Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[F:12])[CH2:8][C:7]1([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]1)[C:6]2=[N:20]S(C(C)(C)C)=O.CCOCC>O1CCOCC1>[Br:2][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][C:7]3([CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:6]2=[NH:20])=[CH:10][C:11]=1[F:12]
Reactant: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=NS(=O)C(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC1CCC2(CC1)Cc1cc(F)c(Br)cc1C2=N
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
HCl (4 M in 1,4-dioxane) (7.84 mL, 31.4 mmol) was added to a solution of N-(5′-bromo-6′-fluoro-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 12, 1.35 g, 3.14 mmol) in anhydrous 1,4-dioxane (23 mL) and the resulting mixture was stirred under an argon atmosphere for 15 min. Et2O (60 mL) was added and the precipitate was filtered off and washed with Et2O, then partitioned between DCM and saturated aqueous NaHCO3. The phases were separated, the organic phase dried over sodium sulfate and concentrated to give the title compound (0.95 g, 93% yield) that was used without further purification. MS (ES+) m/z 326, 328 [M+H]+.
Reaction SMILES: [CH:1]1([CH:13]([CH3:16])[CH2:14][OH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].S(OCC)(O[CH2:23][CH3:24])(=O)=O>O1CCCC1>[CH2:23]([O:15][CH2:14][CH:13]([CH:1]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:16])[CH3:24]
Reactant: CCOS(=O)(=O)OCC
Reactant: CC(CO)C1CCCCCCCCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(C)C1CCCCCCCCCCC1
Yield: 95.9 %

Procedure:
15 g of 2-cyclododecylpropan-l-ol were stirred with 4 g of sodium hydride in 150 ml of tetrahydrofuran for two hours at the boiling temperature excluding air. 6 g of diethyl sulfate were then added dropwise, and the mixture was refluxed for a further two hours. The cooled reaction mixture was poured onto ice and extracted by stirring with 20 ml of 10% strength NaOH and 50 ml of tert.-butyl methyl ether. The aqueous layer was again extracted by shaking with tert.-butyl methyl ether, and the combined organic layers were again extracted by shaking with 10% strength NaOH and distilled. After removal of the solvents, 9.5 g of 2-cyclododecylpropyl ethyl ether were obtained at 92-95° C. and 0.2 mbar.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([OH:26])=O)[N:6]2[CH2:21][O:22][CH3:23].C[N:28](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:24]([NH2:28])=[O:26])[N:6]2[CH2:21][O:22][CH3:23]
Reactant: CN(C)C=O
Reactant: COCn1c(C(=O)O)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COCn1c(C(N)=O)cc2c(F)ccc(N(C)S(=O)(=O)c3cccs3)c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a mixture of 4-fluoro-1-(methoxymethyl)-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.41 g), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (0.21 g) and N,N-dimethylformamide (15 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.26 g) at 4° C., and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.41 g, yield 100%) as pale-yellow needle crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[NH:8][C:7]=1[CH3:26])=[O:5])[CH3:2].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>O>[CH2:23]([O:22][C:20]([C:10]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH:19][CH2:28][CH2:27][N:29]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:13]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:26])[NH:8][C:9]=1[CH3:25])=[O:21])[CH3:24]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc(N)ccc1Cl
Reactant: CCN(CC)CCCl
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc(NCCN(CC)CC)ccc1Cl

Procedure:
Thirty grams of 2,6-dimethyl-4-(3-amino-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (melting point 210°) and 15 ml of 2-diethylaminoethyl chloride are heated for 15 minutes to about 200° and the mixture is taken up in hot water, rendered alkaline after addition of ice and extracted with ether.
Reaction SMILES: C[O-].[Na+].[CH3:4][C@:5]12[CH2:22][CH:21]=[C:20]3[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:23])[CH:14]=4)[C@@H:9]1[CH2:8][CH2:7][C:6]2=[O:24].[CH3:25]OC(=O)C(OC)=O.C=O>CO.C1COCC1.C(Cl)Cl.O.C(N(CC)CC)C.C(O)(=O)C>[CH2:25]=[C:7]1[CH2:8][C@H:9]2[C@H:10]3[C:20](=[CH:21][CH2:22][C@:5]2([CH3:4])[C:6]1=[O:24])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: COC(=O)C(=O)OC
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)C1=O
Reaction time: 1 h

Procedure:
Sodium methoxide in methanol (25%, 6.85 ml) is added dropwise to a mixture of androst-1,4,9(11)-triene-3,17-dione (IB, 7.05 g) in THF (80 ml) and methylene chloride (8 ml) containing dimethyloxalate (4.38 g) previously cooled to 4°. After one hour at 4°, the preparation of the 16-oxalate salt is complete and the following reagents were added sequentially: acetic acid (0.5 ml), triethylamine (2.6 ml), methanol (10 ml), and aqueous formaline (37%, 2.8 ml). The reaction mixture was warmed to 20°-25° and after one hour the reaction was complete. The reaction mixture was poured into water and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, washed with water, dried over sodium sulfate, and concentrated under reduced pressure to a solid. The solid was dissolved in methylene chloride (2.5 ml), following which the methylene chloride was evaporated. The solid was again dissolved in dry THF (25 ml), following which the THF was evaporated. The solid was then dissolved in dry THF (50 ml) for use in the following reaction.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[C:11]([F:21])[CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[F:21][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:7]2[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=2[CH:10]=1
Reactant: Cc1ccccc1-c1cc(F)cc2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Product: Cc1ccccc1-c1cc(F)cc2c1OC(CN)C2
Yield: 53 %

Procedure:
Treatment of (±)-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.48 g, 3.59 mmol) with sodium azide (0.933 g, 14.35 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.101 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.555 g (53%) of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 229-234° C.; Anal. calcd. for C16H16FNOHCl.0.1H2O: C, 65.02; H, 5.87; N, 4.74. Found: C, 64.99; H, 5.83; N, 4
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)(Cl)Cl>[CH2:23]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:15]=2)[CH2:11][CH2:12][CH3:13])=[CH:2]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: CCCC(c1c[nH]c2ccccc12)c1c[nH]c2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCC(c1cn(Cc2ccccc2)c2ccccc12)c1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
ST 1385 1,1-di-indol-3-yl-butane, 290 mg (1 mmol), was thoroughly mixed and blended with potassium tertbutylate (280 mg) and tetrabutylammonium bromide (20 mg). The mixture thus obtained was held under ultrasonic stirring at ambient temperature. 640 mg (5 mmol) of benzylchloride at 0° C. were then added and the ultrasonic stirring was continued for 2 hours at room temperature. At the end of this period, the reaction mixture was treated with H2O/CHCl3; the chloroform phase was separated, washed with a small amount of water, dried on Na2SO4, filtered and concentrated to dryness. The end product was isolated and purified chromatographically on silica gel, eluting with hexane:ethyl ether 95:5.351 mg of product were obtained with a 78% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:17]([O:19]C)=[O:18])[C:13](=[O:16])[NH:14][N:15]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:17]([C:12]1[C:13](=[O:16])[N:14]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[N:15]=[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[CH:11]=1)([OH:19])=[O:18]
Reactant: COC(=O)c1cc(-c2ccc3c(c2)CCO3)n[nH]c1=O
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6-(2,3-Dihydro-1-benzofuran-5-yl)-4-methoxycarbonyl-2H-pyridazin-3-one (2.0 g, 7.35 mmol) was dissolved in N,N-dimethylformamide (17 mL), and potassium carbonate (2.0 g, 14.7 mmol) and bromomethylcyclopropane (1.2 g, 8.8 mmol) were added to the resultant solution, followed by stirring for two hours at 80° C. The temperature of the reaction mixture was reduced to room temperature, and saturated aqueous sodium hydrogencarbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate, and the solvent was removed through distillation, to thereby yield 2.66 g of a crude product. The crude product was suspended in methanol (20 mL), and a 2-mol/L aqueous sodium hydroxide solution (20 mL) was added thereto, followed by stirring for one hour at 60° C. After the temperature of the reaction mixture had been reduced to room temperature, water was added thereto, and the mixture was acidified with concentrated hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, and the residue was recrystallized from chloroform-hexane, to thereby yield 1.88 g of the title compound as a yellow powder (81.7%).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]([F:27])([C:23]([F:26])([F:25])[F:24])[CH2:15][CH2:16][C:17](N(OC)C)=[O:18]>C1COCC1>[F:13][C:14]([F:27])([C:23]([F:24])([F:25])[F:26])[CH2:15][CH2:16][C:17]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:18]
Reactant: Brc1ccccn1
Reactant: CON(C)C(=O)CCC(F)(F)C(F)(F)F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(CCC(F)(F)C(F)(F)F)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropylmagnesium chloride (2 M in THF) (1.960 mL, 3.92 mmol) was added to a stirred solution of 2-bromopyridine (0.392 mL, 4.11 mmol) in dry THF (3.73 mL) at 25° C. under N2. After 2 h at 25° C. a solution of 4,4,5,5,5-pentafluoro-N-methoxy-N-methylpentanamide (0.8781 g, 3.73 mmol) in dry THF (1.866 mL) was added via cannula and the resulting mixture was stirred at 25° C. overnight. Another 0.2 eq. of Grignard reagent was generated by same procedure as above and added to reaction via cannula and the reaction was stirred for 1 h. Another 0.6 eq. of Grignard reagent was generated by same procedure as above and added to reaction via cannula and the reaction was stirred for 1 h. The reaction was quenched by the addition of saturated aq. NH4Cl and the resulting mixture was extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by silica gel chromatography using a hexanes/EtOAc gradient to afford the desired product, as an oil. 1H NMR (500 MHz, CHCl3-d): δ 8.69 (d, J=4.8 Hz, 1H); 8.05 (d, J=7.9 Hz, 1H); 7.85 (dt, J=9.1, 3.7 Hz, 1H); 7.48 (d, J=7.7 Hz, 1H); 3.56 (t, J=7.8 Hz, 2H); 2.56-2.50 (m, 2H). m/z=254.0 (M+H).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:9]=[C:8]([Br:16])[C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[Cl:17][CH2:18][C:19](Cl)=O>O1CCOCC1>[Cl:17][CH2:18][C:19]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([S:12](=[O:14])(=[O:15])[NH2:13])[CH:9]=[C:8]([Br:16])[C:6]=2[N:7]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(Br)cc(S(N)(=O)=O)cc1S(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc(Br)c2c(c1)S(=O)(=O)NC(CCl)=N2

Procedure:
A mixture of 2,4-disulfamoyl-6-bromoaniline (0.015 mole) and chloroacetyl chloride (0.016 mole) in 50 ml. of dioxane or other inert organic solvent is heated under reflux conditions for about 24 hours and then concentrated to dryness. The residue is dissolved in concentrated sulfuric acid (5 ml. acid/gram), heated in a steam bath at 60°-70° C. for three hours then poured onto ice. The product, 3-chloromethyl-5-bromo-7-sulfamoyl-1,2,4-benzothiadiazine-1,1-dioxide, is purified by recrystallization from a mixture of acetone-alcohol-water.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21](=O)[CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[NH2:37][NH2:38].CC(O)=O>CCO>[Cl:1][C:2]1[C:3]([C:21](=[N:37][NH2:38])[CH2:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)CC3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)cnc21
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC(=NN)c2c(Cl)cnc3[nH]ccc23)CC1
Yield: 44.2 %

Procedure:
To a suspension of tert-butyl 4-(2-(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-oxoethyl)piperidine-1-carboxylate (1.00 g, 1.87 mmol) in EtOH (6.4 mL) were added anhydrous hydrazine (2.94 mL, 94.0 mmol) and AcOH (0.536 mL, 9.36 mmol). The reaction mixture was stirred at reflux for about 16 h. The solvent was removed under reduced pressure and the crude material was taken up in DCM and dried over anhydrous MgSO4. The solvent was removed and DCM (3 mL) was added. The solid was removed by filtration and the filtrate was purified by silica gel chromatography eluting with 0-10% MeOH in DCM to afford tert-butyl 4-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-hydrazonoethyl)piperidine-1-carboxylate (0.324 g, 44%) as a white solid consisting of a 1/1 mixture of E/Z isomers: LC/MS (Table 1, Method r) Rt=1.46 and 1.53 min; MS m/z: 392/394 and 392/394 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)=[C:13](C(OCC)=O)[C:12]2=[O:31])=[CH:2]1>CN(C)C=O>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:31])[CH:13]=[C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(Nc2ccc(C(C)C)cc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Product: CC(C)c1ccc(NC2=CC(=O)C(=Cc3c[nH]c4ncccc34)O2)cc1
Temperature: 25 °C

Procedure:
A solution of the compound (0.12 g, 0.29 mmol) of Example 37 in N,N-dimethylformamide (3.0 mL) was refluxed for 6 h. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford 2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-5-[(4-isopropylphenyl)amino]furan-3(2H)-one as solid (0.0050 g, y. 5%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.[Na+].Cl[C:14]([F:19])([F:18])C([O-])=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:10][O:9][C:7]([C:5]1[N:4]([CH3:11])[N:3]=[C:2]([O:1][CH:14]([F:19])[F:18])[CH:6]=1)=[O:8]
Reactant: O=C([O-])C(F)(F)Cl
Reactant: COC(=O)c1cc(O)nn1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC(F)F)nn1C
Temperature: 80 °C
Yield: 40.6 %

Procedure:
A solution of 2.00 g (12.8 mmol) of methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (preparation: Chem. Ber. 1974, 107, 1318-1328) in 28 ml of N,N-dimethylformamide is admixed with 5.09 g (32.0 mmol, 96%) of chlorodifluoroacetic acid sodium salt and 2.66 g (19.2 mmol) of potassium carbonate, and the reaction mixture is heated at 80° C. overnight. The reaction mixture is added to 300 ml of water and extracted several times with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated by evaporation in vacuo on a rotary evaporator. Chromatographic purification gives 1.07 g of methyl-3-(difluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylate (40%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>COCCO>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:27])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:7])[N:9]=1)#[N:29]
Reactant: NCCCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: Cc1cccc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCCCC(=O)O)c(O)c2c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
A mixture of 1-cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.20 mmol), 4-aminobutyric acid (423 mg, 4.10 mmol) and NaOMe (166 mg, 3.07 mmol) in 2-methoxyethanol (10 mL) was refluxed for 2 h. After the mixture was cooled to r.t., solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 75 mg of the title compound as a pink solid. MS: (+) m/z 420.23 (M+1).
Reaction SMILES: II.[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13]([N+:19]([O-:21])=[O:20])[C:12]=1[O:22][CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[NH4+:25].S([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:25])=[C:13]([N+:19]([O-:21])=[O:20])[C:12]=1[O:22][CH3:23])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [NH4+]
Reactant: COc1c(OCc2ccccc2)ccc(C=O)c1[N+](=O)[O-]
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(OCc2ccccc2)ccc(C#N)c1[N+](=O)[O-]
Yield: 95 %

Procedure:
Iodine (272 g, 1.1 mmol) was added to a mixture of 4-(benzyloxy)-3-methoxy-2-nitrobenzaldehyde (220 g, 766 mmol) and ammonium hydroxide (28% solution, 3 L) dissolved in THF (5 L). After 16 h the reaction mixture was treated with sodium sulfite (49 g, 383 mmol) and concentrated under reduced pressure to afford a thick slurry. The slurry was filtered, washed with water (250 mL) and dried to afford the title compound as a solid (206 g, 95%): 1H NMR (DMSO-d6) δ: 7.89 (1H, d), 7.59 (1H, d), 7.49 (2H, m), 7.40 (3H, m), 5.35 (2H, s), 3.91 (3H, s).
Reaction SMILES: N1C=CC=CC=1.C(O)(C(F)(F)F)=O.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].C1(N=C=NC2CCCCC2)CCCCC1>C1C=CC=CC=1.CS(C)=O>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30]
Reactant: COCCOCOCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: COCCOCOCCCCCCCCC=O

Procedure:
About 5 ml of the solvent mixture benzene/DMSO (1:1) are introduced into a two-neck flask which has been flame-treated and flushed with nitrogen, and 1 mmol of absolute pyridine and 0.5 mmol of CF3COOH, and 1 mmol of 1 and 3 mmol of dicyclohexylcarbodiimide (DCCI), dissolved in benzene/DMSO, are added with stirring. The mixture is stirred overnight at room temperature. Precipitated dicyclohexylurea is filtered off, and the solution is evaporated on a rotary evaporator. DMSO is removed by repeated shaking with water and, if necessary, at 40° C. in a bulb tube. The crude product is filtered again and purified by flash chromatography (PE/CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[NH:5][C:4](=[O:10])[C:3]=1[CH3:11].[CH3:12][Si:13]([CH3:20])([CH3:19])[CH2:14][CH2:15][O:16][CH2:17]Cl.N12CCCN=C1CCCCC2>C(#N)C>[Br:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:20])([CH3:19])[CH3:12])[C:4](=[O:10])[C:3]=1[CH3:11]
Reactant: Cc1c(Br)n(C)c(=O)[nH]c1=O
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1c(Br)n(C)c(=O)n(COCC[Si](C)(C)C)c1=O
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a mixture of C2 (21.9 g, 99.8 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (20 g, 120 mmol) in acetonitrile (400 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 18.3 g, 120 mmol), and the reaction mixture was stirred at 60° C. for 18 hours. Additional 2-(trimethylsilyl)ethoxymethyl chloride (5 g, 30 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g, 30 mmol) were added, and stirring was continued at 60° C. for 18 hours. After the mixture had been concentrated in vacuo, the residue was diluted with water (500 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were concentrated; purification using chromatography on silica gel (Gradient: 20% to 50% ethyl acetate in petroleum ether) afforded the product as a colorless oil. Yield: 22.5 g, 64.4 mmol, 64%. 1H NMR (400 MHz, CDCl3) δ 5.41 (s, 2H), 3.61-3.72 (m, 5H), 2.13 (s, 3H), 0.93-1.02 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][Br:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Br:1][CH2:2][CH:3]([CH2:4][Br:5])[O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C1=COCCC1
Reactant: OC(CBr)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: BrCC(CBr)OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 10 g of 1,3-dibromopropan-2-ol, 5.0 ml of 3,4-dihydro-2H-pyran and 50 ml of chloroform was added a catalytic amount of p-toluenesulfonic acid monohydrate followed by stirring at room temperature for 3 hours. The reaction solution was concentrated, diluted with diethyl ether and washed with saturated sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated to give the title compound.