[CH:33]=[C:32]([CH3:40])[CH:31]=1
Reactant: C=Cc1cc(C)cc(C(F)(F)F)c1
Reactant: C=CCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Agent: CCCOc1ccc(S(=O)(=O)N(C)C)cc1C=[Ru-4](Cl)(Cl)=C1N(c2c(C)cc(C)cc2C)CCN1c1c(C)cc(C)cc1C
Solvent: ClCCl
Product: Cc1cc(/C=C/CC[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Temperature: 60 °C
Yield: 73.7 %

Procedure:
To a 100 mL RBF equipped with a reflux condenser was added benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (0.5 g, 1.13 mmol), 1-ethenyl-3-methyl-5-(trifluoromethyl)benzene (421 mg, 2.26 mmol) and dichloromethane (10 mL). The system was flushed with nitrogen and 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene[2-(1-propoxy)-5-(N,N-dimethylaminosulfonyl)phenyl]methyleneruthenium(II)dichloride (41 mg, 0.57 mmol) (Zhan catalyst-1B) was added before heating at 60° C. for 20 min. The reaction was cooled to room temperature and was directly purified by column chromatography to yield benzyl {(1R,4E)-1-[2-bromo-5-(trifluoromethyl)phenyl]-5-[3-methyl-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (500 mg, 0.833 mmol). 1H NMR (500 MHz, CDCl3) δ7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 6.4 (d, J=8.2 Hz, 1H), 6.25 (m, 1H), 5.35 (m, 1H), 5.20 (m, 1H), 5.10 (s, 2H), 2.40 (s, 3H), 2.19 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:12][S-:13].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:13][CH3:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: C[S-]
Reactant: Clc1c(Br)cnc2[nH]ccc12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1c(Br)cnc2[nH]ccc12
Temperature: 80 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mmol) was combined with sodium thiomethoxide (151 mg, 2.16 mmol) and dissolved in N,N-dimethylformaldehyde (5 mL). The solution was at 80° C. for 15 hours when additional sodium thiomethoxide (75 mg, 1.08 mmol) was added. The solution was stirred for at 80° C. for 2 hours. Water (50 mL) was added to the reaction mixture, and the precipitate was collected by vacuum filtration to afford 5-Bromo-4-methylsulfanyl-1H-pyrrolo[2,3-b]pyridine (524 mg, 2.16 mmol, >99% yield) as a white solid. 1H-NMR [500 MHz, d6-DMSO] δ: 11.99 (s, 1H), 8.22 (s, 1H), 7.54 (d, 1H), 6.69 (d, 1H), 2.74 (s, 3H); MS [MH+] m/z: 243.0, 244.9
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][O:7][C:8]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:9]=1[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([O-:19])=O)[CH2:12]1.[CH3:26][O:27][NH:28][CH3:29].O>C1COCC1>[CH3:6][O:7][C:8]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:9]=1[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([N:28]([O:27][CH3:26])[CH3:29])=[O:19])[CH2:12]1
Reactant: COc1ccc(CN2CC(C(=O)[O-])CC2=O)c(OC)c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CC(C(=O)N(C)OC)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (15.3 mL, 30.6 mmol) was added to a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (3.0 g, 10 mmol) and O,N-dimethyl-hydroxylamine (1.5 g, 15 mmol) in THF (100 mL) at −10° C. The mixture was stirred at 0° C. for 1 hour then the mixture was added to water and concentrated under reduced pressure to afford 1-(2,4-dimethoxybenzyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide. 1H NMR (400 MHz, CDCl3) δ 7.13-7.15 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.67 (s, 3H), 3.46-3.49 (m, 3H), 3.18 (s, 3H), 2.70-2.77 (m, 1H), 2.57-2.63 (m, 1H). MS ESI calc'd. for C16H23N2O5 [M+H]+ 323. found 323.