Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]3[CH:20]=[CH:19][NH:18][C:10]=3[N:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29].[Cl-].[Na+]>CN(C)C=O>[CH:1]1([NH:7][C:8]2[C:9]3[CH:20]=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:10]=3[N:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)c1cnc2[nH]ccc2c1NC1CCCCC1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(S(C)(=O)=O)cnc21
Yield: 60 %

Procedure:
N-Cyclohexyl-5-(methylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-amine (7.0 mg, 0.024 mmol) in N,N-dimethylformamide (1 mL) was stirred with sodium hydride (55 wt % dispersion in mineral oil, 3.0 mg, 0.069 mmol) and [2-(chloromethoxy)ethyl]trimethylsilane (10 μL, 0.057 mmol) at room temperature for 2 hours. After addition of saturated aqueous sodium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1→3/1 (v/v)) to give the title compound as a colorless oil (6.1 mg, yield 60%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].C1COCC1.Cl[C:13]([O:15][CH3:16])=[O:14]>C(=O)([O-])[O-].[Na+].[Na+]>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([CH3:3])[C:4]([OH:6])=[O:5])=[O:14]
Reactant: C[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)C(=O)O
Reaction time: 4.5 h

Procedure:
L-Alanine (2.0 g, 22.5 mmol) was dissolved in 10% aqueous sodium carbonate solution (50 mL), and a THF (50 mL) solution of methyl chloroformate (4.0 mL) was added to it. The reaction mixture was stirred under ambient conditions for 4.5 hours and concentrated in vacuo. The resulting white solid was dissolved in water and acidified with 1N HCl to a pH ˜2-3. The resulting solutions was extracted with ethyl acetate (3×100 mL), and the combined organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to provide a colorless oil (2.58 g). 500 mg of this material was purified by a reverse phase HPLC (H2O/methanol/TFA) to provide 150 mg of Cap-12 as a colorless oil. 1H NMR (DMSO-d6, δ=2.5, 500 MHz) 7.44 (d, J=7.3, 0.8H), 7.10 (br s, 0.2H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J=7.3, 3H).
Reaction SMILES: C(OC([N:8]([C@H:20]([CH2:43][O:44][Si](C)(C)C)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:30])=[CH:24][CH:23]=1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCCl>[OH:44][CH2:43][C@@H:20]([NH:8][CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[C:34]([CH:40]=[CH:41][CH:42]=2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cccc(NC(=O)Nc2ccc(C[C@@H](CO[Si](C)(C)C)N(C[C@H](O)COc3ccccc3)C(=O)OC(C)(C)C)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCOC(=O)c1cccc(NC(=O)Nc2ccc(C[C@@H](CO)NC[C@H](O)COc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of ethyl 3-[[[[4-[(2S)-2-[N-(tert-butoxycarbonyl)-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-[(trimethylsilyl)oxy]propyl]phenyl]amino]carbonyl]amino]-benzoate (204 mg) in 1,2-dichloroethane (2.0 ml) was added trifluroacetic acid (2.0 ml) and the solution was stirred at room temperature for 1 hour. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate (10 ml). The solution was washed with aqueous saturated sodium bicarbonate solution (5 ml×1) and brine (10 ml×1) successively, dried over magnesium sulfate, and evaporated to give ethyl 3-[[[[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]amino]carbonyl]amino]-benzoate (148 mg) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][CH2:28][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])=O)(C)(C)C.O1CCOCC1.[ClH:37]>>[ClH:37].[OH:27][CH:17]([C@@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:10](=[O:11])[C@@H:9]1[CH2:28][CH2:29][CH2:30][NH:8]1)[CH2:18][O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C([C@@H]1CCCN1)N1CCC[C@H]1C(O)COCc1ccccc1
Reaction time: 0.67 h

Procedure:
(S)-1-[N-(tert-Butoxycarbonyl)-L-prolyl]-2-[1-hydroxy-2(phenylmethyloxy)ethyl]pyrrolidine (4.99 g) was dissolved in a 3.6N hydrogen chloride-1,4-dioxane solution, and the mixture was left standing at room temperature for 40 minutes. The reaction mixture was concentrated to give the title compound (2.66 g). c) (S)-2-[[(S)-2-(1-Hydroxy-2-(phenylmethyloxy)ethyl]-1-pyrrolidinyl]carbonyl]-N-(2-phenylethyl)-1-pyrrolidinecarboxamide
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C@@H:12]1[CH2:15][NH:14][C@H:13]1[CH3:16].C(N(CC)CC)C.[F:24][C:25]1[C:43](F)=[CH:42][C:28]2=[N:29][C:30]3[N:31]([CH3:41])[CH:32]=[C:33]([C:38]([OH:40])=[O:39])[C:34](=[O:37])[C:35]=3[CH:36]=[C:27]2[CH:26]=1.O>CS(C)=O>[NH2:11][C@@H:12]1[CH2:15][N:14]([C:43]2[C:25]([F:24])=[CH:26][C:27]3[C:28]([CH:42]=2)=[N:29][C:30]2[N:31]([CH3:41])[CH:32]=[C:33]([C:38]([OH:40])=[O:39])[C:34](=[O:37])[C:35]=2[CH:36]=3)[C@H:13]1[CH3:16]
Reactant: Cn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: C[C@@H]1NC[C@H]1N
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: C[C@H]1[C@H](N)CN1c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)O)cn3C
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 78.1 %

Procedure:
A solution of 18 g of trans-3-amino-2-methylazetidine dimethanesulphonate and 12.7 g of triethylamine in 150 cm3 of dimethyl sulphoxide is heated with stirring to approximately 70° C. for 20 minutes. At the same temperature, 14.5 g of 7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are added in small portions in the course of 10 minutes, and the mixture is heated to approximately 90° C. for 2 hours. After cooling to approximately 20° C., the reaction mixture is poured into 400 cm3 of water at the same temperature. The insoluble matter is drained, washed with twice 100 cm3 of water and twice 100 cm3 of ethanol and recrystallized in 300 cm3 of dimethylformamide. 13.9 g of 8-(trans-3-amino-2-methyl-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 265°-267° C.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Reactant: Nc1ccc(S(=O)(=O)NCC(O)CO)cc1
Solvent: ClCCl
Product: CN(c1cc(C(=O)Nc2ccc(S(=O)(=O)NCC(O)CO)cc2)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-amino-N-(2,3-dihydroxypropyl)benzenesulfonamide (Intermediate 14), the title compound was obtained as a white solid after trituration in DCM.
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4]>CO>[OH:4][CH2:3][C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(CO)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.2 %

Procedure:
NaBH4 (0.39 g, 10.30 mmol) was added to a solution of 5-formyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile (5 g, 17.17 mmol) in methanol (30 mL) at 0° C., and then the mixture was stirred at rt for 30 min. The reaction mixture was quenched by acetone and concentrated. The residue was purified via ISCO (DCM:MeOH=20:1) to afford the title compound as a clear oil (5.5 g, 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1=[N:6][N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:8](=[O:21])/[C:9]/1=[C:10](\[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH2:11]Cl.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1=[N:6][N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:8](=[O:21])/[C:9]/1=[C:10](\[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH2:11][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(/CCl)NCc1ccccc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(/CN1CCOCC1)NCc1ccccc1
Yield: 98 %

Procedure:
The mixture of the above obtained methyl[(4Z)-4-[1-(benzylamino)-2-chloroethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (XIII), 0.32 g), morpholine (1 eq.) and DIPEA (1 eq.) was stirred at room temperature in toluene (3 mL) under nitrogen for 0.5 h at 90° C. Additional 0.5 eq. of morpholine wad added to push reaction to completion. The solvent was removed in vacuo. The resulting brown residue was proved to be the pure methyl[(4Z)-4-[1-(benzylamino)-2-morpholin-4-ylethylidene]-1-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (0.37 g). Yield 98%. MS (ESI+): 483.9; MS (ESI−): 481.8.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24]1([O:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([O:30][C:31](=[O:32])[NH:1][C:2]2[C:3]([C:7]3[NH:23][C:10]4=[CH:11][C:12]5[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=5[CH:17]=[C:9]4[N:8]=3)=[N:4][NH:5][CH:6]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)Oc4ccccc4)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid phenyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.96 mmol) and phenylchloroformate (146 μl, 1.16 mmol). The title compound was obtained as brown powder (55 mg, 13%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]#[N:21]>CC(C)=O>[CH2:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:19][C:20]#[N:21])=[CH:7][CH:6]=1)[C:9]([CH3:10])=[O:11]
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cc1ccc(OCC#N)cc1
Reaction time: 4 h

Procedure:
A mixture of 4-hydroxyphenylpropan-2-one, ethylene ketal (4.7 g), potassium carbonate (3.5 g) and chloroacetonitrile (1.83 g) in acetone, was heated under reflux for 5 h, cooled, filtered, and treated with 2N hydrochloric acid (1 ml). The solution was allowed to stand at room temperature for 4 h, the solvent was evaporated in vacuo and the residue partitioned between ethylacetate and water. The organic layer was dried, (magnesium sulphate), filtered and evaporated. The residue was purified by column chromatography on silica using chloroform as eluent to give 4-acetonylphenoxyacetonitrile, (3.0 g)
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1/[CH:10]=[N:11]/[C:12]1[C:17]([Cl:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[Cl:20])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:20][C:13]1[CH:14]=[C:15]([F:19])[CH:16]=[C:17]([Cl:18])[C:12]=1[N:11]1[CH:10]=[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: [N-]=[N+]=Nc1ccncc1/C=N/c1c(Cl)cc(F)cc1Cl
Solvent: Cc1ccccc1
Product: Fc1cc(Cl)c(-n2cc3cnccc3n2)c(Cl)c1
Temperature: 105 °C
Yield: 84 %

Procedure:
A mixture of [1-(4-azidopyridin-3-yl)meth-(E)-ylidene]-(2,6-dichloro-4-fluorophenyl)amine (2.09 g, 6.75 mmol) in toluene (20 mL) was heated to 105° C. for 45 minutes. The reaction was cooled and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (50-100% ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (1.60 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 9.38 (s, 1H), 8.45-8.30 (m, 2H), 7.70 (d, J=6.5 Hz, 1H), 7.32 (d, J=7.7 Hz, 2H).
Reaction SMILES: [CH2:1]1[O:5][CH:4]([CH:6]([OH:9])[CH2:7][OH:8])[C@@H:3]([OH:10])[CH:2]1[OH:11].[C:12](OC)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CO.C[O-].[Na+].[PH2]([O-])=O.[Na+]>>[CH3:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([O:8][CH2:7][CH:6]([OH:9])[C@H:4]1[O:5][CH2:1][C@H:2]([OH:11])[C@H:3]1[OH:10])=[O:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Reactant: OCC(O)C1OCC(O)[C@@H]1O
Agent: C[O-]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Temperature: 65 °C
Reaction time: 1 h

Procedure:
After 469 g of a 70% by weight sorbitan aqueous solution (aldehyde value of sorbitan: 7.4 ppm) and 872 g of methyl stearate were charged into a 2000 mL four-neck flask fitted with a stirring apparatus, a thermometer, and a nitrogen gas inlet, dehydration was performed at 110° C. under a nitrogen stream at normal pressure for 1 hour and further at 110° C. under a nitrogen stream at 4 kPa for 1 hour. The whole was cooled to 65° C. and, after 30.0 g of a 20% by weight sodium methoxide methanol solution and 0.06 g of sodium hypophosphite were added thereto, was heated under a nitrogen stream at normal pressure to 190° C. as a reaction temperature. After the temperature reached 190° C., pressure was reduced to 6.5 kPa and the reaction was carried out under a nitrogen stream. At the time point when the spot of methyl stearate as a raw material disappeared on thin-layer chromatography, it was judged that the reaction was completed. The reaction time was 5 hours and, after the completion of the reaction was confirmed, the mixture was filtrated at 80° C. to obtain sorbitan monostearate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][CH3:10])[CH:3]=1.C(N(CC)CC)C.[CH:18]([O:20]CCCC)=[CH2:19]>CN(C=O)C.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].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18](=[O:20])[CH3:19])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: C=COCCCC
Reactant: COc1cc(Cl)ccc1I
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C(C)=O
Temperature: 80 °C
Yield: 65 %

Procedure:
A solution of Example 59A (2.68 g, 10 mmol) in DMF (40 mL) was treated with triethylamine (1.53 mL, 11 mmol), n-butyl vinyl ether (6.5 mL, 50 mmol), DPPF (554 mg, 1 mmol) and Pd(OAc)2 (112 mg, 0.5 mmol), purged with nitrogen, heated to 80° C. for 6 hours, cooled to room temperature, and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 4:1 hexanes/ethyl acetate to provide 1.20 g (65%) of the desired product. MS (ESI) m/e 185 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.60 (d, J=8.14 Hz, 1H), 7.27 (d, J=1.70 Hz, 1H), 7.09 (dd, J=8.31, 1.86 Hz, 1H), 3.92 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][S:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=1[S:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CSc1ccccc1N
Product: CSc1ccccc1Nc1cc(F)ccc1[N+](=O)[O-]

Procedure:
Prepared according to Step D1 in General Procedure D using 2,4-difluoronitro-benzene (3.46 mL, 31.5 mmol) and 2-(methylthio)aniline (3.88 mL, 31.5 mmol) to give 5-fluoro-N-(2-(methylthio)phenyl)-2-nitroaniline as an orange solid: 1H NMR] (400 MHz, DMSO-d6) δ ppm 9.52 (1H, s), 8.26 (1H, dd, J=9.4, 6.1 Hz), 7.34-7.45 (3H, m), 7.26-7.32 (1H, m), 6.67-6.75 (1H, m), 6.35 (1H, dd, J=11.6, 2.6 Hz), 2.43 (3H, s); LC-MS (ESI) m/z 279.0 [M+H]+ at 2.176 min; m/z 277.0 [M−H]− at 2.169 min.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[CH3:31][O:32][CH2:33][C:34](Cl)=[O:35].N>C(Cl)Cl.CO>[CH3:31][O:32][CH2:33][C:34]([NH:21][C:17]1[CH:16]=[C:15]([O:14][C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:20]=[CH:19][N:18]=1)=[O:35]
Reactant: COCC(=O)Cl
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirred suspension of 4-(4-nitronaphthalen-1-yloxy)pyridin-2-amine (71.8 g, 255 mmol) in dry DCM (1.1 L) and DIPEA (84.0 mL, 511 mmol), cooled in an ice bath, was added dropwise 2-methoxyacetyl chloride (35.0 mL, 383 mmol) over 20 min. The resulting red solution was stirred at RT for 1 hr and was then treated with a solution of NH3 in MeOH (7 M, 100 mL). A precipitate formed immediately and the reaction mixture was stirred for a further 15 min and the volatiles were evaporated in vacuo. The solid residue was triturated with water (900 mL), collected by filtration and washed with water (2×250 mL) to give the title compound as a yellow solid (89.1 g, 96%): m/z 354 (M+H)+ (ES+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>C1COCC1.C(Cl)(Cl)Cl.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>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)c(O)c1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combined with trimethylsilylacetylene (3.71 mL, 26.3 mmol), bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) and cuprous iodide (54 mg, 0.28 mmol) in THF (20 mL)/CHCl3 (40 mL) in a dry flask, under nitrogen. Triethylamine (8.14 mL, 58.4 mmol) is added and the mixture is heated to 50° C. for 4 h. The mixture is diluted with CHCl3 (60 mL), washed with 5% HCl (2×40 mL), dried (MgSO4) and concentrated to a brown oily-solid (8.31 g). The crude material is chromatographed over a standard 90 g Biotage column, eluting with 10% EtOAc/hexane (1 L) followed by 15% EtOAc/hexane (1 L). The appropriate fractions are combined and concentrated to afford 4.22 g (91%) of methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS (FAB) calcd for C13H16O3SI+H: 249.0947, found 249.0947 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:16]=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=1)[OH:10]>>[CH2:1]([O:10][C:9]1[CH:16]=[CH:15][C:13]([OH:14])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: BrCc1ccccc1
Product: Oc1ccc(OCc2ccccc2)cc1

Procedure:
Benzylbromide and hydroquinone are reacted to obtain 4-benzyloxyphenol (i),which is reacted with optical active perfluoro-2-(perfluoroalkoxy) propionic chloride in pyridine as a solvent to obtain 4-benzyloxyphenyl-perfluoro-2-(Perfluoroalkoxy) propionate (ii), which is then subjected to the hydrogenation in the presence of a palladium/carbon catalyst to obtain 4-hydroxyphenyl-perfluoro-2-(perfluoropropoxy) propionate (iii), which is reacted to 4-alkyloxybenzoic acid and thionyl chloride in pyridine as a solvent to obtain an objective optically active compound, 4-[perfluoro-2-(perfluoropropoxy)propionyloxy]phenyl4'-n-octyloxybenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.Cl[C:19]1[N:20]=[CH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:19]([C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[CH3:17])[NH2:1])[N:20]=1
Reactant: Cc1ccc(N)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc2ccccc2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(N)cc1-c1cc2ccccc2cn1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask containing 5-amino-2-methyl-phenylboronic acid pinacol ester (233 mg, 1 mmol), 3-chloro-isoquinoline (245 mg, 1.5 mmol), Pd(PPh3)4 (128 mg, 0.1 mmol) is added toluene (4 ml), EtOH (1 ml) and aqueous 2M Na2CO3 solution (2 ml). The flask is purged with argon and sealed. The mixture is stirred at 90° C. for 18 hours, cooled to room temperature and extracted using water and ethyl acetate. The organic layer is separated, washed with brine, dried over MgSO4 and concentrated. The residue is subjected to silica gel flash chromatography, eluted with ethyl acetate in hexanes from 30% to 50% to afford 3-(isoquinolin-3-yl)-4-methylaniline as a brown oil. LC-MS m/z: 235.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][O:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Br:1])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C#N)cc1Br
Reaction time: 0.17 h
Yield: 100.1 %

Procedure:
A solution of 3-bromo-4-hydroxybenzonitrile (Lancaster; 3.00 g; 15.2 mmol) in acetone (30 mL) was treated with potassium carbonate (2.30 g; 16.7 mmol), stirred for 10 minutes then treated with tert-butyl bromoacetate (2.24 mL; 15.2 mmol). The reaction mixture was stirred at 65° C. for 18 hours, then the mixture was filtered, the solid was washed with acetone and the filtrate was concentrated to dryness under vacuum to give the title compound as a yellow sticky solid (4.75 g, quant).