Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:6]=1[CH:7]=[CH:8][C:9](OC)=[O:10])(=O)C.C([O-])(O)=O.[Na+]>Cl>[N+:17]([C:16]1[CH:15]=[CH:14][CH:13]=[C:6]2[C:5]=1[NH:4][C:9](=[O:10])[CH:8]=[CH:7]2)([O-:19])=[O:18]
Reactant: COC(=O)C=Cc1cccc([N+](=O)[O-])c1NC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1ccc2cccc([N+](=O)[O-])c2[nH]1

Procedure:
Methyl 2-acetamido-3-nitrocinnamate, as described above in Step B, (5.76 g, 21.8 mmol) was dissolved in 3 N aqueous HCl (220 mL) and the solution was heated at reflux for 72 hours, cooled, neutralized with NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [CH2:1]([C:3]1([C:34]([O:36]CC)=[O:35])[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:30](=[O:33])[CH2:31][CH3:32])[C:18]4[S:22][C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[N:20][C:19]=4[CH:29]=3)=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([C:3]1([C:34]([OH:36])=[O:35])[CH2:4][CH2:5][N:6]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:16]=[C:17]([C:30](=[O:33])[CH2:31][CH3:32])[C:18]4[S:22][C:21]([NH:23][C:24]([NH:26][CH2:27][CH3:28])=[O:25])=[N:20][C:19]=4[CH:29]=3)=[CH:11][N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(C(=O)CC)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)O)CC4)nc3)cc(C(=O)CC)c2s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.8 %

Procedure:
To a solution of ethyl 4-ethyl-1-(5-(2-(3-ethylureido)-7-propionylbenzo[d]thiazol-5-yl)pyrimidin-2-yl)piperidine-4-carboxylate (0.025 g, 0.046 mmol) in EtOH (5 mL) was added an aqueous solution (1 mL) of NaOH (0.0092 g, 0.232 mmol) and the mixture stirred overnight at 80° C. After reaction completion (by TLC), the EtOH was evaporated under reduced pressure, water (10 mL) was added to the residue and extracted with EtOAc (3×25 mL) and the organic layers discarded. The aqueous layer was acidified to pH 4-5 with 1N HCl, extracted with EtOAc (3×25 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4, filtered then concentrated under reduced pressure. The residue was purified by preparative TLC (5% MeOH in DCM) to obtain Compound 207 as white solid (0.007 g, 30%). 1H NMR (DMSO-d6): δ 10.82 (br s, 1H), 8.86 (s, 2H), 8.23 (s, 1H), 8.14 (s, 1H), 6.95 (br s, 1H), 4.46 (m, 2H), 3.36 (m, 2H), 3.13-3.24 (m, 4H), 2.08 (m, 2H), 1.51-1.53 (m, 2H), 1.32 (m, 2H), 1.16 (t, J=7.2 Hz, 3H), 1.10 (t, J=7.2 Hz, 3H) and 0.81 (t, J=7.2 Hz, 3H). MS: 511.24 [M+H]+.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:6]([C:7](OC)=[O:8])[CH:5]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Br:14][C:12]1[CH:13]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc(Br)cc(CO)c1
Temperature: 0 °C
Yield: 99.2 %

Procedure:
To a solution of 5-bromo-isophthalic acid dimethyl ester (4.54 g, 16.63 mmol) in methylene chloride (50 mL) cooled to 0° C. under argon was added diisobutylaluminum hydride (80 mL, 80 mmol, 1 M in toluene) via syringe. The reaction was quenched by Rochelle salt solution after 1 h of stirring at 0° C. The biphasic mixture was then stirred at room temperature for 12 h before work-up. The product was extracted with diethyl ether (2×50 mL). The organic layers were washed with water, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo to afford (3-bromo-5-hydroxymethyl-phenyl)-methanol as a white solid (3.582 g, 99%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+].O>CC(C)=O>[Cl:14][CH2:15][CH2:16][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: ClCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 43.2 %

Procedure:
17.9 g (107 mmol) of carbazole and 500 ml of acetone as solvent were placed in a 1000 ml four-necked flask with a mechanical stirrer and bulb-shaped cooler. To this was added an aqueous solution prepared from 22.0 g (93.7 mmol)of 2-chloroethyl-p-toluene sulfonate, 12.5 g of sodium hydroxide and 9.2 ml of water. The resultant product was heated to 60° C. in a silicone oil bath, and subjected to the reaction for 20 hours. After the reaction was completed, the product was cooled to the ambient temperature. The precipitated solid was subjected to suction filtration with a glass filter. The resultant liquid was concentrated in an evaporator and dried under vacuum to obtain a brown solid, which was recrystallized in the presence of ligroin to obtain 9.3 g of a white crystal.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=[O:13].[C:15](Cl)(=[O:17])[CH3:16]>C1C=CC=CC=1>[C:15]([O:1][C:2]1[C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]=2[CH:9]=[CH:10][CH:11]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: O=C(O)c1cccc2c(O)cccc12
Solvent: c1ccccc1
Product: CC(=O)Oc1cccc2c(C(=O)O)cccc12
Reaction time: 0.25 h

Procedure:
A solution of 20 g. of 5-hydroxy-1-naphthoic acid in 200 ml. of benzene and 40 ml. of acetyl chloride is refluxed for 3 hours. Solvent and excess acetyl chloride are evaporated. The mixture is dissolved in methanol (150 ml.) and water (20 ml.) added. After 15 minutes, addition of more water results in the precipitation of 1-acetoxy-5-naphthoic acid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[C:22]3[O:23][CH2:24][C:25](=O)[NH:26][C:21]=3[C:20](=[O:28])[N:19]([CH3:29])[CH:18]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].Cl.C([O-])(O)=O.[Na+]>C1COCC1.CC(=O)OCC.CO.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:8][C:7]=2[C:17]2[CH:22]3[O:23][CH2:24][CH2:25][NH:26][CH:21]3[C:20](=[O:28])[N:19]([CH3:29])[CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3c2OCC(=O)N3)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(C2=CN(C)C(=O)C3NCCOC23)c1
Reaction time: 0.5 h

Procedure:
The title compound of Example 365, step 3 in anhydrous THF was treated with excess 1M LAH in THF at room temperature. After about 30 min, ice, water, methanol and 1M HCl were added followed by saturated aqueous NaHCO3 and EA extractive work up. Silica gel chromatography (EA, followed by 5% methanol in EA) gave the title compound as a clear glass. 1H NMR: (DMSO-d6, 400 MHz) δ ppm 0.32 (br. s., 2H) 0.54 (br. s., 2H) 1.03-1.30 (m, 4H) 3.45 (br. s., 3H) 3.94 (br. s., 2H) 4.09 (br. s., 2H) 5.03 (br. s., 1H) 7.05 (br. s., 1H) 7.22 (br. s., 1H) 7.62 (br. s., 1H) 7.78 (br. s., 1H). 1H NMR: (DMSO-d6/DCl, 400 MHz) δ ppm 0.29 (br. s., 2H) 0.55 (br. s., 2H) 1.10 (br. s., 4H) 3.25 (br. s., 2H) 3.45 (br. s., 2H) 3.51 (br. s., 3H) 3.93 (br. s., 2H) 4.43 (br. s., 2H) 7.27 (br. s., 1H) 7.69 (br. s., 1H) 7.84 (br. s., 2H). LCMS: 405 (M+H)+
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:20])[CH:7](OC(=O)C)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2][CH2:3][CH3:4].[O:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.C(Cl)Cl>B(F)(F)F.CCOCC.C(OCC)(=O)C>[CH2:1]([O:5][C:6](=[O:20])[CH:7]([NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C:22]1[O:21][CH:25]=[CH:24][CH:23]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1ccoc1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccco1
Temperature: 25 °C

Procedure:
A solution of 1.6 g. (0.006 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester and 0.7 g. (0.01 mol.) of redistilled furan in 75 ml. of methylene chloride was cooled to -78° and 4 drops of boron trifluoride etherate was added with stirring. The reaction mixture was warmed to room temperature and left for 3 hours Chromatography on silica gel with methylene chloride and methylene chloride containing increasing amounts of ethyl acetate gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[CH3:17][CH2:18][O:19][C:20](/[CH:22]=[CH:23]/[CH2:24]P(OCC)(OCC)=O)=[O:21].[H-].[Na+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:24]/[CH:23]=[CH:22]/[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 28.1 %

Procedure:
By the method of Preparation 1, 4,4'-dichlorobenzophenone (5.00 g, 19.9 mmol) was hologated using triethyl 4-phosphonocrotonate (5.23 g, 20.9 mmol) and sodium hydride (0.528 g, 22 mmol) to give, after purification, 1.94 g (28% yield) of title product, mp 99-100° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:23])=[C:12]([CH:22]=1)[NH:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16](SC)[N:15]=1)=[O:6].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:23])=[C:12]([CH:22]=1)[NH:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:15]=1)=[O:6]
Reactant: CSc1nccc(Nc2cc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)ccc2C)n1
Reactant: C1COCCN1
Solvent: O
Product: Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)cc1Nc1ccnc(N2CCOCC2)n1
Temperature: 150 °C

Procedure:
A mixture of 4-[5-(3-fluoro-5-morpholinobenzamido)-2-methylanilino]2-methylthiopyrimidine (0.228 g) and morpholine (1 ml) was stirred and heated to 150° C. for 10 days. The reaction mixture was allowed to cool to ambient temperature and poured into water (10 ml). The resultant precipitate was collected by filtration and dried in a vacuum oven at 60° C. for 16 hours. There was thus obtained the title compound (0.175 g); NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.21 (m, 4H), 3.59 (m, 8H), 3.74 (m, 4H), 5.98 (d, 1H), 6.96 (m, 1H), 7.09 (m, 1H), 7.18 (m, 1H), 7.26 (m, 1H), 7.38 (m, 1H), 7.89 (d, 1H), 8.01 (m, 1H), 8.49 (s, 1H), 10.07 (s, 1H); Mass Spectrum: M+H+ 493.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](C(C)=O)C(C)C.S(OC)(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: CC(=O)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cccc(Cl)c1N
Temperature: 20 °C
Yield: 95 %

Procedure:
85.5 g (0.50 mol) of 2-amino-3-chlorobenzoic acid, 300 ml of MIBK (methyl isobutyl ketone), 16.1 g (0.05 mol) of tetrabutylammonium bromide, and 69.4 g (0.55 mol) of dimethyl sulfate were added to a 1000 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a dropping funnel, and a mixture of 76.0 g (0.55 mol) of potassium carbonate and 150 ml of MIBK was added dropwise with stirring at 20° C. Then, the mixture was stirred at room temperature for 1 hour. 250 ml of water was added to the reaction mixture, and the reaction solution was separated at room temperature. Then, the MIBK phase was washed with 250 ml of water, and the MIBK was distilled off under reduced pressure. 88.2 g of methyl 2-amino-3-chlorobenzoate as brown crystals was obtained with a yield of 95%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[N:27]1([CH2:26][CH2:25][C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Fc1ccc2nnc(CCN3CCCC3)n2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(CCN4CCCC4)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 63.8 %

Procedure:
Intermediate A (189 mg, 1.16 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 139 mg, 3.48 mmol) in DMF (5 mL). The reaction was stirred for 20 mins, then Intermediate 1b (292 mg, 1.16 mmol) was added in DMF (5 mL) and the reaction heated to 60° C. for 2 h. The mixture was cooled and quenched by dropwise addition of MeOH. The solution was loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (270 mg, 0.74 mmol, 64%). 1H NMR (400 MHz, d4-MeOD): 1.80-1.86 (4H, m), 1.92-2.02 (1H, m), 2.05-2.18 (2H, m), 2.30-2.40 (1H, m), 2.62-2.70 (4H, m), 2.99-3.05 (2H, t, J 7.8), 3.28-3.36 (2H, t, J 7.8), 3.98-4.04 (1H, dd, J 8.6, 5.2), 5.46-5.50 (1H, t, J 4.3), 7.22-7.40 (4H, m), 7.54-7.58 (1H, d, J 7.8), 7.63-7.68 (1H, dd, J 9.8, 0.7), 7.97 (1H, s), 8.09-8.11 (1H, d, J 1.6).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:14]([C:19](=O)[CH3:20])[CH2:15][C:16](=O)[CH3:17])=[CH:11][CH:12]=2)[C@H:7]([NH:22][C:23](=[O:28])[O:24][CH:25]([CH3:27])[CH3:26])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+:34].C(O)(=O)C.[OH-].[Na+]>C(Cl)Cl.CO.CCOC(C)=O>[CH3:27][CH:25]([O:24][C:23](=[O:28])[NH:22][C@H:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([N:14]3[CH:15]=[C:16]([CH3:17])[N:34]=[C:19]3[CH3:20])[CH:9]=2)[N:4]([C:1](=[O:3])[CH3:2])[C@@H:5]([CH3:29])[CH2:6]1)[CH3:26]
Reactant: CC(=O)CN(C(C)=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N1c2ccc(-n3cc(C)nc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 120 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
A mixture of 1-methylethyl {(2S,4R)-1-acetyl-6-[acetyl(2-oxopropyl)amino]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see Intermediate 110) (130 mg, 0.322 mmol), ammonium acetate (124 mg, 1.611 mmol) and acetic acid (2 mL, 34.9 mmol) was stirred at 120° C. under nitrogen for 24 h then cooled to room temperature and basified with NaOH (2N in water). The mixture was then partitioned between AcOEt (10 mL) and water (5 mL) and the phases were separated. The organic layer was washed with a saturated NaHCO3 aqueous solution, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 100% AcOEt then 0 to 10% MeOH in DCM) gave 1-methylethyl[(2S,4R)-1-acetyl-6-(2,4-dimethyl-1H-imidazol-1-yl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (28 mg, 0.062 mmol, 19%) as a yellow gum.
Reaction SMILES: C[O:2][CH:3]=[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:5]>C1COCC1.O.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([CH3:5])[CH:3]=[O:2])[N:7]=1
Reactant: COC=C(C)c1cccnn1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: C1CCOC1
Solvent: O
Product: CC(C=O)c1cccnn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.1 %

Procedure:
To a solution of 1-methoxy-2-(pyridazin-3-yl)propene (0.26 g, 1.72 mmol) in THF (50 ml) and water (10 ml) under nitrogen at ambient temperature was added mercury(II)acetate (1.66 g, 5.2 mmol). This mixture was stirred at room temperature for 2 hours, and was then poured onto potassium iodide solution (7%, 350 ml) and extracted with toluene (2×50 ml). The combined organic phases were washed with potassium iodide (7%, 140 ml) and brine (90 ml), dried (Na2SO4) and evaporated to give the title compound (54 mg, 23%), as an orange gum. The crude aldehyde was used directly without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][C@H:4]([CH3:17])[C@:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)(O)[CH2:6][CH3:7].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[H][H]>CC1CCCO1.[Pd]>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C@H:5]([CH2:6][CH3:7])[C@@H:4]([CH3:17])[CH2:3][N:2]([CH3:18])[CH3:1])[CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: CC[C@](O)(c1cccc(OC)c1)[C@@H](C)CN(C)C
Agent: [Pd]
Solvent: CC1CCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC[C@@H](c1cccc(OC)c1)[C@@H](C)CN(C)C
Temperature: 5 °C
Yield: 97.9 %

Procedure:
A solution of compound (4) (50.3 g) dissolved in 2-methyltetrahydrofuran (120 ml) was stirred and cooled to 5° C. Then trifluoroacetic anhydride (30.6 ml) was added slowly over a period of 10 minutes while the temperature of the reaction mixture was kept below 20° C. After addition, the reaction mixture was allowed to stir for 1 hour at 20° C. b) Palladium 10% on activated carbon (50% wetted) (2.52 g) was added and the reaction mixture was stirred at 800 rpm and pressurized to 2 atmosphere (202.65 kPa) with hydrogen gas. The reaction mixture was heated to 40° C. and stirred for 4 hours at 40° C. The mixture was allowed to cool to 20° C. and filtered under nitrogen atmosphere. The filter was washed with 2-methyltetrahydrofuran (10 ml). Water (160 ml) was added to the filtrate and the mixture was stirred, then an aqueous NaOH solution (28.6 ml, 50% w/w) was added over a period of 10 minutes while the temperature was kept below 20° C. The organic and water layer were allowed to separate, the organic layer was isolated and washed with water (50 ml), and concentrated under reduced pressure to dryness, yielding (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethyl-pentanamine (5) as a colourless oil (46.10 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25][CH:26]([CH3:28])[CH3:27])[O:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH:25][CH:26]([CH3:28])[CH3:27])[O:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(OC(C)C)n3)c3cc(-c4noc(NC(C)C)n4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1nc(-c2ccc3[nH]cc(-c4cncc(OC(C)C)n4)c3c2)no1
Temperature: 100 °C
Yield: 28.2 %

Procedure:
To a solution of 3-(3-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,2,4-oxadiazol-5-amine (200 mg, 0.375 mmol) in 1,4-dioxane (2.0 mL) was added 10% aq NaOH (1.0 mL) and the reaction was heated at 100° C. for 2 h. The mixture was cooled to RT and treated with ice cold water (2.0 mL). The precipitate was collected through filtration and the crude product was purified with preparative HPLC (eluent: 60-90% MeCN in water with 0.01% TFA) to give 3-(3-(6-isopropoxypyrazin-2-yl)-1H-indol-5-yl)-N-isopropyl-1,2,4-oxadiazol-5-amine (40 mg, 28.0%). MS (ESI, pos. ion) m/z: 379.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 9.11 (s, 1H), 8.73 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.24 (d, J=7.6 Hz, 1H), 7.93 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 5.55-5.49 (m, 1H), 3.93-3.85 (m, 1H), 1.47 (d, J=6.0 Hz, 6H), 1.25 (d, J=6.4 Hz, 6H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:11])=[O:10])#[N:4].Br[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27].CCCCCC.CCOC(C)=O>CN(C=O)C>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:8]([CH2:7][CH2:6][CH2:5][C:3]#[N:4])[S:9]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])(=[O:10])=[O:11])#[N:27]
Reactant: N#CCCCCBr
Reactant: Cc1cc(C)c(S(=O)(=O)NCCCC#N)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(S(=O)(=O)N(CCCC#N)CCCCC#N)c(C)c1
Yield: 79.4 %

Procedure:
NaH (60%, 0.90 g, 23 mmol), 36 (5.02 g, 18.85 mmol), and 5-bromovaleronitrile (2.4 mL, 21 mmol) in DMF were combined and worked up by the method of 43. Column chromatography (1:1 hexane/EtOAc) provided 5.20 g (79%) of 38 as an oil: NMR δ 1.49-1.66 (m, 4 H), 1.82 (m, 2 H), 2.22 (t, 2 H, J=7), 2.25 (t, 2 H, J=7), 2.29 (s, 3 H), 2.57 (s, 6 H), 3.19 (t, 2 H, J=7), 3.29 (t, 2 H, J=7), 6.95 (s, 2 H). Anal. (C18H25N3O2S) C, H, N.
Reaction SMILES: N[C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[Br:16].N([O-])=O.[Na+].[PH2](O)=O>S(=O)(=O)(O)O.O>[Br:8][C:7]1[CH:6]=[C:5]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:4]=[C:3]([Br:16])[CH:2]=1
Reactant: Nc1c(Br)cc(C(=O)CCC(=O)O)cc1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: O
Product: O=C(O)CCC(=O)c1cc(Br)cc(Br)c1
Temperature: -2.5 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.5 g (0.01 mol) of 4-(4-amino-3,5-dibromophenyl)-4-oxobutanoic acid in 50 ml of 1N aqueous sulphuric acid was treated dropwise with a solution of 0.76 g (0.011 mol) of sodium nitrite in 10 ml of water while maintaining a reaction temperature of −5 to 0° C. The mixture was stirred for a further 30 minutes at a temperature of 0° C., then 50 ml of hypo-phosphorous acid were added dropwise while maintaining the same temperature and stirred for another 1 hour at a temperature of 0° C. The mixture was decolorised and a colourless crystalline substance was precipitated. The mixture was diluted with 100 ml of water, the precipitate formed was suction filtered, washed thoroughly with water and then dried in a circulating air dryer. 3.1 g (92% of theoretical) of colourless crystals were obtained, m.p. 137–138° C.
Reaction SMILES: [Cl:1][CH:2]([Cl:8])[CH:3]1[NH:7][CH2:6][CH2:5][O:4]1.C(N(CC)CC)C.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>C(Cl)(Cl)Cl>[Cl:1][CH:2]([Cl:8])[CH:3]1[N:7]([C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])[CH2:6][CH2:5][O:4]1
Reactant: ClC(Cl)C1NCCO1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCOC1C(Cl)Cl
Yield: 98.4 %

Procedure:
2nd part: By operating as in the second part of Example 13, but using 23.5 g (0.15 mole) of 2-dichloromethyl-1,3-oxazolidine, 18 g (0.18 mole) of triethylamine and 24.3 g (0.165 mole) of dichloroacetyl chloride in 200 ml of chloroform, after the removal of the chloroform by distillation under vacuum, 39.4 g (yield 98%) of crude 2-dichloromethyl-3-dichloroacetyl-1,3-oxazolidine is obtained.