Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:68]([O:72][C:73]([NH:75][CH2:76][C:77]1([C:80](O)=[O:81])[CH2:79][CH2:78]1)=[O:74])([CH3:71])([CH3:70])[CH3:69].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:21])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH:34][C:80]([C:77]5([CH2:76][NH:75][C:73](=[O:74])[O:72][C:68]([CH3:70])([CH3:69])[CH3:71])[CH2:79][CH2:78]5)=[O:81])(=[O:33])=[O:32])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC1(C(=O)O)CC1
Reactant: NS(=O)(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(C(=O)NS(=O)(=O)c2ccc(Nc3nc(NC4(c5ccc(Cl)cc5)CC4)nc(OCC(F)(F)F)n3)cc2)CC1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzenesulfonamide (1 g, 1.94 mmol) in DCM (10 mL) solution were added PyBOP (1.21 g, 2.33 mmol), 1-((tert-butoxycarbonylamino)methyl)cyclopropanecarboxylic acid (0.46 g, 2.14 mmol) and DIEA (1.36 mL, 7.77 mmol). The mixture was stirred at room temperature for 16 hs. All solvents were removed under vacuum and the residue was purified by silica gel column (MeOH/hexane: 5%) to give tert-butyl (1-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)phenylsulfonylcarbamoyl)cyclopropyl)methylcarbamate (1.38 g, 100%) as a brown solid. LC-MS (Condition A), MS m/z 712.0 (M++H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[Cl:7][C:8]1[CH:9]=[C:10]([C:15](=[CH2:1])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: C=C(CCC(=O)OC)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.8 %

Procedure:
1.75 g (49.0 mmole) of methyltriphenylphosphonium bromide and 5.50 g (49.0 mmole) of potassium t-butoxide were suspended in 200 ml of dried benzene, and the mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. At the end of this time, 8.50 g of methyl 4-(3,4-dichlorophenyl)-4-oxobutanoate [prepared as described in step (a) above] were dissolved in 40 ml of benzene, and the resulting solution was added to the reaction mixture. The mixture was then stirred for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and diethyl ether ranging from 19:1 to 23:2 by volume as the eluent, to give 4.20 g of the title compound as a pale orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[Cl-].[Al+3].[Cl-].[Cl-].[Br:15][CH2:16][C:17](Br)=[O:18].O>ClCCl>[Br:15][CH2:16][C:17]([C:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[F:1])[NH:8][CH:9]=1)=[O:18]
Reactant: Fc1ccnc2[nH]ccc12
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)c1c[nH]c2nccc(F)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-fluoro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 0.0147 mol) (Org. Lett., 2003, 5, 5023-5025) in dichloromethane was added aluminum chloride (3.92 g, 0.0294 mol) in portions, the mixture was stirred at RT for 30 min, then bromoacetyl bromide (4.45 g, 0.022 mol) was added dropwise. The reaction mixture was stirred at 50° C. for 1 h, when TLC indicated no starting material. To the reaction mixture was added 150 mL water, and the resulting suspension was heated at 100° C. for 1 h, then filtered to afford the desired product, 90% pure. H NMR, DMSO-d6: 4.72(s, 2H), 7.12(m, 1H), 8.36(m, 1H), 8.67(s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:33]=[CH:32][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][C:19]3[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:21][C:20]=3[F:31])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[F:31][C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][C:19]=1[CH2:18][NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]3[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=3)=[CH:33][CH:32]=2)[CH2:10][CH2:11]1)=[O:16])[O:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: COC(=O)COc1ccc(CNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)c(F)c1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Product: O=C(O)COc1ccc(CNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)c(F)c1
Yield: 27.5 %

Procedure:
Methyl 2-(4-{[({4-[4-(2-aminoethyl)anilino]-1-piperidinyl}carbonyl)amino]methyl}-3-fluorophenoxy)acetate (0.605 g, 1.2 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.477 g, 1.2 mmol) according to Procedure G to furnish the title compound (0.280 g, 0.33 mmol).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:15]3[C:14](=[O:26])[N:13]([CH3:27])[C:12](=[O:28])[N:11]([CH3:29])[C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=[O:32].[Na+]>O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[CH2:17][N:16]1[C:15]2[C:14](=[O:26])[N:13]([CH3:27])[C:12](=[O:28])[N:11]([CH3:29])[C:10]=2[N:9]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:32])[CH:3]=1
Reactant: O=N[O-]
Reactant: Cn1c(=O)c2c(nc(-c3cccc(N)c3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2c(nc(-c3cccc(O)c3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of 8-(3-aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (88 mg, 0.21 mmol) in 310 μL water was treated with concentrated HCl and then sodium nitrite (19 mg, 0.23 mmol) dissolved in ˜300 μL water. The reaction mixture was stirred at 0° C. for 30 min and then heated to 100° C. for 15 min. The reaction mixture was cooled, dried under reduced pressure, and purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (2:1) to give 37 mg (43% yield) of the title compound as a pale orange solid: 1H NMR (CDCl3, 400 MHz) 7.22-7.16 (m, 1H), 7.12-7.01 (m, 2H), 6.96-6.91 (m, 2H), 6.86-6.81 (m, 1H), 6.80-6.74 (m, 1H), 5.82 (s, 2H), 3.60 (s, 3H), 3.37 (s, 3H); MS (ESP+) m/e 415 (MH+); TLC (EtOAc:hexanes/2:1) Rf=0.41.
Reaction SMILES: C1C=CC([As](C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[C:25]2[N:26]=[C:27]([N:35]([CH3:37])[CH3:36])[N:28]=[C:29]([C:30]3[O:31][CH:32]=[CH:33][CH:34]=3)[C:24]=2[S:23][CH:22]=1.C([Sn](CCCC)(CCCC)[C:43]1[O:44][CH:45]=[CH:46][CH:47]=1)CCC.O>CN(C=O)C>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:29]1[C:24]2[S:23][CH:22]=[C:21]([C:43]3[O:44][CH:45]=[CH:46][CH:47]=3)[C:25]=2[N:26]=[C:27]([N:35]([CH3:37])[CH3:36])[N:28]=1
Reactant: CN(C)c1nc(-c2ccco2)c2scc(Br)c2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([As](c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nc(-c2ccco2)c2scc(-c3ccco3)c2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.5 %

Procedure:
A mixture of AsPh3 (73 mg, 0.24 mmol) in DMF (2 mL) was treated with Pd(OAc)4 (13 mg, 0.06 mmol), stirred at room temperature for 10 min, treated with 7-bromo-N,N-dimethyl-4-(2-furyl)thieno[3,2-d]pyrimidine-2-amine (194 mg, 0.6 mmol) and 2-(tributylstannyl)-furan (340 μL, 1.1 mmol), heated to 100° C. for 16 h, cooled, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (SiO2:EtOAc:Heptane, 1:9) to give the title compound (27 mg, 15%) as a orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([O:32]CC)=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2.[OH-].[Na+]>O1CCOCC1.CO>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH2:12][CH2:13][CH2:14][C:15]1([C:30]([OH:32])=[O:31])[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:16]1)=[CH:9][C:8]([O:35][CH3:36])=[CH:7][CH:6]=2
Reactant: CCOC(=O)C1(CCCc2c(F)cnc3ccc(OC)cc23)CCN(CCSc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2ncc(F)c(CCCC3(C(=O)O)CCN(CCSc4ccccc4)CC3)c2c1
Temperature: 70 °C
Reaction time: 17 h
Yield: 81.4 %

Procedure:
A mixture of 0.39 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-4-carboxylate in 3 cm3 of dioxane, 3 cm3 of methanol and 2.3 cm3 of aqueous SN sodium hydroxide solution was stirred at a temperature in the region of 70° C. for 17 hours. After cooling to about 20° C., the reaction mixture was concentrated to dryness under a pressure gradually reduced from 30 kPa to 2.5 kPa and at a temperature in the region of 45° C. The residue was taken up in 5 cm3 of a dichloromethane/methanol/aqueous ammonia mixture (40/5/0.5 by volume) and was then purified by chromatography under atmospheric pressure, on a cartridge of silica gel (Bond Elut; particle size 70-200μ; mass 10 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (90/9/0.9 by volume) and then with a chloroform/methanol/aqueous ammonia mixture (77.5/19.5/3). The fractions containing the product were combined, concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. and dried in a desiccator (10 kPa). 0.3 g of 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-4-carboxylic acid was obtained in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br>CN(C)C=O.O>[C:4]([C:3]1[C:2]2[O:1][CH2:20][CH2:19][O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([OH:6])=[O:5]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc2c1OCCO2
Temperature: 65 °C

Procedure:
A mixture of 10.8 g (70 mmol) of 2,3-dihydroxybenzoic acid, 38.6 g (280 mmol) of dry potassium carbonate and 24 ml (278 mmol) of 1,2-dibromoethane in 40 ml of N,N-dimethylformamide is heated at 65° C. for 24 hours under an inert atmosphere. After cooling, the reaction mixture is diluted with water and then extracted with ether. The aqueous phase is then acidified with a 3N hydrochloric acid solution and subsequently extracted with dichloromethane. After removal of the solvent by evaporation in vacuo, the residue obtained is recrystallised from toluene to yield the title acid in the form of a white solid.
Reaction SMILES: CN1CC[O:5][CH2:4]C1.[CH3:8][C@@H:9]1[NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]([NH2:20])[C:12]=2[NH:11][CH2:10]1.ClC(OC(Cl)(Cl)Cl)=O>ClCCl>[CH3:8][C@@H:9]1[NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[C:19]3[NH:20][C:4](=[O:5])[N:11]([C:12]=23)[CH2:10]1
Reactant: C[C@H]1CNc2c(N)cccc2CN1
Reactant: CN1CCOCC1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@H]1Cn2c(=O)[nH]c3cccc(c32)CN1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
300 ml of dichloromethane and 22.8 ml of 4-methylmorpholine are added to 12.7 g (0.072 mol) of (S)-3-methyl-2,3,4,5-tetrahydro-(1H)-1,4-benzodiazepin-9-amine. The mixture is then poured into a solution of 9.1 ml (0.0072 mol) of trichloromethyl chloroformate in 340 ml of dichloromethane cooled beforehand with an ice bath. The mixture is left stirring for 10 minutes at 0° C. and then for 20 minutes at room temperature. The solvent is evaporated under vacuum and the residue taken up in 200 ml of water and 34 ml of dioxane. The mixture is heated in a water bath for 45 minutes and then a concentrated aqueous ammonia solution is added. The mixture is left to cool, is sucked dry, is washed with water and is dried under vacuum. There are obtained 11.5 g of product which is recrystallized from boiling water. There are obtained 7.6 g of product which is used as is in the following stage.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][O:17][CH:18]=3)[N:11]=[C:10]([C:19]3[CH:20]=[C:21]([C:25]4([NH:29]C(=O)OC(C)(C)C)[CH2:28][O:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)[CH:9]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]1[CH:18]=[C:14]([CH2:13][N:12]2[C:8]([O:7][C:6]3[CH:37]=[CH:38][C:3]([C:2]([F:1])([F:39])[F:40])=[CH:4][CH:5]=3)=[CH:9][C:10]([C:19]3[CH:20]=[C:21]([C:25]4([NH2:29])[CH2:28][O:27][CH2:26]4)[CH:22]=[CH:23][CH:24]=3)=[N:11]2)[N:15]=[CH:16]1
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(Cc4cocn4)n3)c2)COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)n(Cc4cocn4)n3)c2)COC1
Reaction time: 1.5 h

Procedure:
A stirred solution of tert-butyl (3-{3-[5-(4-trifluoromethylphenoxy)-1-(1,3-oxazol-4-ylmethyl)-1H-pyrazol-3-yl]phenyl}oxetan-3-yl)carbamate (48 mg, 0.086 mmol) in 0.6 mL of CH2Cl2 was cooled in an ice bath, and to the solution was added 0.6 mL of TFA. The solution was stirred for 1.5 h and then quenched with 10% Na2CO3. The organic phase was washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure to give 3-{3-[1-(1,3-oxazol-4-ylmethyl)-5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl]phenyl}oxetan-3-amine as a glass. Calcd (M+1)+: 457.4. found: 457.1.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][C:23]1[C:27](B(O)O)=[C:26]([CH3:31])[O:25][N:24]=1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:27]3[C:23]([CH3:22])=[N:24][O:25][C:26]=3[CH3:31])=[CH:14][C:6]1=2
Reactant: Cc1noc(C)c1B(O)O
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: Cc1noc(C)c1-c1cnc2c(c1)N(Cc1c(F)ccc(F)c1Cl)CCN2
Yield: 45 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (75 mg) was reacted with 3,5-dimethylisoxazole-4 boronic acid as in General Procedure 4A to give the title compound as a pale yellow solid (45% yield). M.p. 215-216° C., LCMS: m/z=393.42 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.22 (s, 3H), 2.36 (s, 3H), 3.31 (t, J=5.0 Hz, 2H), 3.52-3.58 (m, 2H), 4.47 (s, 2H), 4.98 (bs, 1H), 6.71 (s, 1H), 6.98-7.05 (m, 1H), 7.09-7.17 (m, 1H), 7.36 (d, J=1.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:67]([CH2:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][NH:72]1)[CH2:68][CH3:69])[CH2:64][CH2:65][CH3:66]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][CH2:76][CH:71]1[CH2:70][N:67]([CH2:63][CH2:64][CH2:65][CH3:66])[CH2:68][CH3:69])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCCCN(CC)CC1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)CC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and N-butyl-N-ethyl-C-(piperidin-2-yl)-methylamine in DMSO at ambient temperature.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C:6]([N:8]([CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35])[C:9]1[C:10]([C:23]([O:25]CC)=O)=[N:11][CH:12]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)=[O:7])[CH3:2].C1CCN2C(=NCCC2)CC1>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:13]2[CH:14]=[C:9]3[C:10]([C:23]([OH:25])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:36])[C:6](=[O:7])[N:8]3[CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][C:31]3=[O:35])=[N:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)N(CCN1CCCC1=O)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reaction time: 0.33 h

Procedure:
A solution of ethyl 3-{[3-(ethyloxy)-3-oxopropanoyl][2-(2-oxo-1-pyrrolidinyl)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (1.80 g, 3.98 mmol) in ethanol (20 mL) was treated with DBU (1.53 mL, 10.3 mmol). After stirring under nitrogen for 20 min., the reaction was quenched with 1N HCl (7.8 mL) and evaporated in vacuo. Trituration with water and filtration provided the product as a white solid: 1H NMR (CDCl3) δ 8.50 (1H, d, J=1.4 Hz), 8.11 (1H, s), 7.26 (2H, m), 7.00 (2H, ddd, J˜9, 9, 2 Hz), 4.52 (2H, q, J=7 Hz), 4.33 (2H, br t, J˜7 Hz), 4.14 (2H, s), 3.52-3.44 (4H, m), 2.35 (2H, t, J=8 Hz), 2.00 (2H, m), 1.48 (3H, t, J=7 Hz); ES+ MS: 476 (M+Na+).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[NH2:16][CH:17]([CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19].C(OC(N[C@H](C(O)=O)COCC1C=CC=CC=1)=O)(C)(C)C>C(N(CC)CC)C>[CH2:29]([O:28][CH2:27][CH:17]([NH:16][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1)[C:18]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[O:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1nc(-c2ccccc2)nc(Cl)c1C
Reactant: CCCN(CCC)C(=O)C(N)COCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)C(COCc1ccccc1)Nc1nc(-c2ccccc2)nc(C)c1C
Temperature: 150 °C
Reaction time: 5 h
Yield: 92.3 %

Procedure:
A mixture of 4-chloro-5,6-dimethyl-2-phenylpyrimidine (1.8 g), 2-amino-3-benzyloxy-N,N-dipropylpropanamide (4.6 g), which is prepared from N-(tert-butoxycarbonyl)-O-benzylserine, and triethylamine (1.7 g) is stirred at 150° C. for 5 hours. The reaction mixture is treated in the same manner as in Example 1 to give 3-benzyloxy-2-(5,6-dimethyl-2-phenyl-4-pyrimidinylamino)-N,N-dipropylpropanamide (3.5 g) as an oily product.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH:12]1([N:22]=[C:23]=[S:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[CH3:2][O:3][NH:4][C:23]([NH:22][CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14][CH2:13]1)=[S:24]
Reactant: S=C=NC1CCCc2ccccc21
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=S)NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice-cold, stirred mixture of 0.02 mole of methoxyamine hydrochloride and methylene chloride is added 0.02 mole of triethylamine. The mixture is then allowed to warm to about 15° to 25° C. while a solution of 0.01 mole of 1,2,3,4-tetrahydro-1-naphthyl isothiocyanate in methylene chloride is added dropwise. The mixture is stirred overnight at room temperature and then filtered. The filtrate is washed with water, dried (sodium sulfate), and the solvent evaporated at reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19](B(O)O)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)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>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[C:19]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)=[C:20]2[CH2:25][CH2:24][CH2:23][N:21]2[N:22]=1
Reactant: OB(O)c1c(-c2ccccn2)nn2c1CCC2
Reactant: Brc1cncc2cccnc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nn3c(c2-c2cncc4cccnc24)CCC3)nc1
Temperature: 60 °C
Yield: 65.1 %

Procedure:
Add 8-bromo-[1,6]naphthyridine (Spec; 32 mg, 0.152 mmol), 2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-boronic acid (Preparation 5; 35 mg, 0.153 mmol), and potasium phosphate (97 mg, 0.458 mmol) to DMF (1 mL) and water (0.5 mL). De-gas the solution with argon and add tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.076 mol). Heat the mixture at 60° C. for 18 h under an argon atmosphere. Cool the mixture to room temperature and dilute with water. Filter the mixture, and separate the filtrate. Extract the aqueous layer with dichloromethane. Dry the combined organic layers over sodium sulfate, filter, and concentrate. Purify the crude residue by column chromatography (12 g Redisep column, gradient dichloromethane through CMA over 40 min, 20 mL/min) to provide the title compound (31 mg, 64%) as an off white solid. Mp 180-184° C. MS (APCI) m/e=314 (M+1). 1H NMR (CDCl3) δ 8.88 (dd, J=1.6, 4.2 Hz, 1H), 8.60 (d, J=4.7 Hz, 1H), 8.28 (d, J=8.5 Hz, 1H), 8.19 (d, J=8.9 Hz, 1H), 7.73-7.68 (m, 3H), 7.58 (dd, J=4.2, 8.5 Hz, 2H), 4.30 (t, J=7 Hz, 2H), 3.30 (t, J=7 Hz, 2H), 2.73 (p, J=7 Hz, 2H). HPLC: >99%, Rt=7.1 min.
Reaction SMILES: [CH:1]([C:3]1[C:7]2[NH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[O:5][CH:4]=1)=O.Cl.[NH2:15]O>CN(C=O)C>[C:1]([C:3]1[C:7]2[NH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]=2[O:5][CH:4]=1)#[N:15]
Reactant: NO
Reactant: O=Cc1coc2cc(C(=O)O)[nH]c12
Agent: Cl
Solvent: CN(C)C=O
Product: N#Cc1coc2cc(C(=O)O)[nH]c12
Temperature: 125 °C
Yield: 2 %

Procedure:
To a solution of 3-formyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid (0.20 g, 0.2 M, 1.12 mmol) in DMF (6.0 mL) was added hydroxylamine hydrochloride (0.16 g, 2.24 mmol). The reaction mixture was heated at 125° C. overnight, then cooled to rt. The mixture was partitioned between EtOAc (20 mL) and H2O (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic phases were washed with H2O and saturated aq NaCl, filtered and concentrated in vacuo. The crude product was chromatographed over silica gel (0 to 40% MeOH in CH2Cl2 over 30 min) to give 3-cyano-4H-furo[3,2-b]pyrrole-5-carboxylic acid 51 (4 mg, 2.1%) as a brown solid. 1H NMR (400 MHz, CD3OD) δ ppm 6.65 (d, J=0.68 Hz, 1H) 7.33 (d, J=0.68 Hz, 1H). LCMS m/e 175 (M−H).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10]>>[CH2:7]([NH:11][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][OH:5])[CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCCO1
Reactant: CCCCN
Product: CCCCNC(=O)CCCO
Temperature: 85 °C

Procedure:
To 30 mL (390 mmol) of g-butyrolactone was added 45 ml (455 mmol) of n-butylamine. The solution was heated at 85° C. for 1.5 hr, then the excess n-butylamine was removed in vacuo. The product crystallized on standing to give about 62 g of a colorless, low melting solid.