Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]3[O:37][CH:38]=[C:39]([C:41]([O:43]C)=[O:42])[N:40]=3)[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[C:3]([NH:28][C@H:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([NH:35][C:36]3[O:37][CH:38]=[C:39]([C:41]([OH:43])=[O:42])[N:40]=3)[CH2:30]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1coc(N[C@@H]2CCC[C@H](Nc3nc(-c4cn(S(=O)(=O)c5ccc(C)cc5)c5ncc(F)cc45)ncc3F)C2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1coc(N[C@@H]2CCC[C@H](Nc3nc(-c4c[nH]c5ncc(F)cc45)ncc3F)C2)n1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 2-[[(1R,3S)-3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]-amino]oxazole-4-carboxylate, 71a, (0.028 g, 0.045 mmol) in THF (1 mL) was added LiOH (1 mL of 1 M solution, 1.000 mmol) and the reaction mixture was warmed to 130° C. via microwave irradiation. After heating and stirring for 20 minutes, the mixture was cooled to room temperature. All volatiles were removed under a stream of nitrogen and heat. The crude residue was suspended in MeOH and a few drops of trifluoroacetic acid were added to protonate molecule (solution occurs). The mixture was filtered and purified by reverse phase HPLC (5-95% CH3CN/H2O) to afford 5 mg of the desired product as a TFA salt: 1H NMR (300 MHz, MeOD) δ 8.83 (s, 1H), 8.67-8.09 (m, 4H), 2.67 (s, 3H), 2.18 (m, 5H), 1.34 (d, J=29.6 Hz, 3H); LCMS RT=1.78 (M+1) 456.07.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26]Cl)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([N:17]=CN(C)C)[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4].C(C1N(CCCCCl)C2C3C=CC=CC=3N=C(N)C=2N=1)CCC.[Na+].[C:52]1([S:58]([O-:60])=[O:59])[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.Cl.O1CCOCC1.C>CO.C(OCC)(=O)C.CN(C)C=O>[CH2:1]([C:5]1[N:6]([CH2:23][CH2:24][CH2:25][CH2:26][S:58]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)(=[O:60])=[O:59])[C:7]2[C:16]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[N:17]=[C:9]([NH2:10])[C:8]=2[N:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S([O-])c1ccccc1
Reactant: CCCCc1nc2c(N=CN(C)C)nc3ccccc3c2n1CCCCCl
Agent: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCl
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCS(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A round bottom flask was charged with a magnetic stir bar, a 2:1 mixture of N′-[2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-yl]-N,N-dimethylimidoformamide and 2-butyl-1-(4-chlorobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.3 g), benzenesulfinic acid sodium salt (1.67 g, 10.11 mmol), and anhydrous dimethyl formamide (15 mL) under a nitrogen atmosphere. The resulting solution was heated to 100° C. to give a homogeneous solution that was maintained at 100° C. for 90 hours at which time the starting materials were completely consumed. The solution was cooled and then partitioned between chloroform and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a dark yellow gum. The material was dissolved in methanol (20 mL) and a 4 M solution of hydrochloric acid in dioxane (3.02 mL, 12.1 mmol). The light orange solution was stirred at ambient temperature for 12 hours at which time the reaction was judged to be complete. The volatiles were removed under reduced pressure to give a light yellow gum. The material was partitioned between chloroform and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with chloroform (1×). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford a light yellow solid. The material was purified by chromatography over silica gel (95/5 dichloromethane/methanol) to give an off-white solid. The solid (0.63 g) was dissolved in ethyl acetate (50 mL) and brought to reflux. Activated charcoal (0.6 g) was added and the resulting mixture was heated at reflux for 5 minutes. The charcoal was removed by filtration through fluted paper to provide a colorless solution. The solution was concentrated under reduced pressure to give a solid that was recrystallized from ethyl acetate and hexanes to provide 2-butyl-1-[4-(phenylsulfonyl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.37 g, 0.85 mmol) as a white fluffy solid, m.p. 179-180° C. Analysis. Calculated for C24H28N4O2S: % C, 66.03; % H, 6.46; % N, 12.83. Found % C, 65.88; % H, 6.49; % N, 12.76.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[N+:28]([O-:30])=[O:29].C(Br)(Br)[Br:32]>C(#N)C>[Br:32][C:9]1[N:13]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][C:15]=2[Cl:25])[N:12]=[C:11]([C:26]#[N:27])[C:10]=1[N+:28]([O-:30])=[O:29]
Reactant: BrC(Br)Br
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[N+](=O)[O-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1[N+](=O)[O-]
Temperature: 55 °C

Procedure:
Tertiary butyl nitrite (6.6 ml) was added at room temperature to a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitropyrazole (3.7 g), bromoform (13.3 ml) and acetonitrile (10 ml). The mixture was heated at 50-60° C. for 4.5 hours and the solvents were evaporated to give an orange oil. This was purified by medium pressure liquid chromatography (eluant hexane/ether 2:1) to give 5-bromo-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-nitropyrazole (3.4 g) as a solid, m.p. 147-150° C.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C@H:16]([O:34][P:35]([O:39][CH3:40])([O:37][CH3:38])=[O:36])[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:6][CH:5]=1.C1COCC1.O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C@H:16]([O:34][P:35]([O:37][CH3:38])([O:39][CH3:40])=[O:36])[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:33]=[CH:32][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@@H](OP(=O)(OC)OC)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COP(=O)(OC)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Temperature: 35 °C
Yield: 56.6 %

Procedure:
A mixture of lithium hydroxide (107 mg, 4.48 mmol), (R)-ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(dimethoxyphosphoryloxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 121, 500 mg, 0.9 mmol), THF (10 ml), water (2.5 ml), and MeOH (2.5 ml) was heated at 35° C. overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (10 ml) and acidified with an aqueous solution of 6 N HCl, resulting in a precipitate. The solid was collected by filtration to give the title compound (270 mg, yield: 57%). The title compound was used in the preparation of EXAMPLE 30 without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH2:17][CH:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19]>CC(C)=O>[CH3:19][C@@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:17][CH2:16][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)=CCCC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCC[C@H](C)CCOc1ccc(C#N)cc1
Yield: 91.4 %

Procedure:
A mixture of 4-cyanophenol (6.0 g, 50.0 mmol), potassium carbonate (27.6 g, 200 mmol) and citronellylbromide (13.15 g, 60.0 mmol) in acetone (200 mL) was heated under reflux for 24 hours. The solvent was evaporated and the residue was taken up with CH2Cl2 (60 mL×2) and the solution filtered. The solvent was evaporated and the resulting oil was purified by flash column chromatography over silica gel (EtOAc/hexanes 1:1) as eluant to give 4-[(3S)-3,7-dimethyl-6-octenyloxy]cyanobenzene (11.76 g, 45.7 mmol, 91.4% yield) as a white oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([NH:18][C:19]([C:21]3[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=4)=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:20])=[CH:12][CH:11]=2)[CH2:16][CH2:17][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 97.8 %

Procedure:
4 g (8 mmol) of 6-[(4'-trifiuoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and 6 ml (78 mmol) of TFA were mixed in 60 ml of methylene chloride for 5 hrs. 40 ml of methylene chloride was added and organic was extracted with 3×50 ml of saturated sodium bicarbonate and brine. Organic layer was dried over sodium sulfate and concentrated to yield 3.1 gm of solid.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([CH2:12][C:13]([OH:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:16]CN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C(Cl)Cl>CO>[CH3:16][O:14][C:13](=[O:15])[CH2:12][CH:11]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=C(O)CC1Cc2ccccc2NC1=O
Reactant: CCN=C=NCCCN(C)C
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC1Cc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
(2-Oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid (2.73 mmol), EDCI (3.27 mmol) and DIEA (3.27 mmol) are dissolved in 10 mL MeOH. About 2 mL of CH2Cl2 is also added to help dissolving the solid. The reaction mixture is stirred at room temperature for 2 hours before removal of the solvent under reduced pressure. The residue is purified by silica gel chromatography (hexane/EtOAc) to give (2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester as a white solid. Yield: 60%. 1H NMR (400 MHz, CDC13): δ 7.88 (br, 1H), 7.18 (m, 2H), 7.00 (td, 1H), 6.75 (d, 1H), 3.73 (s, 3H), 3.13-2.98 (m, 3H), 2.89 (m, 1H), 2.51 (dd, 1H). MS: (ES+): 220.2 [M+1].
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH3:12][NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:14]([N:13]([CH3:12])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: CNCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCOc1ccc(O)cc1)Cc1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
Compound 8a (0.25 g, 1.15 mmol) and N-methyl-1-phenylmethanamine (0.18 g, 1.38 mmol) were stirred in acetonitrile (12.0 mL) for 20 mins before diisopropylethylamine was added (0.40 mL, 2.30 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours and monitored by TLC. The reaction mixture was concentrated, purified by column chromatography to isolate the compound 8 as a brownish oil (0.20 g, 0.77 mmol, 67% yield). MS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.15, found: 257.98. 1H NMR (CDCl3, 400 MHz) δ 7.30-7.37 (m, 4H), 6.74-6.82 (m, 5H), 4.05 (t, J=6 Hz, 2H), 3.78 (s, 1H), 3.645 (s, 2H), 2.83 (t, J=6.0 Hz, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:20]=[C:19]([NH:21][C@@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]4[NH:28]C(OC(C)(C)C)=O)[CH:18]=[C:17]([C:36]#[N:37])[C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[N:20]=[C:19]([NH:21][C@@H:22]4[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]4[NH2:28])[CH:18]=[C:17]([C:36]#[N:37])[C:12]=3[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1ccc2cn[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc2cn[nH]c2c1

Procedure:
A solution of methyl 2-(1H-indazol-6-ylamino)-6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyanonicotinate (110 mg, 0.218 mmol) and TFA (2 mL, 26.9 mmol) in DCM (1 mL) was stirred at room temperature for 3 h. Following reaction, the mixture was concentrated in vacuo to give the title compound, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21]CC2CC2)[CH:12]=1)[OH:10].Cl.[OH-].[Na+]>O>[Cl:26][C:6]1[CH:5]=[N+:4]([O-:27])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([OH:21])[CH:12]=1)[OH:10]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(O)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (5 g, 11.90 mmol) was added to 100 mL of 37% HCl and stirred at room temperature for about 3 min., to obtain a yellow solution. After stirring for further 3 min. the solution was poured into a solution of NaOH (48 g) in water (500 mL). The red solution was added with 1 M HCl to pH 1. The brown solid was filtered, washed with water and triturated with hot EtOH (50 mL). After stirring at r.t. for 1 h the solid was filtered, washed with EtOH and dried under vacuum at 40 C yielding 2.4 of the title compound.
Reaction SMILES: [C:1]([C:3](=[CH:10][CH:11]([CH3:13])[CH3:12])[CH2:4][C:5]([O:7]CC)=[O:6])#[N:2].CO.[OH-].[K+]>O>[C:1]([C:3](=[CH:10][CH:11]([CH3:13])[CH3:12])[CH2:4][C:5]([OH:7])=[O:6])#[N:2]
Reactant: CCOC(=O)CC(C#N)=CC(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C=C(C#N)CC(=O)O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
A glass liner is charged with ethyl 3-cyano-5-methylhex-3-enoate (starting material prepared above), methanol (100 mL), and water (18 mL). Potassium hydroxide is added with stirring. A liner is placed in a 600 mL PARR hydrogenation vessel. The vessel is purged with nitrogen and then with hydrogen via charging to 60 psi and releasing the pressure on 5 cycles. The vessel is heated to 55° C. A solution of [(R,R)-MeDuPHOS]Rh(COD)+BF4− in deoxygenated methanol (18.0 mg in 20 mL) is added via syringe. The vessel is again purged with hydrogen and then pressurized to 60 psi with stirring. Periodically, hydrogen is added to maintain the pressure between 50 to 60 psi. Hydrogen uptake ceases after 5 hours. After an additional 1 hour, the mixture is cooled to room temperature, and the pressure is released. The mixture is transferred to a flask, and the solvent is removed in vacuo to give the product. A small sample is removed and converted to (S)-3-cyano-5-methylhexanoic acid by reaction with 1N hydrochloric acid. GC analysis shows 98.7% conversion to the desired cyano alkanoic salt with 96.6% e.e S isomer.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[NH:16][S:15]2(=[O:25])=[O:24])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[NH:16][S:15]2(=[O:25])=[O:24])[CH2:12][CH2:13]1
Reactant: O=S1(=O)Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=S1(=O)Nc2ccccc2CN1C1CCNCC1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
3-(1-Benzyl-piperidin-4-yl)-3,4-dihydro-1H-benzo[1,2,6]thiadiazine-2,2-dioxide (0.46 g, 1.29 mmol) in methanol (10 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 46 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 0.26 g (75%) of the desired material. 1H-NMR (CD3OD) δ 1.53–1.61 (m, 2H), 1.80 (m, 2H), 2.55 (m, 2H), 2.95–3.05 (m, 2H), 3.30 (m, 2H), 3.70 (m, 2H), 4.65 (s, 2H), 6.70 (d, J=7.9, 1H), 7.40 (dd, J=8.2, 6.7, 1H), 7.10 (m, 2H). Mass spec.: 268.10 (MH)+.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH:5]([NH:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36](Cl)[N:35]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:20][CH:19]=3)[O:15][N:14]=2)=[C:9]([F:32])[CH:8]=1)C.C(OC(=O)C(N)CC1C=CC(C2N=C([C:59]3[CH:64]=[CH:63][C:62]([NH:65][C:66](OC(C)(C)C)=O)=CC=3)ON=2)=C(F)C=1)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].ClC1N=C(Cl)C=CN=1>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-]>[C:28]([O:27][C:25]([NH:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]2[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([NH:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([N:65]5[CH2:62][CH2:63][CH2:64][CH2:59][CH2:66]5)[N:35]=4)[C:4]([OH:3])=[O:41])=[CH:8][C:9]=3[F:32])[N:17]=2)=[CH:19][CH:20]=1)=[O:26])([CH3:29])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1)Nc1ccnc(Cl)n1
Reactant: CCOC(=O)C(N)Cc1ccc(-c2noc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)c(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nc(-c3ccc(CC(Nc4ccnc(N5CCCCC5)n4)C(=O)O)cc3F)no2)cc1
Temperature: 50 °C

Procedure:
3-{4-[5-(4-tert-Butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluoro-phenyl}-2-(2-chloro-pyrimidin-4-ylamino)-propionic acid ethyl ester. To solution of 2-Amino-3-{4-[5-(4-tert-butoxycarbonylamino-phenyl)-[1,2,4]oxadiazol-3-yl]-3-fluorophenyl}propionic acid ethyl ester in DMF (20 mL) were added sodium carbonate (360 mg, 3.4 mmol), potassium iodide (10 mg), TBAB (10 mg), and 2,4-dichloro-pyrimidine (503 mg, 3.4 mmol). The mixture was heated at 50° C. for 4 hrs. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The combined organic layers were washed with brine, dried over sodium sulfate, filtrated, concentrated, and purified by chromatography to give the title compound (96 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14].O[CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[C:29]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]([F:44])([F:43])[F:42])[NH:30][C:31]3=[O:34])=[CH:26][CH:25]=2)[CH2:19]1.COCCOCCOCCO>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([O:15][CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:33]=[C:32]3[C:27]([CH:28]=[C:29]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]([F:43])([F:42])[F:44])[NH:30][C:31]3=[O:34])=[CH:26][CH:25]=2)[CH2:19]1)=[O:14].[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: COCCOCCOCCO
Agent: COCCOCCOCCOCC(=O)O
Product: COCCOCCOCCOCC(=O)OC[C@@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1

Procedure:
The title compound was synthesized by a condensation method similar to that of Step A of Example 3-1 using {2-[2-(2-methoxyethoxy)ethoxy]ethoxy}acetic acid instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14. However, {2-[2-(2-methoxyethoxy)ethoxy]ethoxy}acetic acid was synthesized by a method similar to that of Step A of Example 4-39 using triethylene glycol monomethyl ether instead of pentaethylene glycol monobenzyl ether.
Reaction SMILES: C1CCCCC1.C1(O)CCCCC1.C1(=O)CCCCC1.C1(=O)NC(=O)C2=CC=CC=C12.C1([O:38][N:39]2[C:43](=[O:44])[C:42]3=[CH:45][CH:46]=[CH:47][CH:48]=[C:41]3[C:40]2=[O:49])CCCCC1.C(O)(=O)C1C(=CC=CC=1)C(O)=O>N1C=CC=CC=1>[OH:38][N:39]1[C:40](=[O:49])[C:41]2=[CH:48][CH:47]=[CH:46][CH:45]=[C:42]2[C:43]1=[O:44]
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Agent: O=C(O)c1ccccc1C(=O)O
Agent: O=C1NC(=O)c2ccccc21
Solvent: OC1CCCCC1
Solvent: C1CCCCC1
Solvent: O=C1CCCCC1
Product: O=C1c2ccccc2C(=O)N1O
Temperature: 97 °C
Reaction time: 1 h
Yield: 260 %

Procedure:
A mixture of 1500 g (17.82 mol) of cyclohexane, 3.16 g (0.019 mol) of N-hydroxyphthalimide, and 0.045 g (0.18 mmol) of cobalt acetate was reacted at 160° C. and 40 kgf/cm2 (3.92 MPa) in atmosphere of oxygen for 2 hours to obtain a mixture containing 1334 g (15.84 mol) of cyclohexane, 83.89 g (0.84 mol) of cyclohexanol, 59.47 g (0.61 mol) of cyclohexanone, 1.77 g (0.012 mol) of phthalimide, and 1.30 g (0.005 mol) of N-cyclohexyloxyphthalimide. From the reaction mixture, cyclohexane was distilled off, 2N (2 mol/L) of sodium hydroxide aqueous solution (30 mL) was added thereto, completely mixed for 2 hours at 97° C. and stood for 1 hour to be liquid-separated into an aqueous layer and an organic layer. Phthalimide and N-cyclohexyloxyphthalimide were distributed into the aqueous layer by converting into sodium salt of phthalic acid. To the aqueous layer was added diluted hydrochloric acid to convert into phthalic acid, and phthalic acid was recovered by condensation and filtration. After hydroxylamine hydrochloride NH2OH.HCl (1.39 g, 40 mmol) was dissolved in 50 mL of pyridine, the recovered phthalic acid was added thereto, and stirred at 97° C. for 4 hours. The mixture was condensed, filtrated and washed with hexane to form N-hydroxyphthalimide (2.05 g, 0.013 mol). The regeneration ratio of N-hydroxyphthalimide (a ratio of N-hydroxyphthalimide regenerated relative to N-hydroxyphthalimide used in the reaction) was 65%.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH2:15][S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]=2[NH:8][CH:7]=1)[CH3:3].[C:24]([OH:29])(=[O:28])[C:25]([OH:27])=[O:26]>C(O)C>[CH3:1][N:2]([CH2:4][CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH2:15][S:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]=2[NH:8][CH:7]=1)[CH3:3].[C:24]([O-:29])(=[O:28])[C:25]([O-:27])=[O:26]
Reactant: O=C(O)C(=O)O
Agent: CN(C)CCc1c[nH]c2ccc(CS(=O)(=O)N3CCCC3)cc12
Solvent: CCO
Product: O=C([O-])C(=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Almotriptan crude (10 gms, purity 92.5%) is dissolved in Ethanol (60 ml) at room temperature. Reaction mass is stirred for 15 min for the complete dissolution. Oxalic Acid solution (4.0 gms in 15 ml Ethanol) is added to the above solution over 30 min at room temperature. Reaction mass temperature is raised to reflux and maintained for about 6 hrs. Slowly cooled the reaction mass to 0° C. and maintained for about 1 hr at 0±3° C. The precipitated material is filtered and washed with 15 ml of Ethanol.