Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13](Cl)=[O:14])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH2:25][CH3:26])=[N:10][CH:9]2[CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([C:13]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:14])[C:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[O:24][CH2:25][CH3:26])=[N:10][CH:9]2[CH2:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.1 %

Procedure:
A solution of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (50 mg, 0.105 mmol) in methylene chloride (2 mL) was added to a stirred mixture of 1-methylpiperazine (18 μL, 0.158 mmol) and triethylamine (29 μL, 0.210 mmol) in methylene chloride (3 mL) cooled to 0° C. The reaction mixture was stirred at room temperature for 30 min then concentrated in vacuo. Purification of the crude residue by preparative HPLC (Zorbax C18) gave [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (64 mg, 93%, white solids) as trifluoroacetic acid salt. HR-MS (ES, m/z) observed 539.2789, calculated for C30H40N4O3Cl [(M+H)+]539.2784.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([N:33]2[CH:37]=[N:36][N:35]=[N:34]2)=[C:22]([CH:32]=1)[CH2:23][NH:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]([CH3:16])[C@H:9]1[C:10]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:25]([NH:24][CH2:23][C:22]1[CH:32]=[C:18]([Cl:17])[CH:19]=[CH:20][C:21]=1[N:33]1[CH:37]=[N:36][N:35]=[N:34]1)=[O:31])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1CCN(C(=O)OC(C)(C)C)C1C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCCN1
Solvent: ClCCCl
Product: CC1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1

Procedure:
The title compound was prepared as a mixture of diastereomers from 1-(tert-butoxycarbonyl-3-methyl-dl-proline (16 mg, 0.07 mmol) and N-[5-chloro-2-(1H-tetraazol-1-yl)benzyl]-L-prolinamide (Example 26, Step B, 21 mg, 0.07 mmol), essentially according to the EDC coupling procedure described in Example 39, Step D. The diastereomeric products were separated by reverse phase HPLC and were carried on directly to deprotection.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].O(CC)[C:12]([S-])=[S:13].[K+]>C(O)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:12]([SH:13])[O:10][C:3]=2[CH:4]=1
Reactant: CCOC(=S)[S-]
Reactant: COc1ccc(N)c(O)c1
Agent: [K+]
Solvent: CCO
Product: COc1ccc2nc(S)oc2c1
Yield: 79.3 %

Procedure:
Next, a mixture of 2-amino-5-methoxyphenol (3c) (6.03 g, 43.33 mmol) and potassium ethyl xanthate (6.95 g, 73.33 mmol) in ethanol (80 mL) was heated at reflux for 18 h. The reaction was subsequently cooled and the solvent was removed in vacuo. The residue was taken up in ethyl acetate (150 mL), washed successively with 4N HCl, water, and brine. The organic solution was subsequently dried over Na2SO4. After filtration to remove the drying aid, the solvent was evaporated to give 6.23 g (79%) of 6-methoxybenzoxazole-2-thiol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[CH:14]=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:18]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][C:11]=1[F:10]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(F)c(Cl)c1
Product: O=Cc1ccc(Oc2ccc(F)c(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-chloro-4-fluorophenol and 3,4-difluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11]C(=O)C)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])c(Cl)c1
Agent: Cl
Solvent: O
Product: Nc1ccc([N+](=O)[O-])c(Cl)c1
Yield: 33.5 %

Procedure:
A mixture of N-(3-chloro-4-nitro-phenyl)-acetamide (18.55 g, 86.4 mmol) and an aqueous solution of hydrochloric acid (6 M, 120 mL) was heated at reflux for 2 hours. The resulting mixture was cooled and poured into water (800 mL); the yellow solid which crushed out was collected by filtration, washed with water and dried under reduced pressure to give 5 g of 3-chloro-4-nitro-phenylamine. The water layer was basified until pH 8 by addition of potassium carbonate and then was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 7.2 g of 3-chloro-4-nitro-phenylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[O:16]([C:18]#[N:19])[Na].C(C(O)=O)(F)(F)F>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:18]([NH2:19])=[O:16])=[CH:4][CH:3]=1
Reactant: N#CO[Na]
Reactant: Fc1ccc(Nc2ccc(F)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Di(p-fluorophenyl)amine (102.5 g., 0.5 mole) and NaOCN (65 g, 1.0 mole) were stirred in 700 ml CH2Cl2 at 16° C. F3CCOOH (84.5 ml, 117 g, 1.025 mole) was added as a thin stream over 5 minutes, during which the reaction mixture exothermed to 28° C. The exotherm peaked at 32° C. shortly after addition was complete. The reaction mixture was stirred at 23°-25° for 21 hours, diluted with 350 ml H2O and stirred 0.5 hour. The organic layer was separated and stirred 0.25 hour with 40 g NaOH in 500 ml H2O. The layers were separated, and the aqueous layer back washed with 100 ml CH2Cl2. The combined organic layer and back wash was dried (MgSO4), concentrated to 600 ml, diluted with 600 ml isopropanol, reconcentrated to 600 ml, rediluted with 600 ml of fresh isopropanol, reconcentrated to 800 ml, rediluted with 400 ml fresh isopropanol and again reconcentrated to 800 ml. The mixture was cooled to room temperature (product began to crystallize) and then to 0°-5° C. Title product was recovered by filtration, 104.9 g, m.p. 150°-153° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (14 g, 42.7 mmol) in dichloroethane (150 mL) was added acetaldehyde (3.75 g, 85.2 mmol) and acetic acid (15.3 g, 256 mmol). The resulting reaction mixture was stirred at room temperature for 15 minutes. The mixture was cooled to 0° C. and sodium triacetoxyborohydride (27 g, 128 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. Upon completion of the reaction as determined by TLC, aqueous sodium bicarbonate solution was added to the reaction mixture until a pH 7-8 was obtained, the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with ethyl acetate:hexane to afford the desired compound as a viscous liquid (14 g, 93%). 1H NMR (DMSO-d6, 400 MHz) δ 7.62 (s, 1H), 7.52 (s, 1H), 3.80 (bs, 5H), 3.31 (t, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1.37-1.50 (m, 2H), 0.87 (t, 3H, J=6.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[C:9]([O:13][C:14](=[O:28])[NH:15][C@@H:16]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17]O)([CH3:12])([CH3:11])[CH3:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[C:9]([O:13][C:14](=[O:28])[NH:15][C@@H:16]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(C)(C)O[SiH2]C(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(Br)c1)C(C)(C)O[SiH2]C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A 100 mL RBF was charged with 3-bromo-5-hydroxypyridine (1.20 g, 6.87 mmol), (R)-[1-(tert-butyl-dimethyl-silanyloxymethyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (2.1 g, 6.87 mmol) and Ph3P (2.34 g, 8.93 mmol), and was purged with nitrogen. THF (30 mL) was added at 0° C. After stirring at 0° C. for 10 min, DEAD (1.41 mL, 8.93 mmol) was added via syringe. The reaction mixture was stirred at 0° C. for 0.5 h and at rt for 2 h. The reaction mixture was concentrated and the residue was separated by flash chromatography (5-25% EtOAc in hexane) to provide the desired product (3.14 g, 99%). MS (DCI) m/z 461, 463 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[C:6]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)[CH3:2].C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1Nc2ccccc2N(C)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CC1Nc2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Methyl-3-oxo-3,4-dihydro-1H-quinoxalin-2-ylidene-acetic acid ethyl ester (1.1 g, 4.47 mmol) was suspended in 25 mL of MeOH/HOAc (2:1) at rt and sodium cyanoborohydride was added portionwise (281 mg, 4.47 mmol). The mixture became clear after five minutes and was continuously stirred at rt for 2 hours. The solvent was removed under reduced pressure. The crude residue was mixed with water (50 mL) and extracted with EtOAc (3×40 mL). The organic layers were combined, washed with water, brine and dried over MgSO4. After removal of the solvent, a pale brown oil was obtained as the desired pure product: 1H NMR (CDCl3) δ=6.97-6.94 (m, 3H), 6.74 (d, J=9.0 Hz, 1H), 4.28 (dd, J=3.0, 9.0 Hz, 1H), 4.23 (q, J=9.0 Hz, 2H), 3.37 (s, 3H), 3.11 (dd, J=3.0, 18.0 Hz, 1H), 2.68 (dd, J=9.0, 19.0 Hz, 1H), 1.28 (t, J=9.0 Hz, 3H).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](O)=[O:10])[N:3]=[CH:4][CH:5]=1.B.C1COCC1.CO.O>C1COCC1>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:12]=[CH:13][CH:14]=2)[N:3]=[CH:4][CH:5]=1
Reactant: O=C(O)c1cccc(-n2nccn2)c1
Agent: B
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCc1cccc(-n2nccn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A cooled (0° C.) solution of the major isomer 3-(2H-1,2,3-triazol-2-yl)benzoic acid (500 mg; 2.64 mmol) in anh. THF (7 ml) was treated dropwise with a BH3.THF (1.0 M in THF; 6.60 ml; 6.60 mmol), and this mixture was stirred at 0° C., under nitrogen, for 1 h, and then at rt for 1.5 h. The resulting reaction mixture was then cooled to 0° C., and treated successively with MeOH (10 ml) and water (10 ml). The organic solvents were removed under reduced pressure, and the resulting aq. layer was extracted with DCM (3×10 ml). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (3-(2H-1,2,3-triazol-2-yl)phenyl)methanol as a colorless oil. LC-MS (conditions A): tR=0.51 min.; no ionisation.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([NH:15][C:16]1[CH:33]=[CH:32][C:19]([C:20]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[OH:2][CH2:3][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([NH:15][C:16]1[CH:33]=[CH:32][C:19]([C:20]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14]
Reactant: COC(=O)c1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(=O)N2CCCc3ccccc32)cc1)c1ccccc1-c1ccccc1CO
Temperature: 0 °C
Yield: 28.3 %

Procedure:
A solution of 1-{4-[2-(2-methoxycarbonylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (300 mg) and dry tetrahydrofuran (15 ml) was cooled to 0° C., and lithium aluminum hydride (46 mg) was added. The reaction mixture was maintained at 0° C. for 1 hour, and then was quenched by adding 1N hydrochloric acid. The resulting mixture was filtered through a bed of celite, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. Purification of the residue by column chromatography (silica gel, 15 g; ethyl acetate-n-hexane, 1:2) gave 1-{4-[2-(2-hydroxymethylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (80 mg) as a amorphous.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][OH:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25])([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[OH:10][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:16]([CH3:18])[CH3:17])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=1)=[O:11]
Reactant: CC(C)c1ccccc1S
Reactant: O=C(CO)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccccc1Sc1ccc(C(=O)CO)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
Then 2-hydroxy-1-(4-(2-isopropyl-phenylsulfanyl)-3-trifluoromethyl-phenyl)-ethanone 28 was prepared as follows. To a solution of compound 27 (0.4 g, 1.8 mmole) and o-isopropylthiophenol (0.31 ml, 1.8 mmole) in DMF (10 ml) was added Cs2CO3 (0.59 g, 1.8 mmole). The mixture was stirred for 10 minutes and EtOAc (30 ml) was added. The mixture was filtered, concentrated and chromatographed on a silica gel column eluting with 30% EtOAc in hexane. The desired product 28 was obtained as an oil, 0.22 g, 34.8%. 1H-NMR (CDCl3, 300 MHz) δ1.17 (d, J=7.0 Hz, 6H), 3.40–3.46 (m, 2H), 4.80 (s, 2H), 6.82 (d, J=8.4 Hz, 1H), 7.27–7.31 (m, 1H), 7.51–7.55 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 8.17 (s, 1H); MS (DCI/NH3) m/z 355 (M+H)+, 372 (M+NH4)+.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][C:8]=1[N:16]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:23]=2)[N:18]=[CH:17]1>>[CH:1]1([NH:5][C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([CH3:6])=[C:8]([N:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N:27]5[CH2:32][CH2:31][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:29][CH2:28]5)[CH:23]=4)[N:18]=[CH:17]3)[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O
Reactant: NC1CCC1
Product: Cc1ccc(C(=O)NC2CCC2)cc1-n1cnc2ccc(N3CCN(C(C)C)CC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 6 which is concerned with the preparation of starting material, cyclobutylamine was reacted with 4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzoic acid to give N-cyclobutyl-4-methyl-3-[6-(4-isopropylpiperazin-1-yl)-4-oxoquinazolin-3(4H)-yl]benzamide (AZ12239932); NMR Spectrum: (CDCl3) 1.11 (d, 6H), 1.75 (m, 2H), 1.93 (m, 2H), 2.23 (s, 3H), 2.41 (m, 2H), 2.75 (m, 5H), 3.38 (m, 4H), 4.57 (m, 1H), 6.30 (d, 1H), 7.26 (s, 1H), 7.44 (m, 2H), 7.66 (m, 2H), 7.79 (m, 2H); Mass Spectrum: M+H+ 460.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH:23]1([CH2:22][O:21][C:17]2[N:16]=[CH:15][C:14]([CH:12]([N:9]3[C:10](=[O:11])[C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[O:27])[C:7]=4[CH2:8]3)[CH3:13])=[CH:19][C:18]=2[CH3:20])[CH2:25][CH2:24]1
Reactant: O=COc1ccccc1
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC1CC1
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC1CC1
Yield: 45 %

Procedure:
The title compound is prepared in 45% yield (275 mg, white solid) from 4-chloro-2-(1-(6-(cyclopropylmethoxy)-5-methylpyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (492 mg, 1.37 mmol, Intermediate-124, single enantiomer) and phenyl formate (336 mg, 1.37 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[N:3]1.[B-](F)(F)(F)[F:11].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:11][C:5]1[C:4]([C:7]([OH:9])=[O:8])=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: Cn1ccc(C(=O)O)n1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: Cn1cc(F)c(C(=O)O)n1
Temperature: 80 °C

Procedure:
To a 200 mL round-bottomed flask equipped with a reflux condenser and stir bar, were added 1-methyl-1H-pyrazole-3-carboxylic acid (1.5 g, 11.9 mmol), dry acetonitrile (60 mL), and Selectfluor® (12.6 g, 35.7 mmol). The reaction vessel was heated to 80° Celsius for 32 h. Additional Selectfluor® (8.5 g, 24.0 mmol) was added to the reaction mixture and it was stirred at 80° Celsius for 5 days. The reaction mixture was cooled to RT and the solids were removed by filtration. The filtrate was concentrated to dryness and subjected to FCC to yield crude title compound (330 mg, 13% yield). The impure material was then recrystallized from hot methanol to give the title compound as long yellow crystals. Additional title compound could be obtained from the mother liquor by filtration of the solid that forms upon concentration (11.53 g total combined yield, 70%). The crystallized title compound contained minor impurities, but was used in subsequent steps without further purification. Analytically pure title compound can be obtained by subjecting it to HPLC purification. MS (ESI): mass calcd. for C5H5FN2O2 144.03, m/z found 145.0 [M+H]+ (low intensity).
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][CH2:11][CH2:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=O)[CH2:19]Br)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CO>[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:8]3[N:9]([CH2:10][CH2:11][CH2:12]3)[CH:19]=2)=[CH:16][CH:15]=1
Reactant: c1ccc(CC2=NCCC2)cc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Yield: 56 %

Procedure:
(according to Laufer et al. J. Med. Chem. 1994, 37, 1894-1897) 2-Benzyl-1-pyrroline (Example 1 a, 19.8 g, 80% strength, 0.1 mol), dissolved in MeOH (300 ml) is treated with 4-chlorophenacyl bromide (23,4 g, 0.1 mol) and then with NaHCO3 (10 g, 0.12 mol) and stirred at RT for 16 h with exclusion of light. Precipitated crystallizate is filtered off with suction and washed with MeOH. 16.4 g (56%) of product are obtained after drying.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:19][CH3:20])[CH2:6][C:5](C(OC(C)C)=O)(C(OC(C)C)=O)[CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:27]([O:29]CC)C>>[OH:29][CH2:27][CH:6]1[CH2:5][CH2:4][C:3]1([O:2][CH3:1])[O:19][CH3:20]
Reactant: CCOCC
Reactant: COC1(OC)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COC1(OC)CCC1CO
Yield: 41 %

Procedure:
Diisopropyl 3,3-dimethoxy-cyclobutane-1,1-dicarboxylate (6.0 g, 20.8 mmol), prepared as described by P. E Pigou and C. H Schiesser, J Org Chem, 53, 3841-3 (1988), was dissolved in 200 mL of anhydrous diethyl ether and the ether solution was cooled to 0° C. with stirring under a nitrogen atmosphere. Lithium aluminum hydride (1.6 g, 42 mmol) was added to the ether solution in portions and the reaction mixture was stirred at 0° C. for 0.5 h. The reaction was then quenched by the addition of 1.6 mL of water, followed by 1.6 mL of 15% aqueous sodium hydroxide solution and 4.8 mL of water. The reaction mixture was filtered, the filter cake washed with diethyl ether and the combine ether filtrates were concentrated under reduced pressure. The residue (3.0 g) was dissolved in 2 mL of methylene chloride and purified on a 1.5×45 cm silica gel column eluted @2-3 psi with 200 mL of acetone:hexane (1:2 v/v), followed by 200 mL of acetone:hexane (1:1 v/v) to give 1.51 g (41% yield) of the title compound; MS DCI/NH3M-Z: 194 (M+NH4)+ ; 1H NMR (CDCl3) δ 1.99 (s, 4H), 2.35 (t, 2H-OH), 3.16 (s, 6H), 3.77 (d, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[S:5][C:6]=1[C:7]#[N:8].[C:13]([NH:20][CH2:21][CH2:22][NH2:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CCN(C(C)C)C(C)C.O>CS(C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][CH2:21][NH:20][C:13](=[O:14])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[S:5][C:6]=1[C:7]#[N:8]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CS(=O)(=O)c1nc(N)c(C#N)s1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCNc1nc(N)c(C#N)s1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2.2 g (7.22 mmol) of 4-amino-2-(methylsulphonyl)-1,3-thiazole-5-carbonitrile (Example 18A) are dissolved in 24 ml of DMSO, and 1.74 g (10.84 mmol) of N-Boc-ethylenediamine and 933 mg (7.22 mmol) of DIPEA are added. The mixture is stirred at 120° C. for 16 h and, after the reaction is complete, water and ethyl acetate are added. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulphate and purified by silica gel chromatography. 633 mg (31% of theory) of the product are obtained.
Reaction SMILES: [N-]=C=O.C[C:5]1[C:6](N=C=O)=[CH:7][C:8]([N:11]=[C:12]=[O:13])=[CH:9][CH:10]=1>>[NH:11]([CH:12]=[O:13])[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Agent: [N-]=C=O
Product: O=CNc1ccccc1

Procedure:
41.4 parts, by weight, of an isocyanate mixture consisting of 40%, by weight, of a tolylene diisocyanate mixture (2,4- and 2,6-isomer in proportions of 65:35) and 60%, by weight, of a polyphenyl-polymethylene polyisocyanate (viscosity approximately 200 cP at 25° C.). The polyphenyl-polymethylene polyisocyanate was obtained by anilineformaldehyde condensation followed by phosgenation.