Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[O:6][C:5](=S)[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].CC(C)=[O:31]>O>[CH3:1][C:2]1([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[O:6][C:5](=[O:31])[N:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15]
Reactant: CC1(c2ccc(Oc3ccccc3)cc2)OC(=S)N(Nc2ccccc2)C1=O
Reactant: CC(C)=O
Solvent: O
Product: CC1(c2ccc(Oc3ccccc3)cc2)OC(=O)N(Nc2ccccc2)C1=O
Temperature: 50 °C

Procedure:
A solution of 5-methyl-5-(4-phenoxyphenyl)-3-phenylamino-2-thioxooxazolidin-4-one (2 g, 0.0051 moles) in 50 mls of acetone (0.1M) was treated at room temperature with a solution of KHSO5OXONE®, 4.72 g, 0.0154 moles) in 20 mls of water. The white slurry was heated at 50° C. for two hours then cooled to room temperature and filtered. The residue was washed with fresh acetone and the filtrates were evaporated under reduced pressure until all the acetone distilled away. The residue was dissolved in methylene chloride and washed with water and brine. The organic layer was dried (MgSO4), filtered, and evaporated to give the crude product. Recrystallization from 1-chlorobutane and petroleum ether afforded 1.68 g (88% of theoretical) of pure product as a white solid with a melting point of 140°-142° C.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[C:9]([C:18]#[N:19])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].N(OCCC(C)C)=O>O1CCCC1>[C:18]([C:9]1[CH:8]=[C:7]([N:6]2[CH:2]=[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:4]=[N:5]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH:15]([CH3:17])[CH3:16])#[N:19]
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)C)c(C#N)c2)c1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(OCC(C)C)c(C#N)c2)c1
Yield: 88.2 %

Procedure:
Then, to a solution (16 ml) of ethyl 5-amino-1-(3-cyano-4-isobutoxyphenyl)pyrazole-4-carboxylate (1.64 g) obtained in Example 1 in tetrahydrofuran was added isoamyl nitrite (1.75 g) with stirring, and the mixture was refluxed under heating for 1.5 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure and the obtained residue was recrystallized from ethyl alcohol to give 1.38 g of ethyl 1-(3-cyano-4-isobutoxyphenyl)pyrazole-4-carboxylate, melting point 138-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:24]([NH2:27])([CH3:26])[CH3:25].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:18])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)NC(C)C)c2)=C(C)C1=O
Yield: 37 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (85 mg, 0.27 mmol) obtained in Example 41, isopropylamine (0.035 ml, 0.41 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (78 mg, 0.41 mmol) in dry methylene chloride (3.4 ml) were stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and then was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound (37 mg, 0.10 mmol, yield 37%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH:34]=2)=[CH:29][CH:28]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g), triethylamine (4.2 cc) and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (5.7 g) in toluene (80 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. Stirring is continued for 8 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (50 cc), 2-{3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-l-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.9 g) is obtained, m.p. 111° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][N:9]2C(OC)=O)=[CH:4][CH:3]=1.Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C@H:8]2[CH2:13][C@H:12]([C:14]3[O:18][NH:17][C:16](=[O:19])[CH:15]=3)[CH2:11][CH2:10][NH:9]2)=[CH:24][CH:25]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CCc1ccc(F)cc1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](CCc3ccc(F)cc3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
Trans-methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (137 mg, 0.39 mmol) dissolved in hydrogen bromide (33% in acetic acid, 3.1 mL, 17.70 mmol) to give a yellow solution. The mixture was stirred at room temperature for 16 h, the solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(4-fluorophenethyl)piperidin-4-yl)isoxazol-3(2H)-one (80 mg, 70%). 1H NMR (400 MHz, dmso) δ 1.42-1.78 (m, 5H), 1.82-1.95 (m, 1H), 2.52-2.68 (m, 4H), 2.74-2.84 (m, 1H), 3.05-3.13 (m, 1H), 5.73 (s, 1H), 7.01-7.10 (m, 2H), 7.15-7.25 (m, 2H). HRMS Calculated for [C16H19FN2O2+H]+: 291.1509. Found: 291.1522
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:30])([CH3:29])[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:14](=[O:31])[C:13]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)C>O.CO>[OH:10][CH2:11][C:12]1[O:17][CH2:16][N:15]([C:18]([CH3:30])([CH3:29])[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:14](=[O:31])[C:13]=1[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)OCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)OCc2ccccc2)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C(=O)OCc1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
A solution of potassium carbonate (0.96 g) in water was added in portions to a stirred solution of benzyl 2-(6-acetoxymethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (2.70 g) in methanol at 0° C. The mixture was stirred at ambient temperature for 1 hour and the solvent was evaporated under reduced pressure. The residue was acidified with 2 M hydrochloric acid, extracted with diethyl ether, the extract was dried (magnesium sulphate) and the solvent evaporated under reduced pressure to give benzyl 2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (2.51 g) as a yellow gum, NMR (CDCl3) 1.6(s,6H), 4.15(s,2H), 5.1(s,2H), 5.3(s,2H), 7.26-7.42(m,10H).
Reaction SMILES: [S:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[O-:12]I(=O)(=O)=O.[Na+]>O.[Cl-].[Na+].O>[S:1]([CH2:2][C:3]([O:5][CH3:6])=[O:4])([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:12]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)CSCC(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CS(=O)CC(=O)OC
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To the mixture of dimethyl 2,2′-thiodiacetate (4.54 g, 25.5 mmol, 1 eq) in water (50 mL) at 0° C. was added sodium (meta)periodate (5.786 g, 1.05 eq) and the resulting reaction mixture was stirred overnight. The mixture was then diluted with brine and extracted with CHCl3 (5×). All organics were combined and dried with anhydrous sodium sulfate. The solution was decanted, concentrated under reduced pressure, and the clear oily residue was subject to column chromatography (EtOAc-Hex 1:5 to 1:1) giving dimethyl 2,2′-sulfinyldiacetate as a clear oil (4.522 g).
Reaction SMILES: Cl[C:2]1C=CC=C(C(OO)=O)C=1.[Cl:12][CH:13]1[CH:25]=[C:17]2[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:15]([C:16]=32)[C:14]1([C:28]1[N:33]=[C:32]([S:34](=O)(=[O:37])NC)[N:31]=[C:30]([NH2:39])[N:29]=1)[C:26]#[N:27]>C(Cl)Cl>[Cl:12][CH:13]1[CH:25]=[C:17]2[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:15]([C:16]=32)[C:14]1([C:28]1[N:33]=[C:32]([S:34]([CH3:2])=[O:37])[N:31]=[C:30]([NH2:39])[N:29]=1)[C:26]#[N:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNS(=O)(=O)c1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Solvent: ClCCl
Product: CS(=O)c1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
m-Chloroperbenzoic acid (7.10 g, 31.9 mmol) was added to a solution of 4-(5-chloro-6-cyano-1H,3H benzo[de]isochromen-6-yl)-6-methylsulfamyl-[1,3,5]triazin-2-ylamine (10.0 g, 29.0 mmol) in methylene chloride (100 mL) at room temperature. After the reaction solution was stirred at room temperature for 15 hours, the precipitate was collected by filtration. The resulting precipitate was suspended in methylene chloride, and stirred at room temperature for 3 hours. The insoluble material was collected by filtration, washed with methylene chloride, and dried under reduced pressure. The title compound was obtained as light brown solid (8.34 g, 79%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:32]=3[CH:33]=[CH:34][NH:35]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Nc1cccc2[nH]ccc12
Product: CCOC(=O)c1cnn2c(Nc3cccc4[nH]ccc34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 98.3 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.20 g, 0.48 mmol) obtained in Example 19, step 4 and 4-aminoindole (0.128 g, 0.97 mmol), the title compound (0.240 g, 98%) was obtained.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@@H:2]([C:11](O)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C(OCC)(=O)C.CO>[CH:20]1[C:19]2[CH:18]([CH2:17][O:16][C:14]([NH:1][C@@H:2]([CH2:11][OH:12])[CH2:3][C:4]([O:5][C:6]([CH3:7])([CH3:9])[CH3:8])=[O:10])=[O:15])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C

Procedure:
A solution of Fmoc-D-Asp(OtBu)-OH (9.0 g, 21.8 mmol) and N,N-diisopropylethylamine (4.6 mL) in TBF (100 mL) at −40° C. was treated with isobutyl chloroformate (3.1 mL, 24.1 mmol), warmed to 0° C. over 30 minutes, cooled to −20° C., and treated slowly with sodium borohydride (1.64 g, 43.6 mmol) and methanol (10 mL). The reaction was gradually warmed to room temperature over 2 hours, diluted with ethyl acetate (200 mL), washed with water (100 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+))m/e 398 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>>[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([N:2]([CH3:1])[CH3:21])=[O:20])=[CH:9][CH:8]=1)[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1)([CH3:23])[CH3:24]
Reactant: CCc1ccc(NCc2ccc(C(=O)N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCc1ccc(N(Cc2ccc(C(=O)N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 1 using N,N-dimethyl-4-[(4-ethylphenyl)aminomethyl]benzamide (0.6 g) and 2,6-diisopropylphenyl isocyanate (0.46 mL) as starting materials, 4-[3-(2,6-diisopropylphenyl)-1-(4-ethylphenyl)ureidomethyl]-N,N-dimethylbenzamide (0.34 g) was obtained. melting point: 170–172° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[C@:4](C1C=CC(C2C=CC=CC=2)=CC=1)([NH:6][C:7]([C:9]1[CH:14]=[N:13][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)=[CH:11][N:10]=1)=[O:8])[CH3:5].[Li+].[OH-].[CH2:43]1[CH2:47]O[CH2:45][CH2:44]1.CO>O>[C:43]1([C:47]2[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:4][C:3]([CH2:5][C@H:4]([NH:6][C:7]([C:9]2[CH:14]=[N:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:26])([F:27])[F:25])[CH:18]=3)=[CH:11][N:10]=2)=[O:8])[C:3]([OH:2])=[O:40])=[CH:45][CH:44]=1
Reactant: C1CCOC1
Reactant: COC(=O)[C@@](C)(NC(=O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1)c1ccc(-c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1cnc(COc2cccc(OC(F)(F)F)c2)cn1

Procedure:
A solution of biphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionic acid methyl ester (0.170 g, 0.308 mmol) in THF:MeOH (4:1, 5 mL) was treated with LiOH (0.064 g, 1.54 mmol) in 1.5 mL of water by the general procedure C to give 0.140 g of pure 3-biphenyl-4-yl-2(S)-{[5-(3-trifluoromethoxy-phenoxymethyl)-pyrazine-2-carbonyl]-amino}-propionic acid as a white solid. LCMS: 539 (M+2)+
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].[ClH:10].[CH2:11](OC(OCC)C)[CH3:12]>C(O)C(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[ClH:10].[NH2:8][C:7]1[NH:6][C:4]([N:2]([CH3:3])[CH3:1])=[N:5][CH:11]([CH3:12])[N:9]=1
Reactant: CN(C)C(=N)N=C(N)N
Reactant: CCOC(C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)CO
Solvent: O
Product: CC1N=C(N)NC(N(C)C)=N1
Temperature: 10 °C
Yield: 77.6 %

Procedure:
Comparative experiment: A mixture of 250.2 g of metformin hydrochloride, 213.6 g of acetaldehyde diethyl acetal and 12.5 g of toluene-4-sulfonic acid monohydrate in 500 ml of isobutanol was heated under reflux for 40 hours. Some of the solvent was removed by distillation. The mixture was cooled to 10° C., and the white precipitate was separated off, giving 224.7 g (77.4%) of 4-amino-3,6-dihydro-2-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12](F)=[O:13])[C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[OH:28][CH:29]([C:43]1[CH:48]=[CH:47][C:46](/[C:49](=[N:51]/O)/[NH2:50])=[CH:45][CH:44]=1)[CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:32]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C(#N)C.C(OCC)(=O)C>[OH:28][CH:29]([C:43]1[CH:48]=[CH:47][C:46]([C:49]2[N:51]=[C:12]([C:9]3[C:8]([C:15]([F:18])([F:17])[F:16])=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:11][N:10]=3)[O:13][N:50]=2)=[CH:45][CH:44]=1)[CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:32]1
Reactant: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(F)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4noc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Phenyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride, Int-II-D (150 mg, 0.58 mmol) was dissolved in acetonitrile (10 mL) and DIEA (0.185 mL, 1.061 mmol) and ethyl 2-((3R)-1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (185 mg, 0.530 mmol) were added. After one hr, TBAF in THF (0.530 mL, 0.530 mmol) was added and the reaction mixture was stirred overnight at room temperature. LCMS shows two new peaks. One is the desired mass and the other has a much higher mass which corresponds to double addition of acid fluoride. The reaction mixture was diluted with ethyl acetate and washed with saturated NaCl. The organic layer was dried with MgSO4, filtered, and concentrated. Solids were purified by a silica gel cartridge using an EtOAc/hexanes gradient to yield 72 mgs of ethyl 2-((3R)-1-(2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetate. MS (m+1)=571. HPLC Peak RT=3.39 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([CH3:29])[C:20]=1[O:21][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:16]=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[C:16]([C:15]1[CH:14]=[C:13]([CH3:12])[C:20]([O:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:19]([CH3:29])[CH:18]=1)[NH:6][C:4]2=[O:5]
Reactant: NC(=O)c1cccc(Cl)c1N
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3c(Cl)cccc3c(=O)[nH]2)cc(C)c1OCCN1CCCC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-3-chloro-benzamide (0.85 g, 5.00 mmol) and 3,5-dimethyl-4-(2-pyrrolidin-1-yl-ethoxy)-benzaldehyde (1.23 g, 5.00 mmol) in N,N-dimethylacetamide (20 mL) were added sodium hydrogen sulfite (58.5 wt %, 1.37 g, 7.50 mmol) and p-toluenesulfonic acid monohydrate (3.80 g, 20.0 mmol). The reaction mixture was stirred at 140° C. for 16 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure. Water (100 mL) was added, and the mixture was neutralized, to pH approximately 8 with 2 N aqueous NaOH solution. The separated solid was filtered, washed with water (50 mL), and dried under vacuum. Crude compound was purified by the Simpliflash system (0-5% methanol in CH2Cl2 and then 5% 7.0 M ammonia in methanol and CH2Cl2 as eluent) to give the title compound as a brown solid. Yield: 0.49 g (25%). MP 216-217° C. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J=7.81 Hz, 1H), 8.01-7.87 (m, 3H), 7.43 (t, J=7.81 Hz, 1H), 3.89 (t, J=5.85 Hz, 2H), 2.81 (t, J=5.85 Hz, 2H), 2.53 (br s, 4H), 2.30 (s, 6H), 1.75-1.60 (m, 4H). MS (ES+) m/z 398.11 (100%), 400.13 (40%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([CH:16]=[O:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([CH2:29][N+:30]#[C-:31])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[O:17][CH:31]=[N:30][CH:29]=2)=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(C=O)sc1C(=O)NCc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nc(-c2cnco2)sc1C(=O)NCc1ccccc1
Reaction time: 50 h
Yield: 63 %

Procedure:
To a solution of N-benzyl-2-formyl-4-methylthiazole-5-carboxamide (1.09 g, 4.17 mmol) in methanol (60 mL) was added tosylmethyl isocyanide (1.15 g, 5.88 mmol) and potassium carbonate (1.47 g, 10.69 mmol). The reaction mixture was stirred for 50 hours and concentrated in vacuo. The residue was diluted with chloroform and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound in 63% yield (1.00 g): 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 1H), 7.70 (s, 1H), 7.42-7.26 (m, 5H), 6.06 (t, J=5.6 Hz, 1H), 4.61 (d, J=5.6 Hz, 2H), 2.72 (s, 3H); MS (ES+) m/z 300.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].C(N(CC)CC)C.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:20])[CH:18]=[CH2:19])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 3,4-dichloroaniline (3.6 g, 22.3 mmol) and 4.2 mL (30.2 mmol) of triethylamine in 20 mL of anhydrous methylene chloride was cooled to 0° C. under a nitrogen atmosphere and treated with acryloyl chloride (2.1 g, 23.2 mmol). The ice bath was removed and the mixture was stirred at room temperature for 1 hour after which time it was diluted with 120 mL of methylene chloride and washed with water and saturated aqueous sodium chloride (NaCl). After drying with calcium sulfate (CaSO4), the solvent was removed in vacuo to give a yellow solid, 4.84 g.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]3[O:20][C:21]([C:24]4[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=4)=[CH:22][N:23]=3)=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[S:37]1[CH2:38][CH2:39][N:34]([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([C:19]4[O:20][C:21]([C:24]5[N:29]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:26][CH:25]=5)=[CH:22][N:23]=4)=[O:18])=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)[CH2:35][CH2:36]1
Reactant: C1CSCCN1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(C=O)cc4)cc3)o2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCSCC5)cc4)cc3)o2)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60.5 %

Procedure:
Methyl 6-(2-(3-(4′-formylbiphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (124 mg, 0.282 mmol) and thiomorpholine (0.040 mL, 0.42 mmol) were dissolved in dichloroethane (12 mL) and NaBH(OAc)3 (179 mg, 0.845 mmol) was added. The reaction solution was stirred under an atmosphere of Ar at ambient temperature for 3.5 h and then quenched with saturated aqueous NaHCO3. The crude product was extracted with EtOAc and the solvent was removed in vacuo. The crude product was purified by flash chromatography (SiO2, 50-90% EtOAc/hexanes) to furnish methyl 6-(2-(3-(4′-(thiomorpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate as a pale tan solid (90 mg, 61%): 1H NMR (CDCl3, 600 MHz) δ 8.12 (d, 1H, J=7.7 Hz), 8.04-8.02 (m, 2H), 7.97 (t, 1H, J=7.8 Hz), 7.52 (dd, 4H, J=8.2, 1.8 Hz), 7.35 (t, 4H, J=8.6 Hz), 4.03 (s, 3H), 3.55 (s, 2H), 3.51 (t, 2H, J=7.6 Hz), 3.16 (t, 2H, J=7.6 Hz), 2.74-2.73 (m, 4H), 2.70-2.68 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 165.1, 157.4, 152.4, 148.5, 146.5, 139.7, 139.3, 139.0, 138.3, 137.0, 129.4, 128.9, 128.0, 127.1, 126.8, 125.2, 123.3, 63.3, 54.9, 53.0, 40.6, 29.3, 28.0; HR ESI-TOF m/z 528.1950 (M+H+, C30H29N3O4S, requires 528.1951).