Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[SH:9].[OH-].[K+].[CH2:12]([OH:14])[CH3:13]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:12](=[O:14])[CH:13]([C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=3)[S:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1S
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: O=C1Nc2ccc(Cl)cc2SC1c1ccc(Cl)cc1

Procedure:
To a solution of 2-amino-5-chlorothiophenol (4.49 g) in ethanol (30 ml) is added 96% potassium hydroxide (1.63 g), and the mixture is distilled to remove ethanol. The resulting solid material is suspended in toluene (70 ml) and thereto is added methyl α-bromo-4-chlorophenylacetate (7.38 g), and the mixture is refluxed overnight. The reaction mixture is concentrated, and the resulting precipitate is separated by filtration, washed, dried, and then recrystallized from tetrahydrofuran-n-hexane to give 7-chloro-2-(4-chlorophenyl)-3-oxo-3,4-dihydro-2H-1,4-benzothiazine (6.58 g) as crystals. M.p. 230°-233.5° C.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:19]([N:21]1CCOC[CH2:22]1)C.C(OC(Cl)=O)C(C)C.O>CN(C)C=O>[CH3:19][N:21]([CH3:22])[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:7][CH2:8][CH3:9])=[CH:18][CH:17]=1
Reactant: CCCC(c1ccc(C(=O)O)cc1)n1ccnc1
Reactant: CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(c1ccc(C(=O)N(C)C)cc1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.2 g of 4-[1-(1-imidazolyl)-butyl]-benzoic acid is dissolved in 10 ml of dimethylformamide, mixed at 0° C. with 1 ml of N-ethylmorpholine and 1 ml of chloroformic acid isobutyl ester. It is stirred for 30 minutes at 0° C., 2 ml of dimethylamino solution is instilled and stirred for 2 hours at 0° C. It is stirred into 500 ml of water, extracted with ethyl acetate and the organic phase is concentrated by evaporation in a vacuum. The remaining residue is distilled on a bulb tube. Boiling point: 260° C./0.03 mbar. 0.9 g of 4-[1-(1-imidazolyl)butyl]-benzoic acid dimethylamide is obtained.
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][C@@:4]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3([OH:25])[CH2:24][NH:23][CH2:22]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:35]([O:37][CH3:38])=[O:36]>>[OH:25][C:21]1([C:20]#[C:19][C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:32])[CH3:33])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[CH2:24][N:23]([C:35]([O:37][CH3:38])=[O:36])[CH2:22]1
Reactant: COC(=O)Cl
Reactant: C[C@@H](c1ccc(C#CC2(O)CNC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: COC(=O)N1CC(O)(C#Cc2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)C1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-((3-hydroxyazetidin-3-yl)ethynyl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and methyl chloroformate following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.43 min, m/z=507, 449; 1H NMR (CDCl3) 1.12 (s, 3H), 1.19 (s, 3H), 1.52 (d, 3H), 2.10-2.45 (5H), 2.83 (m, 1H), 3.69 (s, 3H), 4.15 (d, 2H), 4.33 (d, 2H), 5.66 (q, 1H), 6.87 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=C2N[C:9](=O)[CH2:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:15].O.[CH3:17][N:18]([CH:20]=[O:21])[CH3:19]>[Cl-].[Na+].O.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:17]2[N:18]([CH3:19])[C:20](=[O:21])[C:10]([CH3:9])([CH3:15])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)nc2N1
Reactant: CI
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1C(=O)C(C)(C)c2ccc(Cl)nc21
Reaction time: 0.08 h

Procedure:
To a solution of 6-chloro-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (50 mg, 0.30 mmol) in DMF (1 mL) at 0° C. was added NaH (48 mg, 1.2 mmol, 60%), and the reaction was stirred for 5 minutes. Iodomethane (210 mg, 1.5 mmol) was added and the reaction became a thick slurry. DMF (0.5 mL) was added and the reaction was stirred at room temperature for 90 minutes. Water, EtOAc, and brine were added, the layers were separated and the organic layer was washed with brine. The organics were dried over MgSO4, filtered and concentrated to afford 6-chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2(3H)-one 7.28 which was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C10H12ClN2O: 211.1; found: 211.0.
Reaction SMILES: [CH:1]([N:3]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][CH2:4]1)=[O:2].[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[Cl:14][CH2:15][CH2:16][C:17]([C:11]1[CH:12]=[CH:13][C:7]2[O:6][CH2:5][CH2:4][N:3]([CH:1]=[O:2])[CH2:9][C:8]=2[CH:10]=1)=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: O=CN1CCOc2ccccc2C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=CN1CCOc2ccc(C(=O)CCCl)cc2C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 75.9 %

Procedure:
To a solution of 1.7 g of 4-formyl-2,3,4,5-tetrahydro-1,4-benzoxazepine and 1.28 g of 3-chloropropionyl chloride in 20 ml of 1,2-dichloroethane was added 3.0 g of aluminum chloride by portions. The mixture was stirred for 6 hours under reflux. The reaction mixture was poured into ice-water, and the resultant was subjected to extraction with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography (developing solvent: ethyl acetate) to give 1.95 g of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C@H:10]([CH2:24][C:25]([OH:27])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.CN(CCCN=C=NCC)C.C(N(CC)CC)C.[NH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1>CN(C)C=O.O>[ClH:1].[N:50]1[CH:51]=[CH:52][CH:53]=[C:48]([NH:47][C:25](=[O:27])[CH2:24][C@@H:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:14]3[C:15]([CH3:19])=[C:16]([CH3:18])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH:49]=1
Reactant: Nc1cccnc1
Reactant: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)Nc1cccnc1)c1nnc(C)n1-2
Yield: 52.1 %

Procedure:
(S)-(4-Chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetic acid (2.64 g) is dissolved in dimethylformamide (30 ml). N-Dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (1.51 g) and triethylamine (1.08 ml) are added in order and the mixture is stirred. Five minutes later, 3-aminopyridine (0.66 g) is added to the reaction mixture and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water, and the obtained crystals are purified by column chromatography (chloroform: methanol =50: 1). The crystals are converted to hydrochloride with ethanol/hydrochloric acid in ethyl acetate, and recrystallized from ethanol/ethyl acetate to give 0.88 g of (S)-N-(3-pyridyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide hydrochloride, melting point 198°-201° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[K+:16]>CN(C)C=O>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S-:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+:16]
Reactant: Sc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Product: [S-]c1ccc(Oc2ccccc2)cc1

Procedure:
4-Phenoxythiophenol (4.8 g) was stirred for 45 min with potassium hydride (0.98 g) in N,N-dimethylformamide (100 ml) to produce a homogeneous solution of potassium 4-phenoxythiophenolate. The lactone, (S)-3-carbobenzyl-oxyamino-2-oxetanone (5.3 g) (Arnold, L. D. et al., J. Am. Chem. Soc., 107, 7105 (1985)), dissolved in N,N-dimethylformamide (50 ml) was then added at room temperature. After stirring for 30 minutes the mixture was poured into water and extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate, and solvent removed under reduced pressure to give (R)-2-(benzyloxycarbonylamino)-3-(4-phenoxyphenylthio)-propionic acid (9.2 g). It can be used directly in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[OH:20][CH:21]([CH2:31][OH:32])[CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:26][CH:25]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Nc1ccc(OCC(O)CO)cc1
Product: OCC(O)COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine and 4-(2,3-dihydroxypropoxy)aniline were reacted to produce N2-[4-(2,3-dihydroxypropoxy)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.09 (s, 1H), 8.95 (s, 1H), 7.98 (d, 1H, J=3.5 Hz), 7.51 (d, 2H, J=8.8 Hz), 7.32 (d, 1H, J=2.3 Hz), 7.17 (dd, 1H, J=2.3 and 8.8 Hz), 6.77 (dd, 3H, J=8.8 Hz), 4.90 (d, 1H, J=5.3 Hz), 4.64 (t, 1H, J=5.8 Hz), 4.23-4.19 (m, 4H), 3.91-3.89 (m, 1H), 3.80-3.73 (m, 2H), 3.41 (t, 2H, J=5.3 Hz); LCMS: ret. time: 15.04 min.; purity: 96%; MS (m/e): 429 (MH+)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[N:7]([CH:8]([CH3:11])[CH2:9][OH:10])[C:6]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:5]=2[N:4]=1.[Cr](O)(O)(=O)=[O:33].S(=O)(=O)(O)O>CC(C)=O.O.[O-2].[O-2].[O-2].[Cr+6]>[F:31][C:2]([F:1])([F:30])[C:3]1[N:7]([CH:8]([CH3:11])[C:9]([OH:33])=[O:10])[C:6]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:5]=2[N:4]=1
Reactant: CC(CO)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Reactant: O=[Cr](=O)(O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(C)=O
Solvent: O
Product: CC(C(=O)O)n1c(C(F)(F)F)nc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, 4.3 grams (0.010 mole) of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl) benzimidazol-1-yl]propan-1-ol in 120 mL of acetone was stirred, and 16 mL chromic acid (prepared by dissolving about five grams of chromium trioxide in 12 mL of water, then adding five mL of concentrated sulfuric acid), was added dropwise during a one hour period. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction was quenched with about three mL of 1-methylethanol, and the mixture was made basic with an aqueous solution saturated with sodium bicarbonate. The mixture was filtered to remove chromium salts, and the filtrate was extracted with ethyl acetate. The combined extracts were then washed with an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.0 grams of 2-[2-trifluoromethyl-5-fluoro-6-(1-methyl-6-trifluoromethyluracil-3-yl)benzimidazol-1-yl]propanoic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[C:28]1([CH2:27][CH2:26][CH2:25][N:17]([CH2:16][CH:13]2[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11][CH2:12]2)[C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)C(F)(F)F)CC1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN(CCCc2ccccc2)C(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, 0.25 g (6.25 mM) of a 60% suspension of sodium hydride in liquid paraffin was added to a solution of 1.73 g (5.57 mM) of N-(1-tert-butoxycarbonylpiperidin-4-ylmethyl)trifluoroacetoamide in N,N-dimethylformamide (20 ml) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. To this mixture was added 1.0 ml (6.58 mM) of 1-bromo-3-phenylpropane and the mixture was stirred at room temperature for 2.5 hours and further at 60° C. for one hour. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (ethyl acetate-hexane 30%) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([NH:11][CH3:12])=[O:10].[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=S)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1.C(Cl)CCl>CC#N>[Cl:20][C:21]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[NH:19][C:18]3[CH:17]=[CH:16][C:4]([O:5][C:6]4[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=4)[C:9]([NH:11][CH3:12])=[O:10])=[CH:3][C:2]=3[N:1]=2)=[CH:31][C:22]=1[CH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1
Reactant: CNC(=O)c1cccc(Oc2ccc(N)c(N)c2)c1
Reactant: CN1CCN(Cc2cc(N=C=S)ccc2Cl)CC1
Solvent: CC#N
Solvent: ClCCCl
Product: CNC(=O)c1cccc(Oc2ccc3[nH]c(Nc4ccc(Cl)c(CN5CCN(C)CC5)c4)nc3c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(3,4-Diamino-phenoxy)-N-methyl-benzamide (Step C, 400 mg, 1.5 mmol, 1.0 eq.) was dissolved in anh. CH3CN (10 mL) and a solution of 1-(2-chloro-5-isothiocyanato-benzyl)-4-methyl-piperazine (330 mg, 1.2 mmol, 0.8 eq.) in CH3CN (10 mL) was added dropwise. The reaction was stirred at RT for 2 h. EDC (240 mg, 1.3 mmol, 0.9 eq.) was added, the mixture was heated to 80° C. and stirred for 2 h. The CH3CN was evaporated and the crude compound was dissolved in CH2Cl2, washed with water and sat. NaHCO3 (aq.). The organic layer was dried (MgSO4), filtered and concentrated. Further purification by column chromatography (0-10% EtOH/CH2Cl2, two runs were required) gave pure 3-{2-[4-chloro-3-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-1H-benzimidazol-5-yloxy}-N-methyl-benzamide. MS m/z=505.2 (M+H)+; MW Calc'd for C27H29N6O2: 504.20.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[CH2:10][C@H:9]1[C:15]([O:17][CH3:18])=[O:16])=O)(C)(C)C.[ClH:19].O1CCOCC1>>[ClH:19].[CH3:14][O:13][C@H:11]1[CH2:12][NH:8][C@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10]1
Reactant: COC(=O)[C@@H]1C[C@@H](OC)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H](OC)CN1

Procedure:
A solution of (2S,4R)-1-tertbutoxycarbonyl-2-methoxycarbonyl-4-methoxy pyrrolidine (9 g, 34.74 mmol) in 4 M HCl-dioxane (13 mL) was stirred at RT overnight. The reaction mixture was concentrated to dryness, washed with hexane followed by ether and dried under vacuum to afford (2S,4R)-methyl 4-methoxypyrrolidine-2-carboxylate hydrochloride (6 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1>Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([C:4]2[N:3]=[C:2]([NH:25][C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=1
Reactant: Cc1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1-c1cc(N)cc(Cl)n1
Agent: Cl
Product: COc1ccc(Cl)cc1-c1cc(N)cc(Nc2ccc(C)cc2)n1
Temperature: 190 °C
Yield: 79 %

Procedure:
A mixture of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyridin-4-yl-amine, prepared in Example 1, (120 mg, 0.45 mmol) and p-tolylamine (1.0 g, 9.3 mmol) was heated at 190° C. for 45 minutes. After cooling to room temperature, the mixture was treated with hydrochloric acid (1 M, 50 ml). The mixture was extracted with ethyl acetate (50 ml). The organic extract was dried over magnesium sulfate and purified by flash chromatography on silica gel column eluting with ethyl acetate-hexane (1:4 followed by 1:1) to give the title compound (120 mg, 79% yield). 1H NMR (acetone-d6) δ 2.27 (s, 3H, CH3), 3.89 (s, 3H, CH3), 5.30 (d, 2H, J=6.4 Hz, NH2), 6.11 (d, 1H, J=1.7 Hz, Ar), 6.89 (d, 1H, J=1.7 Hz, Ar), 7.07 (d, 2H, J=8.3 Hz, Ar), 7.10 (d, 1H, J=8.8 Hz, Ar), 7.32 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.51-7.54 (m, 2H, Ar), 7.68 (s, 1H, NH), 7.99 (d, 1H, J=2.8 Hz, Ar).
Reaction SMILES: N#N.[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH3:13])[CH:7]=[CH:6][N:5]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O>>[NH2:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[C:8]([CH:13]=[CH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)[CH:7]=[CH:6][N:5]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Agent: N#N
Product: Nc1nccc(C=Cc2ccccn2)c1[N+](=O)[O-]
Yield: 49.9 %

Procedure:
Similarly to Example N2, the condensation of 2.58 g of 2-amino-4-methyl-3-nitropyridine and 1.8 g of pyridine-2-carbaldehyde gives 2.03 g of the title compound of m.p. 161–163° C. The mass spectrum shows the molecular peak MH+ at 243.0 Da.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH3:33])[NH:30]2)=[CH:26][C:25]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH3:33])[NH:30]2)=[CH:26][C:25]=1[O:34][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cc1cc2cc(O)c(F)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc(C)[nH]c4cc3F)ncnc2cc1OCCCN1CCCC1
Yield: 57.3 %

Procedure:
Using an analogous procedure to that described in Example 248, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (268 mg, 0.833 mmol), (prepared as described for the starting material in Example 9), was reacted with 6-fluoro-5-hydroxy-2-methylindole (165 mg, 1 mmol) in DMF (3.5 ml) containing potassium carbonate (173 mg, 1.25 mmol) to give 4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (215 mg, 57%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[C:10]([Cl:25])=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22])=[CH:16][CH:15]=[CH:14][CH:13]=2>C(#N)C>[Cl:25][C:10]1[C:9]([NH:8][C:5](=[O:6])[CH2:4][CH2:3][O:2][CH3:1])=[C:18]([NH:19][CH2:20][C:21]([OH:23])([CH3:22])[CH3:24])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: COCCC(=O)Cl
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Solvent: CC#N
Product: COCCC(=O)Nc1c(Cl)nc2ccccc2c1NCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
3-Methoxypropionyl chloride (5.5 g, 0.045 mole) was slowly added with stirring to a solution of 1[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (10 g, 0.038 mole) in acetonitrile (140 mL). After the addition was completed, the reaction mixture was heated at reflux for 30 minutes then allowed to stir at room temperature overnight. The reaction mixture was filtered to provide 12.4 g of the desired product as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[C:9]([C:21](OCC)=[O:22])=[N:8]1>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]3[NH:18][CH:19]=[CH:20][C:13]=23)[C:9]([CH2:21][OH:22])=[N:8]1
Reactant: CCOC(=O)c1nn(C2CCCCO2)cc1-c1ccnc2[nH]ccc12
Solvent: C1CCOC1
Product: OCc1nn(C2CCCCO2)cc1-c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a stirred solution of ethyl 1-(oxan-2-yl)-4-{1H-pyrrolo[2,3-b]pyridin-4-yl}-1H-pyrazole-3-carboxylate (7.8 g, 22.94 mmol) in THF (100 mL), was added LiALH4 (3 g, 70 mmol) in three portions at 0° C. The resulting mixture was stirred at room temperature for overnight. When the reaction was deemed complete, it was quenched by water (3 mL), extracted with ethyl acetate. The combined organic layer was dried ove Na2SO4, filtered and concentrated in vacuo to give 5.5 g of the title compound as an off-white solid. [M+H] found 299.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH3:15]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCO
Product: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
To 500 ml of ethanol containing 4-hydroxy-3-nitrobenzoic acid (50.0 g) was added concentrated sulftuic acid (33.0 ml) and the resulting mixture was refluxed with stirring for 20 hours. After this reaction mixture was concentrated under a vacuum, the residue was diluted with water and then the crystal was collected by filtration. This crystal was suspended in water and neutralized in saturated aqueous sodium hydrogencarbonate solution. Thereafter, the crystal was collected by filtration, washed with water, and dried under a vacuum, thereby yielding 54.0 g of ethyl 4-hydroxy-3-nitrobenzoate. As in the case of Reference Example 4, this compound (46.6 g) was benzylated with 4-fluorobenzyl bromide (50.0 g) folowed by hydrolysis with potassium hydroxide, thereby yielding 58.0 g of 4-(4-fluorobenzyloxy)-3-nitrobenzoic acid. To 180 ml of a chloroform solution containing this compound (16.0 g), triethylamine (15.3 ml) and diphenylphosphinic chloride (10.5 ml) were added. After the resulting mixture was stirred for 1 hour, 1-isobutylpiperazine dihydrochloride (11.8 g) and triethylamine (15.3 ml) were added and the mixture was stirred for 13 hours at room temperature. The reaction mixture was successively washed with water, saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over magnesium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 to 1:1), thereby yielding 19.8 g of 1-[4-(4-fluorobenzyloxy)-3-nitrobenzoyl]-4-isobutylpiperazine as a crystal. To 20 ml of ethyl acetate solution containing this compound (1.38 g), 1N hydrogen chloride ether solution (3.4 ml) was added. After the mixture was stirred for 15 minutes at room temperature, the resulting crystals were collected by filtration, thereby yielding 1.48 g of the aimed compound.