Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:14][CH:13]([C:15]#[N:16])[CH2:12]1)=[O:10])(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:12][CH:13]([C:15]#[N:16])[CH2:14]1)=[O:10]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[(R)-2-(3-cyanoazetidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (47 mg, 0.185 mmol) was dissolved in dichloromethane (1 ml) and cooled in an ice bath. Trifluoroacetic acid (0.5 ml) was slowly added and the reaction was stirred at room temperature for 2 h then evaporated and dried under high vacuum to afford 1-((R)-2-amino-propionyl)-azetidine-3-carbonitrile trifluoroacetate which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)=[O:3].[F:16][C:17]([F:22])([F:21])[C:18]([NH2:20])=[O:19]>C(Cl)Cl>[CH3:1][S:2]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1)(=[N:20][C:18](=[O:19])[C:17]([F:22])([F:21])[F:16])=[O:3]
Reactant: NC(=O)C(F)(F)F
Reactant: COC(=O)CCc1ccc(S(C)=O)cc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 49.2 %

Procedure:
In a 100 mL round bottom flask, methyl 3-(4-(methylsulfinyl)phenyl)propanoate (0.4 g, 1.77 mmol) was added to CH2Cl2 (18 mL). Subsequently the reaction was treated with MgO (0.285 g, 7.08 mmol), trifluoroacetamide (0.400 g, 3.54 mmol), PhI(OAc)4 (0.884 g, 2.66 mmol), and Rh2(OAc)4 (19.55 mg, 0.0443 mmol). The suspension was stirred overnight then filtered through celite. The filtrate was the concentrated. The resulting residue was purified via column chromatography (silica gel, gradient eluant mixture: 20% EtOAc in hexanes to 100% EtOAc) to give the title compound (0.294 g, 69%).
Reaction SMILES: CCN(CC)CC.Br[C:9]1[CH:10]=[C:11]([NH:15][C:16](=[O:24])[CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:13][CH:14]=1.[CH2:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:26]=[CH2:27].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:18]([CH:17]([CH2:21][CH2:22][CH3:23])[C:16]([NH:15][C:11]1[CH:10]=[C:9](/[CH:27]=[CH:26]/[CH2:25][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:14]=[CH:13][CH:12]=1)=[O:24])[CH2:19][CH3:20]
Reactant: CCCC(CCC)C(=O)Nc1cccc(Br)c1
Reactant: C=CCNC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)Nc1cccc(/C=C/CNC(=O)OC(C)(C)C)c1
Temperature: 90 °C

Procedure:
Et3N (1.2 mL) was added to a solution of N-(3-bromophenyl)-2-propylpentanamide (0.6 g, 2.01 mmol), tert-butyl allylcarbamate (1.026 g, 6.55 mmol) and P(o-tol)3 (0.06 g, 0.201 mmol) in DMF (10 mL). The reaction mixture was degassed for 30 min and then added Pd(OAc)2 (0.09 g, 0.409 mmol) was added. The reaction mixture was again degassed for 15 min and then refluxed at 90° C. for 8 h. The reaction mixture was diluted with EtOAc, washed with H2O, brine. The organic layer was concentrated under reduced pressure. Purification by column chromatography(100-200 mesh silica, elution 10% to 15% EtOAc in hexane) gave (E)-tert-butyl 3-(3-(2-propylpentanamido)phenyl)allylcarbamate as a yellow oil. Yield (0.7 g, 37%). 1H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.08 (dd, J=1.2, 7.2 Hz, 2H), 6.48 (d, J=16.0 Hz, 1H), 6.26-6.16 (m, 1H), 4.67 (bs, 1H), 3.89 (bs, 2H), 2.17-2.04 (m, 1H), 1.73-1.64 (m, 4H), 1.48 (s, 9H), 1.45-1.14 (m, 4H), 0.91 (t, J=7.2 Hz, 6H).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][CH2:9][C:10]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C(O)(=O)C>[C:1]1([C:7]2[N:22]([CH2:23][C:24]([OH:26])=[O:25])[C:10]([CH:12]3[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC1CCC(C(=O)CCC(=O)c2ccccc2)CC1
Reactant: NCC(=O)O
Solvent: CC(=O)O
Product: CCCC1CCC(c2ccc(-c3ccccc3)n2CC(=O)O)CC1
Yield: 55.9 %

Procedure:
A solution of 1.43 g (5 mmol) 1-phenyl-4-(4-propyl-cyclohexyl)-butane-1,4-dione and 0.75 g (10 mmol) glycine 16 mL of acetic acid was heated to reflux for 100 min. The solution was concentrated and redissolved in 5% aqueous H2SO4. The solution was extracted with ethyl acetate. The organic phase was dried over MgSO4 and concentrated to afford 0.91 g [2-phenyl-5-(4-propyl-cyclohexyl)-pyrrol-1-yl]-acetic acid as a tan solid which was carried on to the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:13][C:12]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=1[F:10])=[O:9]
Reactant: COc1ccc(N)c(F)c1
Reactant: O=C(O)c1sccc1Br
Product: COc1ccc(NC(=O)c2sccc2Br)c(F)c1
Yield: 86.5 %

Procedure:
Following Step 1 from General Procedure A, 3-bromothiophene-2-carboxylic acid (7.3 g, 35 mmol) was reacted with 2-fluoro-4-methoxyaniline (5.0 g, 35 mmol) to afford the desired product (10 g, 90%) as an orange solid: ESI MS m/z 331 [C12H1FNO2S+H]+.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34]C(=O)OC(C)(C)C)[CH2:30]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.Cl>C(Cl)(Cl)Cl>[NH2:34][C@H:31]1[CH2:32][CH2:33][N:29]([CH:3]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([C:10]([C:13]4[CH:22]=[CH:21][C:20]5[C:15](=[CH:16][C:17]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])=[CH:18][CH:19]=5)[N:14]=4)=[N:11][N:12]=3)[CH:9]=2)[C:2]([F:43])([F:42])[F:1])[CH2:30]1
Reactant: CC(C)C(=O)Nc1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1ccc2ccc(-c3nnc4ccc(C(N5CC[C@H](N)C5)C(F)(F)F)cn34)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
tert-Butyl (3S)-1-(2,2,2-trifluoro-1-(3-(7-isobutyramido quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (56 mg, 0.094 mmol) was weighed into a 100 mL 1 neck round bottom flask, and dissolve in 5 mL of chloroform, followed by addition of HCl (937 μL, 3.7 mmol). The reaction was then allowed to stir at ambient temperature for 1 hour, at which time the deprotection was complete and light yellow precipitate formed. The reaction was concentrated under vacuum, affording N-(2-(6-(1-((S)-3-aminopyrrolidin-1-yl)-2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-7-yl)isobutyramide (32 mg, 69% yield) as a light yellow semi-solid. LCMS APCI (+) m/z 498.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)(O)[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C(N(S(F)(F)[F:32])CC)C>C(Cl)Cl>[F:32][C:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)([CH3:16])[CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]1=2
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CC(C)(F)c2cccnc2)CCN(C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol (500 mg, 1.492 mmol) was dissolved in 20 mL DCM, cooled to 0° C. and diethylaminosulfur trifluoride (720 mg, 4.477 mmol) in DCM (5 mL) was added dropwise at the same temperature and stirred for 1 h. The reaction was monitored by TLC and LCMS. After consumption of starting material, the reaction mixture was quenched with saturated bicarbonate and extracted with DCM. The organic layer was washed with bicarbonate and brine solution, dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 60 mg of 5-(2-Fluoro-2-pyridin-3-yl-propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, freebase) δ (ppm): 8.61 (s, 1H), 8.56 (d, 1H), 7.55 (d, 1H), 7.23 (d, 1H), 7.16 (s, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 4.3 (m, 2H), 3.8 (dd, 2H), 2.96 (m, 1H), 2.9 (m, 1H), 2.7 (m, 1H), 2.6 (m, 1H), 2.58 (s, 3H), 2.41 (s, 3H), 1.75 (d, 3H). Separation by chiral HPLC provided enantiomers II-212a-b.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][C:6](=O)[C:5]=12.P(Cl)(Cl)([Cl:18])=O.O.[OH-].[NH4+]>C(Cl)Cl>[Cl:18][C:6]1[C:5]2=[CH:1][CH:2]=[CH:3][N:4]2[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1
Reactant: O=C1Nc2ccccc2Cn2cccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: ClC1=Nc2ccccc2Cn2cccc21
Temperature: 25 °C

Procedure:
A slurry of 881 g of 10,11-dihydro-5-H-pyrrolo-[2,1-c][1,4]benzodiazepin-11-one is stirred in 12 L of methylene chloride, and 819 g of 99% phosphorus oxychloride is added all at once. The mixture is stirred and refluxed for 19 hours. The reaction mixture is cooled to room temperature. A mixture of 5 L of crushed ice, 7.5 L of cold water and 1.81 kg of 28% ammonium hydroxide solution is stirred and 1.25 L portions of the reaction mixture are added over a period of 15 minutes. The reaction temperature is kept below 25° during the addition. After stirring for 15 minutes, the layers are separated, the methylene chloride layer is washed by stirring with 1 L of cold water then dried by stirring with magnesium sulfate for 1 hour. Charcoal (90 g) is added and the mixture is filtered through filter-cel. The methylene chloride solution is concentrated to dryness in vacuo to give 11-chloro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, m.p. 102°-104°.
Reaction SMILES: [OH-].[Na+:2].[C:3]1([C:9]2[CH:10]=[C:11]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH:24]=[CH:23][C:19]=3[C:20]([OH:22])=[O:21])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[C:3]1([C:9]2[CH:10]=[C:11]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH:24]=[CH:23][C:19]=3[C:20]([O-:22])=[O:21])=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[Na+:2]
Reactant: O=C(Nc1cc(-c2ccccn2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc(-c2ccccn2)ccc1C(=O)[O-])c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethanol (2.0 mL) and a 2 mol/L aqueous solution of sodium hydroxide (0.094 mL) were sequentially added to the obtained 2-(5-phenylpyridine-3-carboxamido)-4-(pyridin-2-yl)benzoic acid (74 mg), followed by stirring at room temperature for 1 hour and 30 minutes. The solid substance was collected by filtration to obtain 59 mg of sodium 2-(5-phenylpyridine-3-carboxamido)-4-(pyridin-2-yl)benzoate as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:30])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[CH3:30]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e=408.1 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].[CH3:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1B(O)O>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][C:26]=4[CH3:25])=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: Cc1ccncc1B(O)O
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: Cc1ccncc1-c1ccc2c(c1)-c1nc(C(=O)N(CCO)C(C)C)sc1CCO2
Yield: 8 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.3 mg, 0.127 mmol) and 4-methylpyridin-3-ylboronic acid (21.0 mg, 0.153 mmol) were reacted to give 280 (4.3 mg, 8% yield, M+1 424.1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:29])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:43][OH:44]>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:29])[CH2:16][C:17]([NH:43][OH:44])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C(CC(=O)O)N2Cc3ccccc3C2=O)cc1OC1CCCC1
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2Cc3ccccc3C2=O)cc1OC1CCCC1
Yield: 91.5 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide was prepared by the procedure of Example 1 from 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (1.00 g, 2.53 mmol), carbonyldiimidazole (430 mg, 2.66 mmol) and hydroxylamine hydrochloride (230 mg, 3.29 mmol) in tetrahydrofuran (5 mL) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(1-oxoisoindolinyl)propionamide as a white solid (950 mg, 91% yield): mp, 183.0-184.5° C.; 1H NMR (DMSO-d6) δ1.54-1.82 (m, 8H, C5H8), 2.82-2.86 (m, 2H, CH2), 3.70 (s, 3H, CH3), 4.13 (d, J=17.5 Hz, NCHH), 4.55 (d, J=17.5 Hz, 1H, NCHH), 4.73 (m, 1H, CH), 5.74 (t, J=7.6 Hz, 1H, NCH), 6.85-6.93 (m, 3H, Ar), 7.47-7.70 (m, 4H, Ar), 8.84 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ23.50, 32.11, 32.18, 46.20, 51.17, 55.53, 79.52, 112.21, 114.00, 119.14, 122.78, 123.43, 127.85, 131.31, 131.86, 132.27, 141.65, 146.87, 149.07, 166.04, 166.91; Anal Calcd for C23H26N2O5 0.7H2O: C, 65.30; H, 6.53; N, 6.62. Found: C, 65.59; H, 6.38; N, 6.65; H2O, 2.94.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:40])[CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:30](=[O:40])[CH2:31][C@H:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH2:33])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@H](CC(=O)NCc1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N[C@H](CC(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Yield: 81.9 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (154 mg, 0.53 mmol, 1.0 eq), L-β-phenylalanine N-benzylamide (286 mg, 1.06 mmol, 2.0 eq) and dichloromethane (1.5 mL), was treated with triethylamine (442 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (673 uL, 2.0 eq), to provide 229 mg (81%) of L-β-phenylalanine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13](=O)[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.[NH2:19][OH:20].[OH-].[Na+].Cl>CCO.O>[CH:1]([C:4]1[C:12]([C:13](=[N:19][OH:20])[CH:14]([CH3:16])[CH3:15])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C(=NO)c1c(C(C)C)nn2ccccc12
Temperature: 0 °C
Yield: 48.9 %

Procedure:
To a solution of 2.3 g (10 mmol) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added hydroxylamine hydrochloride 1.5 g (20 mmol), followed by dropwise addition of 2.4 g NaOH in 6 ml of water. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 8.3 ml of 6N HCl and 380 ml ice water with stirring for 30 minutes. The precipitate was filtered and washed with ethyl ether-hexane to furnish 1.2 g (74.5%) of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime (as a mixture of cis- and trans-isomers), which was separated on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 0.3 g (cis-) and 0.325 g (trans-) isomers of 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1012.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:10][C:5]2=[N:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:10][C:5]2[N:6]([C:2]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:3][N:4]=2)[N:7]=1
Reactant: C1CCNCC1
Reactant: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Product: Clc1ccc(-c2cc3nnc(N4CCCCC4)n3nc2-c2ccccc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
A suspension of 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (22 mg, 0.06 mmol) in piperidine (0.5 mL) was stirred at 100° C. for 16 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The crude product was purified using reverse phase preparative HPLC (Conditions: Phenomenex Luna 5μ C18 21.2×100 mm; Eluted with 60% to 100% B, 8 min gradient, 100% B hold for 7 min, (A=90% H2O, 10% MeOH, 0.1% trifluoroacetic acid and B=10% H2O, 90% MeOH, 0.1% trifluoroacetic acid); Flow rate at 20 mL/min, UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3, water, saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was lyophilized in acetonitrile to afford 12 mg (48%) of the title compound as a yellow powder. HPLC/MS (method A): retention time=3.82 min, (M+H)+=424.1. 1H NMR (CDCl3, 400 MHz): δ 7.92 (s, 1H), 7.29-7.39 (m, 4H), 7.21 (d, J=8.56 Hz, 2H), 7.04 (d, J=8.56 Hz, 2H), 3.66 (s, 4H), 1.72-1.81 (m, 4H), 1.69 (d, J=4.89 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][CH2:29][C:30]1[N:31]=[N:32][N:33]([CH3:35])[N:34]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[OH:21])[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cn1nnc(CNc2ccccc2O)n1
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(Cc2nnn(C)n2)c2ccccc2O)[C@H]1O
Yield: 21 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (370 mg, 1.32 mmol) obtained in step 1 of example 2 and N-(2-hydroxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=1:2), to give desired compound (140 mg, yield: 21%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:10][C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)([CH3:17])[C:8]([C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:3][CH:4]=1)=[O:18]
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C(=O)c1ccc(N2CCOCC2)cc1)N1CCOCC1
Temperature: 160 °C
Reaction time: 18 h

Procedure:
15.08 g (0.06 mol) of 1-(4-fluorophenyl)-2-methyl-2-morpholinopropan-1-one and 5.23 g (0.06 mol) of morpholine are dissolved in 25 ml of dimethyl sulfoxide, and the solution is heated to 160° C. together with 8.3 g (0.05 mol) of potassium carbonate. After 18 hours of stirring at about 160° C. the suspension is cooled down and is poured onto an ice-water mixture. The crystals are filtered off, are washed with water and are recrystallised from ethanol. Melting point 114°-116° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:11]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Product: Oc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
0.005 mol of 4-aminoresorcinol hydrochloride were dissolved in 7.5 ml of benzoyl chloride, while heating, and the solution was then boiled under reflux for 7 hours. The excess benzoyl chloride was subsequently distilled off in vacuo, 10 ml of ethanol were added to the residue and the mixture was boiled up briefly and, after cooling, rendered alkaline with 10M NaOH solution. The alkaline solution was introduced into 200 ml of water and brought to pH 3 with concentrated hydrochloric acid, using a pH-meter. The crystal mass which precipitated here was filtered off with suction and recrystallized from 15 ml of toluene. The dried product (250 mg) was uniform according to thin layer chromatography (silica gel plate, ethyl acetate/glacial acetic acid 24:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH2:12][CH:14]1[CH2:15][O:16]1
Reactant: ClCC1CO1
Reactant: COc1ccc(O)cc1OC
Product: COc1ccc(OCC2CO2)cc1OC

Procedure:
The title compound was prepared from 3,4-dimethoxy-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.