Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])(C(C)=O)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:2][C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(Cl)(Cc1ccccc1C)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1ccccc1C=CC(=O)O
Reaction time: 6 h

Procedure:
292 g (1.08 moles) of ethyl 2-chloro-2-(o-methylbenzyl)-acetoacetate were added dropwise to 4.85 moles of 25% strength aqueous NaOH solution in the course of 1 hour. The refluxed mixture was then stirred for a further 6 hours. The reaction solution was reacted twice by shaking with toluene and then acidified with semiconcentrated hydrochloric acid, and the precipitate which had separated out was filtered off under suction. It was rinsed with water and toluene and dried in a drying oven. 157 g (90% of the theoretical yield) of o-methylcinnamic acid of melting point 176° to 177° C. were obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:10][CH:11]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]2[CH:31]=[N:32][N:33]([CH2:35][C@H:36]3[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]3)[CH:34]=2)[N:24]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:13][CH2:14][N:15]([C:23]3[N:28]=[CH:27][N:26]=[C:25]([NH:29][C:30]4[CH:31]=[N:32][N:33]([CH2:35][C@H:36]5[O:41][CH2:40][CH2:39][N:38]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37]5)[CH:34]=4)[N:24]=3)[CH2:16][CH2:17]2)=[N:10][CH:11]=1
Reactant: Fc1ccccc1Oc1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(Oc6ccccc6F)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5-(2-fluorophenoxy)-2-(piperazin-1-yl)pyrimidine HCl salt (27 mg, 0.1 mmol), (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)-morpholine-4-carboxylate (40 mg, 0.1 mmol) and diisopropylethylamine (25 mg, 2.0 mmol) in dioxane (2 mL) was stirred at room temperature for 2 hours. The reaction mixture was directly evaporated and used in the next step.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=2)[N:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:45][C:46]1[CH:50]=[C:49]([Sn](C)(C)C)[S:48][N:47]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:45][C:46]1[CH:50]=[C:49]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=3)[N:7]=2)[S:48][N:47]=1
Reactant: Cc1cc([Sn](C)(C)C)sn1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)sn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A pressure vessel was purged with Ar and charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (5.00 g, 17.6 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.807 g, 0.881 mmol), 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol). DMF (50 mL) was added, immediately followed by 3-methyl-5-(trimethylstannyl)isothiazole (6.46 g, 24.7 mmol). The reaction mixture was stirred at 100° C. for 1 h. Two more portions of tris(dibenzylideneacetone)dipalladium(0) (0.807 g, 0.881 mmol) and 2-dicyclohexylphosphinobiphenyl (0.618 g, 1.76 mmol) were added every hour for the first two hours of stirring. Reaction was then stirred was at 100° C. overnight, cooled to room temperature and concentrated in vacuo. Purification by MPLC (EtOAC/MeOH: 100/0 to 90/10) afforded the title compound (1.80 g, 30% yield). MS m/z=347.1 [M+H]+. Calc'd for C15H18N6O2S: 346.41
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[N:4]1)[CH3:2].[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([N+:20]([O-:22])=[O:21])[C:9]3[O:15][CH2:14][O:13][C:10]=3[CH:11]=2)[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[N:4]1)[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCn1nc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCn1nc(C(=O)O)c(=O)c2c([N+](=O)[O-])c3c(cc21)OCO3
Temperature: 10 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
To a solution of 1-ethyl-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid (5 g, 19.07 mmol) in sulfuric acid (15 mL) cooled to 0° C. was added potassium nitrate (2.121 g, 20.97 mmol) in small portions to maintain temperature bellow 10° C. with ice water. The mixture was stirred at 10° C. for 1 h and at room temperature for 12 h, and was then poured into ice cold water (200 ml). The mixture was filtered, the solid was washed with water and ethanol to afford 1-ethyl-5-nitro-4-oxo-1,4-dihydro-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid (4.4 g, 14.32 mmol, 75% yield). LCMS: (M+H)+: 308.2
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]N1C(=O)CCC1=O>CC(C)=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([I:19])[CH:10]=[C:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(C)n1Cc1ccccc1
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(I)c(C)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 123A (564 mg) in acetone (8 mL) at 0° C. was added N-iodosuccinimide (600 mg). The mixture was stirred at room temperature overnight, and diluted with ethyl acetate and washed with water. The organic layer was concentrated and the residue was purified by flash chromatography, and eluted with 50% dichloromethane in hexane to provide the title compound.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[N:2]([CH3:1])[CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCc6ccccc6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Compound 7B (20 mg, 0.058 mmol) and triethylamine (9.1 μL, 0.064 mmol) were dissolved in dichloromethane (1 mL). Benzyl chloroformate was added to it. The mixture was stirred at room temperature for 2 hours. The crude reaction mixture was purified on silica gel column using 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (18.4 mg, 66.2% yield).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10](N)[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][O:14][CH3:15])[N:8]=2)[N:3]=1.C(O)(=[O:18])C>[OH-].[Na+]>[NH2:1][C:2]1[NH:11][C:10](=[O:18])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][O:14][CH3:15])[N:8]=2)[N:3]=1
Reactant: COCc1cnc2nc(N)nc(N)c2n1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COCc1cnc2nc(N)[nH]c(=O)c2n1
Yield: 83 %

Procedure:
The diaminopteridine, vide supra, was hydrolyzed in 1N NaOH at 70° C. for 3 hr. The resulting basic solution was then acidified with acetic acid, and the yellow product was filtered, washed with 95% ethanol and ethyl ether, and dried under vacuum overnight to yield 0.5 g (83%) of 2-amino-6-methoxymethyl-4(3H)-pteridinone as a yellow powder: UV (0.1N NaOH) λmax 255 nm (22300), 277.5 nm sh (6200), 364 nm (7100); NMR: δ (d6 -DMSO) 3.36 (s, OMe); 4.53 (s, CH2O); 7.32 (br s, NH2); and 8.63 (s, 7-H). Anal. calcd. for C8H9N5O2.7/10H2O: C, 43.72; H, 4.77; N, 31.86. Found: C, 43.77; H, 4.77; N, 31.63.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[CH:11][C:10]=2[CH3:17])=[O:5])C.[NH2:19][CH:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:28]([CH:20]([NH:19][C:7]1[C:6]([C:4]([OH:3])=[O:5])=[CH:15][C:14]2[C:9](=[C:10]([CH3:17])[CH:11]=[C:12]([Cl:16])[CH:13]=2)[N:8]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:30])=[O:29]
Reactant: NC(Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)c1cc2cc(Cl)cc(C)c2nc1Cl
Product: Cc1cc(Cl)cc2cc(C(=O)O)c(NC(Cc3ccccc3)C(=O)O)nc12

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloro-8-methyl-quinoline-3-carboxylic acid ethyl ester is reacted with DL-phenylalanine to provide the title compound in moderate yield as yellow powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:51])([F:50])[C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][CH:49]=1)/[CH:42]=[CH:43]/[C:44](O)=[O:45]>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:44](=[O:45])[CH:43]=[CH:42][C:41]1[CH:47]=[CH:48][CH:49]=[C:39]([C:38]([F:50])([F:51])[F:37])[CH:40]=1)[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Product: CCCCCc1ccc(CN(C(=O)C=Cc2cccc(C(F)(F)F)c2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 69.9 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with trans-3-trifluoromethyl-cinnamic acid (21.4 mg, 0.099 mmol) gave 42.9 mg (69%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(3-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=682.48.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:17]2[CH:18]=[C:19]([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][C:16]=2[O:15][C:14]([CH3:30])([CH3:29])[C:13]=1[OH:31])=[O:11])#[N:6].C(O)(=O)C.O1CCCC1>C(OCC)(=O)C>[C:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]1[C:17]2[CH:18]=[C:19]([C:22]([F:27])([F:28])[C:23]([F:24])([F:26])[F:25])[CH:20]=[CH:21][C:16]=2[O:15][C:14]([CH3:29])([CH3:30])[CH:13]1[OH:31])=[O:11])#[N:6]
Reactant: CC1(C)Oc2ccc(C(F)(F)C(F)(F)F)cc2C(C(=O)NCCC#N)=C1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)Oc2ccc(C(F)(F)C(F)(F)F)cc2C(C(=O)NCCC#N)C1O
Yield: 99.5 %

Procedure:
1.1 g of tertiary-butoxy potassium and 2 ml of a dimethylformamide solution of 2 g of 2-cyanoethyl isothiocyanate were subsequently added to a mixture of 2.6 g of 6-pentafluoroethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one and 28 ml of dimethylformamide while stirring at -5° C., followed by stirring at 5° C. for 15 hours. Then, 2N hydrochloric acid was added thereto, and the mixture was extracted with ether. After washing the organic layer with water and drying, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (a developing solution, hexane:methylene chloride=1:2) to obtain 2.6 g of N-(2-cyanoethyl)-6-pentafluoroethyl-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbamide. 2.1 g of sodium cyanoborohydride was added to a mixture of 2.6 g of N-(2-cyanoethyl)-6-pentafluoroethyl-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbamide obtained above, 15 ml of acetic acid and 45 ml of tetrahydrofuran while ice-cooling and stirring, and the resulting mixture was stirred at room temperature for 13 hours. The mixture was diluted with ethyl acetate, and, after washing the organic layer with a saturated aqueous solution of sodium bicarbonate and water and drying, the solvent was distilled off to obtain 2.6 g of N-(2-cyanoethyl)-6-pentafluoroethyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbamide. Then, the product was added to 90 ml of pyridine and 3.4 g of tosyl chloride, and the mixture was heated while refluxing for 1 hour. After concentration under reduced pressure, water and concentrated hydrochloric acid were added thereto, followed by extracting with methylene chloride. After washing the organic layer with water and drying, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (a developing solution, hexane:ethyl acetate=1:1) to obtain 460 mg of N-(2-cyanoethyl)-6-pentafluoroethyl-2,2-dimethyl-2H-1-benzopyran-4-carbamide having a melting point of 163°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.O.[NH2:14]N.O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([NH2:14])[C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 20.3 %

Procedure:
To a cooled mixture of 1.81 g (10 mmol) 4-chloro phthalimide in 20 mL ethanol (96%) was added 0.5 mL (10 mmol) hydrazine monohydrate. The reaction mixture was stirred for 2 min. at room temperature and 2 min. at reflux. By adding 50 mL cold water pale yellow crystals formed after 1 h. Resulting crystals was filtered and recrystallized from ethanol to give 0.4 g (20%)4-chloro-N-amino-phthalimide :top 172°-175° C.; 1H NMR (200 MHz, DMSO-d6) d 4.90 (s, 2H, NH2), 7.82-7.92 (m, 3H, C6H3); it solidifies after melting and melts again around 345° C.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[C:18]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:17][C:16]([Cl:26])=[CH:15][N:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C1COCC1>[Cl:26][C:16]1[CH:17]=[C:18]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:13]([NH:12][C:10]([NH2:9])=[S:11])=[N:14][CH:15]=1
Reactant: O=C(NC(=S)Nc1ncc(Cl)cc1Oc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=S)Nc1ncc(Cl)cc1Oc1ccccc1
Temperature: 90 °C
Yield: 94.7 %

Procedure:
A 250 mLround-bottomed flask was charged with 1-benzoyl-3-(5-chloro-3-phenoxypyridin-2-yl)thiourea (13.752 g, 35.826 mmol) and THF (100 mL). 3M NaOH (119.42 mL, 358.26 mmol) was added and the reaction mixture was heated to 90° C. for 18 hours. The reaction mixture was cooled to room temperature and concentrated. The resulting solids were filtered, washed with water, and dried to provide the title compound (9.49 g, 94.689% yield) as a yellow solid. 1H NMR (d6-DMSO) δ 9.97 (s, 1H), 9.25 (s, 1H), 8.87 (s, 1H), 8.11 (d, 1H), 7.49 (t, 2H), 7.31 (d, 1H), 7.28 (m, 2H), 7.23 (d, 2H); Mass spectrum (apci) m/z=279.9 (M+H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:42]=[CH:41][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:43])[CH:10]=1>C(Cl)Cl>[Br:8][C:9]1[CH:42]=[CH:41][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:43])[CH:10]=1
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
TFA (3 ml) was added to a suspension of 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (673 mg, 1.2 mmol) in methylene chloride (10 ml). After stirring for 1 hour at ambient temperature, the volatiles were removed under vacuum. The residue was triturated with a mixture of water/ether. The organic layer was separated. The aqueous layer was washed again with ether. The aqueous layer was adjusted to pH10 with 2N aqueous sodium hydroxide. The aqueous layer was extracted with methylene chloride. The organic layer was dried (MgSO4) and the solvent was removed under vacuum. The solid was triturated with a mixture ether/petroleum ether (1/1), filtered, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (390 mg, 70.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[N:13]([CH3:18])[C:14]([C:15]([OH:17])=O)=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].[NH4+:35].C(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[N:13]([CH3:18])[C:14]([C:15]([NH2:35])=[O:17])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1
Reactant: Cn1c(C(=O)O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: [NH4+]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1c(C(N)=O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.5 h

Procedure:
A stirred suspension of 3 g (0.0075 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-carboxylic acid in 90 ml of methylene chloride was cooled in an ice bath and treated with 1.9 g (0.009 mole) of phosphorus pentachloride in portions. Stirring in the cold under a drying tube was continued for 30 min. Ammonia was then bubbled into the cold solution for 5 min and stirring in the cold was continued 30 min. longer. Evaporation at reduced pressure gave a tan solid. The solid was stirred with 3N ammonium hydroxide and extracted with methylene chloride. An emulsion formed but was destroyed by filtering to remove some high melting solid. The methylene chloride layer was dried over sodium sulfate and evaporated to give a yellow solid which was recrystallized from benzene to give off-white needles with mp 158°-160°. Uv λ sh 215 mμ (ε=43000) max 272 (15500) sh 330 (2500); ir (CHCl3) 3510, 3400 cm-1 (NH2) 1703 (CO) 1685 (CONH2).
Reaction SMILES: [F:1][CH:2]([F:57])[C:3]1[C:11]2[C:10]([F:13])([F:12])[CH2:9][CH2:8][C:7]([F:15])([F:14])[C:6]=2[N:5]([CH2:16][C:17]([NH:19][C@H:20]([C:30]2[C:35]([C:36]3[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=3)[C:41]([NH2:43])=[O:42])=[CH:34][C:33]([N:46]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:32][N:31]=2)[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)=[O:18])[N:4]=1.FC1(F)C2N(CC(N[C@H](C3C(C4C=CC(F)=C(C=4)C(N)=O)=CC(N4C(=O)C5C(=CC=CC=5)C4=O)=CN=3)CC3C=C(F)C=C(F)C=3)=O)N=C(C(F)(F)F)C=2[C@H]2C[C@@H]12>>[NH2:46][C:33]1[CH:34]=[C:35]([C:36]2[CH:37]=[CH:38][C:39]([F:45])=[C:40]([CH:44]=2)[C:41]([NH2:43])=[O:42])[C:30]([C@@H:20]([NH:19][C:17](=[O:18])[CH2:16][N:5]2[C:6]3[C:7]([F:14])([F:15])[CH2:8][CH2:9][C:10]([F:12])([F:13])[C:11]=3[C:3]([CH:2]([F:1])[F:57])=[N:4]2)[CH2:21][C:22]2[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=2)=[N:31][CH:32]=1
Reactant: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Agent: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)ccc1F
Product: NC(=O)c1cc(-c2cc(N)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
Compound 33 was prepared according to the method presented in the synthesis of Example 31 substituting compound 32 for compound 30K. 1H NMR (400 MHz, CD3OD) δ 8.08 (d, 1H), 7.39 (m, 2H), 7.28-7.17 (m, 1H), 7.14 (d, 1H), 7.00-6.60 (m, 2H), 6.37 (m, 2H), 5.19-5.01 (m, 3H), 3.12 (m, 1H), 2.99 (m, 1H), 2.66-2.34 (m, 4H). MS (m/z) 671.01 [M+H]+.
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]([CH:15]=O)=[O:14]>C(O)(=O)C>[OH:12][C:10]1[C:9]([C:13](=[O:14])[CH3:15])=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=1
Reactant: CC(=O)C=NNc1ccccc1
Reactant: O=CC=O
Solvent: CC(=O)O
Product: CC(=O)c1nn(-c2ccccc2)cc1O
Yield: 43.4 %

Procedure:
To 2-oxopropanal phenylhydrazone (5.00 g, 30.8 mmol) in acetic acid (60 mL) was added a 40% aqueous solution of glyoxal (5.9 g, 4.6 mL, 30.8 mmol) and the mixture was heated at reflux for 45 minutes. The acetic acid was removed under reduced pressure. The resultant mixture was diluted with ethyl acetate (100 mL), washed with NaHCO3 and sat. aq. NaCl. Solids were removed by filtration, the filtrate was dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (180 g column, 0-20 EtOAc/heptane gradient) to afford 1-(4-hydroxy-1-phenyl-1H-pyrazol-3-yl)ethanone as a yellow solid (2.70 g, 43%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[O:19][CH:20]([C:22]1[S:26][C:25]([N:27]=[C:28]=[O:29])=[N:24][N:23]=1)[CH3:21]>CCCCCC>[CH3:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[O:19][CH:20]([C:22]1[S:26][C:25]([NH:27][C:28](=[O:29])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:24][N:23]=1)[CH3:21]
Reactant: Cc1cccc(OC(C)c2nnc(N=C=O)s2)c1
Reactant: CNCC(OC)OC
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2cccc(C)c2)s1)OC

Procedure:
Methylaminoacetaldehyde dimethylacetal (3.7 grams, 0.031 mole) was added to a 50 milliliter benzene solution containing 3.7 grams (0.031 equivalent) of the 5-[1-(3-methylphenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above) and the resulting solution was refluxed for 15 minutes and then cooled. Hexane (100 milliliters) was added and the resulting solution formed crystals which were filtered off, and dried in a vacuum oven at 80° C. to 9.0 grams of white crystals of [5-[1-(3-methylphenoxy)ethyl]-1,3,4thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea (melting point 122°-125° C.).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][C:8]([CH3:20])([O:10][CH2:11][CH:12](O)[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:9].[ClH:21]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:21][CH:12]([CH2:11][O:10][C:8]([CH3:20])([CH3:9])[CH3:7])[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OCC(O)CN1CCCC1
Reactant: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OCC(Cl)CN1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred, cooled suspension of 34.7 g (0.167 ml) of phosphorous pentachloride in 20 ml of dry toluene (argon atmosphere) was added a solution of 31.93 g (0.159 m) of 1-[3-(1,1-dimethylethoxy)-2-hydroxypropyl]pyrrolidine (the product of Example 13a) and excess hydrogen chloride (gas) in 46 ml of dry toluene and 50 ml of dry tetrahydrofuran at a rate to keep the reaction temperature at 10°-25° C. When the addition was completed, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 1.5 hr. The reaction mixture was added portionwise, with stirring to a cooled solution of 122 ml of 45% potassium hydroxide and 230 g of ice at a rate to keep the reaction temperature at 25°-35° C. The reaction mixture was partitioned between ether and water. The ether portion was dried and concentrated in vacuo to give 31.69 g of oily title compound.