Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)=S)[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH:21]O>C(O)(=O)C>[F:1][C:2]1[C:3]([CH:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=2)=[O:21])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=S)Nc1ccc(Br)cn1)c1ncccc1F
Reactant: OO
Solvent: CC(=O)O
Product: CC(NC(=O)Nc1ccc(Br)cn1)c1ncccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.6 %

Procedure:
A solution of 400 mg (1.13 mmole) of N-(3-fluoropyrid-2-yl)eth-2-yl-N'-(5-bromopyrid-2-yl)-thiourea (see Example 920 of W093/03022) in 11.5 ml of glacial acetic acid was treated with 0.8 ml (7.83 mmole) of 30% hydrogen peroxide. After stirring 1.5 hrs at room temperature, the solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate (1×). The organic layer was back washed with brine (1×) and dried over sodium sulfate. Purification by flash silica gel chromatography (50% ethyl acetate/hexanes) gave 75 mg (19.6%) of the titled compound as a white solid: mp 151°-154° C.; IR (KBr, cm-1) 3200, 3100, 3000, 1685, 1557, 1467, 1360, 1290, 1230, 839; 1H NMR (300 MHz, DMSO-d6) δ 9.30 (br. s., 1H), 8.40 (d, 1H), 8.22 (d, 1h), 7.85 (dd, 1H), 7.79 (br.t., 1H), 7.70 (dt, 1H), 7.45 (d, 1H), 7.30-7.40 (m, 1H), 3.58 (q, 2H), 3.00 (t, 2); MS (FD) m/e 340 (Mt). Anal. Calc'd. for C13H12BrFN4O: C, 46.04; H, 3.57; N, 16.52. Found: C, 46.25; H, 3.66; N, 16.54.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[N:5]=1.[CH3:21][S:22]([CH3:24])=[O:23]>O1CCCC1>[CH3:20][C:16]1[N:15]=[C:14]([C:6]2[N:5]=[C:4]([CH2:21][S:22]([CH3:24])=[O:23])[C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:19]=[CH:18][CH:17]=1
Reactant: CS(C)=O
Reactant: Cc1cccc(-c2cc3ccccc3c(Cl)n2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc3ccccc3c(CS(C)=O)n2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A suspension of 6 g of sodium hydride (55-60% in paraffin) in 80 ml of anhydrous dimethyl sulphoxide was stirred for 2 hours at 70° C. A solution of 8.8 g of 1-chloro-3-(6-methyl-2-pyridyl)isoquinoline (prepared as described in Example XI) in anhydrous tetrahydrofuran was added dropwise to the mixture with ice-cooling, to obtain a deep red-coloured reaction mixture. The mixture was stirred for 2 hours at 50° C. and was then extracted with dichloromethane, after addition of ice-water. The organic layer was washed with a saturated aqueous sodium chloride solution and with water and the solvent was then distilled off. The residue was dissolved in diethyl ether and ethereal hydrogen chloride was added to the solution. The precipitate obtained was filtered off and dissolved in water. The solution was made alkaline with aqueous sodium hydroxide and extracted with diethyl ether. The ether was distilled off and the residue was crystallised from a mixture of ethanol and pentane. 3-(-6-Methyl-2-pyridyl)-1-methylsulphinylmethylisoquinoline was obtained, melting point 198.0° -198.5° C. A portion of the base was converted into the hydrochloride which, after crystallisation from isopropyl alcohol, melted at 120°-121° C. (decomp.).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([C:19]([O:21]CC)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Li+].[OH-].CO.Cl>O.[Cl-].[Na+].O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:24][CH3:25])=[C:10]([C:19]([OH:21])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1C(=O)O
Temperature: 80 °C
Yield: 203.1 %

Procedure:
A mixture of ethyl 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (2 g, 4.30 mmol), LiOH (901 mg, 21.48 mmol), water (4 mL) and methanol (8 mL) was heated in a microwave oven for about 20 min at about 80° C. The reaction mixture was diluted with water and then washed with ethyl acetate to get rid of starting material. The aqueous layer was then acidified with 2N HCl, saturated with brine and then extracted with a mixture of DCM and IPA (3:1 ratio) twice. The combined organic layer was dried under vacuum to give the crude product. It was then triturated with ether to give pure product 1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid as a yellow solid (2.78 g, 95%). LC-MS m/z 319 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22](C=O)=[CH:21][CH:20]=1.N1CCCCC1.CC(N(C)C)=O>O>[OH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22](/[CH:11]=[CH:10]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(OCCCO)cc1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(OCCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
4-Nitrophenylacetic acid (131.4 g, 0.73 mole), 4-(3-hydroxypropyloxy)benzaldehyde (130.8 g, 0.73 mole, prepared as in U.S. Pat. No. 2,824,084), piperidine (14.2 g, 0.17 mole) and dimethylacetamide were placed in a 1 L round-bottom flask fitted with a mechanical stirrer, a condenser and a thermometer connected to a controller and a heating mantle. The resulting mixture was stirred and warmed to 80° C., at which temperature a brisk evolution of gas was induced. Stirring was continued at 80° C. for 18 h. The mixture was then poured into a beaker and stirred and diluted to 3 L with ice and water. The solid that appeared was collected by filtration, washed with water and dried to give a deep yellow product (142 g). Two crystallizations from aqueous ethanol afforded the analytical sample (76.9 g, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=2)=[CH:5][CH:4]=1>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CC(=O)CC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C2CCC(=O)C2)cc1

Procedure:
To a RT solution of 3-(4-methoxyphenyl)cyclopent-2-en-1-one (Step A) (4.68 g, 24.86 mmol) in EtOAc (100 ml) was added Pd/C (Degussa E101 NE/W, 10% dry weight, 50% water) (2.65 g, 1.243 mmol). The reaction mixture was degassed and flushed with nitrogen, then, degassed and flushed with hydrogen using a balloon. After 2 hours filtered reaction through a pad of Celite® washing with EtOAc. The filtrate was and purified by flash column chromatography on silica gel, eluting EtOAc in hexanes to afford the title compound as a racemic mixture. 1H NMR (500 MHz, CDCl3): δ 7.18 (d, J=8.5 Hz, 1H); 6.88 (d, J=8.6 Hz, 1H); 3.80 (s, 3H); 3.42-3.32 (m, 1H); 2.65 (dd, J=18.1, 7.4 Hz, 1H); 2.48-2.36 (m, 2H); 2.34-2.23 (m, 2H); 2.00-1.90 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:28])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:28])[CH2:9][C:10]2[CH:18]=[C:17]([CH3:19])[C:16]3[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=3)[CH:11]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CC(=O)c2cccc(Br)n2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CC(O)c2cccc(Br)n2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
To a solution of (±)-1-(6-bromopyridin-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethanone (977 mg, 2.12 mmol) in methanol (10 mL) at room temperature under nitrogen was added sodium borohydride (97 mg, 2.55 mmol, 1.2 equiv) in one portion. The solution was stirred at room temperature for 1 h. Methanol was then removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried and concentrated to give a light yellow oil (1 g, 100%). MS (ESI) [M+H]+=463. HPLC tR=1.93 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH3:28])[C:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:29][C:30]1[CH:38]=[C:37]2[C:33]([CH:34]=[N:35][NH:36]2)=[CH:32][CH:31]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:36]1[C:37]2[C:33](=[CH:32][CH:31]=[C:30]([NH:29][C:2]3[N:3]=[C:4]([NH:27][CH3:28])[C:5]4[C:10]([C:11]5[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=5)=[CH:9][NH:8][C:6]=4[N:7]=3)[CH:38]=2)[CH:34]=[N:35]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: CNc1nc(Cl)nc2c1c(-c1cccnc1)cn2S(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CNc1nc(Nc2ccc3cn[nH]c3c2)nc2[nH]cc(-c3cccnc3)c12
Temperature: 115 °C
Yield: 46.3 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-(pyridin-3-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.075 g, 0.182 mmol) in nBuOH (1 mL) was added 6-aminoindazole (0.048 g, 0.36 mmol) and TMSCl (0.06 mL, 0.46 mmol). After heating at 115° C. for 72 h, the mixture was purified by preparative HPLC to give N2-(1H-indazol-6-yl)-N4-methyl-5-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (0.03 g), MS (MH 357.2), λ=203.9, 246.3, 305.6.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:12]([N:19]1[CH2:23][CH2:22][CH:21]([O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCN(Cc3ccccc3)C2)cc1

Procedure:
2.39 g (12.4 mmoles) of toluene-4-sulfonyl chloride, dissolved in 10 ml of pyridine, were added dropwise, under nitrogen atmosphere, to a stirred solution of 2.0 g (11.3 mmoles) of N- benzyl-3-hydroxypyrrolidine [J. Med. Pharm. Chem. 1, (1959) 73,76,77]in 15 ml of pyridine, cooled below -10° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].I[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccccc1Nc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1Nc1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Yield: 76 %

Procedure:
A mixture of 3,4-dichlorophenylboronic acid (880 mg, 2.3 mmol), 2-[(4-iodophenyl)amino]benzoic acid (339 mg, 1 mmol), PdCl2.dppf.CH2Cl2 [1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride, complexed with dichloromethane (1:1)] (67 mg, 0.082 mmol), K2CO3 (829 mg, 6 mmol), and H2O (2 mL) in dioxane (15 mL) was heated to reflux for 1 hour. The reaction mixture was diluted with EtOAc and filtered. The filtrate was treated with 1N HCl, washed with H2O, brine, dried (Na2SO4), and concentrated in vacuum to give a yellow solid. Purification by flash chromatography (silica gel, 10% MeOH/CH2Cl2) yielded 272 mg (0.76 mmol, 76%) of the desired product. mp>220° C.
Reaction SMILES: [P:1]([O-:9])([O-:8])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[OH-].[Na+:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)[Cl:13]>>[P:1]([O-:9])([O:8][CH2:15][CH:14]([OH:16])[CH2:12][Cl:13])([O:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:2].[Na+:11]
Reactant: ClCC1CO1
Reactant: CCCCOP(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCCCOP(=O)([O-])OCC(O)CCl
Temperature: 70 °C
Reaction time: 20 h
Yield: 86.5 %

Procedure:
20 g (0.13 moles) of monobutyl phosphate having a purity of 99% (AV1=360.6, AV2=721.3) was charged into a reactor, to which 129 ml of 1N sodium hydroxide aqueous solution was added and agitated at 70° C. to obtain uniform solution, at which the acid value of the reaction system was 46.7. While keeping the reaction system at 70° C., 59.2 g (0.64 moles) of epichlorohydrin was gradually dropped, followed by agitation at the temperature for 20 hours. The acid value of the reaction system was approximately zero, revealing that the conversion rate of the phosphoric monoester was almost 100%. The resulting product was collected by HPLC and the solvent was distilled off under reduced pressure to obtain 30.2 g (yield 86.5%) of sodium butyl 2-hydroxy-3-chloropropyl phosphate.
Reaction SMILES: FC1C=CC(S(C)(=O)=O)=CC=1N.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][C:15]=1[N+:27]([O-])=O>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:25])([F:24])[F:26])(=[O:22])=[O:21])=[CH:16][C:15]=1[NH2:27]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Agent: CS(=O)(=O)c1ccc(F)c(N)c1
Product: Nc1cc(S(=O)(=O)C(F)(F)F)ccc1Cl

Procedure:
Following the general method as outlined in Intermediate 76, starting from 1-chloro-2-nitro-4-[(trifluoromethyl)sulfonyl]benzene (MDA), the title compound was obtained as a brown solid in quantitative yield.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>C(Cl)Cl>[C:27]1([CH2:26][NH:33][CH:7]2[CH2:8][CH2:9][C:4]3([O:11][CH2:1][CH2:2][O:3]3)[CH2:5][CH2:6]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: c1ccc(CNC2CCC3(CC2)OCCO3)cc1
Reaction time: 20 h
Yield: 99.9 %

Procedure:
1,4-Cyclohexanedione ethylene ketal (5.00 g, 32.0 mmol, 1 eq.), sodium triacetoxyborohydride (8.14 g, 38.4 mmol, 1.2 eq.) and benzylamine (3.50 mL, 32.0 mmol, 1 eq.) were mixed in methylene chloride (100 mL) at room temperature. Stirred for 20 hours. Added 50 mL of 1.0 N NaOH. Stirred for 10 minutes. Extracted 3 times with methylene chloride (50 mL). The organic layers were combined, dried over sodium sulfate and stripped to give N-(phenylmethyl)-1,4-Dioxaspiro[4.5]decan-8-amine (7.91 g) of a light amber oil as product. Yield=100%. LCMS detects (M+H)+=248.26.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:11][C:12]1[C:16]([CH2:17][C:18]2[S:33][C:21]3[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:23](=[O:28])[N:24]([CH3:27])[C:25](=[O:26])[C:20]=3[C:19]=2[C:34]([N:36]2[CH2:40][C@H:39]([OH:41])[CH2:38][O:37]2)=[O:35])=[C:15]([CH3:42])[NH:14][N:13]=1>CN(C)C=O.O>[OH:41][C@@H:39]1[CH2:38][O:37][N:36]([C:34]([C:19]2[C:20]3[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:21]=3[S:33][C:18]=2[CH2:17][C:16]2[C:15]([CH3:42])=[N:14][N:13]([CH:2]([CH3:4])[CH3:3])[C:12]=2[CH3:11])=[O:35])[CH2:40]1
Reactant: CC(C)I
Reactant: Cc1n[nH]c(C)c1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C(C)C)c(C)c1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Iodopropane (0.1 ml) and potassium carbonate (100 mg) were added to a solution of 6-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (example 11, 100 mg) in dimethylformamide (1 ml) and the mixture stirred at 100° C. After 2 hours, further 2-iodopropane (0.2 ml) and potassium carbonate (200 mg) were added. After a further 16 hours, the mixture was cooled to room temperature, diluted with water (20 ml) and extracted with ethyl acetate (2×20 ml). Combined organic extracts were treated with pyrrolidine (0.1 ml) and after 1 hour were dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by reverse-phase HPLC with gradient 0.1% aqueous ammonium acetate/acetonitrile elution to give the title compound (58 mg) as a foam. MS (APCI) 504 [M+H]+. δ 1HDMSO 0.87 (6H, d), 1.31 (6H, d), 1.99-2.14 (7H, m), 3.19-3.21 (3H, m), 3.45-4.13 (8H, m), 4.40 (1H, sept), 4.56-4.79 (1H, m), 5.48-5.55 (1H, m).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:33]([NH:35][C@H:36]([C:48]([OH:50])=[O:49])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1)=[O:34])[C:10]([S:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:12])[CH3:11])=O)(C)(C)C.C([N+](CCCC)(CCCC)CCCC)CCC.N1C(C)=CC=CC=1C.FC(F)(F)S([O-])(=O)=O>ClCCl>[C:14]([S:13][C:10]([CH3:12])([CH3:11])[C@@H:9]([C:33]([NH:35][C@H:36]([C:48]([OH:50])=[O:49])[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1)=[O:34])[NH2:8])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(S(=O)(=O)O)cc1)C(=O)O)C(C)(C)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(SC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](N)C(=O)N[C@@H](Cc1ccc(S(=O)(=O)O)cc1)C(=O)O
Reaction time: 1 h

Procedure:
To the solution of tetrabutylammonium N-t-butoxycarbonyl-S-trityl-L-penicillamyl-p-sulfophenylalanine (B-23)(7.5 g) and 2,6-lutidine (3.8 ml) in dichloromethane (100 ml), was added dropwise at 0° C. the solution of trimethylsylyl trifluoromethanesulfonate (5.5 ml), and the mixture was stirred for 1 hour while the temperature was gradually returned to the room temperature. The solvent was evaporated off under reduced pressure and the residue was washed with diethyl ether and acetone, in this order, to give S-trityl-L-penicillamyl-p-sulfophenylalanine (3.lg).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:23][CH2:22][C:11]2[C:12]3[C:13]([CH3:21])([CH3:20])[CH2:14][CH2:15][C:16]=3[C:17](I)=[CH:18][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:23][CH2:22][C:11]2[C:12]3[C:13]([CH3:21])([CH3:20])[CH2:14][CH2:15][C:16]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: OB(O)c1ccccc1
Reactant: CCCOC(=O)N1CCc2cc(I)c3c(c2CC1)C(C)(C)CC3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1CCOC1
Product: CCCOC(=O)N1CCc2cc(-c3ccccc3)c3c(c2CC1)C(C)(C)CC3
Temperature: 120 °C
Yield: 46.9 %

Procedure:
Into a glass microwave vial, the product from step (a) (166 mg, 0.401 mmol), phenyl boronic acid (59 mg, 0.482 mmol), potassium phosphate tribasic (170 mg, 0.802 mmol), palladium acetate (9 mg, 0.040 mmol), and XPhos (38 mg, 0.080 mmol) in THF (2 ml) were added. The reaction mixture was heated in the microwave to 120° C. for 12 hours and then allowed to cool to room temperature. The mixture was filtered through celite and the filtrate was partitioned between saturated aqueous NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0-20%, EtOAc in hexanes) gave the sub-title compound as a white semi-solid (71 mg). 1H NMR (300 MHz, CDCl3) δ 7.41-7.39 (m, 4H); 7.33-7.30 (m, 1H); 7.00 (s, 1H); 4.17 (q, J=6.9 Hz, 2H); 3.67-3.61 (m, 4H); 3.08-3.05 (m, 2H); 2.95-2.93 (m, 2H); 2.84 (t, J=7.2 Hz, 2H); 1.88 (t, J=7.5 Hz, 2H); 1.40 (s, 6H); 1.27 (t, J=6.9 Hz, 3H); MS: ESI (positive): 400 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH2:8][CH:9]=[CH:10][C:11](=[O:13])[CH3:12].CC(C)([O-])C.[K+]>COCCOC>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])=[CH:5][CH2:4][CH:3]1[CH:8]=[CH:9][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)C=CCC1CC=C(C)C1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: CC(=O)CC=CC1CC=C(C)C1(C)C
Yield: 66 %

Procedure:
The ketone, 5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-3-en-2-one, which had been prepared by using the procedure of U.S. Pat. No. 4,052,341, Example II-2, was reacted essentially following the procedure described in Example I for isomerizing the α,β double bond to the β,γ position. In this case the ketone (28.8 g, 0.15 mole) was reacted with potassium t-butoxide (25.8 g, 0.23 mole) in 1,2-dimethoxyethane (DME) (125 ml). The reaction was quenched by addition of aqueous 20% acetic acid (115 ml), extracted as in Example I and the oil distilled at reduced pressure to yield 19.0 g (66% yield) of 5-(2,2,3-trimethylcyclopent-3-en-1-yl)pent-4-en-2-one as a mixture of Z- (21%) and E- (69%) isomers: bp 80°-100° C. (0.5 mm); mol. wt. 192 (MS); IR 3040 cm-1 (olefin), 1720 (carbonyl), 800 (trisubstituted olefin).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C([N:30]1[CH2:35][CH2:34][NH:33][C:32](=[O:36])[CH2:31]1)(OC(C)(C)C)=O.CNCCNC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:33]4[CH2:34][CH2:35][NH:30][CH2:31][C:32]4=[O:36])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)nn1)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(NCc1cn(-c2ccc(N3CCNCC3=O)cc2)nn1)c1ccc(Cl)s1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (100 mg, 0.22 mmol), 4-N-Boc-2-oxo-piperazine (88 mg, 0.44 mmol), CuI (13 mg, 0.066 mmol), N,N′-dimethylethylenediamine (8 μL, 0.066 mmol), potassium carbonate (61 mg, 0.44 mmol) in 5 mL dioxane in a sealed tube was stirred for 2 days at 120° C. The mixture was diluted with ethyl acetate (200 mL). It was washed with brine, dried, and concentrated in vacuo. The residue was treated with neat TFA for 15 min and directly subjected to prep HPLC to isolate the title compound. MS found for C18H17ClN6O2S (M+H)+ 417.1, 419.1 (Cl pattern).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])(=[O:8])[C:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]=1
Reactant: [H][H]
Reactant: COc1ccccc1NC(=O)c1cccnc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccccc1NC(=O)C1=CNCCC1
Yield: 60 %

Procedure:
Twenty-seven grams of N-nicotinoyl-2-methoxyaniline was dissolved in 800 ml of 10% hydrous ethanol. To the solution, 5 g of 10% palladium-on-carbon was added and the mixture was hydrogenated at 40° to 50° C. under atmospheric pressure. After 2 mols of hydrogen was introduced over a period of about 6 hours, the reaction was stopped and the catalyst was removed. The liquid reaction mixture was concentrated and the residual oil was purified with column chromatography on silica gel and recrystallized from hydrous methanol to give N-(1,4,5,6-tetrahydronicotinoyl)-2-methoxyaniline having a melting point of 126°-128° C. Yield=60%