Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7C(OC(C)(C)C)=O)[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH3:60][O:61][C@H:62]([CH3:72])[C@H:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64]([OH:66])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:71][O:70][C:68]([NH:67][C@H:63]([C:64]([N:44]1[CH2:45][C@@H:46]([CH2:48][O:49][CH3:50])[CH2:47][C@H:43]1[C:41]1[NH:40][C:39]2[C:58]3[C:35]([CH:36]=[CH:37][C:38]=2[N:42]=1)=[CH:34][C:33]1[C:27]2[C:28]([CH2:30][O:31][C:32]=1[CH:59]=3)=[CH:29][C:24]([C:21]1[NH:20][C:19]([C@@H:14]3[CH2:15][C@H:16]([CH3:18])[CH2:17][N:13]3[C:11](=[O:12])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[C@H:7]([CH3:8])[CH2:9][CH3:10])=[N:23][CH:22]=1)=[CH:25][CH:26]=2)=[O:66])[C@H:62]([CH3:72])[O:61][CH3:60])=[O:69]
Reactant: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)[C@@H](NC(=O)OC)[C@H](C)OC)[nH]c54)cc2-3)[nH]1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
tert-butyl (2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (35 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 hr, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S,3R)-1-[(2S,4S)-2-(5-{2-[(2S,4S)-1-[N-(methoxycarbonyl)-O-methyl-L-allothreonyl]-4-(methoxymethyl)pyrrolidin-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl}carbamate (92 mg, 81%).
Reaction SMILES: [C:1]([C@@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].[CH:18](Cl)(Cl)Cl>>[C:1]([C@@:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([O:15][CH3:18])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2]
Reactant: C#C[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: ClC(Cl)Cl
Product: C#C[C@@]1(C)CCc2c(C)c(OC)c(C)c(C)c2O1

Procedure:
By the same procedure as described in Example 28 (R)-2-ethynyl-3,4-dihydro-6-methoxy-,5,7,8-tetramethyl-H-1-benzopyran was prepared from (R)-(-)-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol. This product was produced as white prisms=93°-95° C. [α]D25 -57.14°, (C 0.28, CHCl3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[I-].C[N+]1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CCCCC(NS(=O)(=O)c1ccc(Br)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCC(NS(=O)(=O)c1ccc(Br)cc1)C(=O)Nc1ccc(CC(=O)OCC)cc1
Yield: 9.4 %

Procedure:
The procedure described in Example 177 was repeated, except that (RS)-2-(4-bromobenzenesulfonylamino)hexanoic acid (1 g) and ethyl 4-aminophenylacetate hydrochloride (554.2 mg) were condensed in chloroform (30 ml) in the presence of triethylamine (1.6 ml) and 1-methyl-2-chloropyridinium iodide (875.4 mg) to obtain (RS)-2-(4-bromobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)hexanamide (123.8 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[CH3:15][C@@H:16]1[CH2:21][NH:20][C@@H:19]([CH3:22])[CH2:18][N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:15][C@@H:16]1[CH2:21][N:20]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[N:7]=2)[C@@H:19]([CH3:22])[CH2:18][N:17]1[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24]
Reactant: C[C@@H]1CN[C@@H](C)CN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2ccc3nnc(C(F)(F)F)n3n2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 76 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.45 g, 20 mmol), (2R,5S)-tert-butyl 2,5-dimethylpiperazine-1-carboxylate (5.14, 24 mmol) and DIPEA (5.14 mL, 30.00 mmol) in DMF (40.0 mL) was heated at 125° C. for 2.5 hours. The reaction mixture was evaporated to dryness, redissolved in DCM and washed sequentially with 1M aqueous K2CO3, water and saturated brine. The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by MPLC silica chromatography, eluting with EtOAc. Product fractions were evaporated and triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to afford (2R,5S)-tert-butyl 2,5-dimethyl-4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazine-1-carboxylate (6.09 g, 76%) as a white crystalline solid.
Reaction SMILES: [C:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]1[SH:15])(=[O:3])C.C(N(CC)CC)C.[CH3:23][N:24]=[C:25]=[O:26].O>CN(C)C=O>[CH3:23][N:24]1[C:25](=[O:26])[S:15][C:5]2=[N:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:8][N:4]2[C:1]1=[O:3]
Reactant: CN=C=O
Reactant: CC(=O)n1cc(-c2ccccc2)nc1S
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(=O)sc2nc(-c3ccccc3)cn2c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.6 g (2.75 millimoles) of 1-acetyl-4-phenyl-2-mercaptoimidazole, and 1.0 ml of triethylamine was added to the solution. Then, 0.65 ml (10.9 millimoles) of methyl isocyanate was further added to the solution and the mixture was stirred at room temperature overnight. Then, 20 ml of water was added to the reaction mixture, and the mixture was stirred for 1 hour and the precipitated crystal was recovered by filtration to obtain 0.4 g (yield=56%) of intended 3-methyl-7-phenyl-1,3,5-thiadiazino[3,2-a]imidazole-2,4(3H)-dione (compound No.53).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14](OCC)=[O:15])=[C:9]2[C:19](OCC)=[O:20])=[CH:5][CH:4]=1.O.[NH2:27][NH2:28]>COCCOCCOC>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:9]3[C:19](=[O:20])[NH:27][NH:28][C:14](=[O:15])[C:10]=3[CH:11]=[C:12]2[CH3:13])=[CH:5][CH:4]=1
Reactant: NN
Reactant: CCOC(=O)c1cc(C)n(Cc2ccc(OC)cc2)c1C(=O)OCC
Solvent: O
Solvent: COCCOCCOC
Product: COc1ccc(Cn2c(C)cc3c(=O)[nH][nH]c(=O)c32)cc1
Yield: 87 %

Procedure:
46.0 g (0.133 mol) of diethyl 1-(4-methoxybenzyl)-5-methylpyrrole-2,3-dicarboxylate and 129.5 ml (2.66 mol) of hydrazine hydrate are reacted at 110° C. for 18 h in 290 ml of diglyme. Purification: precipitation from diisopropyl ether/ethyl acetate. Yield: 87%, m.p.: 300° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[N:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH-:21].[Na+].O=[Si]=O>O.C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:6]([S:7]([CH3:8])(=[O:16])=[O:21])=[N:5][N:4]=[C:3]1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CSc1nnc(-c2ccncc2)n1C
Reactant: [OH-]
Agent: O=[Si]=O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cn1c(-c2ccncc2)nnc1S(C)(=O)=O
Temperature: 14.5 °C
Reaction time: 4 h

Procedure:
To a mechanically stirred solution of 4-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine (228 g) from the previous step, in a mixture of water (1.15 L) and acetic acid (1.15 L), was added portion-wise while cooling potassium permanganate (234 g), at such a rate as to maintain the temperature between 12 to 17° C. (ca. 45 min). The reaction mixture was then stirred at r.t. for 4 h before cooling on an ice-bath during the addition of a sodium hydroxide solution (5 N) over 2.5 h to set the pH to ca. 10. Dicalite® (100 g) and chloroform (1.6 L) was then added to the reaction mixture before filtration. The organic phase was separated from the filtrate and the aq. phase from the same was extracted with chloroform (2×1 L). The filter-cake was extracted twice with chloroform (2×1.5 L). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo to provide 158 g of the title compound as a white powder. Another crop (78 g, white powder) was obtained by extraction of the filter cake with chloroform (2×2 L) and concentration of this solution in vacuo. 1H NMR (DMSO-d6): 3.6 (s, 3H), 3.9 (s, 3H), 7.8 (s, 2H), 8.8 (s, 2H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][CH:17]=1.C(=O)(O)[O-].[Na+].O>C1COCC1.C(Cl)(Cl)Cl>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1cccc([Mg]Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1cccc(-c2nc(Cl)nc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyanuric chloride (3.69 g, 20 mmol) in dry THF (20 mL) under nitrogen was treated dropwise with a solution of 3-methoxyphenylmagnesium bromide in THF (20 mL, 1M, 20 mmol). The solution became warm and was stirred for 30 minutes at room temperature followed by stirring overnight at ˜40° C. The reaction was poured into a mixture of saturated sodium bicarbonate (50 mL) and water (50 mL) forming a solid. The mixture was stirred for 20 minutes and separated layers. The aqueous layer was extracted with ethyl acetate (EtOAc) twice. The combined organic layers was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield a tan solid. The solid was dissolved in chloroform and loaded onto 100 g of silica gel. The silica gel was eluted with 10% ethyl acetate/hexanes followed by 20% ethyl acetate/hexanes. The appropriate fractions were concentrated on a rotary evaporator to yield 2,4-dichloro-6-(3-methoxyphenyl)-1,3,5-triazine (VIII) as a white solid (0.52 g, 4.50 g). ESI/MS 256.1, 258.1, 260.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7](C(OCC)=O)[CH2:8][C:9]=1[NH:10]2.[CH3:23][Li].Cl.[CH2:26]1[CH2:30][O:29]CC1>>[Br:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]([NH2:16])=[O:17])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:30]([OH:29])([CH3:26])[CH3:23])[CH2:8][C:9]=1[NH:10]2
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Reactant: [Li]C
Agent: Cl
Product: CC(C)(O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A solution of ethyl 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (Intermediate 46-1, 2 g, 5.48 mmol) in THF (100 mL) cooled in an ice bath was treated with methyllithium (1.6 M in diethyl ether, 17.11 mL, 27.4 mmol). After 1 h, the mixture was treated slowly with a mixture of 1 M hydrochloric acid (20 mL) and ice (20 g). The organic layer was separated, and the aqueous layer was extracted twice with DCM. The combined organic phases were washed with water and brine, dried and concentrated. The residue was triturated with DCM to provide 5-bromo-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a light yellow solid (1.72 g, 89%). 1H NMR (400 MHz, methanol-d4) δ7.38 (1 H, d, J=8.14 Hz), 7.16 (1 H, d, J=8.14 Hz), 3.37-3.45 (1 H, m), 2.90-2.97 (1 H, m), 2.79-2.89 (1 H, m), 2.54-2.64 (1 H, m), 2.20-2.28 (1 H, m), 1.80-1.90 (1 H, m, J=11.94, 11.94, 4.95, 2.20 Hz), 1.41-1.53 (1 H, m, J=12.43, 12.43, 12.32, 5.28 Hz), 1.30 (6 H, s). Mass spectrum m/z 351, 353 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)=O.[NH2:19][C:20]([NH2:22])=[S:21]>CO>[BrH:1].[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]([NH2:22])[S:21][CH:2]=2)[CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(CBr)c1cccc(OCc2ccccc2)c1
Reactant: NC(N)=S
Solvent: CO
Product: Br
Product: Nc1nc(-c2cccc(OCc3ccccc3)c2)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 22.5 g of 2-bromo-1-(3-benzyloxy-phenyl)-ethanone in 150 ml of methanol was treated at room temperature with 7.8 g of thiourea and boiled for 1 hour. 16.1 g of 4-(3-benzyloxy-phenyl)-thiazol-2-ylamine hydrobromide separated as colorless crystals upon cooling to 0° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[CH:14]=[CH:15][O:16][C:12]=3[C:11](=[O:17])[C:10]([C:18]3[N:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C.[Cu]=O>[C:23]1([N:22]2[C:18]([C:10]3[C:11](=[O:17])[C:12]4[O:16][CH:15]=[CH:14][C:13]=4[N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH:33]=[CH:32][CH:31]=[N:30]5)=[CH:3][CH:4]=4)[N:9]=3)=[CH:19][CH:20]=[N:21]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(I)cc2)c2ccoc12
Reactant: c1cn[nH]c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccnn2-c2ccccc2)nn(-c2ccc(-n3cccn3)cc2)c2ccoc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 36.6 %

Procedure:
A suspension of 1-(4-iodophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)furo[3,2-c]pyridazin-4(1H)-one (200 mg), pyrazole (57 mg), copper oxide (6 mg), 2-hydroxybenzaldehydeoxime (23 mg) and cesium carbonate (271 mg) in DMF (5 mL) was stirred at 50° C. for 12 hr, and water was added. The reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (64 mg).
Reaction SMILES: CC(C)([O-])C.[K+].ClC1C=CC(O[CH2:13][C:14]#[N:15])=CC=1.[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][N:23]=1)([CH3:20])[CH3:19].Cl>CN(C)C=O>[NH2:28][C:25]1[C:24]([CH2:13][C:14]#[N:15])=[N:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(N)c(CC#N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
To a stirred solution of potassium-t-butoxide (12.34 g, 110 mmol) in dry dimethylformamide (DMF) (30 mL) cooled at -10° C. under a nitrogen atmosphere was added dropwise a solution of (4-chlorophenoxy)acetonitrile (9.22 g, 55 mmol) and 2-isopropoxy-5-nitro pyridine (prepared according to the methodology of Friedman, et al., J. Am. Chem. Soc. 69, 1204 (1947)) (9.11 g, 50 mmol) in DMF (30 mL). The resulting purple solution was maintained at 0° to 10° C. for 1 hour. Aqueous hydrochloric acid was added (80 mL, 5% HCl) and the resulting mixture was allowed to warm to room temperature. The mixture was extracted twice with methylene chloride. The combined extracts were dried (MgSO4) and concentrated in vacuo to leave an oil which was passed through a thick pad of silica gel, eluting with 1:1 methylene chloride/hexane. The filtrate was evaporated under reduced pressure and the residual oil containing the desired (6-isopropoxy-3-nitro-2-pyridyl) acetonitrile) was dissolved in a 6:1 mixture of ethanol and acetic acid (10 mL) to which was added 5% palladium/carbon (0.8 g). The mixture was hydrogenated on a Parr shaker at 3 atmospheres pressure for 5 hours. The catalyst was removed by filtration of the mixture through diatomaceous earth (Celite (trademark)) and The filtrate was concentrated in vacuo. The residual oil was taken up in water and the pH was adjusted to 10 by addition of sodium carbonate. The mixture was extracted twice with methylene chloride and the combined extracts were dried (MgSO4) and concentrated. The residue was subjected to flash chromatography on silica gel eluting successively with 1:2 ether/hexane, 1:1 ether/hexane and ethyl acetate. Fractions containing the product eluted with ethyl acetate were combined and evaporated to provide (3-amino-6-isopropoxy-2-pyridyl)acetonitrile as an off-white solid (5.60 g, 59%); m.p. 83°-85° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]([NH:35][NH2:36])=[O:34]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:36][NH:35][CH:33]=[O:34])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NNC=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 6.0 mmol) in THF (30 mL) was added 1,1′-carbonyldiimidazole (1.6 g, 7.2 mmol) at 0° C. The reaction mixture was stirred at rt for 1 h, then, formohydrazide (1.1 g, 18.1 mmol) was added rapidly at rt. The reaction mixture was stirred at rt for 3 hrs and then diluted with EtOAc (100 mL). The combined organic layer was washed with saturated sodium chloride (10 mL), dried over Na2SO4, and concentrated to afford (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (1.6 g), which was used directly in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[OH:4].NC[C@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)O.C(N(CC)C(C)C)(C)C.[F:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47](F)[N:46]=1>O1CCOCC1.C(OCC)(=O)C>[F:44][C:45]1[N:46]=[C:47]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:7][CH2:8][CH3:9])[OH:4])[CH:48]=[CH:49][CH:50]=1
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN
Reactant: Fc1cccc(F)n1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CN
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNc1cccc(F)n1
Temperature: 45 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 100 mg (0.41 mmol) of tert-butyl (1S)-1-[(1S)-2-amino-1-hydroxyethyl]pentylcarbamate & tert-butyl (1S)-1-[(1R)-2-amino-1-hydroxyethyl]pentylcarbamate and 0.07 mL (0.46 mmol) of N,N-diisopropylethylamine in 0.5 mL dioxane was added 0.042 mL (0.46 mmol) of 2,6-difluoropyridine. The reaction mixture was stirred at 45° C. for 16 h, then at 50° C. for 20 h. The reaction mixture was then allowed to cool before being diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (3:7) to afford 40 mg (29%) of tert-butyl (1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate. ES-LCMS m/z 364 (M+Na).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Br[CH2:20][CH:21]1[CH2:23][CH2:22]1>>[CH:21]1([CH2:20][N:5]2[C:6]3[C:11](=[C:10]([C:13]([F:15])([F:16])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH:12]=[C:4]2[CH2:1][CH2:2][CH3:3])[CH2:23][CH2:22]1
Reactant: BrCC1CC1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-propyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 2H), 6.57 (s, 1H), 4.05 (d, J=6.4 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 1.83 (m, 2H), 1.16 (m, 1H), 1.08 (t, J=7.4 Hz, 3H), 0.60 (m, 2H), 0.35 (m, 2H); MS (ES) m/z 307 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=O.[CH3:17][O:18][C:19]1[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]>ClCCl.CO>[ClH:1].[CH3:17][O:18][C:19]1[CH:32]=[C:31]([NH:33][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][N:24]([CH2:27][CH3:28])[CH2:25][CH3:26]
Reactant: CCN(CC)CCOc1ccc(N)cc1OC
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)cc1OC
Product: Cl

Procedure:
Prepared analogously to Example 2.3.f. from 75 mg (0.30 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 79 mg (0.33 mmol) of [2-(2-methoxy-4-aminophenoxy)ethyl]diethylamine. Yield: 14 mg (10% of theory); C23H24ClF3N2O3 (M=468.90); calc.: molecular ion peak (M+H)+: 469/471; found: molecular ion peak (M+H)+: 469/471; Rf value: 0.35 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3]C(C)(C)C)=O.[NH2:17][C@H](C(O)=O)CC(C)C.[NH2:26][C@H:27]([C:47]([NH:49][C@@H:50]([C:52]([NH:54][C@H:55](C(N[C@H](C(O)=O)CC(C)C)=O)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:53])[CH3:51])=[O:48])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35]C(OCC2C=CC=CC=2Br)=O)=[CH:31][CH:30]=1.N>CO>[NH2:26][C@H:27]([C:47]([NH:49][C@@H:50]([C:52]([NH:54][C@H:55]([C:1]([NH:8][C@H:9]([C:14]([NH2:17])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:3])[CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:53])[CH3:51])=[O:48])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(OC(=O)OCc2ccccc2Br)cc1)C(=O)O
Agent: N
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Boc-leucine was esterified to chloromethyl polystyrene-1% divinylbenzene in the standard way (cf. Stewart and Young) to give a product containing 0.347 mmoles leucine per gram resin. The peptide sequence was assembled on the resin in the standard way described for Example 1 above, using the Beckman 990 synthesizer. H-Tyr(BrZ)-DAla-Phe-Leu-resin was suspended in anhydrous methanol in a pressure vessel. The solution was chilled to -20°, saturated with ammonia gas, and the vessel was closed and stirred at room temperature for 2 days. Excess ammonia was removed under reduced pressure, the resin was filtered off and discarded, and the peptide solution evaporated to dryness. The blocking group was removed from the tyrosine by treatment with HF-anisole as described in Example 1 above. The peptide was purified by CCD in nBAW (4:1:5); the partition coefficient was 3.0. On paper electrophoresis at pH 5.0 the peptide had Elys =0.50.