Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:25][C:26]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[CH2:29][CH2:30][C:26]([F:31])([F:25])[CH2:27]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Reactant: FC1(F)CCNC1
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(N4CCC(F)(F)C4)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from rac-(1S,35)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and 3,3-difluoro-pyrrolidine to afford the desired product as a light yellow oil. MS (EI): 458.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6](=[O:12])[CH:5]=1.[C:13]([O:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21]Cl)(=[O:15])[CH3:14].[Cl-].[Na+]>CS(C)=O>[C:13]([O:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][N:7]1[C:6](=[O:12])[CH:5]=[C:4]([NH2:3])[N:9]([CH3:10])[C:8]1=[O:11])(=[O:15])[CH3:14]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: CC(=O)O[C@H](C)CCCCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a stirring suspension of sodium hydride (5.52 g, 230 mmol) in anhydrous dimethylsulfoxide (500 ml) was added 6-amino-1-methyluracil (28.2 g, 200 mmol). After stirring at room temperature under argon for 2 hours, (R)-5-Acetoxy-1-chlorohexane (37.5 g, 210 mmol) was added neat and the mixture was stirred at 80° C. for 16 hours. After cooling to room temperature, the mixture was poured into saturated aqueous sodium chloride solution (1500 ml) and extracted with ethyl acetate (9×200 ml). The combined extracts were washed with water (2×50 ml), with saturated aqueous sodium chloride solution (50 ml) and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting oil was treated with ethyl ether (400 ml). After stirring overnight at room temperature, the precipitate was filtered and rinsed with ether (2×50 ml) to provide (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (44.0 g, 78% yield) as a beige powder.
Reaction SMILES: [CH:1]([S:4][CH:5]([C:17]([OH:19])=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:35][C:36]1[CH:49]=[CH:48][CH:47]=[CH:46][C:37]=1[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39]>C(Cl)Cl>[CH:1]([S:4][CH:5]([C:17]([NH:35][C:36]1[CH:49]=[CH:48][CH:47]=[CH:46][C:37]=1[C:38]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:39])=[O:19])[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8])([CH3:2])[CH3:3]
Reactant: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)SC(NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
α-(isopropylthio)-N-(benyloxycarbonyl)glycine 22B was dissolved in methylene chloride (200 mL) under nitrogen atmosphere at 0° C. in a three necked flask carrying an additional funnel. To the stirred solution was added N-methylmorpholine (2.11 mL, 19.3 mmol) followed by isobutylchloroformate (2.48 mL, 19.2 mmol). This was stirred for 15 minutes at 0° C. and then heated to reflux. To the refluxing reaction mixture was added a solution of 2-aminobenzophenone 23 (3.59 g, 18.19 mmol) in dry methylene chloride (26 mL) over 20 minutes. The reaction mixture was stirred for 20 more minutes after the addition and then left stirring overnight at room temperature. The reaction mixture was washed with 10% citric acid, saturated sodium bicarbonate solution and brine, then dried over magnesium sulphate. Solvent evaporated at reduced pressure to give 9.30 g of the crude product 24. This was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1([NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].C(N(CC)CC)C.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[C:11]1([C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[O:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(=O)NC1(c2ccc(C(C)C)cc2O)C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)C(C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A solution of pentanoic acid [2-(2-hydroxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl]-amide (0.10 g, 0.26 mmol) in anhydrous methylene chloride (10 ml) was added triethylamine (0.03 g, 0.31 mmol) and pivaloyl chloride (0.047 g, 0.39 mmol) and then stirred for 2 hrs. The reaction mixture was concented and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.11 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]([CH2:24][NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)([CH3:4])([CH3:3])[CH3:2].N#N.[H][H]>CCO.[Pd]>[C:1]([O:5][C:6](=[O:37])[NH:7][C@H:8]([CH2:24][NH:25][C:26]([C:28]1[C:33]([NH2:34])=[N:32][C:31]([NH2:35])=[C:30]([Cl:36])[N:29]=1)=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CNC(=O)c1nc(Cl)c(N)nc1N
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of ((S)-5-benzyloxycarbonylamino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (680 mg, 1.27 mmol) in EtOH (20 mL) under an inert atmosphere of N2 is treated with activated palladium on charcoal (10%). The reaction mixture is then placed under a positive pressure of hydrogen and stirred at RT. After 3 h, the mixture is purged with N2 and the catalyst is removed by filtration through Celite® (filter material). The filtrate is concentrated in vacuo and the resulting colourless oil is dissolved in MeOH (10 mL) and allowed to stand at RT overnight. The cream precipitate which forms is removed by filtration and the solution is concentrated in vacuo. The resulting crude product is purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water with 0.1% NH3) to afford the title compound. [M+H]+ 402.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH3:17][S:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:9][CH2:8][CH2:7][CH2:6]1)(=[O:15])=[O:16]
Reactant: COC(=O)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)CCCCC1(C(=O)O)CCCC1
Temperature: 52.5 °C
Yield: 92.3 %

Procedure:
To a solution of 1-[4-(methylsulfonyl)butyl]cyclopentane carboxylic acid methyl ester (18.8 mmol, 4.94 g) in a mixture of THF (38 mL) and methanol (38 mL) was added 1 N sodium hydroxide (38 mL). The mixture was heated to 50-55° C. for 15 h at which point TLC analysis of the reaction mixture indicated the absence of starting material and the mixture was allowed to cool to room temperature. The solvent was removed under vacuum and the residue was diluted with water (100 mL) and extracted with ether (2×50 mL) to remove any neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2×75 mL). The combined extracts were washed with brine solution and dried over anhydrous sodium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was dried under high vacuum to afford 4.31 g (92%) of the title compound as a low melting white solid. LR MS (C11H20O4S): 249 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13](O)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[C:9]1=[O:22].[CH3:23][C:24]1[C:25]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[N:26][C:27]([CH3:30])=[CH:28][N:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]([C:13]([N:34]2[CH2:35][CH2:36][N:31]([C:25]3[C:24]([CH3:23])=[N:29][CH:28]=[C:27]([CH3:30])[N:26]=3)[CH2:32][CH2:33]2)=[O:14])[CH2:11][N:10]([S:16]([CH:19]([CH3:21])[CH3:20])(=[O:17])=[O:18])[C:9]1=[O:22]
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Reactant: CC(C)S(=O)(=O)N1CC(C(=O)O)N(c2ccccc2Cl)C1=O
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)C(C)C)C(=O)N3c3ccccc3Cl)CC2)n1

Procedure:
In analogy to example 1, (RS)-3-(2-chloro-phenyl)-2-oxo-1-(propane-2-sulfonyl)-imidazolidine-4-carboxylic acid (example 85, step 2) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl to give the title compound as a colorless solid. MS: 521.3 ([M+H]+)
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21](=[O:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CO>C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: CO
Product: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
The (1α,3β)-1,3-bis((tert-butyl(dimethyl)silyl)oxy)pregna-5,7,16-trien-20-one synthesized in Example 24 (45.0 g) was dissolved in toluene (240 ml) and then cooled to −20° C., followed by stirring for 30 minutes. Borane-dimethylsulfide complex (22.9 ml) was added to the resulting solution at −20° C. and stirred for 5 minutes. A 1M toluene solution of (R)-2-methyl-CBS-oxazaborolidine (22.9 ml) was further added to the solution at −20° C. and stirred for 1 hour. Methanol was added to the reaction mixture, which was then extracted with ethyl acetate. The extracted solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (liquid phase: hexane/ethyl acetate=9/1) to give the titled compound (23.3 g, yield 89%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:29]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCOCC1
Reactant: O=C(O)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(Br)c1-c1cc(NC(=O)C2CCCC2)ccc1OCCN1CCOCC1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (76 mg, 0.2 mmol), cyclopentyl carboxylic acid (27 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 30 min. The crude was purified by HPLC to give title compound (20 mg, 21%) as a brown solid as TFA salt. 1H NMR (CD3CN, 400 MHz) δ 1.66-1.95 (m, 8H), 2.70-2.80 (m, 1H), 2.85-3.02 (m, 2H), 3.13-3.27 (m, 2H), 3.43 (t, 2H), 3.73 (s, 3H), 3.74-3.80 (m, 2H), 3.82-3.96 (m, 2H), 4.34-4.48 (m, 2H), 7.13 (d, J=9.09 Hz, 11), 7.55 (d, J=2.53 Hz, 1H), 7.57 (s, 1H), 7.76 (dd, J=2.78, 9.35 Hz, 1H), 8.38 (s, 1H). Exact mass calculated for C22H2979BrN4O3 476.1. found 477.3 (M+H 79Br, 100), 479.3 (M+H 81Br, 98).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][NH:18][CH2:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:35]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:34]=[CH:33][C:16]([CH2:17][N:18]([CH2:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:42](=[O:43])[CH2:41][CH2:40][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNCc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc4c(c3)C(=O)OC(C)(C)O4)C(=O)CCC3CCCC3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using 6-[({4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride as a colorless oil (72%). 1H NMR (CDCl3, 300 MHz) δ 7.74 (m, 1H), 7.50 (m, 2H), 7.43 (m, 2H), 7.35-7.21 (m, 1H), 7.20-6.85 (m, 5H), 4.56 (m, 2H), 4.52-4.40 (m, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.42 (m, 2H), 1.80-1.62 (m, 11H), 1.61-1.30 (m, 8H). 1.18-1.00 (m, 2H), 0.92 (t, J=7.2 Hz, 3H). HPLC, Rt: 6.11 min (Purity; 98.7%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:4]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(CO)cc1S(C)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: Cc1ccc(CN=[N+]=[N-])cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A round bottom flask was charged with (4-methyl-3-(methylsulfonyl)phenyl)methanol (6.0 g, 30.14 mmol), toluene (70 mL). Diphenyl phosphoryl azide (7.8 mL, 36.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 mL, 36.1 mmol) were added at 0° C. and the reaction mixture was stirred over night at room temperature. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organic phases were concentrated under reduced pressure and the residue was purified by column chromatography to get the title compound (4 g, 62% yield).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8]1([NH2:11])[CH2:10][CH2:9]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:8]1([NH:11][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH2:9]1
Reactant: CCOC(=O)CBr
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
Ethyl bromoacetate (1 eq.) was added slowly to an ice-cold solution of cyclopropylamine (17.5 mmol, 3 eq.) and K2CO3 (2 eq.) in DMF (25 ml) and the reaction mixture was then stirred at room temperature for 16 h. For working up, the mixture was diluted with an excess of water and extracted with 20% ethyl acetate/hexane solution. The organic phase was washed with water and sat. NaCl solution and dried over Na2SO4. After the solvent had been removed completely, the crude product was employed in the next stage without further purification. Yield: 52%
Reaction SMILES: [CH3:1][C:2]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:3][OH:4].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][C:2]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:3][O:4][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(CO)[N+](=O)[O-]
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(COCc1ccccc1)[N+](=O)[O-]
Reaction time: 48 h
Yield: 15.2 %

Procedure:
To a suspension of 2-methyl-2-nitro-1-propanol (2.3975 g, 20.13 mmol) and Ag2O (4.6385 g, 20.02 mmol) in DMF (25 ml) was added benzyl bromide (2.65ml, 22.28 mmol) and stirred for 48 hours. The mixture was filtered and the filtrate was added to 5% KHSO4 aqueous solution, extracted three times with ethyl acetate/hexane=1/1 and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (toluene) to give the title compound (639.4 mg; 15%).
Reaction SMILES: C[CH2:2][CH2:3][CH:4]([C:6]1(CC)C(=O)NC(=O)[NH:9][C:7]1=O)[CH3:5].Cl[C:18](Cl)(Cl)[CH:19]([OH:21])O.C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)CO)=CC=C([N+]([O-])=O)C=1>>[NH2:9][CH2:7][CH2:6][C:4]1[CH:5]=[CH:18][C:19]([OH:21])=[CH:2][CH:3]=1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CCCC(C)C1(CC)C(=O)NC(=O)NC1=O
Agent: *CC*
Agent: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Product: NCCc1ccc(O)cc1
Reaction time: 2 h

Procedure:
Rats were anesthetized with a mixture of pentobarbital (30 mg/kg) and chloral hydrate (120 mg/kg) by intraperitoneal injection. The left carotid artery and jugular vein were cannulated with fine polytene tubing (artery) or fine silicone rubber tubing connected to polyethylene tubing (vein), the distal end of which was brought under the skin to an anchor point behind the neck. The tubing was filled with heparinized saline solution, and plugged with a fine steel rod. The animals were treated with 20 mg chloramphenicol by intramuscular injection and allowed to recover from the operation overnight. The following day, the rats were placed in a high-walled container permitting free movement. The arterial catheter was connected to a pressure transducer via a 100 cm length of saline-filled, fine-bore polyethylene tubing, and the venous catheter connected to a 1 ml syringe via a similar length of tubing, which, together with the syringe, contained a solution of tyramine hydrochloride in saline (1 mg/ml). Following an equilibration period of 30 to 40 minutes, tyramine injections (50 or 100 μg) were given and blood pressure responses recorded. An interval of at least 15 minutes was maintained between injections after return of blood pressure to control values. Control pressor responses were established, then one of the drugs was injected intraperitoneally, and tyramine responses were repeated over the next 4 hours. The area under the blood pressure response curve was estimated, and the ratio of this area after treatment to before treatment and to 1 to 3 hours after injection of the compounds, was determined using the average of 3 to 4 values obtained in the control period.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[H-].[Na+].CN(C)C=O.Br[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:35][C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: BrCc1cccs1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(Cc2cccs2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.8 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-(bromomethyl)thiophene (4.5 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.74 g, 58%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[N:23](C5CCCCO5)[CH:22]=[N:21][N:20]=4)=[CH:15][CH:14]=3)[N:11]=2)[NH:6][C:5](=[O:30])[CH2:4]1)[CH3:2].[ClH:31]>C(O)C.O1CCOCC1>[ClH:31].[N:21]1[N:20]=[C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:10]3[N:11]=[C:12]4[N:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:30])[NH:6][C:7]4=[N:8][CH:9]=3)=[CH:14][CH:15]=2)[NH:23][CH:22]=1
Reactant: CCN1CC(=O)Nc2ncc(-c3ccc(-c4nncn4C4CCCCO4)cc3)nc21
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCN1CC(=O)Nc2ncc(-c3ccc(-c4nnc[nH]4)cc3)nc21
Temperature: 75 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
4-Ethyl-6-(4-(4-(tetrahydro-2H-pyran-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one in ethanol was treated with 2 N hydrogen chloride in dioxane. The solution was stirred at 75° C. for 1 h. The solution was condensed partially and cooled. Cold ethanol was added to the slurry and the resulting precipitate filtered and washed with additional cold ethanol followed by hexanes to afford the title compound as the hydrochloride salt in 82% yield. 1H NMR (400 MHz, METHANOL-d4) δ (ppm) 9.18 (s, 1H), 8.22 (d, J=8.59 Hz, 2H), 8.04-8.09 (m, 3H), 7.66-7.74 (m, 1H), 7.58-7.64 (m, 1H), 4.24 (s, 2H), 3.74 (q, J=7.03 Hz, 2H), 1.29 (t, J=7.03 Hz, 4H), 0.79-0.98 (m, 4H); MS (ESI) m/z 322.2 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C:16](=[O:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:19][Mg]Br>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[F:9][C:6]1[CH:5]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C:16]([OH:18])([CH3:19])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:3]=[C:2]([F:1])[C:7]=1[F:8]
Reactant: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1

Procedure:
To a solution of 1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanone (529 mg) in tetrahydrofuran (25 mL) was, under a nitrogen atmosphere, dropwise added methylmagnesium bromide (0.97 M tetrahydrofuran solution, 4.63 mL) at 0° C. The resultant solution was stirred for 1 hour at the same temperature, and then diluted with aqueous ammonium chloride and ethyl acetate. The organic layer was partitioned, washed with brine, and then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate), to thereby obtain the titled compound (330 mg). The physical properties of this crude product were as follows.