Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[NH:3]1.Cl.Cl.[CH3:30][C:31]1([CH3:40])[CH2:36][NH:35][CH2:34][C:33]2[CH:37]=[N:38][NH:39][C:32]1=2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CO>[CH3:30][C:31]1([CH3:40])[CH2:36][N:35]([C:18]([C:17]2[CH:16]=[C:15]([N:12]3[CH2:13][CH2:14][CH:9]([N:8]4[CH2:7][CH2:6][C:5]5[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=5[NH:3][C:2]4=[O:1])[CH2:10][CH2:11]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:34][C:33]2[CH:37]=[N:38][NH:39][C:32]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: O=C(O)c1cccc(N2CCC(N3CCc4ccccc4NC3=O)CC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)CN(C(=O)c2cccc(N3CCC(N4CCc5ccccc5NC4=O)CC3)c2)Cc2cn[nH]c21
Temperature: 0 °C

Procedure:
70.0 mg (0.19 mmol) 3-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-benzoic acid, 60 mg (0.27 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-dihydrochloride, 100 μL (0.71 mmol) triethylamine and 70.0 mg (0.22 mmol) TBTU in 1 mL DMF were stirred overnight at RT. The reaction mixture was combined with 1 mL methanol and 10 mL ice water. The precipitated product was suction filtered, washed with water and diethyl ether and purified by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5](O)=O)[CH2:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[Br:30][C:31]1[CH:32]=[C:33]([NH2:38])[C:34]([NH2:37])=[CH:35][CH:36]=1.C(O)(=O)C>C(#N)C>[Br:30][C:31]1[CH:36]=[CH:35][C:34]2[NH:37][C:5]([C@@H:2]([NH:1][C:8](=[O:9])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH3:4])=[N:38][C:33]=2[CH:32]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Solvent: CC#N
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2cc(Br)ccc2[nH]1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 51 %

Procedure:
To a solution of Boc-Abu-OH (2.979 g, 14.66 mmol) in acetonitrile (50 mL) and 4-methylmorpholine (1.78 mL, 16.2 mmol) cooled to −20° C. was added isobutyl chloroformate (1.92 mL, 14.8 mmol) dropwise. The mixture was stirred for an additional 90 minutes at −20° C. and then 4-bromo-1,2-benzenediamine (2.86 g, 15.3 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. The solvent was evaporated, redissolved in ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetic acid (5.0 mL, 88 mmol) and stirred at room temperature for 18 hours. The acetic acid was removed in vacuo and purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient. The residue was recrystallised from a mixture of ethyl acetate/hexanes to afford the title compound (2.65 g, 51%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(O)(=O)C.[H][H]>CO.O1CCCC1.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 18.5 %

Procedure:
A solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylate (1.4 g) in a mixture of methanol (25 ml) and tetrahydrofuran (60 ml) was added to a mixture of 10% palladium-on-carbon (1.7 g), glacial acetic acid (7 ml) and methanol (20 ml) in an atmosphere of nitrogen. Hydrogen gas was introduced into the mixture and shaken for 8.5 hours at room temperature. After removing the insoluble substance by filtration, the filtrate was concentrated under reduced pressure. The residue was pulverized with diethyl ether, and the resultant substance was dissolved in an aqueous solution of sodium bicarbonate, washed with ethyl acetate and diethyl ether in turn and then the remaining ether was removed by bubbling with nitrogen gas. The resultant solution was adjusted to pH 4.5 with dilute hydrochloric acid, subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), and eluted with 20% isopropyl alcohol. Isopropyl alcohol was distilled off under reduced pressure and the remaining solution was lyophilized to give 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (185 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:39])[C:35]([F:38])([F:37])[F:36].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:32][CH2:33][C@H:34]([OH:39])[C:35]([F:38])([F:37])[F:36])=[O:30])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: NC[C@H](O)C(F)(F)F
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)C(F)(F)F)[nH]2)c1
Reaction time: 2 h
Yield: 64.8 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (408 mg, 0.94 mmol) synthesized in Example (18a), (2S)-3-amino-1,1,1-trifluoro-2-propanol (177 mg, 1.37 mmol) and 4-dimethylaminopyridine (224 mg, 1.87 mmol) were dissolved in dichloromethane (20 mL), and WSCI•HCl (193 mg, 1.01 mmol) was added at room temperature, followed by stirring for 2 hours under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (200 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-70%) to afford the desired product (339 mg, yield 67%) as a white amorphous substance.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=O)=[CH:11][N:10]=1.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C(N(CC)CC)C>[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([CH2:13][N:34]=[N+:35]=[N-:36])=[CH:11][N:10]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCc1ccc(C(F)(F)F)nc1
Reaction time: 3 h
Yield: 99 %

Procedure:
Into ethyl acetate was suspended 1.91 g of 6-(trifluoromethyl)nicotinic acid, and then 1.52 g of triethylamine and 3.03 g of DPPA were added thereto, followed by 3 hours of stirring. The reaction solution was washed with a saturated sodium bicarbonate aqueous solution and saturated saline and the solvent was removed by evaporation to obtain 2.0 g of 6-(trifluoromethyl)nicotinyl azide as a solid. The resulting acid azide was dissolved into 20 ml of toluene and the solution was heated and refluxed to convert the acid azide into 5-isocyanato-2-(trifluoromethyl)pyridine. Thereafter, 1 ml of methanol was added thereto at room temperature, followed by 1 hour of stirring. The reaction solution was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by evaporation to obtain 1.2 g of the title compound.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])=[O:8].[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>O.C(O)C>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[NH2:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][CH2:10][C:11]([NH:13][CH:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:15][C:16]([OH:18])=[O:17])=[O:12])=[O:8]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(N)c1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Solvent: O
Product: Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
LiOH x H2O (648 mg) was added to a solution of ethyl 3-{2-[(3-(amino)-benzoyl)amino]acetamido}-3-phenyl-propanoate from II.3b (1.5 g) in 300 ml of water and the mixture was stirred at room temperature for 24 h. It was then neutralized with trifluoroacetic acid and concentrated. After chromatographic purification (methylene chloride/methanol (2:1)), a solid was isolated. This was taken up in ethanol, filtered and a white solid was obtained after concentration of the filtrate (yield: 1.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH:9]([CH3:13])[N:8]=[C:7](C3C=CC=CC=3)[C:6]=2[CH:20]=1.[C:21]1([CH2:27][C:28]([NH:30][NH2:31])=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N#N>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:28]([CH2:27][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:30][N:31]=[C:10]3[CH:9]([CH3:13])[N:8]=[CH:7][C:6]=2[CH:20]=1
Reactant: NNC(=O)Cc1ccccc1
Reactant: CC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S
Agent: N#N
Solvent: CCCCO
Product: CC1N=Cc2cc(Cl)ccc2-n2c(Cc3ccccc3)nnc21
Yield: 48 %

Procedure:
A stirred mixture of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4-benzodiazepine-2-thione (3.0 g, 0.01 mol), phenyl acetic acid hydrazide (4.95 g, 0.033 mol) and butanol (150 ml) was refluxed for 16 hours while N2 was being bubbled through the mixture. The reaction mixture was concentrated under high vacuum, and the residue mixed with iced H2O. The product was filtered and dissolved in CH2Cl2. The CH2Cl2 was washed with dilute HCl and brine, dried over Na2SO4 and concentrated in vacuo. At this point it appeared that complete cyclization had not been achieved. Therefore, the residue was combined with acetic acid (100 ml) and refluxed for 2 hours under N2. The reaction mixture was concentrated in vacuo and the residue mixed with CH2Cl2 and H2O. The CH2Cl2 was washed with NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The material was crystallized from EtOAc-Skelly B to give 1.55 g, mp 195°-197° of the subtitled intermediate, which had a C:H:N:Cl ratio of 72.38:4.85:14.16:8.81. Calculated for C24H19N4Cl: 72.26:4.80:14.05:8.89.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[Cl-].[NH4+:11].[OH-].[NH4+].C[Si](C)(C)[C:16]#[N:17]>O.C(O)C>[NH2:11][C:4]1([C:16]#[N:17])[CH2:5][CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3]1
Reactant: C[Si](C)(C)C#N
Reactant: CC1(C)CCCC(=O)C1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)CCCC(N)(C#N)C1
Temperature: 70 °C

Procedure:
To a solution of 3,3-dimethylcyclohexanone (1.89 g) in water (3.8 mL) and ethanol (4.5 mL) was added ammonium chloride (920 mg), followed by concentrated ammonium hydroxide solution (2 mL) and trimethylsilanecarbonitrile (1.71 g). The reaction was heated to 70° C. for 18 hours. The reaction was concentrated to dryness, and was partitioned between water and methylene chloride. The layers were separated, and the aqueous layer was extracted with additional methylene chloride (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography, eluting with 40% ethyl acetate in petroleum ether, to give the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([F:26])=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1)(=[O:51])[CH3:50]>CN(C)C=O>[C:49]([N:52]1[CH2:57][CH2:56][N:55]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([O:15][C:16]4[C:17]([F:26])=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([CH3:25])=[CH:19]5)=[N:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:27][CH3:28])[CH2:54][CH2:53]1)(=[O:51])[CH3:50]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCBr
Reactant: CC(=O)N1CCNCC1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A mixture of 7-(2-bromoethoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (310 mg of a sample containing triphenylphosphine oxide (approx. 12% w/w), 0.61 mmol) and 1-acetylpiperazine (258 mg, 2.02 mmol) in N,N-dimethylformamide (5 ml) was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (202 mg, 67%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C@@H:18]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:19][C:20]3[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=3)=[N+:13]([O-])[CH:14]=[CH:15][CH:16]=2)=[C:7]2[C:3]=1[C:4]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[N:5][N:6]2[CH3:35].O=P(Cl)(Cl)[Cl:43]>>[Cl:43][C:14]1[N:13]=[C:12]([C@@H:18]([NH:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31])[CH2:19][C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[C:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]3[C:7]=2[N:6]([CH3:35])[N:5]=[C:4]3[NH:36][S:37]([CH3:40])(=[O:38])=[O:39])=[CH:16][CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc[n+]([O-])c3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Product: Cn1nc(NS(C)(=O)=O)c2c(Cl)ccc(-c3ccc(Cl)nc3[C@H](Cc3cc(F)cc(F)c3)NC(=O)C(F)(F)F)c21
Temperature: 115 °C
Reaction time: 2 h

Procedure:
(S)-3-(4-chloro-1-methyl-3-(methylsulfonamido)-1H-indazol-7-yl)-2-(2-(3,5-difluorophenyl)-1-(2,2,2-trifluoroacetamido)ethyl)pyridine 1-oxide (57C, 1.0 g, 1.66 mmol) was treated with POCl3 (2.32 mL, 24.84 mmol). The reaction mixture was stirred at 115° C. for 2 hours. Upon cooling, the reaction was concentrated in vacuo, taken in DCM, and vigorously stirred with saturated aqueous NaHCO3 for 1 hour. The organic layer was collected, and the aqueous layer was extracted an additional time with DCM. The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column chromatography, eluting with 0-100% EtOAc in hexanes to give the title compound. MS (m/z) 622.13 [M+H]+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:36]=[CH:35][C:11]([C:12]([NH:14][CH2:15][C:16]([N:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]2)(C(OC)=O)[C:17]([O:19]C)=[O:18])=[O:13])=[CH:10][CH:9]=1)[C:4]#[C:5][CH3:6].Cl>O1CCCC1.CO.C(OCC)(=O)C>[CH2:3]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH2:15][CH:16]([N:25]2[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]2)[C:17]([OH:19])=[O:18])=[O:13])=[CH:35][CH:36]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCOc1ccc(C(=O)NCC(C(=O)OC)(C(=O)OC)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.4 %

Procedure:
0.5 ml (0.5 mmol) of an aqueous solution of sodium hydroxide having a concentration of 1N are added to a solution of 100 mg (0.2 mmol) of dimethyl 2-[(4-but-2-ynyloxybenzoylamino)methyl]-2-(4-methanesulphonylpiperazin-1-yl)malonate in 4 ml of tetrahydrofuran and 1 ml of methanol. The reaction medium is stirred at ambient temperature for 48 h then hydrolysed, diluted with ethyl acetate and brought to pH=6 with an aqueous solution of hydrochloric acid having a concentration of 1N. After extraction with ethyl acetate, the organic phase is washed with water then with a saturated aqueous solution of sodium chloride. After drying over magnesium sulphate and filtering, the solvent is concentrated under vacuum. The crude product obtained is purified by recrystallization in ethyl acetate. 30 mg (32%) of 3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2OC(=O)[C:13](=[C:17]=[O:18])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:19][NH:20][NH2:21].[CH2:22]([OH:24])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]([CH2:22][OH:24])[CH2:13][C:17](=[O:18])[N:20]([CH3:19])[N:21]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CNN
Reactant: COc1ccc(C2CC(=C=O)C(=O)O2)cc1OC
Reactant: CCO
Product: COc1ccc(C2=NN(C)C(=O)CC2CO)cc1OC
Reaction time: 17 h

Procedure:
7.5 g (0.03 mol) of 4-(3,4-dimethoxyphenyl)-carbonyl-γ-butyrolactone and 2 ml (0.03 mol) of methylhydrazine are stirred in 50 ml of ethanol at room temperature for 1 hour and then at 90° C. for 17 hours. After the mixture has been cooled, the precipitated product is filtered off with suction and dried.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[CH2:13]([Li])[CH2:14][CH2:15]C.[CH:18]([C:20]1[N:21]=[CH:22][N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:24]=1)=[O:19].O>C1COCC1.CCCCCC>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:18]([C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([OH:19])[CH:14]([CH3:15])[CH3:13])[CH:11]=[CH:10]2
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: [Li]CCCC
Reactant: Brc1ccc2cc(Br)ccc2c1
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2cc(Br)ccc2c1)c1c[nH]cn1
Temperature: -50 °C
Reaction time: 0.33 h

Procedure:
2,6-Dibromonaphthalene (25.0 g) was dissolved in THF (1250 ml). The solution was cooled to −50° C. To the solution was slowly added a solution of n-butyllithium in hexane (1.6 M; 57 ml), and the mixture was stirred at −50° C. for 20 min. To the mixture was added dropwise a solution of 4-formyl-1-trityl-1H-imidazole (22.2 g) in THF (200 ml). The mixture was stirred at 50° C. for 20 min. To the mixture was added water, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried and concentrated. The residue was purified by silica gel chromatography (eluent, hexane:THF=1:1), and recrystallized from hexane-THF to give the titled compound (31.2 g) as a pale brown powder.
Reaction SMILES: C[S-:2].[Na+].Br[C:5]1[CH:6]=[C:7]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:8]=[N:9][CH:10]=1>CN(C)C=O>[SH:2][C:5]1[CH:6]=[C:7]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:8]=[N:9][CH:10]=1
Reactant: CN(C)C(=O)c1cncc(Br)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cncc(S)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Sodium thiomethoxide (3 g) was added to a stirred solution of 5-bromo-N,N-dimethyl-3-pyridinecarboxamide (2.5g, WO2000055168) in N,N-dimethylformamide (40 ml) and the suspension stirred at 100° C. for 4 h. The solvent was concentrated in vacuo, the residue dissolved in 2M sodium hydroxide (35 ml) and water (50 ml), and the solution washed with chloroform (4×75 ml). The aqueous layer was acidified with 2M hydrochloric acid to pH 4 and extracted with chloroform (5×80 ml), and the combined organic layers were washed with brine (20 ml), dried over magnesium sulphate and concentrated in vacuo to give the title compound as an orange oil (1.8 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C1(C)C=CC=CC=1.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[C:10]([Cl:12])[N:11]=[C:2]([C:25](=[O:27])[CH3:26])[CH:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)nc(C(C)=O)c1
Reaction time: 8 h

Procedure:
Add methyl 2,6-dichloroisonicotinate (3.0 g, 15.0 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (105 mg, 0.15 mmol) and toluene (10 mL) in a previously nitrogen filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(1-ethoxyvinyl)tin (5.57 mL, 16.5 mmol) under nitrogen and heat the sealed mixture at 100° C. overnight with vigorous stirring. Cool the reaction to room temperature, dilute with diethyl ether and filter through a filtering agent. Concentrate to near dryness and dilute the residue with THF (10 mL). Add dropwise 5 N HCl (5 mL) and stir the mixture overnight. Concentrate to near dryness and extract the organic material by diethyl ether, partitioning with water. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the title compound as a solid over two steps (47%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]=1[C:9](=[O:11])[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[N:6]=2.[O:18]1[CH:22]=[CH:21][CH2:20][CH2:19]1.B(F)(F)F.CCOCC>CN(C=O)C>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[N:4]1[C:5]2=[N:6][C:7]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:8][C:9](=[O:11])[C:10]2=[C:2]([CH3:1])[NH:3]1
Reactant: C1=COCC1
Reactant: CC1=C2C(=O)N=C(c3ccncc3)N=C2N=N1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1[nH]n(C2CCCO2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 108 h
Yield: 37 %

Procedure:
A solution of 3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one (2.3 g, 0.01 mol), DMF (50 ml) and 2,3-dihydrofuran (14.0 g, 0.20 mol) was stirred at 0° C. for 10 minutes and BF3.Et2O (1.5 ml, 0.012 mol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 108 hours. The reaction was quenched with concentrated ammonium hydroxide until pH of 7.5 and the resulting precipitate was collected by filtration. The solid residue was taken up in isopropanol (200 ml), heated to reflux and filtered to remove insoluble material. Concentration of the filtrate to 75 ml and cooling caused precipitation of the product. The product was collected by filtration and washed with ether to afford 1.1 g (37%) of 1-(2-tetrahydrofuranyl)-3-methyl-6-(4-pyridyl)-pyrazolo-[3,4-d]pyrimidin-4-one as a white powder, m.p. 268°-9° C. when dried at 70° C. in high vacuum.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH3:9])[N:3]=1.[Na+].[I-].[CH2:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH3:13].C(N(C(C)C)C(C)C)C>CCO>[CH3:9][NH:8][C:4]1[N:3]=[C:2]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH2:12][CH3:13])[CH2:19][CH2:18]3)=[CH:26][CH:25]=2)[N:7]=[CH:6][N:5]=1
Reactant: CNc1ncnc(Cl)n1
Reactant: CCN1CCN(c2ccc(N)cc2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN(c2ccc(Nc3ncnc(NC)n3)cc2)CC1
Temperature: 80 °C

Procedure:
A mixture of (4-chloro-[1,3,5]triazin-2-yl)-methyl-amine (290 mg, 2.00 mmol), NaI (28 mg) and 4-(4-ethylpiperazin-1-yl)-aniline (410 mg, 2.0 mmol) in EtOH (20 ml) and N-ethyl-diisopropyl amine (350 μl, 2.0 mmol) is heated to 80° C. for 3 h under a nitrogen atmosphere. The reaction mixture is cooled to RT, concentrated partially in vacuo and diluted with hexane at 0° C. The precipitate is filtered off, washed with Et2O and re-dissolved in EE and water. The separated off aqueous phase is extracted twice with EE, the organic layer washed with water and brine, dried (Na2SO4) and concentrated, yielding the title compound: ESI-MS: 314 [MH]+; TLC: Rf=0.10 (DCM/MeOH 9:1).