Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:22]=[CH:21][C:11]([C:12]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].S(=O)(=O)(O)O.[N+:28]([O-])([OH:30])=[O:29]>>[N+:28]([C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:8]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:12]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:13])([O-:30])=[O:29]
Reactant: CCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCCCCCc1ccc(C(=O)CCCCC(=O)O)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
5-(4-n-heptylbenzoyl)pentanoic acid (30.5 g; 0.1 mole) is added slowly to concentrated sulfuric acid (3 ml) while maintaining the mixture temperature below 5° C. with external cooling. A mixture of concentrated nitric acid (8 ml) and sulfuric acid (12 ml) is added dropwise over one hour with the reaction temperature maintained below 5° C. The reaction mixture is poured into ice water (1 liter). The precipitate is collected, dissolved in 2N potassium hydroxide (200 ml), diluted with water (to 400 ml) and washed with ether (2×100 ml). The aqueous phase is acidified with concentrated hydrochloric acid and the product extracted with ether (3×150 ml). The ether solution is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on a silica gel column (hexane: ether: acetic acid, 74:25:1) to give 5-(3-nitro-4-n-heptylbenzoyl)pentanoic acid (5.25 g) which on recrystallization from heptane is obtained as pale yellow crystals, m.p. 53°-56° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:18]([OH:24])[CH:19]=1
Reactant: Nc1ccc(F)cc1O
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Temperature: 140 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.5 g), 2-amino-5-fluorophenol (265.0 mg), p-toluenesulfonic acid monohydrate (75.0 mg) and dioxane (5.0 ml) were combined in a microwave tube. The mixture was heated at 140° C. for 15 min under microwave irradiation. Then the mixture was allowed to cool to room temperature and a precipitate formed. The precipitate was collected by filtration, washed with dioxane, methanol and Et2O to yield the title compound.
Reaction SMILES: I.[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6].[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:24](=[N:27][CH3:28])SC)[N:18]=1)[C:11]([NH2:13])=[NH:12].C(=O)([O-])[O-:30].[K+].[K+]>O>[OH2:6].[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6].[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:24]([NH:27][CH3:28])=[O:30])[N:18]=1)[C:11]([NH2:13])=[NH:12].[NH:10]([C:14]1[S:15][CH:16]=[C:17]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:24]([NH:27][CH3:28])=[O:6])[N:18]=1)[C:11]([NH2:13])=[NH:12].[C:2]([OH:9])(=[O:8])/[CH:3]=[CH:4]\[C:5]([OH:7])=[O:6]
Reactant: CN=C(NCCSCc1csc(NC(=N)N)n1)SC
Reactant: O=C([O-])[O-]
Agent: I
Agent: O=C(O)/C=C\C(=O)O
Agent: [K+]
Solvent: O
Product: CNC(=O)NCCSCc1csc(NC(=N)N)n1
Reaction time: 16 h

Procedure:
A solution of 2-guanidino-4-[2-(2,3-dimethylisothioureido)ethylthiomethyl]thiazole hydrogen maleate hydriodide (0.8 g.) in water (10 ml.) was treated with an aqueous solution of potassium carbonate (0.3 g. in 5 ml. water) and the solution heated on the steam bath for 4 hours. After cooling and allowing to stand for 16 hours the aqueous layer was decanted from the brown gum and the gum taken up into ethanol and filtered. The filtrate was evaporated to dryness and the residue converted to the hydrogen maleate salt which was recrystallized from ethanol to give 2-guanidino-4-[2-(3-methylureido)ethylthiomethyl]thiazole hydrogen maleate hemihydrate, m.p. 167°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([CH3:14])[N:9]=2)=[C:4]([F:15])[CH:3]=1.[OH-].[Na+].Cl[CH:19]([F:21])[F:20]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:19]([F:21])[F:20])[N:10]([CH3:14])[N:9]=2)=[C:4]([F:15])[CH:3]=1
Reactant: FC(F)Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2F)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(-c2ccc(Cl)cc2F)cc1OC(F)F
Yield: 82.6 %

Procedure:
57.1 g of 3-(4-chloro-2-fluorophenyl)-5-hydroxy-1-methyl-1H-pyrazole from Example 2.1 were initially charged in 500 ml of dioxane. A solution of 18.8 g of NaOH in 50 ml of H2O was added, the mixture was heated at reflux and 85 g (0.98 mol=3.9 eq.) of gaseous chlorodifluoromethane were introduced. The mixture was poured into 1.5 l of water and extracted twice with 500 ml of MTBE, and the combined organic phases were extracted once with 500 ml of water and once with 500 ml of saturated sodium chloride solution. Drying and concentration of the organic phase gave 57.6 g of 53% pure 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole as an oil which was purified further by vacuum distillation. This gave the title compound in a purity of 94% in a yield of 43.8%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:41][CH2:42][N:43]([CH2:46][CH3:47])[CH2:44][CH3:45])(=O)=O.O>CN(C=O)C>[CH2:42]([N:43]([CH2:46][CH3:47])[CH2:44][CH2:45][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:19]=[C:14]([NH:13][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([N:3]4[CH2:4][CH2:5][CH2:6][CH:2]4[CH3:1])[N:12]=3)[C:15]3[N:16]([CH:27]=[CH:28][N:29]=3)[N:17]=2)=[CH:21][CH:22]=1)[CH3:41]
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3ccc(O)cc3)nn3ccnc23)n1
Reactant: CCN(CC)CCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc(-c2cc(Nc3cccc(N4CCCC4C)n3)c3nccn3n2)cc1
Temperature: 50 °C
Yield: 41.2 %

Procedure:
To a mixture of 4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenol (40 mg, 0.1 mmol) and K2CO3 (28 mg, 0.2 mmol) in DMF (5 mL) was added 2-(diethylamino)ethyl methanesulfonate (30 mg, 0.15 mmol). The mixture was heated at 50° C. for 15 h. After cooling, the mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration, the residue was purified by chromatography (silica, EtOAc) to give 6-(4-(2-(diethylamino)ethoxy)phenyl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (20 mg, 40%). 1H NMR (300 MHz, CDCl3): δ 8.59 (s, 1H), 8.06-7.90 (m, 4 h), 7.58 (s, 1H), 7.42 (t, 1H, J=7.6 Hz), 7.03-7.00 (m, 2H), 6.23 (d, 1H, J=7.2 Hz), 6.05 (d, 1H, J=8.1 Hz), 4.57 (brs, 2H), 4.27 (brs, 1H), 3.67 (brs, 1H), 3.52-3.41 (m, 3H), 3.22-3.20 (m, 4 h), 2.16-2.06 (m, 3H), 1.80 (brs, 1H), 1.45 (t, 6H, J=6.9 Hz), 1.28 (d, 3H, J=6.3 Hz). LC/MS: 486 [M+H]+, tR=1.12 min. HPLC: 98.72% at 214 nm, 99.10% at 254 nm, tR=5.46 min.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([NH:1][C:2]1[C:3](=[O:16])[NH:4][C:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[CH:11]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1cc2c([nH]c1=O)CCc1ccccc1-2
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc2c([nH]c1=O)CCc1ccccc1-2

Procedure:
To 2.0 gm of 2-amino-5,6-dihydrobenzo[f]quinolin-3(4H)-one, in 100 ml of chloroform containing 1 ml of pyridine add 0.80 gm of acetyl chloride. Stir the reaction at room temperature for 5 hours. Filter and wash the solution with water. Remove the solvent by stripping to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[CH:19]=[N:20][NH:21][C:15]=2[CH:14]=1.[I:22]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([I:22])=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]ncc3cn2)c1Cl
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
At r.t. to a stirring solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridine (0.62 g, 1.9 mmol) in methylene chloride (10 mL) was added N-iodosuccinimide (0.47 g, 2.1 mmol). The mixture was stirred at r.t. for 2 h. It was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product 0.50 g.
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.C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)CCC>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[O:33][CH:34]=[CH:35][CH:36]=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)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ccco5)cc34)cc2)cc1
Yield: 99.6 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromo-quinazolin-4-yl)-amine (300 mg, 0.74 mmol), 2-(tributylstannyl)-furan (290 mg, 0.81 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxane (3.5 ml) and heated at reflux under nitrogen for 2 hr. The cooled reaction mixture was absorbed onto silica and purified by flash column chromatography (silica gel, eluting with 1:1 ethyl acetate/iso-hexane) to give the title product (290 mg, 79%) as a pale yellow solid; δH [2H6]-DMSO 9.94 (1H, b, NH), 8.85 (1H, s, 5-H), 8.53 (1H, s, 2-H), 8.21 (1H, d, 7-H), 7.91 (1H, d, furan-H), 7.81 (1H, d, 8-H), 7.72 (2H, d, 2′-H, 6′-H), 7.57-7.33 (5H, m, 5×Ph-H), 7.16 (1H, d, furan-H), 7.10 (2H, d, 3′-H, 5′-H), 6.72, (1H, dd, furan-4H), 5.17 (2H, s, CH2); m/z 394 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[NH:17]2)=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:19]=[C:18]3[C:14]([CH:15]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[NH:17]3)=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COC(=O)c1cc2ccc(N)cc2[nH]1
Product: COC(=O)c1cc2ccc(Nc3nc(Cl)ncc3F)cc2[nH]1

Procedure:
In a like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2-(methoxycarbonyl)-(1H)-indole were reacted to provide 2-chloro-5-fluoro-N4-[2-(methoxycarbonyl)-(1H)-indol-6-yl]-4-pyrimidineamine which was used without further purification. LCMS: purity: 65%; MS (m/e): 322(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:13]3([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:14]3)[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:5]2=[CH:6][CH:7]=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:1][C:2]2[CH:3]=[C:4]3[C:13]4([CH2:17][O:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[N:14]4)[C:10]4([CH2:11][CH2:12]4)[CH2:9][O:8][C:5]3=[CH:6][CH:7]=2)=[O:34])=[N:31][CH:32]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(N)ccc1OCC21CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=NC2(CO1)c1cc(NC(=O)c3ccc(F)cn3)ccc1OCC21CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 87.2 %

Procedure:
A mixture of tert-butyl (6′-aminodispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl)carbamate (115 mg, 0.333 mmol), 5-fluoropyridine-2-carboxylic acid (62.3 mg, 0.433 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (83.0 mg, 0.433 mmol), 1-hydroxybenzotriazole (58.5 mg, 0.433 mmol), N,N-diisopropylethylamine (0.074 mL, 0.433 mmol) and CH2Cl2 (1.2 mL) was stirred for 2.5 days at ambient temperature. The reaction mixture was purified with column chromatography on silica gel (hexane-EtOAc, a linear gradient of EtOAc from 10 to 90%) to afford tert-butyl (6′-{[(5-fluoropyridin-2-yl)carbonyl]amino}dispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl)carbamate (136 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](O)(=O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[OH:13][CH2:12][C:11]1[NH:1][C:2]2[C:7]([N:8]=1)=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=2
Reactant: Cc1cc(C)c(N)c(N)n1
Reactant: O=C(O)CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2nc(CO)[nH]c2n1
Yield: 15.2 %

Procedure:
A mixture of 13.72 g of 2,3-diamino-4,6-dimethylpyridine and 25 g of glycolic acid in 200 ml of toluene was heated under reflux for 3.5 hours, whilst distilling off azeotropically the water formed in the course of the reaction. At the end of this time, the reaction mixture was freed from the toluene by decantation and the oily residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethanol and ethyl acetate in ratios ranging from 2:3 to 1:1 by volume as a eluent, to give 2.7 g of the title compound, melting at 244-246° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5](OC)=[O:6].O.[NH2:14][NH2:15].O>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([I:12])[CH:11]=1)[C:5]([NH:14][NH2:15])=[O:6]
Reactant: COC(=O)c1cc(I)cc(I)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cc(I)cc(I)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To Methyl 3,5-diiodobenzoate (5.0 g, 12.89 mmol) in ethanol (70.0 ml) was added hydrazine hydrate (20.0 ml) under stirring. During heating, white solid was appeared. The reaction was kept 50° C. for 1 h. Heating was stopped and then water (100.0 ml) was added. After cooling down to room temperature, the white product solid was collected by filtration. The product was washed with water and dried under vacuum. Final white product was obtained in 4.6 g (92.0%). 1H NMR (400 MHz, DMSO-d6, δ): 9.92 (s, 1H, NH), 8.22 (t, J=1.6 Hz, 1H), 8.12 (d, J=1.6 Hz, 2H), 4.53 (s, 2H, NH2).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][N:4]=1)=[O:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:11]=3[C:3]([CH:1]=[O:2])=[N:4]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2[nH]nc(C=O)c12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc2c1c(C=O)nn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 9.5 %

Procedure:
A mixture of methyl 3-formyl-1H-indazole-4-carboxylate (B1) (3.3 g, 16.1 mmol), 4-fluorophenylboronic acid (4.5 g, 32.3 mmol) and copper(II) acetate (3.99 g, 21.9 mmol) was degassed under nitrogen (3×). Anhydrous dichloromethane (240 ml) and triethylamine (4.5 ml, 13.5 mmol) were added. The mixture was degassed under nitrogen (2×) and stirred at ambient temperature for 21 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford methyl 1-(4-fluorophenyl)-3-formyl-1H-indazole-4-carboxylate (454 mg, 9%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 10.38 (s, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.91-7.88 (m, 2H), 7.80 (d, J=7.1 Hz, 1H), 7.69 (dd, J=8.4, 7.3 Hz, 1H), 7.53 (t, J=8.7 Hz, 2H), 3.93 (s, 3H); MS (ESI+) m/z 299 (M+H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:10](=[O:11])[CH2:9][CH2:8][C:7]=1[CH3:12].P([O-])([O-])([O-])=[O:14].[K+].[K+].[K+]>C(O)C>[OH:14][CH:8]1[CH2:9][C:10](=[O:11])[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[C:7]1[CH3:12]
Reactant: CCCCCC1=C(C)CCC1=O
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCCC1=C(C)C(O)CC1=O
Reaction time: 0.03 h

Procedure:
Experimental description: 270 μL dihydrojasmone was dissolved in 1.2 mL ethanol and added to 150 mL potassium phosphate buffer pH 8.0. Var2 was added to the mixture at a final concentration of 2 μM. The mixture was split in 4.8 mL aliquots into 15 mL scintillation vials equipped with a stir bar. 600 μL 10 mM NADPH in KPi buffer was added to each vial and stirred for 2 minutes. 600 μL cofactor regeneration solution containing 500 mM glucose-6-phosphate and 10 units/mL glucose-6-phosphate dehydrogenase were then added to each vial. The resulting mixtures were stirred at room temperature. After 36 hours, the reaction mixtures were joined together and extracted with chloroform (3×50 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the activated product (4-hydroxy-3-methyl-2-pentylcyclopent-2-enone, 222 mg). 210 mg (1.15 mmol) of activated product was dissolved in 2 mL dry dichloromethane (CH2Cl2) and a catalytic amount (4 drops) of ethanol was added to the solution. The solution was cooled to −78° C. (dry ice) and then 215 μL DAST (1.5 mmol) was added. The reaction was stirred in dry ice for 12 hours. The reaction mixture was then added with 5 mL saturated sodium bicarbonate (NaHCO3) and extracted with dichloromethane (3×15 mL). The organic phase was then dried over magnesium sulfate (MgSO4) and evaporated in vacuo. Purification of the resulting oil by silica gel chromatography (0-30% ethyl acetate/hexane) afforded the fluorinated product, 4-fluoro-3-methyl-2-pentylcyclopent-2-enone (193 mg, 92% yield, yellow oil). 1H-NMR (300 MHz, CDCl3): δ 0.88 (t, J=6.6 Hz, 3H, CH3), δ 1.25-1.40 (m, 6H, CH2), δ 2.10 (d, J=2.1 Hz, 2H, CH3), δ 2.20 (t, J=7.1 Hz, 2H), δ 2.44-2.60 (m, 1H), δ 2.70-2.82 (m, 1H), δ 5.47 (dd, J=54.2 Hz, J=5.8, 1H); 13C-NMR (75 MHz, CDCl3): δ 13.7, 14.2, 22.6, 23.1, 27.9, 29.9, 31.9, 41.4 (d, J=19.6 Hz), δ 91.2 (d, J=174 Hz): 19F-NMR (282 MHz, CDCl3): δ −179.08 (ddd, J=51.88 Hz, J=21.43 Hz, J=9.3 Hz). HRMS (EI+): exact mass calculated for C11H17FO requires m/z 184.1263, found 184.1255.
Reaction SMILES: [CH:1](N(C(C)C)CC)([CH3:3])[CH3:2].[CH3:10][O:11][C:12]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]4)[CH:18]=2)[CH2:16][CH2:15][NH:14][CH2:13]1.C(Br)C#C>>[CH3:10][O:11][C:12]1([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]([CH3:35])[C:30](=[O:36])[CH:29]=[CH:28]4)[CH:18]=2)[CH2:16][CH2:15][N:14]([CH2:3][C:1]#[CH:2])[CH2:13]1
Reactant: COC1(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCNC1
Reactant: CCN(C(C)C)C(C)C
Agent: C#CCBr
Product: C#CCN1CCC(OC)(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)C1
Yield: 21 %

Procedure:
Using an analogous procedure to that described in Example 3 except that diisopropylethylamine was used in place of potassium carbonate, 3-methoxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]pyrrolidine was reacted with 2-propynyl bromide to give 3-methoxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]-1-(prop-2-ynyl)pyrrolidine as a gum in 21% yield.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH2:6])[CH2:3][CH2:2]1.[CH3:7][C:8]1[N:9]=[C:10]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[O:18])[S:11][C:12]=1[C:13](O)=[O:14]>>[CH:1]1([CH2:4][CH2:5][NH:6][C:13]([C:12]2[S:11][C:10]([NH:16][C:17](=[O:18])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:9][C:8]=2[CH3:7])=[O:14])[CH2:3][CH2:2]1
Reactant: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)O
Reactant: NCCC1CC1
Product: Cc1nc(NC(=O)c2ccncc2)sc1C(=O)NCCC1CC1
Yield: 20 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-cyclopropylethylamine in place of benzylamine to react with 4-methyl-2-[(pyridine-4-carbonyl)amino]thiazole-5-carboxylic acid, the title compound was obtained as a white solid in 20% yield; 1H NMR (DMSO-d6, 300 MHz) δ 8.82-8.80 (m, 2H), 8.08-7.72 (m, 3H), 3.27-3.16 (m, 2H), 2.45 (s, 3H), 1.41-1.34 (m, 2H), 0.73-0.65 (m, 1H), 0.48-0.25 (m, 2H), 0.12-0.80 (m, 2H); MS (ES+) m/z 331.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[CH:5][CH:4]=1.[OH-].[K+].[I:16]I.C(OCC)(=O)C>CN(C=O)C>[I:16][C:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[NH:9][N:8]=1
Reactant: II
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
A mixture of 6-(trifluoromethyl)-1H-indazole (0.5 g, 2.69 mmol), KOH (0.45 g, 8.1 mmol) and I2 (1.37 g, 5.38 mmol) in dry DMF (20 mL) was stirred for 16 hours at room temperature. Ethyl acetate (100 mL) was added and the mixture was washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was then washed with ether (2 mL) and filtered to afford 3-iodo-6-(trifluoromethyl)-1H-indazole (688 mg, crude) as a yellow solid. LCMS: (M+H)+=313.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C:12]1([CH3:19])[C:16](O)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]CCl>>[Cl:20][C:16]([C:12]1([CH3:19])[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:17]
Reactant: CC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Reactant: ClCCl
Product: CC1(C(=O)Cl)CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid (1.0 g, 3.8 mmol) in anhydrous dichloromethane (10 mL) thionyl chloride (0.54 g, 4.56 mmol) was added drop wise at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl 2-(chlorocarbonyl)-2-methylpyrrolidine-1-carboxylate.