Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:9]=[CH:10][C:11]3[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][NH:14][C:12]=3[N:13]=2)[CH2:4][CH2:3]1.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([N:14]1[C:12]2[N:13]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:9]=[CH:10][C:11]=2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ncc3c(=O)c(C(=O)O)cn(Cc4ccccc4)c3n2)CC1
Temperature: 95 °C

Procedure:
A mixture of 1.0 g of 5,8-dihydro-2-(4-methyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid, 0.6 ml of benzyl chloride, 20 ml of a 12% aqueous solution of potassium carbonate, and 150 ml of dimethylformamide was heated at 95°C for 2 hours. After removal of the solvent and an excess of the reagent, the resulting residue was taken up in water and the aqueous solution neutralized with acetic acid. The solid that separated was collected and recrystallized from dimethylformamide to give 0.7 g of the product, m.p. 251° - 255°C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](O)=[O:6])[C:3]=1[NH2:11].[NH2:12][C:13](N)=[O:14].C1(O)C=CC=CC=1>C(O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:3]=1[NH:11][C:13](=[O:14])[NH:12][C:5]2=[O:6]
Reactant: NC(N)=O
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: CCO
Solvent: Oc1ccccc1
Product: Cc1cccc2c(=O)[nH]c(=O)[nH]c12
Temperature: 100 °C
Yield: 75 %

Procedure:
3-Methylanthranilic acid (15 g., 0.1 mole), urea (36 g., 0.6 mole) and phenol (86 g.) were mixed together and heated to reflux for three hours. The reaction was then allowed to cool to 100° C. and ethanol (75 ml.) added dropwise. The resulting solid was filtered and washed twice with cold ethanol to afford 13.2 g. (75% yield); m.p. 170° C.
Reaction SMILES: [NH2-].[Na+].N.[CH:4]1[C:17]2[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.Br[CH2:19][CH2:20][CH2:21][Cl:22]>>[Cl:22][CH2:21][CH2:20][CH2:19][N:16]1[C:17]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[O:9][C:10]2[C:15]1=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: ClCCCBr
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Agent: N
Agent: [NH2-]
Agent: [Na+]
Product: ClCCCN1c2ccccc2Oc2ccccc21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium amide (1.72 g) in 100 ml of liquid ammonia, 7 g (0.038 mol) of phenoxazine was added. After stirring for 30 minutes, 6.3 g (0.04 mol., 3.96 mL) of 1-bromo-3-chloropropane was added slowly with constant stirring. After one more hour, ammonia was allowed to evaporate and solid ice pieces were added carefully followed by cold water. When the reaction ceased, the mixture was extracted three times with ether. The ether solution was washed three times with water, dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on silica gel. Petroleum ether-ethylacetate (9 mL+3 mL) eluted the pure title compound (7.94 g) as white crystals. VU-λmax (MeOH) 218, 238 and 321 nm; IR (KBr) 3070, 2860, 1630, 1490, 1380, 1275, 920, 815 and 740 cm-1 ; 1H-NMR (δ) 6.47-6.82 (m, 8H, ArH, H1 -H4 and H6 -H9), 2.11 (m, 2H, H1), 3.63 (m, 2H, HK), and 3.69 (m, 2H, Hm); 13C-NMR (1H decoupled) 111.23 (C1 and C9), 115.50 (C4 and C6), 121.07 (C3 and C7), 123.70 (C2 and C8), 133.03 (C1' and C9'), 144.92 (C4' and C6'), 27.82 (C1), 41.09 (CK) and 42.63 (Cm); EIMS (m/z) 259 (M+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)C1(CN)CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1(CNC(=O)OCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(aminomethyl)piperidine-1,4-dicarboxylate (0.300 g, 1.1 mmol) and N,N-diisopropylethylamine (0.229 mL, 1.32 mmol) in CH2Cl2 (5 mL) at 0° C. was added benzyl chloroformate. The reaction was stirred overnight, and then diluted with CH2Cl2 and washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc:hexanes gradient) to give the title compound in 82% yield. MS (ES+) [M+H]+=407.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18](OCC)=[O:19])[CH:13]=[N:14]2)=[N:9][CH:8]=1.[NH3:27].CO>>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:17][C:18]([NH2:27])=[O:19])[CH:13]=[N:14]2)=[N:9][CH:8]=1
Reactant: CCOC(=O)Cc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Reactant: N
Solvent: CO
Product: NC(=O)Cc1cnc2cc(OCc3ccc(F)c(F)c3)cnc2c1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Ethyl 2-(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetate (1.95 g, 5.44 mmol) was treated with a solution of ammonia in MeOH (7 M, 30 mL, 245 mmol). The slurry was stirred at ambient temperature for 30 h. The resulting precipitate was filtered and washed with MeOH to give the title compound as a cream colored solid. The crude product was azeotrope dried with toluene to remove traces of ammonia then dried on high vacuum for 48 h to give the title compound (1.79 g, 82%) as a pure white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (t, J=2.0 Hz, 2H), 8.21 (d, J=1.4 Hz, 1H), 7.88 (d, J=2.6 Hz, 1H), 7.75-7.58 (m, 2H), 7.50 (td, J=8.4, 10.7 Hz, 1H), 7.45-7.36 (m, 1H), 7.05 (br s, 1H), 5.34 (s, 2H), 3.66 (s, 2H). [M+H]=330.2.
Reaction SMILES: [CH3:1][C@H:2]([NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:29][NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:31]([N:30]([CH3:29])[C:3](=[O:5])[C@@H:2]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:1])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CNCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84.9 %

Procedure:
To a-30° C. solution of N-t-Boc-L-alanine (20.0 g, 0.106 mol) and triethylamine (16.8 mL, 0.119 mol) in THF (300 mL) was added isobutyl chloroformate (15.0 mL, 0.114 mol) drop wise. The reaction mixture was warmed to ambient temperature over 1.25 h and then stirred for 3.5 h. The reaction mixture was cooled to 0° C. and a solution of N-methylbenzylamine (14.3 mL, 0.111 mol) and triethylamine (18.8 mL, 0.134 mol) in THF (60 mL) was added drop wise. The reaction mixture was allowed to warm to ambient temperature. After 16 h, saturated NaHCO3 (200 mL) was added and most of the THF was removed under reduced pressure. The remaining aqueous layer was extracted with EtOAc (2×250 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 10% EtOAc in hexanes to 40% EtOAc in hexanes) gave (S)-tert-butyl 1-(benzyl(methyl)amino)-1-oxopropan-2-ylcarbamate (26.3 g, 85%) as a colorless oil. 1H NMR consistent.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:27][N:28](C=O)C>CCOC(C)=O.O.[C-]#N.[Zn+2].[C-]#N.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:27]([C:7]1[CH:24]=[CH:23][C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)#[N:28]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2cc(C#N)ccc2C1
Temperature: 80 °C

Procedure:
A mixture of 1,1-dimethylethyl 8-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Preparation 31) (0.397 g, 0.999 mmol), zinc cyanide (0.176 g, 1.499 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.100 mmol) in DMF (4 ml) was stirred and heated at 80° C. for 2 hours then cooled and diluted with EtOAc/water (40 ml of each) and the organic washed with 3×20 ml of water, dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 1:4 EtOAc/iso-hexane to give the title compound (198 mgs) as a gum which crystallised slowly. MS (ES) C15H18N2O3 requires 274; found 175 [M+H−100]+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([OH:18])=[O:17].C([BH3-])#N.[Na+]>C(O)C.O>[C:16]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([NH2:10])=[O:9])=[O:5])[CH3:3])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:18])=[O:17]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(N)=O
Reactant: O=C(O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
Couple L-alanyl-L-proline amide, prepared as in Example 51, with 2-oxo-4-phenylbutyric acid employing sodium cyanoborohydride in 50% ethanol-water by the method described in example 2. After eluting from the ion-exchange resin, concentrate in vacuo to a small volume, flush with water, and freeze-dry to obtain N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline amide as a mixture of diastereoisomers.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([F:11])[C:3]=1[F:12].C([Li])CCC.[CH2:18]([CH:21]1[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[CH2:22]1)[CH2:19][CH3:20].[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2([OH:32])[CH2:28][CH2:27][CH:26]([CH:23]3[CH2:24][CH2:25][CH:21]([CH2:18][CH2:19][CH3:20])[CH2:22]3)[CH2:31][CH2:30]2)=[C:3]([F:12])[C:4]=1[F:11])[CH3:10]
Reactant: CCOc1ccc(Br)c(F)c1F
Reactant: CCCC1CCC(C2CCC(=O)CC2)C1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1CCC(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
THF (100 ml) was added to 1-bromo-4-ethoxy-2,3-difluorobenzene (5.1 g) in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to −78° C. n-Butyllithium (1.57 M, in a hexane solution) (13.8 ml) was added dropwise at a temperature of −70° C. or lower. The stirring was continued at −78° C. for another 2 hours, and 4-(3-propylcyclopentyl)-cyclohexanone (3.0 g) in a THF (10 ml) solution was added dropwise at a temperature of −70° C. or lower. After the mixture had been stirred at −78° C. for another 1 hour, it was warmed to room temperature, and a saturated aqueous solution of ammonium chloride (50 ml) was added. The mixture was separated, and the water layer was extracted with ethyl acetate three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=1/9 by volume) to give 1-(4-ethoxy-2,3-difluorophenyl)-4-(3-propylcyclopentyl)cyclohexanol (5.0 g).
Reaction SMILES: C(O)(=O)C.C(C1C=CC=C(O)C=1O)CCCCCCCCCCCCCCCCCC.[CH3:32][O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=O.[BH4-].[Na+].P(Br)(Br)[Br:47]>>[CH3:32][O:33][C:34]1[C:41]([O:42][CH3:43])=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][Br:47]
Reactant: COc1cccc(C=O)c1OC
Reactant: BrP(Br)Br
Agent: CCCCCCCCCCCCCCCCCCCc1cccc(O)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc(CBr)c1OC

Procedure:
The nonadecylcatechol acetate (NDC-AC) used in the tests was prepared as follows: 2, 3 dimethoxybenzaldehyde was reduced in the presence of sodium borohydride and the reduction product reacted with phosphorus tribromide to form 2, 3 dimethoxybenzylbromide. The benzylbromide reaction product was refluxed with triphenyl phosphine in xylene to form 2, 3 dimethoxybenzyl-triphenyl phosphonium bromide which was then reacted with octadecanal in the presence of butyl lithium to form 2, 3 dimethoxy-nonadecenylbenzene. Subsequent steps of reduction and reaction with boron tribromide produced 3-nonadecylcatechol which was purified by chromatography. The catechol was acetylated with acetic anhydride in pyridine to form the acetate (NDC-AC).
Reaction SMILES: [Cl-].[NH4+].C(O)(C)C.[N+:7]([C:10]1[CH:23]=[CH:22][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:12][CH:11]=1)([O-])=O>O>[NH2:7][C:10]1[CH:11]=[CH:12][C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)CC(=O)c1ccc(N)cc1
Temperature: 5 °C
Yield: 83.1 %

Procedure:
Into a mixture comprising 224 g of reduced iron, 13.4 g of ammonium chloride, 1 liter of isopropyl alcohol and 0.2 liter of water was added 237 g of ethyl p-nitrobenzoylacetate in small portions at a temperature between 50° C. and 70° C. with caution against heat generation. The mixture was allowed to react at 70° C. for 1 hour, followed by filtration. To the filtrate was added 1 liter of water, and crystals precipitated upon cooling to 5° C. were separated by filtration to obtain 172 g of ethyl p-aminobenzoylacetate as yellow crystals having a melting point of 82° to 84° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[CH:11][N:10]=1.[Cu][C:16]#[N:17]>CN(C)C=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[C:3]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][N:10]=2)[CH:4]=1
Reactant: N#C[Cu]
Reactant: Cn1ncnc1-c1cc(F)ccc1Br
Solvent: CN(C)C=O
Product: Cn1ncnc1-c1cc(F)ccc1C#N
Temperature: 100 °C
Yield: 74.7 %

Procedure:
A solution of 5-(2-bromo-5-fluorophenyl)-1-methyl-1H-1,2,4-triazole (1.85 g, 7.22 mmol) in N,N-dimethylformamide (10 ml) was treated with copper (I) cyanide (0.71 g, 7.95 mmol). The mixture was then maintained under vacuum for a few minutes, flushed with argon and heated at 100° C. for 16 h. The solvent was then evaporated in vacuo and the residual oil was diluted with ethyl acetate and washed with a solution of 10% ammonium hydroxide followed by 20% ammonium chloride in water. The organic fraction was then washed with brine, dried over anhydrous magnesium sulfate and concentrated. Column chromatography of the residue on silica gel (elution gradient ethyl acetate 0-40% in toluene) gave 1.09 g (75% yield) of the title nitrile as white crystals: mp 134° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.98 (3H, s, CH3), 7.37-7.42 (2H, m, aromatics), 7.90 (1H, dd, J=5.0 Hz and J=8.6 Hz, aromatic), 8.08 (1H, s, CH). Anal. Calcd for C10H7FN4: C 59.40, H 3.49, N 27.71; Found: C 59.22, H 3.28, N 27.68.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:22]=2)[N:17]=[CH:16][N:15]=1.Cl>CN(C=O)C>[ClH:13].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: O=C1Cc2ccccc2N1
Reactant: Clc1ncnc2ccc(N3CCOCC3)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1c1ncnc2ccc(N3CCOCC3)cc12
Yield: 13.1 %

Procedure:
Using a procedure analogous to that described in Example 26, oxindole (0.32 g, 2.4 mmol) was added to sodium hydride (110 mg, 2.8 mmol) in DMF (15 ml) and the solution was treated with 4-chloro-6-morpholinoquinazoline (200 mg, 8 mmol), (EP 0566226), in DMF (8 ml). The product so obtained was treated with ethereal hydrogen chloride to give 4-(oxindol-3-yl)-6-morpholinoquinazoline hydrochloride (120 mg, 43%).
Reaction SMILES: ClC1N=C(NC2C=CC=C(C3NN=NN=3)C=2)C(F)=CN=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[C:25]([F:29])=[CH:24][N:23]=1.[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39]>>[Cl:21][C:22]1[N:27]=[C:26]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([Cl:30])=[C:32]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[C:25]([F:29])=[CH:24][N:23]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Fc1cnc(Cl)nc1Nc1cccc(-c2nnn[nH]2)c1
Product: Fc1cnc(Cl)nc1Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
In like manner to, the preparation of 2-chloro-5-fluoro-N4-[3-(1H-tetrazol-5-yl)phenyl]-4-pyrimidineamine the reaction of 2,4-dichloro-5-fluoropyrimidine with 4-chloro-3-trifluoromethylaniline gave 2-chloro-N4-(4-chloro-3-trifluoromethylphenyl)-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.15 (d, 1H, J=2.1 Hz), 7.96 (d, 1H, J=3 Hz), 7.91 (dd, 1H, J=2.7 Hz and 8.7 Hz), 7.53 (d, 1H, J=8.1 Hz), 7.06 (bs, 1H); 19F NMR (CDCl3): −17892 and −44402; LCMS: purity: 93%; MS (m/e): 326 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:31])[C:9]=2[C:11]2[N:12]=[C:13]([N:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[C:23]([CH3:30])([CH3:29])[CH2:22]3)[C:14]3[CH2:20][NH:19][CH2:18][CH2:17][C:15]=3[N:16]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[N:3]=1.Cl[C:43]1[N:47]([CH3:48])[N:46]=[C:45]([CH:49]([F:51])[F:50])[C:44]=1[CH:52]=[O:53].[F-].[Cs+]>CC(N(C)C)=O>[F:51][CH:49]([F:50])[C:45]1[C:44]([CH:52]=[O:53])=[C:43]([N:19]2[CH2:18][CH2:17][C:15]3[N:16]=[C:11]([C:9]4[C:8]([CH3:31])=[CH:7][CH:6]=[C:5]5[C:10]=4[C:2]([CH3:1])=[N:3][N:4]5[S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:33])=[O:34])[N:12]=[C:13]([N:21]4[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[C:23]([CH3:30])([CH3:29])[CH2:22]4)[C:14]=3[CH2:20]2)[N:47]([CH3:48])[N:46]=1
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CNCC3)CC1(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2c(C=O)c(C(F)F)nn2C)CC3)CC1(C)C
Temperature: 140 °C

Procedure:
A mixture of (R)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (320 mg, 0.557 mmol), 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (217 mg, 1.114 mmol) and cesium fluoride (169 mg, 1.114 mmol) in DMA (2.2 mL) was heated at 140° C. for 1.5 h. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (EtOAc-heptane 10-100%) to provide (R)-3-(difluoromethyl)-5-(2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbaldehyde. MS (ESI+) m/z 733.4 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[NH:17][C:16]2=[O:24])=[CH:13][CH:14]=1
Reactant: O=c1[nH]c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2cccnc2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 370 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (500 mg) and Pd—C (100 mg) in MeOH (30 mL) was stirred at room temperature for 5.5 h. The mixture was filtered by Celite, and the filtrate was concentrated. The resulting solid was rinsed with iPr2O to give 3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (370% mg) as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)=[N:9][C:8]=1[CH3:20].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[N:9][C:8]=1[CH3:20]
Reactant: COC(=O)CCCc1oc(-c2ccccc2OC)nc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)CCCc1oc(-c2ccccc2O)nc1C

Procedure:
Dissolve 4-[2-(2-methoxy-phenyl)-4-methyl-oxazol-5-yl]-butyric acid methyl ester (2.1 g, 7.3 mmol) in CH2Cl2 (20 mL) under nitrogen at room temperature. Add boron tribromide (1M in CH2Cl2, 21.8 mL) and stir at room temperature until the reaction is complete. Quench the mixture with methanol, add water and extract with CH2Cl2. Dry the combined extracts over Na2SO4 and concentrate. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) to allow for isolation of 4-[2-(2-hydroxy-phenyl)-4-methyl-oxazol-5-yl]-butyric acid methyl ester (1.55 g, 77%). MS (ES): (M+1)+ 276.1, 277.2 m/z.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([NH2:20])=O)[CH:3]=1.C(O)(=O)C>P(Cl)(Cl)(Cl)=O>[C:18]([C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=1)#[N:20]
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(N)=O)n1
Solvent: CC(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCOc1ccccc1-c1nc(O)cc(C#N)n1

Procedure:
A stirred solution of 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide (0.50 g) in phosphoryl chloride (16 ml) was heated under reflux for 4 hours and then the reaction mixture was evaporated under reduced pressure to remove excess phosphoryl chloride. Water was added to the residue, which was extracted with chloroform (3×20 ml). The combined extracts were washed with water, dried (magnesium sulfate) and evaporated under reduced pressure to yield an oil which was heated on a steam bath with glacial acetic acid (15 ml) for 4 hours. The cooled reaction mixture was evaporated under reduced pressure to yield a crude product which was combined with further product similarly prepared from 6-hydroxy-2-(2-propoxyphenyl)-pyrimidine-4-carboxamide (0.82 g) and phosphoryl chloride (25 ml). The combined products were eluted from silica with ether:chloroform (9:1) and fractions containing product were combined and evaporated under reduced pressure to yield the title compound, 0.31 g, m.p. 135°-6° C. (from isopropanol/ether).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:14]=[C:13]([C:15]3S[CH:17]=[CH:18][CH:19]=3)[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=3[NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)[CH:27]=[C:26]1CC1N=C(C2C=CC=CC=2)C2C=CC=CC=2NC1=O.ClC1C=CC2NC(=O)C(CC3NC4C(C=3)=CC=CC=4)N=C(C3C=CC=CC=3)C=2C=1>>[CH:15]1([C:13]2[C:12]3[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=3[NH:10][C:9](=[O:24])[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[N:14]=2)[CH2:27][CH2:26][CH2:17][CH2:18][CH2:19]1
Reactant: O=C1Nc2ccccc2C(c2ccccc2)=NC1Cc1cc2ccccc2[nH]1
Reactant: O=C1Nc2ccccc2C(c2cccs2)=NC1c1ccc(O)cc1
Agent: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1Cc1cc2ccccc2[nH]1
Product: O=C1Nc2ccccc2C(C2CCCCC2)=NC1c1ccc(O)cc1

Procedure:
1,3-dihydro-3-(4-hydroxyphenyl)-5-(2-thienyl)-2H-1,4-benzodiazepin2-one; 1,3-dihydro-3-(1H-indol-2-ylmethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one; 7-chloro-1,3-dihydro-3-(1H-indol-2-ylmethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one;