Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[C:11]1([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)c1cccc(-c2ccccc2)n1
Yield: 51.2 %

Procedure:
To a solution 1.0 g (4.9 mmol) of 6-bromo-pyridine-2-carboxylic acid, 0.9 g (7.4 mmol) of phenylboronic acid, 0.4 g (0.36 mmol) of palladium tetrakistriphenyl phosphine in 25 mL of DME was added 9.9 mL of 2 N Na2CO3 solutions under nitrogen. After 12 h reflux under nitrogen, the reaction mixture was cooled and filtered through a filter paper. The filtrate was acidified using 2 N HCl (pH=5). The resulting white precipitate was filtered, washed with water and dried to afford 0.5 g (51%) of 6-phenyl-pyridine-2-carboxylic acid. LCMS: 200 (M+1)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:12])[CH2:10][NH2:11])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:11][CH2:10][C:9]([CH3:12])=[CH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CC(=Cc1ccc(F)cc1)CN
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=Cc1ccc(F)cc1)CNC(=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
To a vigorously stirred mixture of 19.8 g (0.12 mole) of 3-(4-fluorophenyl)-2-methyl-2-propen-1-amine and 30.2 g (0.36 mole) of sodium bicarbonate in 500 ml water at 5° C. was added dropwise 22.2 g (0.14 mole) of 4-fluorobenzoyl chloride. The mixture was stirred another 3 hours at 5° C. then at room temperature overnight. The white solid which had formed was collected, washed with saturated sodium bicarbonate solution, then with water, then with hexane, then air dried to give 33.4 g (97%) of product, m.p. 107°-109° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Br:10])[CH:9]=1)(=[O:3])[CH3:2].[CH3:11][Mg]Br.C(OCC)C>O1CCCC1>[Br:10][C:8]1[CH:9]=[C:4]([C:1]([OH:3])([CH3:11])[CH3:2])[CH:5]=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cncc(Br)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (−78° C.) solution of 3-acetyl-5-bromo pyridine (1.98 g, 9.90 mmol) in tetrahydrofuran (33 mL) was added dropwise a solution of methyl magnesium bromide in diethyl ether (3.0 M, 6.60 mL, 19.8 mmol). The reaction was warmed to room temperature, and the resulting mixture was stirred at room temperature overnight. The reaction was then quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organic extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (0-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 217.83 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.61 (s, 1 H), 8.53 (s, 1 H), 8.01 (d, J=1.9 Hz, 1 H), 2.38 (br s, 1 H), 1.61 (6 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]O)[N:3]=1.P(Br)(Br)[Br:11]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:11])[N:3]=1
Reactant: OCc1cccc(Br)n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: BrCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-6-(hydroxymethyl)pyridine (10.00 g, 53.2 mmol) in CH2Cl2 (150 mL) at 0° C. was added PBr3 (10.03 mL, 106 mmol) dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding saturated NaHCO3 dropwise while stirring. Solid K2CO3 was also added to attain a pH>7. The mixture was separated, and the aqueous layer was extracted with additional CH2Cl2. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (0-20% ethyl acetate/hexanes) to afford the title compound as a colorless solid. LRMS (APCI) calc'd for C6H6Br2N [M+H]+: 250, Found: 250.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1(O)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[Cl:18])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)CC1(O)c2cc(OC)ccc2CCC1Cl
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)CC1=C(Cl)CCc2ccc(OC)cc21
Temperature: 50 °C

Procedure:
(2-Chloro-1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid ethyl ester (42.7 g, 142.9 mmol) is dissolved under an atmosphere of argon in pyridine (250 ml). Trifluoromethanesulfonic acid anhydride (30.7 ml, 185.8 mmol) is added during 30 minutes, while keeping the temperature at 25° C. with occasional cooling with a ice bath. After addition is complete, the reaction mixture is warmed to 50° C. for 2 h. TLC analysis indicates complete conversion of starting material. 2 M aqueous HCl (100 ml) is carefully added, and then the reaction mixture is concentrated to dryness on the rotary evaporator. The residue is taken up in 2 M aqueous HCl (100 ml) and extracted with EtOAc. The organic layer is dried over Na2SO4 and concentrated. Purification by FCC (EtOAc) affords the title compound. ES+-MS: 281.2, 283.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:9]2[N:10]=[C:11]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:24]S(O)(=O)=O.[OH-].[Na+]>>[C:1]([C:5]1[N:9]2[N:10]=[C:11]([CH2:14][C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[O:24])[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Temperature: 90 °C

Procedure:
To a round bottom flask was added 3-tert-butyl-6-((2,4-difluorophenyl)ethynyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.60 g, 1.92 mmol) and 60% aqueous H2SO4 (8.53 mL, 96 mmol). The reaction mixture was heated to about 90° C. for about 2 h. The reaction mixture was diluted with ice water (10 mL) and it was basified with 50% aqueous NaOH to a pH of about 9. The product was dried over MgSO4, filtered, and concentrated in vacuo to afford 2-(3-tert-butyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2,4-difluorophenyl)ethanone which was carried forward without additional purification. To a mixture of 2-(3-tert-butyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1-(2,4-difluorophenyl)ethanone in toluene (3 mL) was added 1,1-dimethoxy-N,N-dimethylethanamine (0.21 g, 1.73 mmol). The mixture was heated to about 100° C. for about 30 min. The toluene was removed in vacuo and the material was redissolved in 1,4-dioxane (3 mL). Anhydrous hydrazine (0.085 mL, 1.7 mmol) was added dropwise to the solution and it was heated to about 95° C. for about 30 min. The mixture was cooled to ambient temperature and the material was concentrated in vacuo. The material was purified by flash chromatography and eluted with DCM/MeOH (gradient, 1-4% MeOH) to afford the title compound (0.31 g, 46%): LC/MS (Table 1, Method a) Rt=1.82 min; MS m/z: 355.2 (M+H)+; 1H NMR (DMSO-d6) δ 1.17 (s, 9H), 7.19 (m, 1H), 7.32 (m, 1H), 7.56 (m, 1H), 7.63 (d, 1H), 8.28 (d, 1H), 8.66 (s (br), 1H), 13.66 (s (br), 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]([OH:17])=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[NH2:18][C:19]1[CH:43]=[CH:42][C:22]2[CH2:23][CH2:24][C:25]3[C:26]([C:39]([NH2:41])=[O:40])=[N:27][N:28]([C:30]4[CH:38]=[CH:37][C:33]5[O:34][CH2:35][O:36][C:32]=5[CH:31]=4)[C:29]=3[C:21]=2[CH:20]=1>>[O:34]1[C:33]2[CH:37]=[CH:38][C:30]([N:28]3[C:29]4[C:21]5[CH:20]=[C:19]([NH:18][C:15]([C:3]6[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([N:8]7[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]7)[N:4]=6)=[O:17])[CH:43]=[CH:42][C:22]=5[CH2:23][CH2:24][C:25]=4[C:26]([C:39]([NH2:41])=[O:40])=[N:27]3)=[CH:31][C:32]=2[O:36][CH2:35]1
Reactant: CN1CCN(c2ccc(Cl)c(C(=O)O)n2)CC1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Product: CN1CCN(c2ccc(Cl)c(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc5c(c3)OCO5)CC4)n2)CC1

Procedure:
The title compound was synthesized from 0.30 g of 3-chloro-6-(4-methylpiperazin-1-yl)-2-pyridine carboxylic acid, obtained by acidification of its K-salt from step 1, and the title compound of step 4 of Example 161 (0.217 g) by the same procedure used for Example 260. The title compound is a brown solid (0.23 g, 61%), m.p. 264–266° C. (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (d6-DMSO): δ 2.70 (s, 3H), 2.72–4.30 (m, 12H), 6.02 (s, 2H), 6.92–7.12 (m, 4H), 7.22–7.36 (m, 3H), 7.42–7.53 (m, 2H), 7.77 (d, 1H, J=9 Hz), 10.32 (s, 1H). ESI mass spectrum for C30H29ClN7O4+: 586 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14]C(OC(C)(C)C)=O)=[C:6]([Cl:28])[C:5]([Cl:29])=[C:4]([Cl:30])[C:3]=1[Cl:31].Cl.C(O)(=O)C>>[ClH:1].[Cl:1][C:2]1[C:7]([O:8][C:9](=[O:27])[CH2:10][NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:24])[CH3:25])[NH2:14])=[C:6]([Cl:28])[C:5]([Cl:29])=[C:4]([Cl:30])[C:3]=1[Cl:31]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)C[C@H](N)C(=O)NCC(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
To 31.7 g of the aforesaid ester was added 295 ml of 2.1lN HCl-acetic acid, and the resulting mixture was subjected to reaction for 1.5 hours while protecting the reaction from moisture, whereby leucyl-glycine-pentachlorophenyl ester.hydrochloride was obtained. For purification, the hydrochloride was recrystallized from methanol and ether to obtain 22.6 g (80.7%) of the hydrochloride in a pure form. Mp: 164°-166° C. [α]D26 =+2.85° (C=1, methanol). Rf value in thin layer chromatography; chloroform-methanol-acetic acid (95:5:3) was used as a developing solvent. Rf=0.82 (for color development, ninhydrin reagent was used).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[CH:18][N:19]([CH3:20])[C:15]=4[CH:14]=3)[OH:12])=[CH:9][N:10]=2)[N:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[CH:18][N:19]([CH3:20])[C:15]=4[CH:14]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1cnc2ccc(C(O)c3cnc4ccc(Cl)nn34)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1cnc2ccc(C(=O)c3cnc4ccc(Cl)nn34)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(rac)-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-(3-methyl-3H-benzoimidazol-5-yl)-methanol (Stage 185.5, 1.03 g, 3.22 mmol) was suspended in DCM (30 mL). Dess-Martin periodinane (1.688 g, 3.86 mmol) was added and the mixture was stirred at rt for 1.5 h. The mixture was evaporated to dryness and the residue was taken in 1 M NaOH and sonicated. After 15 min of stirring, it was filtered. The precipitate was dried under vacuum overnight to afford the title compound (tR 2.18 min (conditions 8), MH+=312)
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([OH:24])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].[Cl:33][C:34]([Cl:38])([Cl:37])[CH2:35]O>CN(C1C=CC=CN=1)C.C(Cl)Cl>[CH3:16][C:17]1([CH3:32])[C@@H:19]([C:20]#[C:21][C:22]([O:24][CH2:35][C:34]([Cl:38])([Cl:37])[Cl:33])=[O:23])[C@H:18]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Reactant: OCC(Cl)(Cl)Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
A mixture of 6.2 g of dicyclohexylcarbodiimide, 7.15 g of tert.-butyl(1R,cis)2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate, 80 mg of dimethylaminopyridine and 35 ml of methylene chloride was stirred for 10 minutes and 4.5 g of 2,2,2-trichloroethanol were added thereto. The mixture was stirred for one hour and was filtered and the filtrate was washed with N hydrochloric acid and then with water until the wash water was neutral, dried and evaporated to dryness. The 14 g of oil residue were chromatographed over silica gel and eluted with a 97-3 benzeneethyl acetate mixture to obtain 9 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[2,2,2-trichloroethoxycarbonyl-ethynyl]-cyclopropane-carboxylate melting at 70°-71° C.
Reaction SMILES: C(O[C:4](=[O:13])[CH2:5][C:6]([C:8]1[O:12][N:11]=[CH:10][CH:9]=1)=O)C.[NH:14]([C:16]1[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([CH3:31])[C:25]([CH3:33])([CH3:32])[CH2:24]2)=[O:21])=[CH:18][CH:17]=1)[NH2:15].C(O)C>C(O)(=O)C>[O:12]1[C:8]([C:6]2[NH:15][N:14]([C:16]3[CH:35]=[CH:34][C:19]([C:20]([NH:22][CH:23]4[CH2:24][C:25]([CH3:32])([CH3:33])[N:26]([CH3:31])[C:27]([CH3:30])([CH3:29])[CH2:28]4)=[O:21])=[CH:18][CH:17]=3)[C:4](=[O:13])[CH:5]=2)=[CH:9][CH:10]=[N:11]1
Reactant: CN1C(C)(C)CC(NC(=O)c2ccc(NN)cc2)CC1(C)C
Reactant: CCOC(=O)CC(=O)c1ccno1
Solvent: CC(=O)O
Solvent: CCO
Product: CN1C(C)(C)CC(NC(=O)c2ccc(-n3[nH]c(-c4ccno4)cc3=O)cc2)CC1(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
3-Isoxazol-5-yl-3-oxo-propionic acid ethyl ester (49 mg) and 4-Hydrazino-N-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-benzamide (93 mg) were dissolved into ethanol (2.5 ml) and acetic acid (0.3 ml) and the solution stirred at 65° C. for 2 h. Concentration in vacuo and purification by HPLC gave the expected product. LC/MS: main peak is product (m/z: 424.3)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[CH3:18])[N:14]([CH2:19][CH:20]([F:22])[F:21])[C:13](=[O:23])[CH2:12][CH2:11]2)(C)(C)C.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[CH3:18])[N:14]([CH2:19][CH:20]([F:22])[F:21])[C:13](=[O:23])[CH2:12][CH2:11]2
Reactant: Cc1cc2c(cc1NC(=O)OC(C)(C)C)CCC(=O)N2CC(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc2c(cc1N)CCC(=O)N2CC(F)F
Reaction time: 2 h
Yield: 88.4 %

Procedure:
The compound (2.29 g, 6.73 mmol) of step C was dissolved in dichloromethane (15 ml), 4N hydrochloric acid-dioxane solution (15 ml, 60 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, the mixture was extracted with ethyl acetate, and the organic layer was dried over saturated brine. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (1.43 g, yield 88%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[NH:8][N:7]=1)=[O:5])[CH3:2].[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[CH2:30]Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[N:8]([CH2:30][C:24]2[CH:25]=[C:26]([Br:29])[CH:27]=[CH:28][C:23]=2[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Reactant: CCOC(=O)c1cc(C(F)(F)F)[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(F)(F)F)n(Cc2cc(Br)ccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 5-trifluoromethyl-1H-pyrazole-3-carboxylic acid ethyl ester (0.114 g, 0.55 mmol) and 1-benzyloxy-4-bromo-2-bromomethyl-benzene (0.196 g, 0.55 mmol) in DMF (2 ml) cooled at RT under N2 atmosphere was added K2CO3 (0.19 g, 1.375 mmol) The mixture was stirred at RT overnight, then acidified with HCl (2M, aq.) and extracted with EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to dryness. The residue was purified by MPLC (10 g SiO2 cartridge, eluent 90% iso-hexane-10% EtOAc) yielding 0.18 g of title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:18]CC=C)[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].CN(C)[C:24]1[CH:29]=CC=C[CH:25]=1>>[C:1]([C:5]1[C:10]([O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:9][C:8]([CH2:29][CH:24]=[CH2:25])=[C:7]([OH:18])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CCOc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1
Reactant: CN(C)c1ccccc1
Product: C=CCc1cc(OC(=O)C(C)(C)C)c(C(C)(C)C)cc1O

Procedure:
4.30 g of 3-t-butyl-4-trimethylacetoxy-1-(2-propenyloxy)benzene was dissolved in 30 ml of dimethylaniline and the solution was refluxed overnight under a nitrogen stream. The solution was allowed to attain room temperature and concentrated under reduced pressure, then extracted with ethyl acetate and 5% hydrochloric acid and the organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 0.5% ethyl acetate) to give 1.70 g of 5-t-butyl-4-trimethylacetoxy-2-(2-propenyl)phenol as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29](O)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([NH:35]C(C1N(C)C(CNS(C2C=CC=CC=2)(=O)=O)=CC(=O)C=1OCC1C=CC=CC=1)=O)([CH3:34])[CH3:33]>>[CH:32]([NH:35][C:29]([C:10]1[N:11]([CH3:28])[C:12]([CH2:16][NH:17][S:18]([C:21]2[C:22]([CH3:27])=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[CH:13][C:14](=[O:15])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:30])([CH3:34])[CH3:33]
Reactant: CC(C)NC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2)n1C
Reactant: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)O)n1C
Product: Cc1ccccc1S(=O)(=O)NCc1cc(=O)c(OCc2ccccc2)c(C(=O)NC(C)C)n1C
Yield: 45.7 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-02) (250.0 mg, 45.70%) was synthesized as a yellow solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-02) (500.0 mg, 1.13 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid isopropylamide (17-01).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O.C(O)(=O)C>[C:13]([O:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:10])=[C:6]([CH3:11])[C:5]1=[O:12])(=[O:15])[CH3:14]
Reactant: CC1=C(C)C(=O)N(CCO)C1=O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)OCCN1C(=O)C(C)=C(C)C1=O
Temperature: 160 °C
Yield: 95 %

Procedure:
126 g (1 mol) of 2,3-dimethylmaleic anhydride and 61 g (1 mol) of ethanolamine are reacted by heating at 180° C. for 1 hour to give 150 g of N-(2-hydroxyethyl)-2,3-dimethylmaleimide (boiling point 110° C. under 13.33 Pa; yield 89% of theory). After drying, the N-(2-hydroxyethyl)-2,3-dimethylmaleimide is mixed with 181.5 g (1.78 mols) of acetic anhydride and 3 drops of concentrated sulfuric acid and the mixture is refluxed for one hour in an oil bath heated to 160° C. The acetic acid formed and the acetic anhydride are then distilled off in vacuo. Fractionation of the residue under a high vacuum yields 179 g of N-(2-acetoxyethyl)-2,3-dimethylmaleimide (boiling point 104° C./6.66 Pa; yield 95% of theory). The N-(2-acetoxyethyl)-2,3-dimethylmaleimide is introduced dropwise, under nitrogen, in the course of 75 minutes into a glass column which is filled with Raschig rings and is heated to 550° C. The pyrolysis products are collected at the lower end of the glass column in a cooled receiver. The yellow oil obtained is taken up in diethyl ether and treated with aqueous sodium bicarbonate solution in order to remove the acetic acid. After drying the organic phase over sodium sulfate, the solvent is removed in vacuo and the product is distilled under a high vacuum. In addition to 39.3 g of unconverted starting material, 84.7 g of (N-vinyl)-2,3-dimethylmaleimide are obtained in the form of a yellowish oil; boiling point 58°-60° C./53.33 Pa; yield: 85% of theory, based on converted starting material.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:22]3[CH2:26][C:25]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[Cl:34])=[CH:24][C:23]3=[O:35])[CH2:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:9]2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:36])[CH:15]([N:22]2[CH2:26][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])=[CH:24][C:23]2=[O:35])[CH2:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:9]1
Reactant: CC(C)(C)CCC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(C)CCC(C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Yield: 78.3 %

Procedure:
In a round bottom flask under argon was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (14 mg, 0.026 mmol) in methanol (2 mL). To this mixture was then added p-toluenesulfonic acid monohydrate (1 mg, 0.004 mmol) and stirred at 25° C. for 16 h. After this time period, the mixture was concentrated in vacuo and purified by AnaLogix IntelliFlash flash chromatography (4 g column, 100% ethyl acetate to 40% methanol/ethyl acetate) To afford 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-5,5-dimethyl-hexanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]amide (10 mg, 77%) as a white foam: HR-ES-MS m/z calculated for C24H31N4O5Cl [M+H]+ 491.2056, observed 491.2052; 1H NMR (300 MHz, CDCl3) δ ppm 0.91 (br. s., 9H), 1.04-1.35 (m, 2H), 1.79 (br. s., 1H), 1.99 (br. s., 1H), 3.38-3.84 (m, 2H), 3.97-4.29 (m, 4H), 4.41 (d, J=17.8 Hz, 1H), 4.66 (br. s., 1H), 4.86 (br. s., 1H), 6.65 (br. s., 1H), 7.26 (br. s., 4H), 7.47 (br. s., 1H), 9.56 (br. s., 1H).
Reaction SMILES: [O:1]([C:3]1[CH:26]=[CH:25][C:6]2[N:7]=[C:8]([C:10]3[CH:24]=[CH:23][C:13]([CH2:14]P(=O)(OCC)OCC)=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1)[CH3:2].[N+:27]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)([O-:29])=[O:28].C[O-].[Na+]>CO>[N+:27]([C:30]1[CH:31]=[C:32]([CH:33]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([O:1][CH3:2])[CH:26]=[CH:25][C:6]=4[N:7]=3)=[CH:24][CH:23]=2)[CH:35]=[CH:36][CH:37]=1)([O-:29])=[O:28]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3ccc(OC)cc3s2)cc1)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2nc(-c3ccc(C=Cc4cccc([N+](=O)[O-])c4)cc3)sc2c1

Procedure:
Prepared as described in the Alkene Formation section using diethyl 4-(6-methoxyl benzothiazol-2-yl)benzylphosphonate (0.10 g, 0.25 mmol) and 3-nitrobenzaldehyde (0.39 g, 0.25 mmol) in dry MeOH (10 ml) and 0.5 M sodium methoxide (1.02 ml, 0.51 mmol) to give the title compound as (0.079 g, 80%) yellow, feathery crystals after work-up and recrystallisation from CHCl3.