Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:8]=2[CH:7]=1)(=[O:5])=[O:4])[CH3:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:20][C@H:21]1[O:23][CH2:22]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:20][C@H:21]3[O:23][CH2:22]3)[C:8]=2[CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1cc2c(O)cccc2o1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)c1cc2c(OC[C@@H]3CO3)cccc2o1
Yield: 105.5 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 1 using 2-(ethylsulfonyl)-4-hydroxybenzo(b)furan (2.75 g), (S)-glycidyl nosylate (3.48 g) and potassium carbonate (5.05 g), a crude product of the title compound (3.62 g) was obtained as a pale-yellow oil.
Reaction SMILES: [I:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:10]([C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][I:1])=[CH:9][CH:8]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCC(=O)c1ccc(CCI)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCc1ccc(CCI)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4′-(2-iodoethyl)octanophenone (200 g) in trifluoroacetic acid (319 ml) is added triethylsilane (195.7 ml) under ice-cooling, and the mixture is stirred at room temperature for 2 hr. The reaction mixture is concentrated, and the residue is distilled away under reduced pressure to give the title compound (7) as a pale-red oil. The resulting Compound (7) has the same physico-chemical characteristics as indicated in Example 15.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:15]([OH:17])=O)[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCCCC1)C.C(Cl)(=O)C(C)(C)C.[CH3:33][O:34][C:35](=[O:53])[C@H:36]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[NH:37][C:38](=[O:45])[C@H:39]([CH2:41][C:42](=[O:44])[NH2:43])[NH2:40].Br>ClCCl.N1C=CC=CC=1>[CH3:33][O:34][C:35](=[O:53])[C@H:36]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[NH:37][C:38](=[O:45])[C@H:39]([CH2:41][C:42](=[O:44])[NH2:43])[NH:40][C:15](=[O:17])[C@H:12]([CH2:13][OH:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Agent: CCN1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.04 h

Procedure:
Benzyloxycarbonylserine (8.4 g; 35 mmoles), N-ethylpiperidine (4.9 ml) and pyridine (3.5 ml) in dichlormethane (100 ml) cooled to -20° C. are treated under constant stirring with pivaloylchloride (4.4 ml); the mixture is stirred and cooled (0° C.) a further 8 minutes. After that, within 2 to 3 minutes, a solution of asparaginyl-phenylalanine methyl ester, liberated from its hydrobromide (13.1 g; 35 mmoles) by the addition of N-ethylpiperidine (4.9 ml), in dichloromethane (100 ml) is added. The reaction mixture is stirred for 2 hours at room temperature and evaporated. The noncrystalline residue is dissolved in ethyl acetate and the solution is successively washed with 1 M hydrochloric acid, water, 5% sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate, and evaporated, after which the residue is crystallized from methanol. The yield is 9.1 g (51%), m.p. 180°-183° C. A sample is recrystallized from the same solvent and has m.p. 184°-186° C. Rf 0.71/S1, 0.82/S2. [α]D20 -13.8° (c 0.2; methanol). Composition: C25H30N4O8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:11]2[NH:16][CH2:15][CH:14]=[CH:13][NH:12]2)[OH:10])[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([CH:11]1[NH:16][CH2:15][CH2:14][CH:13]=[N:12]1)=[O:10]
Reactant: OC(c1ccc(F)c(Br)c1)C1NC=CCN1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccc(F)c(Br)c1)C1N=CCCN1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81 %

Procedure:
A mixture of 1-(3-bromo-4-fluorophenyl)-1-(2-tetrahydropyrimidinyl)methanol (23.4 g, 81.5 mmol) and manganese dioxide (70.8 g, 815 mmol) in methylene chloride is stirred at room temperature for 3 days and filtered through diatomaceous earth. The filtercake is washed with chloroform. The filtrates are combined and concentrated to dryness to afford the title compound as a yellow-green solid, 18.9 g (81% yield), identified by NMR and mass spectral analyses. 1H NMR (500 MHz, CDCl3) δ 8.51 (m, 1H), 8.23 (m, 1H), 7.15 (t, J=8.4 Hz, 1H), 6.10 (br s, 1H), 3.65 (br s, 2H), 3.41 (br s, 2H), 1.83 (m, 2H); ESI MS m/z 284 [C11H10BrFN2O+H]+.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]=[CH:4][CH3:5].C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>ClCCl>[C:14]([O:6][CH:2]([CH3:1])[CH:3]=[CH:4][CH3:5])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: CC=CC(C)O
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC(C)C=CC
Temperature: 0 °C
Yield: 55 %

Procedure:
A 1-liter flask was charged with 43.9 g (0.51 mol) of 3-penten-2-ol, 51.6 g (0.51 mol) of triethylamine and 300 ml of dichloromethane, and the mixture was cooled down to 0° C. While stirring the mixture at 0° C., 52.3 g (0.50 mol) of methacryloyl chloride were added dropwise over 1 hour, and the mixture was stirred additionally for 5 hours at room temperature. Solids were separated by filtration from the resultant reaction mixture, and the filtrate was washed 3 times with water and then distilled in the presence of 5 g of p-methoxyphenol to obtain 42.4 g of 1-methyl-2-butenyl methacrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:37][CH2:38][S:39][CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][N:18]([CH2:37][CH2:38][S:39][CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:26][CH3:27])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCNCC1
Reactant: ClCCSC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1(CCCc2c(Cl)cnc3ccc(OC)cc23)CCN(CCSC2CCCC2)CC1
Temperature: 80 °C
Yield: 56.5 %

Procedure:
1.2 g of ethyl 4-[3-(3-chloro-6-methoxy-quinolin-4-yl)propyl]piperidine-4-carboxylate, 0.51 g of potassium carbonate and 0.61 g of potassium iodide were added, at a temperature in the region of 20° C., with stirring and under an inert atmosphere, to a solution of 0.607 g of (2-chloroethylthio)cyclopentane in 50 cm3 of acetonitrile. After heating for 20 hours at a temperature in the region of 80° C., the reaction mixture was cooled to about 20° C., filtered and concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained was purified by chromatography under a nitrogen pressure of 100 kPa, on a column of silica gel (particle size 40-60μ; diameter 3.5 cm), eluting with a mixture of dichloromethane/methanol (98/2 by volume) and collecting 35-cm3 fractions. Fractions 25 to 31 were combined and then concentrated as above. 0.9 g of ethyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-4-carboxylate was obtained.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[OH-].[Na+].[CH2:16](Br)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:16]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Reaction time: 1 h

Procedure:
1.98 g of caffeic acid was dissolved in 100 mL of dimethylformamide. 2.28 mL of 25% aqueous sodium hydroxide solution was added while stirring. Stirring continued for 1 hr. At the end of this period a solution of 5.7 mL of phenethyl bromide in 10 mL dimethylformamide was added slowly in 30 minutes. The resulting reaction mixture was stirred at room temperature for 50 hrs. Next, the reaction mixture was poured into 200 mL of water and extracted with ethyl acetate (3×100 mL). The combined organic extract was washed with 100 mL of 1N HCl and water (3×100 mL). After drying over sodium sulfate, the solvent was distilled off under vacuum. The residue was crystallized from ethyl acetate/hexane by treatment with activated carbon to obtain caffeic acid phenethyl ester. The yield was 600 mg and the purity was greater than 90%.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1>C(OCC)(=O)C.CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(OC)nc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CCc1ccc(-c2ccc(OC)nc2)cc1
Reaction time: 2.5 h

Procedure:
To a solution of compound obtained from step b above (8.1 g) in a mixture of ethyl acetate/methanol/tetrahydrofuran (˜300 mL), 10% Palladium on charcoal (1.6 g) was added and stirred under hydrogen atmosphere at 30 psi in a Paar apparatus for 2.5 hours. The reaction mixture was filtered through a celite pad, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the title compound as a white solid which was used as such for the next step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([C:30](=[O:36])[CH2:31][CH2:32][C:33](=[O:35])[CH3:34])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[Na]>C(O)C.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]([C:30](=[O:36])[CH2:31][CH2:32][CH:33]([OH:35])[CH3:34])[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(=O)CCC(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCC(C)O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reaction time: 48 h
Yield: 93.4 %

Procedure:
A solution of 0.160 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(4-oxovaleryl)-2′-isobutyl-4-methylvalerohydrazide in 10 ml of ethanol was treated with 0.012 g of sodium borobydride. The mixture was stirred for 48 hours and then diluted with ethyl acetate and washed with water and saturated sodium chloride solution. Drying over anhydrous magnesium sulfate and evaporation gave 0.150 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(4(RS)-hydroxyvaleryl)-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([O:15]CC)=[O:14])[C:9]=2[CH3:18])=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]=2[CH3:18])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc(-c2ccc(Cl)cc2)c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)noc1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 95.8 %

Procedure:
To a solution of ethyl 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylate (63 mg, 0.24 mmol) in tetrahydrofuran (1.5 mL) was added a solution of lithium hydroxide hydrate (10 mg, 0.24 mmol) in water (1.5 mL). After stirring for 20 minutes, the reaction mixture was acidified with 1M HCl and extracted with dichloromethane three times. The combined dichloromethane extracts were washed with brine, dried over magnesium sulfate, and evaporated to obtain 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylic acid (55 mg, 0.23 mmol).
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C@@H:15]([CH:28]([CH3:30])[CH3:29])[C:16]([NH:18][C@@H:19]([CH3:27])[C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[O:13])=[CH:10][CH:9]=1.FC(F)(F)C(O)=O.C(OCC)(=O)C>ClCCl.CCCCCC>[O:7]=[C:4]1[CH:5]=[CH:6][C:2](=[O:1])[N:3]1[C:8]1[CH:32]=[CH:31][C:11]([C:12]([NH:14][C@@H:15]([CH:28]([CH3:29])[CH3:30])[C:16]([NH:18][C@H:19]([CH3:27])[C:20]([OH:22])=[O:21])=[O:17])=[O:13])=[CH:10][CH:9]=1
Reactant: CC(C)[C@H](NC(=O)c1ccc(N2C(=O)C=CC2=O)cc1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccc(N2C(=O)C=CC2=O)cc1)C(=O)N[C@H](C)C(=O)O
Reaction time: 1.25 h

Procedure:
To a mixture of 100 (47 mg, 0.11 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL) and the reaction mixture was monitored by TLC (50% ethyl acetate in hexane, after pumping down the TLC plate under high vacuum for 5 min). After 75 min, no starting material could be detected by TLC. The reaction was performed a second time using the same conditions and material from both reactions were combined and purified on a 2 mm radial chromatotron plate eluting with a gradient from 5-10% methanol in dichloromethane. The yield was 42 mg (49%) of 53: 1H-NMR (400 MHz, CDCl3) δ 7.92 (d, J=6.6 Hz, 2H), 7.51 (d, J=6.6 Hz, 2H), 7.0 (m, 1H), 6.89 (s, 2H), 6.70 (s, 1H), 4.60 M, 1H), 2.22 (m, 1H), 1.18 (d, J=6.6 Hz, 3H), 1.04 (m, 6H); MS (ES+) m/z 388.02 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:15][CH:14]([CH3:16])[CH2:13][C:4]2([CH:10]([CH3:11])[CH2:9][C:8](=[O:12])[C:5]32[O:7][CH2:6]3)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CC1(O)C2(CC(C)CC(C)(C)C2)C(C)CC1O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[OH:7][C:5]1([CH3:6])[C:4]2([CH2:13][CH:14]([CH3:16])[CH2:15][C:2]([CH3:17])([CH3:1])[CH2:3]2)[CH:10]([CH3:11])[CH2:9][C:8]1=[O:12]
Reactant: CC1CC(C)(C)CC2(C1)C(C)CC(=O)C21CO1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC1CC(C)(C)CC2(C1)C(C)CC(O)C2(C)O
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CC1CC(C)(C)CC2(C1)C(C)CC(=O)C2(C)O
Reaction time: 6 h
Yield: 15 %

Procedure:
Following the procedure detailed in Example 1,1,4,7,7,9-pentamethylspiro-[4.5]decan-1,2-diol was prepared by reduction of 6,6,8,10-tetramethyl-1-oxadispiro-[2.0.5.3]dodecan-12-one with lithium aluminum hydride. A solution of Dess-Martin periodinane (780 mg, 1.84 mmol) in CH2Cl2 (20 mL) was added in one dash to a stirred solution of 1,4,7,7,9-pentamethylspiro[4.5]decan-1,2-diol (400 mg, 1.66 mmol) in CH2Cl2 (15 mL). Stirring was continued at room temperature for 6 h, prior to quenching by dropwise addition of a solution of Na2S2O3 (950 mg, 6.00 mmol) in satd. aq. NaHCO3 (40 mL). After stirring for 30 min., water (50 mL) was added, the organic layer was separated, and the aqueous one extracted with CH2Cl2 (50 mL). The combined organic extracts were washed with water (50 mL), dried (Na2SO4), vacuum-filtrated over a pad of Celite®, and concentrated on the rotary evaporator. The resulting residue (430 mg) was separated by repeated silica-gel FC (pentane/Et2O, 9:1, Rf=0.48) to finally provide the weaker, less polar (1R*,4R*,5S*,9R*)-configured diastereoisomer of 1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (60 mg, 15%) in pure form as colorless crystals, mp. 72-73° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.CC(C)([O-])C.[K+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:21]=1[N+:27]([O-:29])=[O:28]>O1CCCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[C:21]=2[N+:27]([O-:29])=[O:28])[CH:3]=1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-fluoro-2-hydroxybenzoate (1.225 g) in anhydrous tetrahydrofuran (25 mL) was added potassium t-butoxide (0.808 g). The mixture was stirred for 20 minutes at room temperature. A solution of 1,3-difluoro-2-nitrobenzene (0.955 g) in tetrahydrofuran (6 mL) was then added dropwise. The resulting mixture was stirred at room temperature for 1 hour, then at 80° C. overnight. The reaction mixture was quenched with water (40 mL) and extracted with dichloromethane. The organic solution was dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column, eluting with 25% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[C:6]2[OH:12].[CH3:13][N:14]1C(=O)O[C:17](=[O:18])[C:16]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:15]12>>[CH3:13][NH:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([OH:12])=[N:7]1)=[O:18]
Reactant: COc1ccc2[nH]nc(O)c2c1
Reactant: Cn1c(=O)oc(=O)c2ccccc21
Product: CNc1ccccc1C(=O)n1nc(O)c2cc(OC)ccc21

Procedure:
5-Methoxy-1H-indazol-3-ol was reacted with N-methylisatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 67.0% yeild; m.p. 175°-177° C.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:11]([N:14]([CH2:27][CH2:28][CH3:29])[S:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:12][CH3:13]>>[CH2:27]([N:14]([CH2:11][CH2:12][CH3:13])[S:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:1][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:23])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:28][CH3:29]
Reactant: NC1CCc2ccccc21
Reactant: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)Cl)cc1
Product: CCCN(CCC)S(=O)(=O)c1ccc(C(=O)NC2CCc3ccccc32)cc1
Yield: 63 %

Procedure:
The title compound was prepared in 63% yield from (rac)-1-aminoindan (10.0 g, 75.2 mmole) and 4-(di-n-propylsulfamoyl) benzoyl chloride (16.3 g, 53.6 mmole, prepared from probenecid and SOCl2) via a procedure analogous to that described in Ex. 46, followed by crystallization from hexane:EtOAc, mp: 124-5° C.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([O:10][CH3:11])[O:8][CH3:9].N1C=CC=CC=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl>[CH3:11][O:10][CH:7]([O:8][CH3:9])[CH2:6][N:5]([CH2:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[F:1])[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(CNCc1ccccc1F)OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1ccccc1F)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C

Procedure:
N-(2-fluorobenzyl)-2,2-dimethoxyethanamine (BB; 33.0 g, 0.154 mol) were dissolved in 200 mL of dichloromethane and pyridine (50.2 g, 0.417 mol) was added. At 0° C. a solution of p-toluene sulphonyl chloride (58.0 g, 0.201 mol) in dichloromethane (500 mL) was added drop wise. The reaction was allowed to warm to room temperature and stirring is continued until conversion was completed. For workup, the reaction mixture was extracted twice with 2M aqueous hydrochloric acid, twice with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulphate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 7.69-7.67 (2H, m), 7.43-7.39 (m, 1H), 7.29-7.21 (m, 3H), 7.12-7.08 (m, 1H), 6.99-6.95 (m, 1H), 4.52 (s, 2H), 4.39-4.37 (t, 1H, J=5.2 Hz), 3.26-3.24 (m, 8H), 2.42 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[C:13]#[N:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][CH2:22][CH:23]([NH2:26])[CH2:24][CH3:25].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:13]([C:12]1[CH:11]=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3][C:2]=1[NH:26][CH:23]([CH2:24][CH3:25])[CH2:22][CH3:21])#[N:14]
Reactant: CCOC(=O)c1ccc(C#N)c(Br)c1
Reactant: CCC(N)CC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(C#N)c(NC(CC)CC)c1
Temperature: 95 °C
Yield: 61.4 %

Procedure:
To a pressure vessel were added ethyl 3-bromo-4-cyanobenzoate (500 mg, 1.97 mmol), cesium carbonate (1.28 g, 3.94 mmol), pentan-3-amine (688 uL, 5.90 mmol), XANTPHOS (114 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (90 mg, 0.10 mmol), and dioxane (3 mL). The vessel was sealed and heated to 95° C. for 15 h. After cooling to room temperature, the mixture was filtered through celite and the filter cake rinsed with ethyl acetate. The filtrate was then concentrated and the residue was purified by column chromatography (10% ethyl acetate in hexanes) to provide ethyl 4-cyano-3-(pentan-3-ylamino)benzoate (315 mg, 1.21 mmol, 61% yield) as a yellow syrup. 1H NMR (400 MHz, CDCl3): 7.43 (d, 1H), 7.33 (s, 1H), 7.25 (dd, 1H), 4.44-4.35 (m, 3H), 3.48-3.40 (m, 1H), 1.72-1.48 (m, 4H), 1.40 (t, 3H), 0.96 (t, 6H); MS (EI) for C15H20N2O2: 261 (MH+).
Reaction SMILES: OO.FC(F)(F)C(OO)=[O:6].[Br:11][C:12]1[C:13]([F:41])=[C:14]([C:36](C=O)=[CH:37][CH:38]=1)[O:15][C:16]1[CH:17]=[C:18]([C:29]([NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:19]=[C:20]([CH:28]=1)[C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O[Li].O>C(Cl)Cl.O.CCOC(C)=O>[Br:11][C:12]1[C:13]([F:41])=[C:14]([C:36]([OH:6])=[CH:37][CH:38]=1)[O:15][C:16]1[CH:17]=[C:18]([C:29]([NH:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH:19]=[C:20]([CH:28]=1)[C:21]([NH:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: CC(C)(C)NC(=O)c1cc(Oc2c(C=O)ccc(Br)c2F)cc(C(=O)NC(C)(C)C)c1
Reactant: O=C(OO)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1cc(Oc2c(O)ccc(Br)c2F)cc(C(=O)NC(C)(C)C)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
step 5a—Trifluoroacetic anhydride (1.3 mL, 12 eq.) and H2O2 (0.24 mL, 2.5 eq.) were combined at 0° C. and stirred for 2 h. The mixture containing trifluoroperacetic acid was added to a mixture of 5-(3-bromo-2-fluoro-6-formyl-phenoxy)-N,N′-di-tert-butyl-isophthalamide from step 4 (0.4 g, 0.81 mmol) and potassium phosphate (2.2 g, 20 eq.) in DCM at 0° C. and the reaction mixture stirred for 5 h. The reaction mixture was diluted with DCM and washed sequentially with sodium bisulfite and brine. The solution containing the formate ester was concentrated in vacuo and the residue was dissolved in THF (4 mL) and a solution of LiOH.H2O (0.43 g, 3 eq.) in H2O (1 mL) was added to the reaction mixture and stirred for 5 h. The reaction mixture was diluted with EtOAc and washed with HCl (aqueous), water, and brine. The organic phase was dried (Na2SO4), filtered and evaporated to afford 0.300 g (75%) of 5-(3-bromo-2-fluoro-6-hydroxy-phenoxy)-N,N′-di-tert-butyl-isophthalamide (D-2b, Ar=3,5-di-tert-butyl-dicarboxamido-phenyl).