Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=O.[NH3:7]>[Ni].[H][H]>[CH3:1][CH:2]([CH3:6])[CH2:3][CH:4]=[N:7][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1]
Reactant: CC(C)CC=O
Reactant: N
Reactant: [H][H]
Agent: [Ni]
Product: CC(C)CC=NCCC(C)C

Procedure:
1000 g 3-methylbutanal are reacted in the presence of 100 g of a commercially available nickel containing carrier catalyst (containing about 52 to 53% by weight nickel and employing chromium (3)-oxide as activator) at 110° C with a mixture of ammonia and hydrogen (volume ratio 1:1) in a flask equipped as described in Example 1. The velocity of the gases is 160 l/h. Altogether, 240 l ammonia and 240 l hydrogen are introduced into the catalyst suspension over a reaction time of 3 hours. After termination of the reaction the catalyst is separated by filtration. 868 g 3-methylbutylidene-3-methylbutylamine are obtained.
Reaction SMILES: [C-]#N.[Na+].C1(C)C=CC=CC=1.C[NH:12][CH2:13][CH2:14]NC.BrC1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1>N>[CH3:25][C:20]1[CH:19]=[C:14]([CH:23]=[C:22]([CH3:24])[CH:21]=1)[C:13]#[N:12]
Reactant: Cc1cc(C)cc(Br)c1
Reactant: CNCCNC
Agent: N
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C#N)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
An oven dried 100 mL three necked round bottom flask was charged, under positive pressure of argon, with NaCN (2.04 g, 41.6 mmol) CuI (660 mg, 3.47 mmol, 10 mol %), KI (1.14 g, 6.87 mmol, 20 mol %), and anhydrous toluene (25 mL). N,N′-Dimethylethylenediamine (3.7 μL, 35 mmol) and 5-bromo-m-xylene (4.7 mL, 35 mmol) were added dropwise under mechanical stirring. The reaction mixture was stirred at 110° C. for 24 h. The resulting suspension was allowed to reach room temperature, diluted with 30% aq ammonia (20 mL) and extracted with toluene (2×10 mL). The combined organic phases were dried over MgSO4, concentrated, and the residue was purified by distillation under reduced pressure (bp 100° C. @ 10 Torr) to provide the desired product as a white crystalline solid (4.08 g, 90% yield). Mp 42-43° C. (lit. 42.9° C., See Birch, S. F.; Dean, R. A.; Fidler, F. A.; Lowry, R. A. J. Am. Chem. Soc. 1949, 71, 1362). 1H NMR (400 MHz, CDCl3; lit. See Nomura, Y.; Takeuchi, Y. Tetrahedron 1969, 25, 3825): δ 7.27 (s, 2H), 7.23 (s, 1H), 2.36 (s, 6H); 13C NMR (100 MHz, CDCl3): 139.4, 135.0, 130.1, 119.7, 112.4, 21.5; IR (neat, cm−1): 2230, 1605, 1378, 907, 854, 682. Anal. Calcd. for C9H9N: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.1 1; H, 6.88; N, 10.52.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Si](C=[N+]=[N-])(C)(C)[CH3:16].C(O)(=O)C>C(Cl)Cl.CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([O:14][CH3:16])=[O:13])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.25 h

Procedure:
Combined 2-(4-(methylsulfonyl)phenyl)acetic acid (1 g, 4.67 mmol) in DCM (15 mL) and MeOH (5 mL) and slowly added TMS-diazomethane (2 M in hexanes) (3.50 mL, 7.00 mmol) and the solution was stirred at 20° C. for 3 h. The reaction was quenched with acetic acid (0.134 mL, 2.334 mmol), let stir for 15 min, then concentrated in vacuo to give the title compound which was used without further purification. MS m/z 229 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[NH:1]1[C:9]2=[N:8][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([C:14](=[O:16])[CH3:15])=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.6 %

Procedure:
(Ref.: J. Org. Chem. 2002, 67, 6226-6227) 7-Azaindole (5 g, 42.3 mmol) is added to a stirred suspension of AlCl3 (22.6 g, 169 mmol) in DCM (300 mL). After stirring at rt for 1 h, acetyl chloride (13.3 g, 169 mmol) is added drop wise and the resulting mixture is stirred for 18 h. The mixture is cooled to 00 C., quenched with MeOH (150 mL) and stirred for 1 h. Silica gel is added to the mixture, the solvents are removed under vacuum, and the residue is purified by silica gel chromatography eluting with 10% MeOH in DCM to afford 1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (1.6 g). 1H NMR (300 MHz, CH3OD): δ 8.93(d, 1H), 8.45(s, 2H), 7.50(t, 1H), 3.30(s, 3H).
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].Cl.[CH3:15][C:16]1[N:17]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)[CH:18]=[CH:19][N:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:3]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:25][C:24]3[CH:23]=[CH:22][C:21]([N:17]4[CH:18]=[CH:19][N:20]=[C:16]4[CH3:15])=[CH:28][CH:27]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Reactant: N#CC1(c2cccc(O)c2)CCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C#N)CCC3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A mixture of 1-cyano-1-(3-hydroxyphenyl)cyclobutane (1.76 g, 10 mmol), 4-(2-methylimidazol-1-yl)benzylchloride hydrochloride (2.10 g, 10 mmol) and potassium carbonate (6.90 g, 50 mmol) in DMF (80 ml) were stirred together at 80° C. for 3 hrs. Water (200 ml) was added and the mixture extracted with ethyl acetate/benzene (2/1, 100 ml×2), washed with water (100 ml×2), brine (100 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 150 g; dichloromethane/methanol (20/1)) to afford 2.90 g (84%) of the titled compound as a clear yellow oil.
Reaction SMILES: [NH2:1][CH:2]([CH:6]([N:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:14]=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:27]O>CN(C=O)C>[NH2:1][CH:2]([CH:6]([N:13]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:14]=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:27])=[O:4]
Reactant: CO
Reactant: NC(C(=O)O)C(c1ccccc1)N(C=O)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(N)C(c1ccccc1)N(C=O)Cc1ccccc1
Reaction time: 20 h

Procedure:
13.5 g (0.04 mol) of 2-amino-3-(N-benzyl-N-formylamino)-3-phenylpropionic acid were dissolved in methanol, and 7.1 g (0.06 mol) of thionyl chloride and 1 drop of DMF were added dropwise. After 20 hours, the solvents were removed, the residue was suspended in diethyl ether and 5% strength NaHCO3 solution was added with stirring. The ether phase was separated off, washed and dried. Removal of the solvents gave 4.0 g of the title compound as a colorless oil which was used without further purification.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH:27]([S:30](Cl)(=[O:32])=[O:31])([CH3:29])[CH3:28]>CCCCCC.C(Cl)Cl>[C:1]1([C@@H:7]([CH3:10])[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C@@H:7]([CH3:10])[CH2:8][NH:9][S:30]([CH:27]([CH3:29])[CH3:28])(=[O:32])=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Agent: C[C@@H](CN)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccccc1
Reaction time: 0.75 h
Yield: 180.3 %

Procedure:
To a solution of the (2R)-2-phenylpropylamine (1.2 g, 8.87 mmol) in hexane (16.0 mL) was added triethylamine (2.47 mL, 17.74 mmol) and is dimethylaminopyridine (0.30 g, 2.47 mmol). Cooled reaction to 5° C., then added a solution of isopropylsulfonyl chloride (0.97 mL, 8.69 mmol) dissolved in methylene chloride (6.0 mL) over a period of 15.0 minutes. Stirred for 45.0 minutes, then stirred at room temperature for 120.0 minutes. Quenched reaction with 1N HCl (20.0 mL) and extracted organic with methylene chloride (25.0 mL). Dried organic layer with anhydrous magnesium sulfate, filtered and concentrated filtrate to provide the final title compound, ((2R)-2-phenylpropyl)[(methylethyl)sulfonyl]amine, (1.93 g, 90.1%) an oil; 1H nmr (CDCl3, 300 MHz) δ 1.25 (d, 3H, J=6.9 Hz), 1.29(d, 3H, J=6.9 Hz), 1.30 (d, 3H, J=7.2 Hz), 2.98 (m, 1H), 3.05 (m, 1H), 3.22 (m, 1H), 3.36 (m, 1H), 3.89 (b, 1H), 7.23 (m, 2H), 7.34 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C([O-])(=O)C.[K+].[CH3:31][O:32][CH:33]1[CH2:38][CH2:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH2:34]1.O>CC#N>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:36]3[CH2:37][CH2:38][CH:33]([O:32][CH3:31])[CH2:34][CH:35]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Reactant: COC1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC1CC=C(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
(1H-Benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (1.0 g, 2.8 mmol), potassium acetate (2.1 g, 21.0 mmol), 2-(4-methoxy-1-cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.88 g, 3.7 mmol), and bis[di-tert-butyl(phenyl) phosphane]dichloropalladium (0.13 g, 0.213 mmol) were taken up in 40 mL of 3:1 MeCN:water. The mixture was purged with nitrogen and heated to 100° C. After 12 hours, the mixture was cooled to room temperature and diluted with 40 mL of water. The mixture was extracted twice with 30 mL of 9:1 chloroform:IPA. The combined organic extracts were dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0.5 to 5% MeOH/DCM) afforded 1H-Benzimidazol-2-yl(4-((3-(4-methoxy-1-cyclohexen-1-yl)-2-pyrazinyl)oxy)phenyl)methanone as a yellow solid. MS (ESI, pos. ion) m/z: 427.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: CO[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1Cl.[N:12]1([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][NH2:30])=[CH:24][CH:23]=1>>[C:22]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][NH:30][C:3](=[O:11])[C:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=2[NH:21][CH2:20][CH2:19][CH2:18][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:26][CH:27]=1
Reactant: NCCCN1CCOCC1
Reactant: NCCc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cccnc1Cl
Product: O=C(NCCc1ccc(-c2ccccc2)cc1)c1cccnc1NCCCN1CCOCC1

Procedure:
The title compound was prepared in analogy to example 1, but starting from 2-chloro-nicotinic acid methyl ester and subsequently using 3-morpholin-4-yl-propylamine in the first step and 2-biphenyl-4-yl-ethylamine in the third step.
Reaction SMILES: [CH2:1]([CH:3]([CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1)[CH2:4][CH3:5])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH2:1]([CH:3]([CH:6]1[CH2:7][C:8](=[O:13])[CH:9]([C:25](=[O:26])[NH:24][S:21]([C:18]2[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])[C:10](=[O:12])[CH2:11]1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CCC(CC)C1CC(=O)CC(=O)C1
Solvent: c1ccccc1
Product: CCC(CC)C1CC(=O)C(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(=O)C1

Procedure:
Reaction of equimolar amounts of 5-(1-ethylpropyl)1,3-cyclohexanedione with p-chlorobenzenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 5-(1-ETHYLPROPYL)-2-(N-p-CHLOROBENZENESULFONYLCARBAMOYL)-1,3-CYCLOHEXANEDIONE, m.p. 121°-122° C. (corr.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[S:10][N:9]=[C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[N:7]=1)[CH3:2].[H-].[Na+].[C:19]([O:23][C:24](=[O:40])[N:25]([CH2:30][C:31]1[CH:39]=[CH:38][C:34]2[O:35][CH2:36][O:37][C:33]=2[CH:32]=1)[CH2:26][CH2:27][CH2:28]Br)([CH3:22])([CH3:21])[CH3:20].O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:6]1[S:10][N:9]=[C:8]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[N:7]=1)[CH2:28][CH2:27][CH2:26][N:25]([CH2:30][C:31]1[CH:39]=[CH:38][C:34]2[O:35][CH2:36][O:37][C:33]=2[CH:32]=1)[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:40])[CH3:2]
Reactant: CCOC(=O)Cc1nc(-n2ccnc2)ns1
Reactant: CC(C)(C)OC(=O)N(CCCBr)Cc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of (3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-acetic acid ethyl ester (240 mg, 1.0 mmol) in DMSO (2 mL) was added NaH (70 mg of a 60% dispersion on mineral oil, 1.8 mmol) and benzo[1,3]dioxol-5-ylmethyl-(3-bromo-propyl)-carbamic acid tert-butyl ester (370 mg, 1.0 mmol) subsequently. The solution was stirred for 2 h at 60° C. Water (4 mL) was added and the solution was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave a residue which was purified by column chromatography to afford 370 mg (70%) of 5-(benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-pentanoic acid ethyl ester as a red oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[Na].[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[C:10](OCC)=O.[C:19](O)(=[O:21])[CH3:20]>Cl>[CH2:17]([O:16][C:9]([C:10]1[C:6]2[C:5]([CH3:7])=[N:4][NH:3][C:2]=2[N:1]=[C:19]([OH:21])[CH:20]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)O
Reactant: Cc1cc(N)n[nH]1
Agent: Cl
Agent: [Na]
Product: CCOC(=O)c1cc(O)nc2[nH]nc(C)c12
Temperature: 80 °C
Reaction time: 14 h
Yield: 35 %

Procedure:
A mixture of 3-amino-5-methylpyrazole (50.0 g), diethyl oxalate sodium salt (127.3 g) and acetic acid (113 mL) in 1N hydrochloric acid (625 mL) was stirred at 80° C. for 14 h, then refluxed for 3 h, cooled to r.t., and the precipitate formed was filtered by suction filtration and dried in vacuum at 60° C. The crude product was stirred in 500 mL ethyl acetate at r.t. and the solid was filtered off and dried in air. 6-Hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (40.2 g, 35%) was obtained as pale yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:33]([NH:40][C@H:41]([C:50](O)=[O:51])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CN1CCOCC1>CN(C=O)C>[CH3:2][O:3][C:4](=[O:10])[CH:5]([NH:6][C:50](=[O:51])[CH:41]([NH:40][C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)C(CCc1ccccc1)NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 142.3 %

Procedure:
To an ice-cooled solution of D-valine methyl ester hydrochloride (1000 mg, 3.58 mmol) and HOBt (in DMF (14 mL) was added EDCl (755 mg, 3.94 mmol). After the mixture was stirred for 30 min, N-boc-L-homophenylalanine (600 mg, 3.58 mmol) and N-methylmorpholine (1 mL, 8.95 mmol) were added. The mixture was warmed to room temperature and stirred overnight. The solvent was removed and the residue was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic phases were dried over anhydrous Na2SO4. After concentration under reduced pressure, the crude title compound (2000 mg) was obtained and used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[C:18]([CH3:19])=[CH:17][O:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].S(OC)(O[CH3:26])(=O)=O.Cl>CO.C(Cl)(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH3:26])[C:10]2[C:11]3[C:18]([CH3:19])=[CH:17][O:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2ncnc3occ(C)c23)cc1
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2ncnc3occ(C)c23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 25 mL round bottom flask was weighed 7 (51 mg, 0.2 mmol) and was added DMF (2 mL) to afford a solution. The flask was purged with argon for five min followed by cooling down to 0° C. using ice bath. Sodium hydride (14.4 mg, 0.6 mmol) was added to the solution at 0° C. The solution was stirred for 30 min at 0° C. under argon atmosphere. Dimethyl sulfate (75.7 mg; ≈57 μl; 0.6 mmol) was injected to the reaction mixture and the flask was warmed to room temperature. The mixture was stirred at room temperature for another 3 h at the end of which 1 N Hydrochloric acid (5 mL) was added carefully to quench the reaction followed by water (20 mL) to afford a precipitate. Product was extracted using ethyl acetate (10 mL×2). Combined organic extracts were washed with brine (10 mL) dried (anhydrous sodium sulfate) and concentrated under reduced pressure. Silica gel (200 mg) was added and solvent evaporated to afford a plug. Column chromatography by elution with hexanes:ethyl acetate (5:1) afforded AAG16 (20 mg; 37%) as light brown semisolid; which was triturated withl hexanes to afford light brown solid. TLC Rf0.79 (CHCl3:MeOH, 10:1); mp 84-85.6° C.; 1HNMR (400 MHz) (DMSO-d6): δ 1.036-1.039 (d, 3H, CH3, J=1.2 Hz); 3.423 (s, 3H, NCH3), 3.752 (s, 3H, OCH3), 6.944-6.967 (d, 2H, C6H4, J=9.2 Hz), 7.176-7.199 (d, 2H, C6H4, J=9.2 Hz), 7.505-7.508 (d, 1H, C6-CH, J=1.2 Hz), 8.234 (s, 1H, C2-CH). Anal. Calcd for C15H15N3O2.0.28 C6H14.0.05 HCl: C, 67.84; H, 6.48; N, 14.22; Found: C, 67.89; H, 6.18; N, 14.06.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]2[O:10][C@@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@H:9]([OH:10])[C@@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: Clc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@H]1O
Yield: 33.8 %

Procedure:
The title compound (76 mg, 34%) was prepared using (2R,3R,4R)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (129 mg, 0.46 mmol) and 4-chlorophenyl-1H-imidazol-2-ylmethylamine (95 mg, 0.46 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [C:1]([N:5]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[CH2:6][C:7]([N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O-:17])=[O:16])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.C1(C)C=CC=CC=1>[C:1]([N:5]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:6][C:7]([N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=[O:16])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N(CC(=O)N1C(=O)CC[C@H]1C(=O)[O-])C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N(CC(=O)N1C(=O)CC[C@H]1C(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Carbamate 4 (0.74 g, 1.97 mmol) was dissolved in dichloromethane (12 cm3) under nitrogen and cooled to 0° C. Trifluoroacetic acid (6 cm3) was added dropwise over a period of 5 min and the solution stirred for 1.5 h. The solution was evaporated under reduced pressure to give an orange gum, that was dissolved in toluene and evaporated under reduced pressure (2×10 cm3) to give crude acid 5 as an orange gum. The material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[C:4]([F:14])[CH:3]=1.[N+](=[CH2:17])=[N-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:17])=[O:12])=[C:4]([F:14])[CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C1CC1c1ccc(Br)cc1F
Solvent: ClCCl
Product: COC(=O)C1CC1c1ccc(Br)cc1F

Procedure:
To a solution of (+)-2-(4-bromo-2-fluorophenyl)cyclopropanecarboxylic acid from step 7 (1 eq) in methylenechloride was added an ethereal solution of diazomethane until reaction is completed by TLC. The resulting mixture was concentrated. The crude ester was used as such in the next step.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][OH:11])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:13][O:14][C:15]([C:17]1[O:21][NH:20][C:19](=O)[CH:18]=1)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[O:21][N:20]=[C:19]([O:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:12])[CH:18]=1)=[O:16]
Reactant: COC(=O)c1cc(=O)[nH]o1
Reactant: CCCCc1noc(C)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 3-butyl-5-methyl-4-isoxazolyl-methanol (1.5 g, 8.9 mmol) in THF (30 mL) was added 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (1.27 g, 8.9 mmol) and triphenylphosphine (2.79 g, 10.6 mmol) at 0° C. under an argon atmosphere. Then diethyl azodicarboxylate (˜40% in toluene, 4.25 mL, 9.8 mmol) was added and the reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:1) afforded the title compound (1.44 g, 55%) as a colourless liquid. MS: m/e=295.0 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.N1C=CC=CC=1.[CH3:39][C:40]([CH3:45])([CH3:44])[C:41](Cl)=[O:42]>C1COCC1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:41](=[O:42])[C:40]([CH3:45])([CH3:44])[CH3:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 mmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, a solution of 2,2-dimethylpropanoyl chloride (20 mg, 164 mmol, 2.5 eq.) in abs. THF (1 ml) was added in two portions. Once analysis of the reaction by HPLC showed substantial conversion (12 h), the reaction mixture was concentrated under reduced pressure and directly purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (26.9 mg, 81% of theory).