Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6](B(O)O)=[C:5]([CH3:10])[O:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:18]1[N:35]=[CH:34][C:21]2[NH:22][C:23](=[O:33])[N:24]([CH3:32])[CH:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]=2[CH:19]=1>>[CH3:1][C:2]1[C:6]([C:18]2[N:35]=[CH:34][C:21]3[NH:22][C:23](=[O:33])[N:24]([CH3:32])[CH:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]=3[CH:19]=2)=[C:5]([CH3:10])[O:4][N:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CN1C(=O)Nc2cnc(Cl)cc2C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1noc(C)c1-c1cc2c(cn1)NC(=O)N(C)C2c1ccccc1
Temperature: 90 °C

Procedure:
3,5-dimethylisoxazole-4-boronic acid (140 mg, 0.993 mmol), cesium carbonate (500 mg, 1.519 mmol) and 1,1-bis(diphenylphosphino)ferocene-palladium(II)dichloride dichloromethane complex are added to a microwave vessel flushed with argon. Dimethyl sulfoxide (5 mL) is added and the mixture purged with argon. Finally, 6-Chloro-3-methyl-4-phenyl-3,4-dihydro-1H-pyrido[3,4-d]pyrimidin-2-one (140 mg, 0.511 mmol) is added and the mixture again purged with argon and heated in a microwave oven at 90° C. for 120 minutes. The mixture is poured onto water and the aqueous phase extracted with dichloromethane. The organic phase is dried over magnesium sulfate. The drying agent is removed by filtration. The filtrate is concentrated to dryness and purified by chromatography on silica gel using a dichloromethane/methanol gradient. The product fractions are evaporated to dryness and purified by reverse phase HPLC. This affordes the desired product as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=O>>[Cl:21][C:22]1[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)[N:16]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cccc(C(F)(F)F)c3Cl)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 2-chloro-3-(trifluoromethyl)benzoic acid: MS (APCI): m/z 471 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH:37][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Cl)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 2-chlorobenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 48 mg of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:13]([OH:15])=O.[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:13]([C:5]3[O:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH2:3][O:2][CH3:1])=[O:15])=[CH:31][CH:32]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCC(Oc2ccc(N)cc2)C1
Reactant: COCc1c(C(=O)O)oc2ccccc12
Product: CCOC(=O)N1CCC(Oc2ccc(NC(=O)c3oc4ccccc4c3COC)cc2)C1

Procedure:
With a procedure similar to the example above, 3-{4-[(3-methoxymethyl-benzofuran-2-carbonyl)-amino]-phenoxy}-pyrrolidine-1-carboxylic acid ethyl ester was prepared from 3-methoxymethyl-benzofuran-2-carboxylic acid and 3-(4-amino-phenoxy)-pyrrolidine-1-carboxylic acid ethyl ester. LCMS calcd for C24H26N2O6 (m/e) 438, obsd 439 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([O:23][C:24]2[C:33]3[C:28](=[CH:29][C:30]([C:36]#[N:37])=[C:31]([O:34][CH3:35])[CH:32]=3)[N:27]=[CH:26][CH:25]=2)=[CH:21][CH:20]=1>C(#N)C>[C:36]([C:30]1[CH:29]=[C:28]2[C:33]([C:24]([O:23][C:22]3[CH:38]=[CH:39][C:19]([NH:18][C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)=[O:17])=[CH:20][CH:21]=3)=[CH:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35])#[N:37]
Reactant: COc1cc2c(Oc3ccc(N)cc3)ccnc2cc1C#N
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1C#N

Procedure:
After adding toluene (5 ml), acetonitrile (1.5 ml) and 4-fluorophenyl isocyanate (0.105 ml) to 4-(4-aminophenoxy)-6-methoxyquinoline-7-carbonitrile (180 mg), the mixture was heated to reflux for 30 minutes. The mixture was cooled, and the precipitated crystals were filtered out and washed with toluene to obtain the title compound (230 mg) as light yellow crystals.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1.[C:9]([N:12]1[CH2:16][C:15](=O)[N:14]=[CH:13]1)(=[O:11])[CH3:10]>>[C:9]([N:12]1[CH2:16][CH2:15][N:14]=[C:13]1[NH:2][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][CH:4]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)N1C=NC(=O)C1
Reactant: Cn1nccc1N
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1ccnn1C

Procedure:
5-Amino-1-methyl pyrazole hydrochloride (mp 143-145, from base described in Ber. 98, 3374, 1965) (40.0 g.) and 1-acetyl-2-imidazolinone (43.0 g.) were reacted as described in Example I to give 42.4 g. product mp 158-166 (crystallized from CH3CN)
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([Br:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]1.[CH3:17][C:18]1[CH:23]=[C:22]([N:24]2[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([CH3:31])=[N:25]2)[CH:21]=[CH:20][C:19]=1[OH:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:9][C:8]1[C:3]([CH2:2][O:32][C:19]2[CH:20]=[CH:21][C:22]([N:24]3[C:28]([CH3:29])=[C:27]([CH3:30])[C:26]([CH3:31])=[N:25]3)=[CH:23][C:18]=2[CH3:17])=[C:4]([N:10]2[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(-n2nc(C)c(C)c2C)ccc1O
Reactant: Cn1nnn(-c2cccc(Br)c2CBr)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(-n2nc(C)c(C)c2C)ccc1OCc1c(Br)cccc1-n1nnn(C)c1=O
Yield: 86.7 %

Procedure:
A mixture of 1-(2-bromomethyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (described in Reference Preparation example 11) 3.1 g, 2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenol (described in Reference Preparation example 20) 1.6 g, potassium carbonate 1.3 g and acetonitrile 70 ml was stirred with heating under reflux for six hours, and the reaction mixture was then filtered and was concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-{ 3-bromo-2-[2-methyl-4-(3,4,5-trimethyl-pyrazol-1-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one 3.1 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1.O.[N:25]([O-])=[O:26].[Na+]>CC(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:3]=1[N:25]=[O:26]
Reactant: Nc1cc(N2CCOCC2)nc(OCCOc2ccccn2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(OCCOc2ccccn2)nc(N2CCOCC2)c1N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
6-Amino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine (1.90 g, 6.00 mmol, 1.0 equiv.) was dissolved in 8 mL HOAc, and 8 mL H2O was added. The solution was cooled to 0° C., and NaNO2 (0.414 g, 6.00 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 0° C. for 1 hour. Water (20 mL) was added to dilute the slurry, and the solid was collected by filtration, washed with water, EtOAc (2 mL), then dried to yield 6-amino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlino-5-nitroso-pyrimidine (1.47 g, 4.25 mmol, 85% yield) as blue solid. The nitroso compound (1.385 g, 4.00 mmol, 1.0 equiv.) was treated with 5 mL water and enough 2 N HCl so that a clear dark blue solution was formed. Na2S2O4 (2.79 g, 16.00 mmol, 4.0 equiv.) was added in three portions, and the solution was stirred at room temperature for 1 hour. The resulting clear yellow solution was carefully neutralized with cold 2 M NaOH solution, and subjected to EtOAc extraction. 5,6-Diamino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine (0.80 g, 2.41 mmol, 60%) was obtained as light yellow solid after usual workup.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[NH:23][C:22](=[O:31])[CH2:21][C:20]2=[O:32])=[CH:15][CH:14]=1.CC1C(C)=CC=CC=1C(Cl)=O>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=3[NH:23][C:22](=[O:31])[CH2:21][C:20]2=[O:32])=[CH:15][CH:14]=1)=[O:6]
Reactant: Cc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Reactant: Cc1cccc(C(=O)O)c1C
Agent: Cc1cccc(C(=O)Cl)c1C
Product: Cc1cccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c(C)cccc43)cc2)c1C
Yield: 92 %

Procedure:
2,3-Dimethylbenzoic acid (21 mg, 0.140 mmol) was made into acid chloride in a conventional manner. By using 1-(4-aminophenyl)-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (20 mg, 0.071 mmol) mentioned above, and 2,3-dimethylbenzoyl chloride mentioned above, the title compound (27 mg, yield 92%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16](SC)[N:15]=[C:14]([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[NH:24][CH:25]=2)[CH:13]=1.ClC1C=C(C=CC=1)[C:31](OO)=[O:32].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:32][CH3:31])[N:15]=[C:14]([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[NH:24][CH:25]=2)[CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)[nH]c2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)[nH]c2)n1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a mixture of above 5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yl}-1H-pyridin-2-one [1 g, 2.56 mmol, Example 31] in a mixture of MeOH (30 mL) and DCM (20 mL), is added 3-chloro-peroxybenzoic acid (70%, 1.32 g, 7.68 mmol) at room temperature. After 3 hours at 20° C., a 25% solution of sodium methoxide in MeOH (12 mL) is added at 0° C. After additional 1 hour, the mixture is concentrated, diluted with water, and neutralized with 3 M hydrochloric acid (pH 7). The resulting solid is filtered, and re-dissolved in a basic solution (pH 12). After acidifying into pH 3, the precipitate is filtered, and dried to give 5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-1H-pyridin-2-one [0.92 g, 96%, Example 32] as a solid. LCMS: RT=2.23 minutes, MS: 375 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:40].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][O:41][C:39](/[N:3]=[C:1](\[NH2:2])/[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([N:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:23])=[CH:21][C:14]=3[N:13]=2)=[CH:8][CH:9]=1)=[O:40]
Reactant: CCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1

Procedure:
Dabigatran etexilate was first described in U.S. Pat. No. 6,087,380, according to which the synthesis of dabigatran etexilate was carried out in three synthetic steps (see Scheme 1). Example 58 describes the condensation between ethyl 3-{[3-amino-4-(methylamino)benzoyl](pyridin-2-yl)amino}propanoate (compound II) and N-(4-cyanophenyl)glycine (compound III) in the presence of N,N′-carbonyldiimidazole (CDI) in tetrahydrofuran to give the hydrochloride salt of ethyl 3-{[(2-{[(4-cyanophenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound IV), which is subsequently reacted with ethanolic hydrochloric acid, ethanol and ammonium carbonate to give the hydrochloride salt of ethyl 3-{[(2-[{(4-carbamimidoylphenyl)amino]methyl}-1-methyl-1H-benzimidazol-5-yl)carbonyl](pyridin-2-yl)amino}propanoate (compound V). Finally, example 113 describes the reaction between compound V and n-hexyl chloroformate (compound VI), in the presence of potassium carbonate, in a mixture of tetrahydrofuran and water, to give dabigatran etexilate after work-up and chromatographic purification. However, no information is given about the purity of the isolated dabigatran etexilate.
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12]([OH:14])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:12](=[O:14])[N:19]([O:20][CH3:21])[CH3:18])[CH2:15][CH2:16]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.3 %

Procedure:
A solution of 30 g (130.9 mmol) of Boc-isonipecotic acid in 1.5 1 CH2Cl2 was treated with 20.42 g (209.3 mmol) of N,O-dimethylhydroxylamine hydrochloride, 23.1 ml (209.3 mmol) of N-methylmorpholine and at 0° C. with 32.6 g (170.1 mmol) of EDCI and 3.53 g (26.2 mmol) of HOBT. The reaction was stirred overnight at room temperature and partitioned between aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to give 37.54 g (quantitative) of 4-(methoxy-methyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 273(MH+).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]([NH2:12])=[O:11].CN(C1C=CC=CN=1)C.[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:25][CH:24]([CH3:26])[CH2:23][C:22]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH:7]([CH3:8])[CH3:9])[C:3]=1[C:10]([NH2:12])=[O:11])=[O:27]
Reactant: CC(C)c1noc(N)c1C(N)=O
Reactant: CC(C)CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)CC(=O)Nc1onc(C(C)C)c1C(N)=O
Reaction time: 16 h

Procedure:
1.7 g of 5-amino-3-isopropylisoxazole-4-carboxamide in a mixture of 40 ml of toluene and 40 ml of pyridine are initially taken together with a pinch of dimethylaminopyridine, and a solution of 2.5 g of isovaleroyl chloride in 20 ml of toluene is added. Stirring is carried out for 16 hours at room temperature, after which the solution is evaporated to dryness and the residue is stirred with ethyl acetate. The organic phase is then extracted with aqueous hydrochloric acid and sodium bicarbonate solution, dried and evaporated down. Purification is effected by chromatography over silica gel (cyclohexane/ethyl acetate).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=[C:13]2[OH:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]#[N:34]>CC(C)=O.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]([F:22])([F:21])[F:23])[CH:14]=[C:13]2[O:24][CH2:32][C:33]#[N:34]
Reactant: Oc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: N#CCOc1cc(C(F)(F)F)nc2ccc(-c3cc4ccccc4o3)cc12
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a stirred solution of 6-(1-benzofuran-2-yl)-4-hydroxy-2-(trifluoromethyl)quinoline (0.770 g, 2.34 mmol) in acetone (40 mL) at room temperature was added Cs2CO3 (0.839 g, 2.57 mmol) followed by bromoacetonitrile (0.326 mL, 4.68 mmol) dropwise. The reaction was stirred at this temperature for 18 hours and then diluted with EtOAc (200 mL). The organic layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was recrystallized from EtOAc:Hexane to afford the product (0.711 g, 82%) as a off-white solid, mp 174-176° C. Mass spectrum (+APCI, [M+H]+) m/z 369. 1H NMR (500 MHz, DMSO-d6): δ 8.61 (d, 1H, J=2.0), 8.48 (dd, 1H, J=2.0, 8.8 Hz), 8.23 (d, 1H, J=8.8 Hz), 7.78 (s, 1H), 7.70-7.75 (m, 2H), 7.67 (s, 1H), 7.39 (t, 1H, J=7.2 Hz,), 7.30 (t, 1H, J=7.6 Hz), and 5.70 ppm (s, 2H), Elemental analysis for C20H11F3N2O2: Calculated: C, 65.22; H, 3.01; N, 7.61. Found: C, 65.02; H, 2.87; N, 7.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[NH:9][C:10]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH3:25].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:15])[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:23][CH2:24][CH3:25])[C:10]=2[CH:11]=1
Reactant: CCCBr
Reactant: O=c1c2ccc(Cl)cc2[nH]n2cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c2cc(Cl)ccc2c(=O)c2cccn21
Temperature: 25 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
7-Chloropyrrolo[1,2-b]cinnolin-10(5H)-one (9.0 g) was taken up in 100 ml of DMF and milled K2CO3 (11.33 g) was added. 1-Bromopropane (10.09 g) was then added dropwise and the solution was stirred at room temperature for 48 h. Water was added and the solution was extracted into dichloromethane and washed several times with H2O and dilute hydrochloric acid. The organics were then dried (MgSO4), charcoaled, filtered and concentrated to an orange oil. The oil was purified by HPLC (silica, dichloromethane) and concentrated to give 6.33 g of an orange powder which was recrystallized from ether to yield 3.4 g of yellow-orange microcrystals, mp 107°-108°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.Cl>CN(C=O)C.O>[ClH:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(C3C(=O)Nc4ccc(C#N)cc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
A solution of 5-cyanooxindole (213 mg, 1.35 mmol), (Tet. Lett., 1987, 28, 4027), in DMF (3 ml) was added dropwise to a suspension of sodium hydride (54 mg, 1.35 mmol, prewashed with hexane) in DMF (2 ml). The mixture was stirred for 20 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (152 mg, 0.45 mmol), (prepared as described for the starting material in Example 5), was added and the mixture was heated at 70° C. for 1 hour. The mixture was allowed to cool and then was diluted with water and adjusted to pH1 with 2M hydrochloric acid. The solution was washed with ether and then basified with aqueous sodium hydrogen carbonate solution. The resulting precipitate was collected by filtration, washed with water, ether and dried under vacuum. The solid was purified by flash chromatography eluting with methylene chloride/methanol (90/10 followed by 80/20). The purified solid was dissolved in methylene chloride/methanol and 5M methanolic hydrogen chloride (0.5 ml) was added. The solution was concentrated by evaporation to a total volume of 2 ml and ether (15 ml) was added. The resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(5-cyanooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (120 mg, 50%).
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:16]O.S([O-])(O)(=O)=O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Br:2][CH2:16][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]=1[Cl:5]
Reactant: OCc1cccc(C(F)(F)F)c1Cl
Reactant: BrP(Br)Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: FC(F)(F)c1cccc(CBr)c1Cl
Reaction time: 1 h
Yield: 57 %

Procedure:
Phosphorus tribromide (11.75 ml, 125 mmol) was added to a solution of crude (2-chloro-3-(trifluoromethyl)phenyl)methanol (9.37 g, 44.5 mmol) in dioxane (200 ml). The reaction mixture was stirred for 1 hour. Another portion of phosphorus tribromide (11.75 ml, 125 mmol) was added. The reaction mixture was stirred for 16 hours at room temperature. It was diluted with ethyl acetate (200 ml). A 10% aqueous solution of sodium hydrogensulphate (200 ml) was added, while cooling with a water bath. The phases were separated. The organic phase was washed with a 10% aqueous solution of sodium hydrogensulphate (100 ml). The combined aqueous layers were extracted with ethyl acetate (100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (150 g), using ethyl acetate/heptane (1:3) as eluent, to give 6.94 g of 1-(bromomethyl)-2-chloro-3-(trifluoromethyl)benzene.