Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]2=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:24]>C(OCC)(=O)C>[ClH:24].[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]2=[O:23])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN2CCOCC2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1CCCN1CCOCC1
Reaction time: 0.5 h

Procedure:
Through a solution of tert-butyl 4-(3-morpholin-4-ylpropyl)-3-oxopiperazine-1-carboxylate (45 mg, 0.14 mmol) in 5 mL of ethyl acetate at 0° C. was bubbled HCl gas for 2 minutes. After stirring an additional 30 minutes, the reaction was concentrated in vacuo to provide the titled product. ESI+MS: 228.4 [M+H]+.
Reaction SMILES: [C-]#N.[K+].[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].[C:13]([O:17][CH2:18]C)(=[O:16])[CH:14]=[CH2:15].O>CN(C)C=O>[CH3:18][O:17][C:13](=[O:16])[CH2:14][CH2:15][C:8]([C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([F:4])[CH:6]=1)=[O:9]
Reactant: O=Cc1cccc(F)c1
Reactant: C=CC(=O)OCC
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(=O)c1cccc(F)c1
Temperature: 45 °C

Procedure:
To a stirred suspension of potassium cyanide (3.25 g) in N,N-dimethylformamide (30 cm3), being maintained at a temperature of 45° C., was added 3-fluorobenzaldehyde (25.0 g). Ethyl acrylate (18.46 cm3) was then added and the resultant mixture was stirred at 40° C. for 2 h. Water (200 cm3) was added and the aqueous mixture was extracted with diethyl ether (2×125 cm3). The organic extracts were washed with water (100 cm3) and saturated aqueous sodium chloride solution (100 cm3) before being dried (Na2SO4) and the solvent was removed under reduced pressure to yield the title compound (25.27 g) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:13])[CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:13])[CH2:9][N:10]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CNC2=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a mixture of 4′-[(7-ethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-thieno[2,3-e][1,4]diazepin-1-yl)methyl]biphenyl-2-carbonitrile (0.52 g), 1-(bromomethyl)-4-fluorobenzene (0.24 mL) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.078 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.38 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[N-:14]=[N+]=[N-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:13])[NH:14][C:11]=2[CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)NC(=O)CCC2
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Combined 7-Methoxy-1-tetralone (5.0 g, 0.028 mol;) with Polyphosphoric acid (80 g, 0.7 mol;) in 2-neck 500 ml Flask fit with overhead mechanical stirrer and septa under nitrogen flow. Sodium azide (2.2 g, 0.034 mol;) added portionwise over 5 min and the reaction was heated to 55° C. Continue stirring overnight. The mixture was poured into water and a white precipitate ensued. The mixture was filtered and washed with water then hexane and dried over 60 h. 8-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one obtained as a white solid (3.34 g, 62%). MP: 103-104° C.; 1H-NMR (CDCl3, 400 MHz) δ 7.45 (broad s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.72-6.69 (m, 1H), 6.54 (d, J=2.1 Hz, 1H), 3.81 (s, 3H), 2.76 (t, J=7.2 Hz, 2H), 2.38 (t, J=7.3 Hz, 2H), 2.25-2.18 (m, 2H); LC/MS: 192.07 (M+H).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(=O)(O)[O-].[K+].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(OC(=O)C)(=O)C>[CH:19](=[C:2]1[C:1](=[O:12])[O:13][C:4]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OC(c2ccccc2)=NC1=Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
1.8 g of hippuric acid and 0.4 g of potassium bicarbonate are dissolved in 4 ml of acetic anhydride, the solution is heated for a few minutes at 50° C. and then cooled to room temperature and 1.49 g of benzaldehyde are added. After 1 hour at room temperature, 20 ml of distilled water are added at 80° C. The solid which precipitates is filtered off, washed with water and ethanol and then dried to give 1.24 g of the expected product in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=O)[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:16]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH2:14][N:15]1[C:20]2[N:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[S:40])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:16]1
Reactant: CCOC(=O)c1nn(Cc2ccc(-c3cccnc3)nc2C)c2ncccc2c1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccc(-c3cccnc3)nc2C)c2ncccc2c1=S
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-[(6-methyl-2,3′-bipyridin-5-yl)methyl]-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxylate (139 mg, 0.346 mmol) was suspended in dioxane (6 mL) and toluene (3 mL), placed into a preheated oil bath at 100° C. and treated with Lawesson's Reagent (84.0 mg, 0.208 mmol, 0.6 equiv) portionwise over 5 minutes. After stirring for 30 minutes, the mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound as brownish-green foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]CC)[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CC)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][O:88][CH2:89][CH2:90][O:91][CH2:92][CH2:93][P:94](=[O:101])([O:98][CH2:99][CH3:100])[O:95][CH2:96][CH3:97]>C(Cl)Cl>[CH2:99]([O:98][P:94]([CH2:93][CH2:92][O:91][CH2:90][CH2:89][O:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][NH:82][C:13](=[O:14])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:16][S:17][CH2:18][C@H:19]([O:35][C:36](=[O:48])[NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:20][O:21][C:22](=[O:34])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:101])[O:95][CH2:96][CH3:97])[CH3:100]
Reactant: CCCCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)OC(=O)NCCCCCCCCCC
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCNC(=O)OC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)NCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-(benzyloxycarbonylamino)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio) propanoic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as an opaque oil.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC.O.Cl>CN(C)C=O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:6]2[C:5]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[C:31](=[O:33])[CH3:32])=[CH:12][CH:13]=1
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 6-chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d (202 mg, 0.49 mmol) and tetrakis(triphenylphosphine) palladium(0) (60 mg, 0.049 mmol) in dimethylformamide (1.5 ml) was degassed and to it was added tributyl-(1-ethoxyvinyl)-stannane (250 μl, 0.74 mmol). The reaction mixture was heated to 100° C. until completed as shown by TLC. A solution of 2:1 of H2O/conc. HCl (1.5 ml) was added to the reaction mixture and the heating continued for 1 hour. The reaction was diluted with ethyl acetate and washed with water. The organic layers were combined, dried (Na2SO4), filtered, and concentrated to dryness. The crude material was purified via TLC preparative plate using 30% ethyl acetate/hexanes as the solvent to afford the desired product I-(15A-1)a (50 mg, 25%): +ESI MS (M+1) 417.3; 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 7.58 9 (d, J=8.7 Hz, 1H), 7.43–7.30 (m, 4H), 7.21 (d, J=8.7 Hz, 2H), 2.92 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]([C:6]=23)=[N:4][NH:3]1.C(Cl)Cl.[CH2:32]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH:35]1[CH3:40])[CH3:33].[BH4-].[Na+]>CC(O)=O>[CH2:32]([N:34]1[CH2:39][CH2:38][N:37]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([CH:13]3[NH:12][C:7]4[C:6]5[C:5](=[N:4][NH:3][C:2](=[O:1])[C:11]=5[CH:10]=[CH:9][CH:8]=4)[CH:14]3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:28][CH:27]=2)[CH2:36][CH:35]1[CH3:40])[CH3:33]
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Reactant: CCN1CCNCC1C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccccc3)cc2)CC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (86 mg, 0.23 mmol) in dryness DCM (15 mL) was added HOAc followed by 1-ethyl-2-methylpiperazine (90 mg, 0.7 mmol), after the addition the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (85 mg, 1.4 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as white solid (90 mg, yield 71%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.30 (t, 3H), 1.42 (m, 3H), 3.23 (s, 1H), 3.47-3.56 (m, 6H), 3.80 (t, 2H), 4.46 (m, 3H) 4.91 (m, 10H), 7.20-7.29 (m, 3H), 7.30-7.32 (m, 3H), 7.46-7.48 (m, 3H), 7.59 (m, 1H), 7.69 (t, 1H). LC-MS (ESI) m/z: 552(M+1)+.
Reaction SMILES: CO.[C:3]([NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([F:22])=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[C:14]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[N:13]=2)[CH2:8]1)(=[O:5])[CH3:4].[OH-].[Na+]>O1CCCC1.O.C(OCC)(=O)C>[C:3]([NH:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]2[C:21]([F:22])=[CH:20][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[N:13]=2)[CH2:8]1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CCC(NC(C)=O)C2)nc1Nc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(=O)NC1CCN(c2nc(Nc3ccc(F)cc3F)c(C(=O)O)cc2F)C1
Yield: 93 %

Procedure:
In a mixture of 30 ml of tetrahydrofuran, 10 ml of methanol and 4 ml of water was suspended 980 mg of methyl 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinate, and 5.3 ml of 1N aqueous sodium hydroxide solution was added thereto, after which the resulting mixture was subjected to reaction at 65° C. for 3 hours. Subsequently, the reaction mixture was added to a mixture of 50 ml of ethyl acetate and 50 ml of water, and the aqueous layer was separated, after which the pH thereof was adjusted to 2.0 with 1N hydrochloric acid. The crystals thus deposited were collected by filtration and washed successively with 2 ml of water and 2 ml of ethanol to obtain 880 mg (yield 93.0%) of 6-(3-acetylamino-1-pyrrolidinyl)-2-(2,4-difluorophenylamino)-5-fluoronicotinic acid having a melting point of 232°-234° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:8][CH2:9][C:10]1[NH:11][C:12](=[O:20])[C:13]2[CH2:19][O:18][CH2:17][CH2:16][C:14]=2[N:15]=1)[CH3:7].[F:21][C:22]1[CH:39]=[CH:38][C:25]([C:26]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35](O)=[O:36])[CH2:30][CH2:29]2)=[O:27])=[CH:24][CH:23]=1.CC#N.O>C(O)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([CH:28]2[CH2:29][CH2:30][N:31]([CH2:34][C:35]([N:8]([CH2:9][C:10]3[NH:11][C:12](=[O:20])[C:13]4[CH2:19][O:18][CH2:17][CH2:16][C:14]=4[N:15]=3)[CH:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[CH3:7])=[O:36])[CH2:32][CH2:33]2)=[O:27])=[CH:38][CH:39]=1
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: CC(NCc1nc2c(c(=O)[nH]1)COCC2)c1cccs1
Solvent: CC#N
Solvent: O
Solvent: O=CO
Product: CC(c1cccs1)N(Cc1nc2c(c(=O)[nH]1)COCC2)C(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1

Procedure:
Following the general procedure of Example 1, the title compound was prepared (0.02 g) from 2-((1-(thiophen-2-yl)ethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. 1H NMR (400 MHz, MeOD) δ ppm 8.04-8.17 (m, 2H), 7.22-7.46 (m, 3H), 6.99-7.17 (m, 1H), 6.86-6.95 (m, 1H), 6.09-6.24 (m, 1H), 5.36-5.47 (m, 1H), 4.24-4.64 (m, 6H), 3.85-3.95 (m, 2H), 3.69-3.83 (m, 2H), 3.38-3.64 (m, 1H), 3.11-3.27 (m, 1H), 2.49-2.68 (m, 2H), 1.99-2.26 (m, 4H), 1.74-1.85 (m, 1H), 1.55 (d, J=7.03 Hz, 2H). HRMS calculated for C29H31F1N4O4S1 539.2128. found (ESI, [M+H]+) 539.2128. MS (ESI) m/z 539.2. (M+H)+. Retention time: 3.21 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@H:24]([C:31]([OH:33])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1.[OH-].[Na+]>O.O1CCOCC1>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@H:24]([C:31]([OH:33])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O

Procedure:
1.25 g of Boc-Pro-OSu [G. W. Anderson et al., J. Amer. Chem. Soc. 86, 1839 (1964)] and 0.68 g of H-His-OH are suspended in 4 ml of H2O and 2 ml of dioxan. While stirring vigorously, 2N NaOH is added by means of a pH stat at a pH value of 9.0. After 45 minutes the absorption of NaOH ceases. The now clear solution is stirred for a further 10 minutes, the pH value is adjusted subsequently to 5.0 with 4N HCl, and the whole is concentrated to approximately 5 ml. After the addition of 20 ml of H2O, the whole is again concentrated to approximately 5 ml and then purified by chromatography over a column of absorber resin, diaion HP-20 (φ=1.6 cm; length=20 cm). The bulk of this product is eluted with 20% isopropanol in H2O. The fractions that are pure according to thin layer chromatography are combined, concentrated almost to dryness and, after the addition of H2O, lyophilised, yielding Boc-Pro-His-OH in the form of an amorphous powder; Rf (E)=0.45; Rf (A)=0.21.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[CH:6][CH:5]=1.Br[CH2:16][C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.[Cl-].[NH4+]>CN(C)C=O>[S:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[CH2:16][S:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[CH:8][CH:9]=1
Reactant: BrCc1nc2ccccc2s1
Reactant: COC(=O)Nc1ccc(S)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)Nc1ccc(SCc2nc3ccccc3s2)cc1
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
100.5 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 418.5 mg of methyl N-(4-mercaptophenyl)carbamate [prepared as described in step (a) above] in 8.4 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 10 minutes, and then 573.1 mg of 2-bromomethylbenzothiazole were added. The temperature of the reaction mixture was then elevated to room temperature and the mixture was stirred for 3.5 hours. At the end of this time, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The resulting extract was washed consecutively with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure to give a crude crystalline solid which was purified by column chromatography through silica gel using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 462.7 mg (yield 81%) of the title compound as a solid having a melting point of 139° to 141° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]#[N:12])[CH:7]=1.[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:19]#[C:20][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][C:10]=3[C:11]#[N:12])[CH:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1cnn2cc(Br)cnc12
Product: N#Cc1cnn2cc(C#Cc3ccccc3)cnc12

Procedure:
The title compound, yellow solid, MS: m/e=245.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo(1,5-A)pyrimidine-3-carbonitrile and phenylacetylene.
Reaction SMILES: [CH2:1]([C:3]([CH2:22][CH3:23])([P:18]([OH:21])([OH:20])=[O:19])[C@H:4]1[CH2:13][CH2:12][C@@H:11]2[C@@H:6]([CH2:7][CH2:8][N:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)[CH2:5]1)[CH3:2].[CH3:24][OH:25]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.C([N+](CC)(CC)CC)C>[CH2:22]([C:3]([CH2:1][CH3:2])([P:18]([OH:20])([OH:21])=[O:19])[CH:4]1[CH2:13][CH2:12][CH:11]2[CH:6]([CH2:7][CH:8]([O:25][CH3:24])[N:9]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)[CH2:5]1)[CH3:23]
Reactant: CO
Reactant: CCC(CC)([C@H]1CC[C@H]2CN(C(=O)OC)CC[C@H]2C1)P(=O)(O)O
Agent: CC[N+](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCC(CC)(C1CCC2CN(C(=O)OC)C(OC)CC2C1)P(=O)(O)O

Procedure:
Four carbon plate electrodes were immersed into a solution containing the compound from Example 1 (250 mg), tetraethylammonium p-toluenesulfonate (21 mg), in methanol (10 ml). A constant current of 0.5 A was applied to the electrodes. Additional methanol (7.8 ml) was added to the reaction to replace methanol which was lost due to evaporation. After 550 coulombs of current had passed, the electrodes were removed and the solution was added to 10% brine. This mixture was extracted with ether (3×15 ml). The combined ether extracts were washed with water and with brine, dried over magnesium sulfate, and concentrated in vacuo at room temperature to give 237 ml of the title compound as an oil. The material was stored in the refrigerator and used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[OH:15].O>CN(C)C=O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]([OH:15])[CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:17][CH:18]=1)[CH3:23]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCc1ccc(C(O)CBr)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 68918.1 %

Procedure:
Into a solution of 9.635 kg (72.99 mol) of 4-hydroxy benzaldehyde dissolved in 50 lit. dimethylformamide was added 5.675 kg (236.45 mol) of sodium hydride in 5 lit. dimethylformamide and stirred for 15 min. To this was added 15 Kg (65.22 mol) of 2-bromo-1-(5-ethyl pyridin-2-yl)-ethanol dissolved in 500 lit dimethylformamide and stirring was continued for 1 hr. at 25 to 30° C. Reaction mixture was heated at 80 to 90° C. for 14 hr., allowed to cool to 25° C. and excess of water was added into it. Product was extracted with diethyl ether. Organic layer was dried (magnesium sulfate) and concentrated to obtain crude product, which was purified in methyl tert-butyl ether as described in example 17 to obtain 12,195 Kg (69%) pure 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde. m.p. 83° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1Br.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][N:42](C(OC(C)(C)C)=O)[CH:43]=2)O1>O.O1CCOCC1.CC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1[C:39]1[CH:40]=[N:41][NH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: O
Product: CC(C)n1nc(-c2nc(-c3cn[nH]c3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
Under nitrogen atmosphere, a solution of sodium carbonate (330 mg) in water (2.4 ml) was added to a suspension of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (300 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (573 mg) and tetrakis(triphenylphosphine)palladium (27 mg) in dioxane (6 ml) and the mixture was stirred at 100-105° C. for 4 hours. After addition of water (30 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (10:90 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-[5-amino-3-phenyl-6-(1H-pyrazol-4-yl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (211 mg).