Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:4][CH:3]=1.Cl[C:37](Cl)([O:39][C:40](=[O:46])OC(Cl)(Cl)Cl)Cl.[N:48]1[CH:53]=[CH:52][C:51](CO)=[CH:50][CH:49]=1.C(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C>[O:8]=[C:7]1[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH:27]([CH3:29])[CH3:28])[CH:14]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:21])[CH3:22])[C:15]([F:18])([F:17])[F:16])=[O:11])[C:5]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:4][CH:3]=[C:2]1[NH:1][C:40]([O:39][CH2:37][C:51]1[CH:52]=[CH:53][N:48]=[CH:49][CH:50]=1)=[O:46]
Reactant: OCc1ccncc1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccncc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (1.1 g) and triphosgene (0.93 g) in dichloromethane at 0° C. was added triethylamine (2.0 mL) and the resulting solution was allowed to stir for 0.5 h. To this solution was added 4-pyridylcarbinol and the resulting solution allowed to stir overnight. The solution was poured into saturated aqueous sodium bicarbonate solution and the product was extracted into dichloromethane. The organic solution was washed (saturated aqueous sodium bicarbonate, water), dried, and evaporated. The resulting oil was purified by chromatography, with methanol:dichloromethane (5:95) as the eluent, to provide 2-[6-oxo-2-phenyl-5-(4-pyridylmethoxycarbonylamino)-1,6-dihydro-1-pyrimidinyl]-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide as a white solid (0.9 g); TLC: Rf =0.4, methanol:dichloromethane (5:95).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[C:25]([O:30]C(=O)CCC)(=[O:29])[CH2:26][CH2:27][CH3:28]>O>[C:25]([OH:30])(=[O:29])[CH2:26][CH2:27][CH3:28].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: CCCC(=O)OC(=O)CCC
Agent: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Solvent: O
Product: CCCC(=O)O

Procedure:
In a manner similar to Example 12, a mixture of 8-chloro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and butyric anhydride was heated on the water bath to give 8-chloro-1-hydroxymethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine butyrate (ester).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[O:10]=[CH:11][C:12](Cl)(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+].Cl.[NH2:24][OH:25]>O.Cl.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11](=[O:10])[CH:12]=[N:24][OH:25])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(C=NO)Nc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Yield: 89 %

Procedure:
A mixture of 3,5-dichloroaniline (10.0 g, 61.7 mmol) in H2O(50 mL), concentrated HCl(12 mL) and 1,4-dioxane (20 mL) was heated to be clear solution, and then added to a mixture of chloral hydrated (10.5 g, 66.9 mmol) and Na2SO4 (66.0 g) in H2O (224 mL) which has been warmed to 50° C. To the above mixture was added hydroxylamine hydrochloride (13.0 g, 180 mmol) in H2O (60 mL), and the mixture was refluxed for 50 mins. After cooling down to room temperature, the insoluble solids was filtered, was washed with excess H2O, and dried in vacuo to provide 12.8 g (89%) of the title compound as a pale yellow solid:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[C:24](N1C=CN=C1)([N:26]1C=CN=[CH:27]1)=O.CNC>O1CCCC1>[CH3:24][N:26]([CH3:27])[C:19](=[O:21])[CH2:18][N:17]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:22])([F:23])[F:1])=[CH:8][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
A suspension of 2-(4-trifluoromethylphenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (10.0 g, 0.031 mole), 1,1'-carbonyldiimidazole (6.0 g, 0.037 mole), and dry tetrahydrofuran (200 ml) was stirred at room temperature for 2 hr. with a stream of nitrogen bubbling through it. The suspension was heated at 50° C. under nitrogen for 2 hr, cooled in ice and treated with a solution of dimethylamine in tetrahydrofuran (4.22 g of dimethylamine in 40 ml of tetrahydrofuran.) The solution was stirred at room temperature overnight, more dimethylamine (0.071 mole in 30 ml of tetrahydrofuran) was added, and the reaction mixture was heated at 45° C. for 3 hr. The reaction mixture was concentrated under reduced pressure; the resulting solid was triturated in water, filtered, rinsed twice with water, twice with 5% potassium hydroxide solution and then twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, and cooled. Water was added and the solid filtered and dried at 80° C. under vacuum to yield 3.55 g (33%) of white solid, mp. 181°-183° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH2:19][CH:18]([CH3:21])[CH2:17][C:16](=[O:22])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:23]([O:25][CH3:26])=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[C:18]([CH3:21])[CH:17]=[C:16]([OH:22])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:23]([O:25][CH3:26])=[O:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CC(C)CC1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1c1c(O)cc(C)cc1n2Cc1ccccc1
Yield: 20.9 %

Procedure:
A solution of the 9-[(phenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one (1.30 g, 3.74 mM) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.93 g, 4.12 mM) in 37 mL of toluene was stirred between 80-90° C. for 5 hours. The mixture was purified by column chromatography on silica gel (elution with methylene chloride) to afford 270 mg (21%) of the 9-[(phenyl)methyl]-2-methyl-4-hydroxy-5-carbomethoxy carbazole. 1H NMR (CDCl3) δ10.45 (s, 1H), 8.0 (d, J=8 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 7.4 (dd, J=8 and 8 Hz, 1H), 7.3 (m, 3H), 7.05 (m, 2H), 6.65 (s, 1H), 6.6 (s, 1H), 5.5 (s, 2H), 4.1 (s, 3H), 2.45 (s, 3H). MS (ES) m/e 314, 346.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[N:3]=[N:2]1.Cl.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C.CCOC(C)=O>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][C:9]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)=[O:21])[CH2:18][CH2:19]2)=[O:11])[N:3]=[N:2]1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: O=C(O)CCCc1c[nH]nn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
4-(1H-1,2,3-Triazol-4-yl)butanoic acid (step 4) (882 mg, 4.95 mmol) and 3,5-dichlorobenzyl 4-aminopiperidine-1-carboxylate hydrochloride (step 2) (1.5 g, 4.95 mmol) were suspended in DMF (20 ml). DIPEA (4.32 ml, 24.74 mmol) was added and the reaction mixture stirred until all components were in solution. 50% T3P® solution in DMF (5.78 ml, 9.89 mmol) was added and the reaction mixture was stirred at RT for 48 hrs. The reaction mixture was diluted with EtOAc and washed twice with 10% citric acid. The aqueous citric acid wash was extracted with DCM (3×) and the combined extracted were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography, using a gradient solvent system of 0-10% MeOH in EtOAc. The resulting product was further purified by stirring in diethyl ether over 72 hours. The mixture was filtered and the solid was dried in a vacuum oven to afford the title compound;
Reaction SMILES: [C:1]1([CH2:11][C:12](O)=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([NH:32][CH2:33][CH2:34][NH2:35])[CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH2:27]([NH:32][CH2:33][CH2:34][NH:35][C:12](=[S:13])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: OC(=S)Cc1cccc2ccccc12
Reactant: CCCCCNCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCNCCNC(=S)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
In 10 ml of anhydrous tetrahydrofuran was dissolved 1.5 g of 1-naphthylthioacetic acid and 1.16 g of carbonyldiimidazole was added to the solution followed by stirring at room temperature for 0.5 hours. After 1.08 g of N-pentylethylenediamine was added to the reaction solution, the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure followed by extraction with water and ethyl ether. After the organic layer was taken by fractionation, the organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 300 g, methylene chloride/methanol=50/1→10/1) to give 1.06 g (yield: 46%) of the title compound as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[NH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29]([NH:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:35])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCC1
Reactant: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(Oc2ncnc3cc(OC)c(OC)cc23)ccc1NC(=O)NN1CCCCC1
Yield: 65 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-methoxyaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (45 mg, yield 65%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:45][C:46]1[CH:47]=[N:48][C:49]2[C:54]([CH:55]=1)=[CH:53][C:52]([CH2:56]O)=[CH:51][CH:50]=2>C1COCC1.CCOC(C)=O>[Br:45][C:46]1[CH:47]=[N:48][C:49]2[C:54]([CH:55]=1)=[CH:53][C:52]([CH2:56][N:5]1[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]1=[O:6])=[CH:51][CH:50]=2
Reactant: OCc1ccc2ncc(Br)cc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2ncc(Br)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phthalimide (281 mg, 1.9 mmol), triphenyl phosphine (500 mg, 1.9 mmol) in 10 mL of THF was added DIAD (386 mg, 1.9 mmol) dropwise at 0° C. and the mixture was stirred at this temperature for 10 min. (3-Bromo-quinolin-6-yl)-methanol (413 mg, 1.7 mmol) was added to the above solution in one portion and the resulting solution was stirred at rt for 30 min, then heated at 40° C. for 5 h. After cooling, the reaction mixture was taken up with EtOAc, washed with water, extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane gradient to afford the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 8.89 (d, 1H), 8.31 (d, 1H), 8.06 (d, 1H), 7.90-7.86 (m, 3H), 7.82-7.73 (m, 3H), 5.04 (s, 2H). LCMS (method A): [MH]+=368/370, tR=5.54 min.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[NH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[NH2:38])[CH2:31][CH2:30][CH2:29]1>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:38][C:36]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:37]=2[NH:28][CH2:29][CH2:30][CH2:31]3)=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: Nc1cccc2c1NCCC2
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c1NCCC2)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 1,2,3,4-tetrahydro-quinolin-8-ylamine (commercially available; CAS RN 54012-92-9) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (88%). MS (ESI): m/z=414.077 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1>CN(C)C=O>[C:3]([N:11]([CH2:13][CH2:14][O:15][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)[CH3:12])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(CCO)C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(C=O)cc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in oil, 1.30 g) was added portionwise to a solution of 2-(N-benzoyl-N-methylamino)ethanol (5.0 g) in dry dimethylformamide (100 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour prior to the addition of 4-fluorobenzaldehyde (5.09 g, 4.4 ml), and the mixture then heated at 80° C. for 15 hours. The solvent was evaporated and the residue dissolved in water (500 ml) and extracted with ethyl acetate (3×500 ml). The combined ethyl acetate layers were washed with water (2×300 ml), brine (300 ml), dried (MgSO4) and evaporated to yield an oil. The oil was triturated with hexane, and the residue chromatographed on silica gel with 1.5% methanol in dichloromethane to afford the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[S:33]1[CH:37]=[N:36][N:35]=[C:34]1[NH2:38].C(N(C(C)C)CC)(C)C>CC#N>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]([CH3:14])([CH3:13])[C:10]([NH:38][C:34]2[S:33][CH:37]=[N:36][N:35]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1nncs1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1nncs1)C(c1ccccc1)c1ccc(Cl)nc1
Yield: 79.3 %

Procedure:
A solution of 3-(6-chloro-pyridin-3-yl)-2,2-dimethyl-3-phenyl-propionic acid (Preparation 4, 100 mg, 0.345 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (132 mg, 0.69 mmol) and 1-hydroxy-7-benzotriazole (HOBt) (93 mg, 0.69 mmol), 1,3,4-thiadiazol-2-amine (103 mg, 1.04 mmol) and diisopropylethyl amine (0.21 ml, 1.21 mmol) in CH3CN (1 mL) was heated at 75° C. for 12 hours. The reaction mixture was filtered, concentrated and purified by silica gel flash chromatography using 50% ethyl acetate in hexanes to give 3-(6-chloro-pyridin-3-yl)-2,2-dimethyl-3-phenyl-N-[1,3,4]thiadiazol-2-yl-propionamide as a white solid. (102 mg, 79.3% yield).). 1H NMR (400 MHz, CDCl3): δ 1.31 (s, 3H), 1.32 (s, 3H), 4.57 (s, 1H), 7.15 (m, 1H), 7.20 (m, 2H), 7.28 (m, 3H), 7.85 (m, 1H), 8.26 (br s, 1H), 8.90 (s, 1H). LC/MS (m/z) 373.19 [(M+H)+]; HPLC Rt: 2.913 min.
Reaction SMILES: [I-].[Na+].[H-].[Na+].[CH2:5]([O:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27]>CN(C=O)C>[C:17]([O:16][C:14]([N:13]([CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[O:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: N#CCCCCCl
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCCCC#N)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
N-(tert-Butoxycarbonyl)-N-(4-cyanobutyl)-O-benzylhydroxylamine (4) was synthesized by adding sodium iodide (84 mg, 0.56 mmol) and then sodium hydride (80% oil dispersion, 0.49 g, 16.3 mmol) to O-benzyl-N-tert-butoxycarbonyl hydroxylamine (2.68 g, 12.0 mmol) in dry DMF (40 ml). After stirring for 15 minutes, 5-chlorovaleronitrile (1.5 mL, 13.3 mmol) was added and the suspension heated at 80°-85° C. for 4 hours under argon. After cooling, the reaction was quenched with H2O (100 mL), then extracted with ether (4×75 mL). The combined organic layers were washed with 100 mL each of 1% aqueous Na2SO3, H2O and brine and then concentrated to give 4.39 g crude product. Column chromatography with 4.5% EtOAc/CHCl3 produced 3.17 g of O-benzyl-N-(tert-butoxycarbonyl)-N-(4-cyanobutyl)hydroxylamine (4) (87% yield): NMR δ 1.5-1.75 (s+m, 13 H), 2.3 (t, 2 H), 3.4 (t, 2 H), 4.77 (s, 2 H), 7.3 (s, 5 H). Anal. calcd. for C17H24N2O3 : C, 67.08; H, 7.95; N, 9.20. Found: C, 67.19; H, 7.99; N, 9.11.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[CH2:14]([C:16]1[C:25]2[O:24][CH2:23][O:22][CH2:21][C:20]=2[CH:19]=[C:18]([CH:26]=O)[CH:17]=1)[CH3:15].C[Si]([C:32]#[N:33])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl>[CH2:14]([C:16]1[C:25]2[O:24][CH2:23][O:22][CH2:21][C:20]=2[CH:19]=[C:18]([CH:26]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)=[CH:8][CH:9]=2)[C:32]#[N:33])[CH:17]=1)[CH3:15]
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Reactant: CCc1cc(C=O)cc2c1OCOC2
Reactant: C[Si](C)(C)C#N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: CCc1cc(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)cc2c1OCOC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
After adding 794 mg of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 871 mg of 8-ethyl-4H-benzo[1,3]dioxine-6-carbaldehyde, 1 g of MS3A and 1 ml of trimethylsilyl cyanide to a solution of 281 mg of Yb(OTf)3 in 20 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 days. The reaction mixture was filtered through celite, and the celite was washed with 100 ml of ethyl acetate. The organic layer was concentrated under reduced pressure to give (8-ethyl-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]acetonitrile (crude product) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[NH:7][C:8](=[O:10])[CH3:9].CN(C)[C:16]1[O:17][C:18](=[O:26])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=1>C(O)(=O)C.O>[Cl:12][C:5]1[CH:4]=[C:3]([F:13])[C:2]([N:1]2[C:18](=[O:26])[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[NH:21][C:16]2=[O:17])=[CH:11][C:6]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: CC(=O)Nc1cc(N)c(F)cc1Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Yield: 78.1 %

Procedure:
A mixture of 5′ -amino-2′-chloro-4′-fluoroacetanilide (1.0 g, 4.9 mmol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (1.0 g, 4.9 mmol) in acetic acid is refluxed for 90 minutes and diluted with water. The resultant aqueous mixture is filtered to obtain the title product as an off-white solid (1.4 g, mp 264-266° C.) which is identified by 1H, 13C and 9F NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([N:18]4[CH:22]=[CH:21][N:20]=[CH:19]4)[CH:15]=[C:16]([CH3:17])[C:10]=3[N:9]=2)=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH2:24][C@@H:25]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][OH:27].C(N(CC)CC)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:24][C@@H:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:26][OH:27])[C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:15]=[C:16]([CH3:17])[C:10]=2[N:9]=1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3Cl)nc12
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(Cl)ncnc3N[C@H](CO)Cc3ccccc3)nc12
Temperature: 80 °C

Procedure:
To a solution of 2-(4,6-dichloro-pyrimidin-5-yl)-6-imidazol-1-yl-4-methyl-1H-benzimidazole (40 mg, 0.16 mmol) in isopropanol (5 mL) was added (S)-(−)-2-amino-3-phenyl-propanol (35 mg, 0.23 mmol) and triethylamine (0.5 mL). The reaction mixture was heated to 80° C. for 4 h, cooled to room temperature and concentrated with high vacuum. The crude product was used for the next step without purification. LCMS (M+H)+ m/z 460 (t=2.13 min.).