Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Al](C)(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:26]2[CH2:27][O:28][C:29](=[O:39])[N:30]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])[C:25]=2[CH:24]=[C:23]([C:40](OC)=[O:41])[CH:22]=1.[Al]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[C:26]2[CH2:27][O:28][C:29](=[O:39])[N:30]([C:31]3[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:38])[C:25]=2[CH:24]=[C:23]([C:40]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]2)=[O:41])[CH:22]=1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)OC2
Reactant: CC(C)N1CCNCC1
Agent: C[Al](C)C
Agent: [Al]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)OC3)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a dry flask charged with anhydrous CH2Cl2 (1 mL) was added 1-isopropylpiperazine (0.057 mL, 0.434 mmol, 2 eq). The mixture was cooled to 0° C. under nitrogen. To this cooled mixture was added Al(CH3)3 (0.217 mL of a 2M toluene solution, 0.434 mmol, 2 eq). After 15 min, methyl 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,4-dihydro-2H-3,1-benzoxazine-7-carboxylate (100 mg, 0.217 mmol, 1 eq) was dissolved in CH2Cl2 (1 mL) and added to the aluminum reagent at 0° C. under nitrogen. After 2 min the cooling bath was removed. Let stir at rt for 5d. The reaction was diluted with CH2Cl2, and washed with water. The aqueous layer was back extracted 2× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash column chromatography on silica gel eluting with 2:1 hexanes/acetone giving 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(4-isopropylpiperazin-1-yl)carbonyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one. Mass spectrum (ESI) 458.0 (M+1); 460 (M+3).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([C:12]([O:14][CH3:15])=[O:13])[NH:3]1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20](O)=[O:21].CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:20]([N:3]1[CH:4]([C:12]([O:14][CH3:15])=[O:13])[CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)=[O:21]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: COC(=O)C1Cc2ccccc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2ccccc2CN1C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate hydrochloride (2.0 g, 9 mmol) and 3,5-dimethylbenzoic acid (1.6 g, 10 mmol) in DMF (15 ml) is treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.9 ml, 10 mmol). The reaction mixture is slowly warmed to r.t. and stirring continued for 2 hours. The homogeneous mixture is diluted with ethyl acetate (500 ml) and washed with three portions of water (200 ml). The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material is chromatographed on silica with ethyl acetate/hexane 1:3 to give methyl N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate as a colorless oil. This material is hydrolized with 1M sodium hydroxide in THF to give N-(3,5-dimethylbenzoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH3:11])=[O:9])[CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:34])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O>>[CH3:11][NH:10][C:8](=[O:9])[C:4]1[CH:3]=[C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:17][CH:18]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)c3ccccc3Nc3ccccc3)cc2)ccn1
Reaction time: 16 h

Procedure:
4-Chloro-N-methylpicolinamide (70 mg, 410 μmol), N-(4-hydroxyphenyl)-2-(phenylamino)benzamide (150 mg, 492 μmol), cesium carbonate (267 mg, 821 μmol), and DMSO (410 μl 410 μmol) were added into a screw-capped test tube. The tube was sealed and placed in a preheated oil bath at 130° C. After 16 h, LC-MS showed mainly desired product. Water was added, and a gray solid precipitated out of the solution. The solid was filtered off and rinsed with water. The product was purified by reverse phase preparative HPLC. Fractions containing the product were combined, neutralized with sat NaHCO3 (aq), washed with brine, dried over MgSO4, and concentrated in vacuo. The product, N-methyl-4-(4-(2-(phenylamino)benzamido)phenoxy)picolinamide was collected as a black solid. MS Calcd for C26H22N4O3: [M]+=438. Found: [M+H]+=439.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[C:14]1([CH2:20][O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][C@H:28]([C:30]([OH:32])=[O:31])[NH2:29])=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:29][C@@H:28]([C:30]([OH:32])=[O:31])[CH2:27][CH2:26][CH2:25][NH:24][C:22]([O:21][CH2:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:23])=[O:13]
Reactant: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(O)c1ccc2ccccc2c1
Product: O=C(NCCC[C@@H](NC(=O)c1ccc2ccccc2c1)C(=O)O)OCc1ccccc1
Yield: 73 %

Procedure:
Prepared analogously to Example 4a) from 2-naphthalene carboxylic acid and (R)-N5 -(phenylmethoxycarbonyl)-ornithine in a yield of 73% of theory. Colourless crystals, Mp. 155-157° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH:17]=[C:16]([C:18]3[C:19]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH:15]=[N:14]2)[CH2:9][CH2:8]1)(=O)=O.[NH2:35][C:36]1[NH:37][C:38]([SH:41])=[N:39][N:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([C:16]3[CH:15]=[N:14][N:13]([C@@H:10]4[CH2:11][CH2:12][C@H:7]([CH2:6][S:41][C:38]5[NH:37][C:36]([NH2:35])=[N:40][N:39]=5)[CH2:8][CH2:9]4)[CH:17]=3)[C:19]=2[CH:26]=[CH:25]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](COS(C)(=O)=O)CC4)c3)ncnc21
Reactant: Nc1nnc(S)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@@H](CSc5nnc(N)[nH]5)CC4)c3)ncnc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
cis-4-[4-(7-[2-(Trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexylmethyl methanesulfonate (prepared as in Example 679A, step 6; 124.56 mg, 0.00024 mol), and 5-amino-4H-1,2,4-triazole-3-thiol (43.00 mg, 0.0003702 mol) were dissolved in DMF (1.20 mL) and potassium carbonate (0.122 g, 0.000887 mol) was added. The reaction was stirred at 50° C. for 18 h, at which time LCMS showed nearly complete reaction, and product present. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel using EtOAc as eluent to give the product. LC/MS (M+H)+: 526, 1H NMR (CDCl3): δ 8.90 (s, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.45 (d, 1H), 6.87 (d, 1H), 5.73 (S, 2H), 4.45 (brs, 2H), 4.41 (m, 1H), 3.60 (m, 2H), 3.22 (d, 2H, J=7.2 Hz), 2.29 (m, 2H), 1.70-2.10 (m, 7H), 0.98 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>CCO.O>[CH:1]1([CH2:7][NH:8][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCCC1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 60 °C
Yield: 113.3 %

Procedure:
Cyclohexylmethylamine (2.86 mL, 2.49 g, 22.0 mmol) was added to a mixture of N-(4-fluoro-3-nitrophenyl)acetamide (3.96 g, 20.0 mmol) and sodium carbonate (4.66 g, 44 mmol) in EtOH (50 mL) at room temperature. The reaction mixture was heated for 48 h at 60° C., and diluted with H2O (800 mL). The orange solid was precipitated out and collected to give the desired product (6.60 g, 100%). MS (ESI) (M+H)+: 292.32.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22](O)=[O:23])=[O:17])(=[O:13])=[O:12].[N:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][C:22]([N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=2)[CH2:36][CH2:35]1)=[O:23])=[O:17])(=[O:13])=[O:12]
Reactant: O=C(O)CCCNC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Reactant: c1cc(N2CCNCC2)ccn1
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NCCCC(=O)N1CCN(c2ccncc2)CC1
Yield: 21 %

Procedure:
Using an analogous procedure to that described in Example 18, 4-[2-(2-naphthalenesulphonamido)acetamido]butyric acid was reacted with 1-(4-pyridyl)piperazine to give 2-(2-naphthalenesulphonamido)-N-{3-[4-(4-pyridyl)piperazin-1-ylcarbonyl]propyl}acetamide in 21% yield as a foam;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([C:22]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[O:29])[C:6]([CH:8]1[CH2:10][CH2:9]1)=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C(=O)c1ccncc1)C(=O)C1CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
7.5 g (48 mmol) of 3-cyclopropyl-3-oxo-propionic acid ethyl ester were dissolved in 250 ml of CH2Cl2, the solution was cooled at 0° C. and successively were added 4.71 g (49.5 mmol) of anhydrous magnesium chloride, 8.1 ml (100 mmol) of pyridine and 12.8 g (72 mmol) of isonicotinoyl chloride.hydrochloride. The yellow suspension was stirred 1 h under ice cooling and 18 h at room temperature. The reaction mixture was poured into crashed ice and extracted twice with CH2Cl2. The organic phases were washed with brine, dried over magnesium sulfate, and evaporated. The residual product was purified by column chromatography (n-heptane:EtOAc 1:1) to afford the title compound as light yellow oil (10 g, 79%). MS: 262.1 (MH+).
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])=O.[CH3:22][O-:23].[Na+].CO>CO>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:2]([O:23][CH3:22])[C:3]2[N:10]=[C:8]([OH:9])[C:7]3[C:6](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=2)=[N:16][CH:17]=1
Reactant: C[O-]
Reactant: NC(=O)c1ccccc1NC(=O)C(Br)c1ccc(F)cn1
Agent: [Na+]
Solvent: CO
Product: COC(c1ccc(F)cn1)c1nc(O)c2ccccc2n1
Temperature: 65 °C

Procedure:
To a 0.3 M solution of 2-(2-bromo-2-(5-fluoropyridin-2-yl)acetamido)benzamide in MeOH is added 25% sodium methoxide/MeOH (2 equiv) and the mixture is heated at 65° C. overnight or until the reaction is substantially complete. The mixture is concentrated under reduced pressure and the residue is purified by chromatography to afford 2-((5-fluoropyridin-2-yl)(methoxy)methyl)quinazolin-4-ol.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([N:23]1[CH:27]([C:28]([OH:30])=O)[CH2:26][S:25][CH:24]1[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[C:37]1([NH:43][NH2:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1>O1CCCC1.C(OCC)(=O)C>[C:37]1([NH:43][NH:44][C:28]([CH:27]2[CH2:26][S:25][CH:24]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[N:23]2[C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])=[O:30])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1C(C(=O)O)CSC1c1cccnc1
Reactant: NNc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(C(=O)NNc2ccccc2)CSC1c1cccnc1
Reaction time: 12 h
Yield: 95.7 %

Procedure:
A solution of 450 mg of dicyclohexylcarbodiimide in 5 ml of tetrahydrofuran was added dropwise to a mixture of 680 mg of N-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carboxylic acid, 240 mg of phenylhydrazine, 450 mg of 1-hydroxybenzotriazole and 20 ml of tetrahydrofuran with ice cooling, and the resultant mixture was stirred with ice cooling for 1 hour and then at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of ethyl acetate, and the insoluble matter was filtered off. The filtrate was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate Concentration under reduced pressure gave 840 mg of N'-phenyl-3-tert-butoxycarbonyl-2-(3-pyridyl)thiazolidine-4-carbohydrazide. Trifluoroacetic acid (5 ml) was added to the thus-obtained compound, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, and the solution was washed in sequence with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate Concentration under reduced pressure gave crystals, which were recrystallized from ethyl acetate. Thus was obtained 180 mg of N'-phenyl- 2-(3-pyridyl)thiazolidine-4-carbohydrazide. Melting point 155° C.
Reaction SMILES: [CH3:1][CH:2]([C:8](OCC)=O)[C:3]([O:5]CC)=[O:4].[Na].[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1CBr.[OH-].[K+]>O>[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:8][CH:2]([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: BrCc1ccccc1-c1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: CC(Cc1ccccc1-c1ccc2ccccc2c1)C(=O)O
Temperature: 130 °C

Procedure:
70 g (0.37 mmol) of diethyl methylmalonate dissolved in 50 cm3 of H2O-free EtOH were added dropwise at room temperature to 8.5 g (0.37 mmol) of sodium in 100 cm3 of H2O-free EtOH. Subsequently, 110 g (0.37 mmol) of 14 in 200 cm3 of H2O-free EtOH were added dropwise and the mixture was heated under reflux for 3 hours. 62 g (1.1 mol) of KOH dissolved in 100 cm3 of H2O were added at room temperature and the mixture was heated under reflux for a further 4 hours. The solvents were removed under reduced pressure, the residue was admixed with H2O until completely dissolved and acidified with concentrated aqueous HCl to a pH of 1. The precipitate formed was filtered off with suction, dried and heated at 130° C. for 1 hour. This gave 90 g (84%) of 15 as a viscous oil.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH:4]=1.[CH2:19]([NH2:22])[CH2:20][OH:21].CCN(C(C)C)C(C)C>CCCCO>[N+:16]([C:12]1[CH:11]=[C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:22][CH2:19][CH2:20][OH:21])[CH:4]=2)[CH:15]=[CH:14][CH:13]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1cccc(Nc2cc(Cl)ncn2)c1
Reactant: NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=[N+]([O-])c1cccc(Nc2cc(NCCO)ncn2)c1
Temperature: 200 °C
Yield: 57 %

Procedure:
73 mg of 6-chloro-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride, 23 mg 2-ethanolamine and 81 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH=10:1. 2-(6-(3-Nitrophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[C:11]([CH2:13][C:14]([O:16]CC)=[O:15])[N:12]=2)=[CH:4][CH:3]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 88.8 %

Procedure:
6 g of ethyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate, 150 ml of methanol, 30 ml of water and 2.2 g of potassium hydroxide are treated in the same manner as described in Example 8. 4.9 g of 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetic acid are thereby obtained.
Reaction SMILES: [CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]1[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[O:2].[CH2:28]([Mg]Br)[CH3:29].C(=O)(O)[O-].[Na+]>C1COCC1.CCOCC>[OH:2][CH:1]([CH:3]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH:4]1[O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[CH2:28][CH3:29]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O[Si](C)(C)C(C)(C)C)C2C=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)C1C(O[Si](C)(C)C(C)(C)C)CCC12CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
A solution of tert-butyl 1-formyl-2-(tert-butyldimethylsilyloxy)-8-azaspiro[4.5]decane-8-carboxylate (0.284 g, 0.714 mmol) from Step C in THF (7 mL) was cooled to −70° C. and ethyl magnesium bromide (3.0M, 0.262 mL, 0.786 mmol) was added. The reaction was stirred for 30 min and then an additional aliquot of ethyl magnesium bromide (3.0M, 0.050 mL, 0.142 mmol) was added. After 5 min, the reaction was diluted with ether, poured into sodium bicarbonate, and extracted three times with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 10 to 20% ethyl acetate in hexanes to afford the title compound (0.248 g) as a mixture of isomers. MS/EI (acetonitrile/water): m/z 354 (100%, M+1–74 (t-BuOH)), 372 (M+1–56 (C4H8); 428 (M+1); retention time=4.29 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([CH3:31])[NH:30][C:26]=2[CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([CH3:31])[NH:30][C:26]=2[CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1nc2ccc(O)cc2[nH]1
Product: COc1cc2c(Oc3ccc4nc(C)[nH]c4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 189, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-yl)methoxyquinazoline, (prepared as described for the starting material in Example 10), was reacted with 5-hydroxy-2-methylbenzimidazole (200 mg, 0.62 mmol) and after work-up and purification on a 10 g silica ISOLUTE column using successively dichloromethane, dichloromethane/methanol (95/5) and dichloromethane/methanol saturated with ammonia (95/5), gave 6-methoxy-4-(2-methyl-1H-benzimidazol-6-yloxy)-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (68 mg, 25%).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH2:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>O>[CH2:18]([O:23][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a dimethylformamide solution (364 ml) containing 2-chloro-5-nitrobenzonitrile (91 g) and neopentyl alcohol (52 g) was added sodium hydride (60% contained, 27.8 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 2-neopentyloxy-5-nitrobenzonitrile (105 g). Subsequently, ammonium chloride (10 g) and iron powder (75 g) were added to a mixed solvent of water (286 ml) and ethanol (753 ml) and the mixture was heated to 65° C. 2-Neopentyloxy-5-nitrobenzonitrile (80.5 g) was added by portions over 20 min and the mixture was stirred at the refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. An aqueous sodium hydroxide solution was added and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g). melting point: 55-56° C.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C([BH3-])#N.[Na+].Cl>O.CO>[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: CCCCCCC=O
Reactant: C=CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CCNCCCCCCC

Procedure:
To 100 mL of methanol is added 2-propenylamine (5.7 g, 0.1 mol), 11.4 g (0.1 mol) of heptaldehyde, and 12 g (0.2 mol) of sodium cyanoborohydride. The pH is adjusted to six with concentrated HCl. Monitor the reaction by thin-layer chromatography. Upon completion, add concentrated HCl until gas evolution ceases. Add 300 mL of H2O and extract once with 200 mL of ether. Add 1N NaOH to the aqueous solution until it is basic and extract twice with 200 mL of ether. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19]O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CN(C)CCCO
Reactant: COc1cc2c(Cl)ncnc2cc1O
Product: COc1cc2c(Cl)ncnc2cc1OCCCN(C)C

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 3-Dimethylamino-propan-1-ol. LC/ESI-MS: m/z=296 [M+H].