Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[N:18][C:17]2[C:8](=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]([N+:20]([O-:22])=[O:21])[C:12]3=[O:23])[CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>O>[C:4]([C:6]1[CH:19]=[N:18][C:17]2[C:8](=[CH:9][CH:10]=[C:11]3[C:16]=2[N:15]=[CH:14][CH:13]([N+:20]([O-:22])=[O:21])[C:12]3=[O:23])[CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2c3c(ccc2c1)C(=O)C([N+](=O)[O-])C=N3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnc2c3c(ccc2c1)C(=O)C([N+](=O)[O-])C=N3
Yield: 98 %

Procedure:
A mixture of 8-ethoxycarbonyl-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline (0.55 g) and 2M sodium hydroxide solution (5 ml) was stirred at reflux for 2 hours. The hot suspension was neutralised with glacial acetic acid, cooled and diluted with water. The mixture was filtered and washed with water to give 8-carboxy-3-nitro-4-oxo-3,4-dihydro-1,10-phenanthroline in 98% yield.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>O1CCCC1>[C:7]([C:6]1[S:21][C:1]([CH3:2])=[N:4][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NNC(=O)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1nnc(C(C)(C)C)s1

Procedure:
A mixture of the product from Example 50A (158 mg, 1 mmol) and Lawesson's reagent (808 mg, 2 mmol) in tetrahydrofuran (4 mL) was heated at reflux for 2 hours. The solution was concentrated, dissolved in dichloromethane (15 mL) and washed with saturated sodium bicarbonate solution (10 mL). The resulting organic layer was passed through a silica pad and washed with dichloromethane and ethyl acetate (10:1). The solvent was evaporated to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 2.67 (s, 3 H); MS (ESI) m/z 157 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:35]>ClCCl.C(OCC)C>[ClH:35].[C:1]1([C@@H:7]([NH:9][C:10]2[CH:11]=[C:12]([N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)[CH:13]=[CH:14][C:15]=2[C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](Nc1cc(N2CCNCC2)ccc1C(=O)C(F)(F)F)c1ccccc1
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of t-butyl 4-(3-(1-phenylethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (50 mg, 0.1 mmol) in dry dichloromethane (1.0 mL) was added a saturated solution of HCl in diethyl ether (20 mL). The reaction mixture was stirred for 2 h. The solvent was removed by rotary evaporation to afford the title compound (31 mg, 72% yield). 1H NMR (400 MHz, CD3OD): δ 7.63 (d, 1H), 7.36 (m, 5H), 6.36 (d, 1H), 5.86 (s, 1H), 4.75 (m, 1H), 3.52 (m, 2H), 3.45 (m, 2H), 3.17 (m, 4H), 1.60 (d, 3H); MS (ESI) m/z: Calculated for C20H23F3N3O: 378.18; Observed: 378.5 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23](CC3C=CC=CC=3)[CH3:24])[C:12]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][N:23]([C:45]([O:44][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:46])[CH3:24])[C:12]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccccc1
Product: COc1ccc([C@@H]2Sc3cc(C)ccc3N(CCN(C)C(=O)OCc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Yield: 104.7 %

Procedure:
A mixture of 10.37 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 125 ml of benzene is refluxed. A solution of 9 g of benzyloxycarbonyl chloride in 25 ml of benzene is added dropwise to the mixture for 30 minutes, and the mixture is refluxed for 4 hours. Then, the mixture is evaporated under reduced pressure to remove solvent. 11.8 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyloxycarbonyl-N-methylamino)ethyl]-8-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are obtained as an oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[CH3:17][O-:18].[Na+].O>CO>[CH3:17][O:18][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(OC)sc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 15.7 %

Procedure:
Under a static N2 atm, a stirred solution of the compound of Example 2 (8.14 g, 32 mol) in 100 ml of methanol was treated dropwise with 7.6 g of 25% sodium methoxide in methanol. After stirring at ambient temperature for 24 hr, the mixture was added to H2O and extracted twice with ether. The ether layer was washed with H2O, dried over MgSO4 and concentrated in vacuo to yield a white solid which was recrystallized from methylcyclohexane to yield 5.5 g of methyl 2-methoxy-5-phenyl-4-thiazolecarboxylate as a white solid, m.p. 86°-88° C., yield 70%.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=2)[C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.CCO>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33](=[O:1])[NH2:34])[CH:28]=2)[C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(C#N)c2)c2ccc3[nH]ccc3c2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(C(N)=O)c2)c2ccc3[nH]ccc3c2)CC1

Procedure:
A solution of NaOH (54 mg, 1.35 mmol) in water (0.2 mL) was added to a solution of 4-[(3-cyano-benzyl)-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (115 mg, 0.27 mmol) (prepared as described in Example 2 Step 1) in EtOH (10 mL). The reaction mixture was heated at reflux for 16 hours, the solvent was evaporated and the residue was purified by flash chromatography (0% to 25% of MeOH in DCM) to give 4-[(3-carbamoyl-benzyl)-(1H-indol-5-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester. This material was dissolved in DCM (5 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred for 16 hours, it was then evaporated under reduced pressure and the residue was basified by addition of an aqueous solution of NH4OH. The crude material was purified first by flash chromatography and then by preparative HPLC (Agilent Technologies Zorbax SB-Phenyl column (21.2 mm inner diameter by 100 mm length, 7 micron particle size), water (0.1% TFA added)/acetonitrile 75/25 gradient to 5/95 over 10 minutes at 20 ml/min flow rate) to give the desired 3-{[(1H-indol-5-yl)-piperidin-4-yl-amino]-methyl}-benzamide trifluoroacetate, MS=349 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[Na+].O>CN(C)C=O>[CH2:24]([O:23][CH2:22][C:11]1[C:12]([CH3:21])=[N:13][N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:10]=1[S:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1COCc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
A solution containing 115 mg of [5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazol-4-yl]-methanol, 54 mg of benzyl bromide and 38 mg of sodium hydride (60% in mineral oil) in 3 ml of anhydrous N,N-dimethylformamide was stirred under nitrogen at 100° C. for 2 hours. Water (10 ml) was added and the mixture was extracted three times with 8 ml of dichloromethane. Combined extracts were dried over magnesium sulphate, filtered and evaporated. The residue was purified twice by flash chromatography on silica gel using ethyl acetate/petroleum ether (bp 40–60° C.) (1:4) then dichloromethane for the elution to give 35 mg of 4-benzyloxymethyl-5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-1H-pyrazole as a colourless gum. Mass spectrum (ES) m/z 455 [M+H]+, 496 [M+H+CH3CN]+. 1H NMR (DMSO-dr) 2.36 (s, 3H), 4.47 (s, 2H), 4.49 (s, 2H), 6.96 (d, 2H), 7.24–7.47 (m, 11H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20](Cl)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:40]1[S:48][C:43]2=[CH:44][N:45]=[CH:46][CH:47]=[C:42]2[CH:41]=1)CCC>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+].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>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:40]2[S:48][C:43]3=[CH:44][N:45]=[CH:46][CH:47]=[C:42]3[CH:41]=2)[C:19]2[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=2[C:17]=1[F:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccncc2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3ccncc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Yield: 56.3 %

Procedure:
A solution of tert-butyl 6-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.401 mmol), 2-(tributylstannyl)thieno[2,3-c]pyridine (510 mg, 1.202 mmol) and tetrakis(triphenylphosphine)palladium(0) (463 mg, 0.401 mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, and the solvent was removed in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 5-50% EtOAc and hexane over a period of 120 minutes. The fractions were collected to give the title compound (135 mg, 56%).
Reaction SMILES: [P:1]([O-:38])([O:34][CH2:35][CH2:36]Br)([O:3][CH2:4][CH:5]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[CH3:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[P:1]([O-:38])([O:34][CH2:35][CH2:36][N+:40]1([CH3:39])[CH2:44][CH2:43][CH2:42][CH2:41]1)([O:3][CH2:4][CH:5]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CN1CCCC1
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCBr)OCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCC[N+]1(C)CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 46.6 %

Procedure:
In 30 ml of toluene were dissolved 7.5 g (12 mmole) of 2-benzyloxy-3-(octadecyloxy)propyl 2-bromoethyl phosphate and 10.2 g (120 mmole) of N-methylpyrrolidine, and the solution was allowed to stand at room temperature for 8 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 60 ml of methanol. 3.3 g (12 mmole) of silver carbonate was added to the solution, followed by heating under reflux for 1 hour. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:water=65:25:4) to give 3.5 g (47 %) of 2-benzyloxy-3-(octadecyloxy)-propyl 2-(N-methylpyrrolidinio)ethyl phosphate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH2:16][F:17])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1)#[N:20]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([C:19]#[N:20])=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH2:16][F:17])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cc(N)ccc2F)[C@@H](F)CO1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@@]3(CF)N=C(N)OC[C@@H]3F)c2)nc1

Procedure:
The condensation of (4S,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-fluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.5) and 5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a light yellow solid. MS (ISP): m/z=390.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:45])[NH:13][CH2:14][C:15]([N:17]2[CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]([CH3:28])[CH2:19][C:18]2([C:36](=[O:44])[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:16])[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[K+]>O.CO>[C:32]([O:31][C:29]([C:18]1([C:36](=[O:44])[NH:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:19][CH:20]([CH3:28])[CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:17]1[C:15](=[O:16])[CH2:14][NH:13][C:12](=[O:45])[NH:11][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:3]([OH:4])=[O:2])=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: COC(=O)c1cccc(NC(=O)NCC(=O)N2C(c3ccccc3)C(C)CC2(C(=O)Nc2ccccc2)C(=O)OC(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CC(C(=O)Nc2ccccc2)(C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)C1c1ccccc1
Yield: 31.3 %

Procedure:
A The reaction is carried out in a way analogous to that described in Example 3, but from 3.6 g of tert-butyl (2RS,4RS,5SR)-1-{2-[3-(3-(methoxycarbonyl)phenyl)ureido]acetyl}-4-methylphenylcarbamoyl-5-phenylpyrrolidine-2-carboxylate and 0.33 g of potassium hydroxide in a mixture of 20 cm3 of distilled water and 60 cm3 of methanol. After treatment, there are obtained 1.1 g of (2RS,4RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-4-methylphenylcarbamoyl-1-pyrrolidinyl)-2-oxoethyl]ureido}benzoic acid, melting at 238° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:11]2[CH:12]=[C:13]([C:28](O)=[O:29])[CH:14]=[C:15]3[C:20]=2[O:19][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:17][C:16]3=[O:27])[CH3:10])=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][NH:35][CH3:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][N:35]([CH3:36])[C:28]([C:13]1[CH:14]=[C:15]2[C:20](=[C:11]([CH:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:10])[CH:12]=1)[O:19][C:18]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[CH:17][C:16]2=[O:27])=[O:29]
Reactant: CNCCN(C)C
Reactant: CC(Nc1ccc(F)cc1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Product: CC(Nc1ccc(F)cc1)c1cc(C(=O)N(C)CCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 15.9 %

Procedure:
8-(1-(4-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (80 mg, 0.19 mmol) was reacted with N1,N1,N2-trimethylethane-1,2-diamine (0.030 mL, 0.23 mmol) using a procedure similar to the one described in Example 2.00 to afford N-(2-(dimethylamino)ethyl)-8-(1-(4-fluorophenylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (15.0 mg, 15.6%) as a white solid. Mass Spectrum: M+H+ 497. NMR Spectrum: (DMSOd6) 1.49 (d, 3H), 1.74 (bs, 3H), 2.01 (bs, 1H), 2.18 (s, 3H), 2.66 (bs, 1.5H), 2.89 (bs, 2H), 3.05 (bs, 1.5H), 3.47 (bs, 1H), 3.50-3.64 (m, 4H), 3.71-3.79 (m, 4H), 4.93-5.01 (m, 1H), 5.59 (s, 1H), 6.29 (bs, 1H), 6.46 (dd, 2H), 6.84 (dd, 2H), 6.54 (d, 1H), 6.73 (d, 1H).
Reaction SMILES: C1COCC1.Br[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][N:8]=1.[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:29]3[S:30][C:31](I)=[CH:32][C:33]=3[O:34][CH3:35])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]>CCOC(C)=O.[Zn].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>[CH2:13]([CH:15]([C:18]1[C:19]2[N:20]([C:25]([C:29]3[S:30][C:31]([C:7]4[N:11]([CH3:12])[N:10]=[CH:9][N:8]=4)=[CH:32][C:33]=3[O:34][CH3:35])=[C:26]([CH3:28])[N:27]=2)[N:21]=[C:22]([CH3:24])[CH:23]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(I)cc3OC)c(C)nc12
Reactant: Cn1ncnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3OC)c(C)nc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a slurry of 0.05 g/mL of Reike® Zn in THF (2.8 mL, 2.11 mmol) is added 5-bromo-1-methyl-1H-[1,2,4]triazole and THF (2 mL). The solution is heated at 65° C. for 1 hour, cooled to ambient temperature and the excess Zn allowed to settle for 1 hour. The solution is transferred to a flask containing 8-(1-ethyl-propyl)-3-(5-iodo-3-methoxy-thiophen-2-yl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.32 g, 0.70 mmol) and Pd(PPh3)4 (0.041 g, 0.035 mmol). The solution is heated at 65° C. overnight, diluted with EtOAc (30 mL) washed with sat. NH4Cl (30 mL). The aqueous phase is extracted with EtOAc (20 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The reside is purified by ISCO column chromatography (20%-65% EtOAc/hexane gradient) followed by ISCO column chromatography (100% Et2O) furnish the title compound (0.19 g, 0.46 mmol, 62%). 1H NMR (CDCl3) δ 0.86 (t, J=7.5 Hz, 6H), 1.73-1.91 (m, 4H), 2.51 (s, 3H), 2.52 (s, 3H), 3.26-3.37 (m, 1H), 3.92 (s, 3H), 4.15 (s, 3H), 6.67 (s, 1H), 7.48 (s, 1H), 7.89 (s, 1H). LC/MS (m/z): calcd. for C21H26N6OS (M+H)+: 411.5. found: 411.3.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])/[CH:3]=[CH:4]/[C:5]([NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH3:21])[CH:12]=1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>O1CCOCC1>[CH3:1][CH:2]([CH3:22])/[CH:3]=[CH:4]/[C:5](=[S:32])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH3:21])[CH:12]=1
Reactant: Cc1cc(NCCNC(=O)/C=C/C(C)C)c2ccccc2n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1cc(NCCNC(=S)/C=C/C(C)C)c2ccccc2n1
Temperature: 130 °C

Procedure:
(E)-4-Methyl-N-[2-[(2-methyl-4-quinolyl)amino]ethyl]pent-2-enamide (50 mg, 0.15 mmol) was dissolved in dioxane (2 ml), Lawesson's reagent (75 mg, 0.18 mmol) was added in one portion and the resulting mixture was stirred at 130° C. under microwave heating for 0.5 hrs. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% ammonia and acetonitrile) to yield 15 mg (0.047 mmol, 28.5%).
Reaction SMILES: [NH2:1][C:2]([CH3:29])([CH3:28])[CH2:3][NH:4][CH:5]([C:9]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](=[O:26])[C:16]2[C:11](=[N:12][C:13]([Cl:27])=[CH:14][N:15]=2)[N:10]=1)[CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41](Cl)=[O:42]>ClCCl>[CH2:19]([N:18]1[C:17](=[O:26])[C:16]2[C:11](=[N:12][C:13]([Cl:27])=[CH:14][N:15]=2)[N:10]=[C:9]1[CH:5]([NH:4][CH2:3][C:2]([NH:1][C:41](=[O:42])[C:40]1[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=1)([CH3:29])[CH3:28])[CH:6]([CH3:8])[CH3:7])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C(NCC(C)(C)N)c1nc2nc(Cl)cnc2c(=O)n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NC(C)(C)CNC(c2nc3nc(Cl)cnc3c(=O)n2Cc2ccccc2)C(C)C)cc1F

Procedure:
Formula 203 where R2 is H; R3 is Cl; R5 is Benzyl; R6 is Isopropyl; R6′ is H; Ra and Rb are Methyl; Rc is 3-Fluoro-4-methyl-phenyl-; W and Z are —N═; X and Y are —C═: To a solution of (±)-2-[1-(2-amino-2-methyl-propylamino)-2-methyl-propyl]-3-benzyl-7-chloro-3H-pteridin-4-one (133 mg, 0.32 mmol) in dichloromethane (3 mL) is added triethylamine (90 μL, 0.64 mmol), followed by 3-fluoro-4-methylbenzoyl chloride (51 μL, 0.35 mmol). The resultant solution is stirred at ambient temperature for 3 hours, quenched with saturated aqueous sodium bicarbonate (5 mL) and diluted with dichloromethane (5 mL). The aqueous layer is extracted with dichloromethane (5 mL) and the combined extracts are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography (10-20% ethyl acetate/hexanes) to give (±)-N{2-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pteridin-2-yl)-2-methyl-propylamino]-1,1-dimethyl-ethyl}-3-fluoro-4-methyl-benzamide.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](OC)=[O:7].[H-].C([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: OCc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
Under a nitrogen atmosphere, to a solution of methyl 3-(bromomethyl)benzoate (10.0 g) in toluene (100 mL) was added a 1.5 M solution (100 mL) of diisobutylaluminum hydride in toluene at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added methanol at 0° C., and the resulting white precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure to give a crude product of the title compound (8.83 g) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].S(=O)(=O)(O)O.[CH3:11][C:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH2:13].CC(N=NC(C#N)(C)C)(C#N)C>CC(N=NC(C#N)(C)C)(C#N)C.C(O)C>[CH3:11][CH:12]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:13][PH:2](=[O:4])[OH:3]
Reactant: C=C(C)CC(C)(C)C
Reactant: O=[PH2][O-]
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C[PH](=O)O)CC(C)(C)C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A 2 L 4-neck flask, equipped with thermocouple well, a dropping funnel, overhead stirrer and reflux condenser is charged with 199 grams (1.88 moles) of sodium hypophosphite monohydrate and 500 mL of 2B ethanol. Into the resultant stirred suspension is added via the dropping funnel, 52 mL (1.87 moles) of concentrated sulfuric acid. During the addition the reaction mixture temperature rises from 21° C. to 27° C. After approximately 15 minutes, 100 mL (0.624 moles) of 2,4,4-trimethyl-1-pentene is added, followed by 10.24 g (0.062 moles) of AIBN powder. The reaction mixture is heated at reflux under a nitrogen atmosphere for 20 hours. An additional 6.84 g (0.042 moles) of AIBN powder is added and the mixture is refluxed under nitrogen for another 20 hours. Solvent is removed under vacuum and the residue is partitioned between 400 mL heptane and 1 L of water. The heptane layer is concentrated under vacuum to give 98 grams (88% of theory) of 2,4,4-trimethylpentyl phosphinic acid as a colorless oil.