Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]Cl)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[OH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][CH2:25][CH:26]2[CH2:28][CH2:27]2)=[O:23])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)=[O:23])=[CH:29][CH:30]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClCCC1CCN(c2ccc(Cl)nn2)CC1
Reactant: O=C(OCC1CC1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(OCC1CC1)c1ccc(OCCC2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of 2.6 parts of 3-chloro-6-[4-(2-chloroethyl)-1-piperidinyl]pyridazine, 1.9 parts of (cyclopropylmethyl) 4-hydroxybenzoate 1.1 parts of sodium carbonate and 94 parts of N,N-dimethylacetamide was stirred overnight at 110° C. After cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dissolved in trichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 2.9 parts (69.7%) of (cyclopropylmethyl) 4-[2-[1-(6-chloro-3-pyridazinyl)-4-piperidinyl]ethoxy]benzoate; mp. 134.0° C. (comp. 129).
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([CH:9]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:34]3[C:39](=[O:40])[CH2:38][O:37][C:36]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:35]3)=[CH:29][CH:28]=2)[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16]([CH3:26])([C:22]([O:24]C)=[O:23])[CH2:17]3)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>C1COCC1.O>[CH:4]1([CH:9]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][N:34]3[C:39](=[O:40])[CH2:38][O:37][C:36]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[N:35]3)=[CH:31][CH:32]=2)[C:10]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2[CH2:15][C:16]([CH3:26])([C:22]([OH:24])=[O:23])[CH2:17]3)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)C1(C)Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)O)Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
11 mg (0.26 mmol) of lithium hydroxide monohydrate were added to a solution of 74 mg (0.13 mmol) of methyl 4-[(cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetyl)amino]-2-methyl-2,3-dihydro-1H-indene-2-carboxylate (Example 131A) in 2 ml of THF and 1 ml of water, and the mixture was stirred at room temperature for 12 h. The reaction mixture was then adjusted to pH 2 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. This gave 64 mg (0.11 mmol, 88% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9]CC)=O)[N:3]=1.[NH3:12]>CO>[CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:12])=[O:9])[N:3]=1
Reactant: CCOC(=O)c1n[nH]c(C)n1
Reactant: N
Solvent: CO
Product: Cc1nc(C(N)=O)n[nH]1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Ethyl 5-methyl-1H-1,2,4-triazole-3-carboxylate (3.0 g, 19.3 mmol) is placed in a sealed tube that is then charged with a solution of 7N NH3 in MeOH (40 mL). The reaction is stirred at 50° C. for 24 h. The solvent was then removed under reduced pressure and the crude material was used directly for the next step without further purification. MS (ES+) C4H6N4O requires: 126. found: 127 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([C:26]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24]C)=[O:23])[CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].[OH-].OS([O-])(=O)=O.[Na+]>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH:14]([C:26]([NH:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)C(Cc2cccc(C(=O)OC)c2)C(=O)Nc2ccc3ccccc3c2)CC1
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)C(Cc2cccc(C(=O)O)c2)C(=O)Nc2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 2-[(1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(3-(methoxycarbonyl)phenyl)ethyl)carbonyl]aminonaphthalene (110 mg, 0.2 mmol) in THF (8 mL) was added a solution of LiOH (27 mg, 0.6 mmol) in water (6 mL). The reaction mixture was stirred at ambient temperature. After 5 hours, the reaction mixture was acidified to pH 2–3 by 2N NaHSO4, then extracted with ethyl acetate (3×10 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to afford 2-[(1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(3-carboxyphenyl)ethyl)carbonyl]aminonaphthalene (90 mg, 0.18 mmol); NMR (DMSO-d6) 1.25 (t, 3), 3.10–3.30 (m, 6), 3.40–3.60 (m, 4), 3.97 (q, 2), 4.14 (t, 1), 7.35–7.55 (m, 5), 7.70–7.87 (m, 5), 8.14 (s, 1), 10.12 (s, 1) ppm.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1C=CC(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC1C=CC(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a suspension of 3.2 g of lithium aluminum hydride in 500 ml of ether, 30 g of 4-benzyl-2-cyclohexen-1-one were added dropwise at 0° C. After stirring the mixture for 2 hours at the same temperature, it was washed with diluted hydrochloric acid and water, and the resultant organic layer was dried and concentrated, thereby obtaining 31 g of a crude product. This product was purified by column chromatography to obtain 30 g (yield: 98%) of 4-benzyl-2-cyclohexen-1-ol. A ratio of a cis-form to a trans-form was found to be 32:68 by 1H-NMR.
Reaction SMILES: [C:1]1(C)C=CC=CC=1.[Na].[CH:9]1([N:15]2[C:20](=[O:21])[N:19]=[C:18]([S:22][CH3:23])[NH:17][C:16]2=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.S(OC)(OC)(=O)=O.[OH-].[Na+]>O>[CH3:1][N:19]1[C:18]([S:22][CH3:23])=[N:17][C:16](=[O:24])[N:15]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[C:20]1=[O:21]
Reactant: Cc1ccccc1
Reactant: CSc1nc(=O)n(C2CCCCC2)c(=O)[nH]1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CSc1nc(=O)n(C2CCCCC2)c(=O)n1C

Procedure:
This toluene slurry of 3-cyclohexyl-6-methylthio-s-triazine-2,4(1H,3H)-dione sodium salt is then agitated with 650 parts of water for 0.15 hrs. The aqueous layer is separated and reacted at 25°-30° during 0.25 hrs with 57 parts of dimethyl sulfate. After the dimethyl sulfate is added, the pH of the reaction is maintained at pH 9-9.5 by addition of a total of 7.5 parts of 50% aqueous sodium hydroxide. The total reaction time is 1.8 hrs at which time filtration and drying gives 70 parts of white 1-methyl-3-cyclohexyl-6-methylthio-s-triazine-2,4(1H,3H)-dione, m.p. 137°-139°.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:21]([OH:23])=[O:22])[CH2:9][C:10]([C@@H:12]([NH2:20])[CH2:13][CH2:14][CH2:15][N:16]=[C:17]([NH2:19])[NH2:18])=[O:11])=[CH:3][CH:2]=1.Cl.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O.C(OCC)C>[C:25]([NH:20][CH:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[NH:18])[C:10](=[O:11])[CH2:9][CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:21]([OH:23])=[O:22])(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC(N)=NCCC[C@H](N)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N=C(N)NCCCC(NC(=O)c1ccccc1)C(=O)CC(Cc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
Arphamenine A hydrochloride (200 mg) was dissolved in 1 ml of water, and to the resulting solution were added 98 μl of benzoyl chloride and 119 mg of sodium carbonate, each in 1/5 portions at 30 minutes-interval and totally five times, under ice-cooling and stirring. After the reaction was completed, the reaction mixture was adjusted to pH 7.0 with 1N HCl, followed by addition of ethyl ether thereto. The precipitate as formed was washed with water and dried to give 225 mg of the titled compound as a colorless powder. This product gave a value of m/z 425 (MH+) in mass spectrometry.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(OCCN2CCOCC2)c1
Yield: 70 %

Procedure:
A mixture of 3-nitrophenol (3.5 g, 25 mmol), N-(2-chloroethyl)morpholine hydrochloride (4.7 g, 25 mmol), and potassium carbonate (13.2 g, 125 mmol) in acetone (100 mL) was heated to reflux for 20 hours. The solvent was removed under vacuum. The residue was partitioned between water (150 mL) and ethyl acetate (150 mL) and the aqueous phase was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (3×100 mL) and extracted with dilute aqueous HCl (2×125 mL). These extracts were washed with CH2Cl2 (2×125 mL), made basic (NaOH) and extracted into ethyl acetate (3×75 mL). These organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 4.4 g, in 70% yield; 1H NMR (CDCl3) δ 2.59 (t, J=4.7 Hz, 4H), 2.84 (t, J=5.6 Hz, 2H), 3.75 (t, J=4.7 Hz, 4H), 4.19 (t, J=5.6 Hz, 2H), 7.22-7.25 (m, 1H), 7.43 (t, J=8.1 Hz, 1H), 7.76 (t, J=2.3 Hz, 1H), 7.82-7.85 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][CH:12]([N:15]([CH3:17])[CH3:16])[CH2:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=[NH:31])(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:16][N:15]([CH3:17])[CH:12]1[CH2:13][CH2:14][C:9]([C:4]2[CH:3]=[C:2]([NH2:31])[CH:7]=[C:6]([F:8])[CH:5]=2)=[CH:10][CH2:11]1
Reactant: CN(C)C1CC=C(c2cc(F)cc(Br)c2)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Product: CN(C)C1CC=C(c2cc(N)cc(F)c2)CC1
Temperature: 100 °C
Yield: 33.5 %

Procedure:
Combine (4-(3-bromo-5-fluoro-phenyl)-cyclohex-3-enyl)-dimethyl-amine (10.8 g, 36.2 mmol), benzhydrylideneamine (7.88 g, 43.5 mmol), toluene (250 mL), BINAP (0.90 g, 1.44 mmol) and sodium t-butoxide (4.87 g, 50.7 mmol) and heat to 90° C. for 10 min. until homogeneous. Add tris(dibenzylideneacetone)dipalladium(0) (0.66 g, 0.72 mmol) and heat to 100° C. for 3 hr. Add 6M HCl solution (60 mL) carefully and continue to heat at 100° C. for 1 hr. Cool to ambient temperature and wash with ethyl acetate (2×100 mL). Basify the aqueous layer with 5N NaOH solution and extract with ethyl acetate (3×250 mL). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the residue by flash chromatography (silica gel, 10% 2M NH3/MeOH in DCM) to obtain 3-(4-dimethylamino-cyclohex-1-enyl)-5-fluoro-phenylamine (2.84 g, 33.5%).
Reaction SMILES: [C:1]1([CH:7]([CH3:12])[CH2:8][SiH:9]([Cl:11])[Cl:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH:13]1([Si:9]([Cl:11])([Cl:10])[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C1=CCCCC1
Reactant: CC(C[SiH](Cl)Cl)c1ccccc1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CC(C[Si](Cl)(Cl)C1CCCCC1)c1ccccc1
Reaction time: 3 h
Yield: 91 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 6.0 g (0.027 mole) of 3-phenyl-1,1-dichloro-1-silabutane, 4.1 g (0.05 mole) of cyclohexene, and 90 μl of 1% chloroplatinic acid in isopropanol were placed under the dry nitrogen atmosphere. The reactor was sealed and the solution was stirred for 3 hours. Vacuum distillation of the reaction products gave 7.4 g (bp, 157°-9° C./0.05 mmHg) of 1-cyclohexyl-1,1-dichloro-3-phenyl-1-silabutane.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[C:7]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(Br)C=C>C1C=CC=CC=1.OS([O-])(=O)=O.[K+].CCOCC.O>[CH2:3]([CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:7]1=[O:14])[CH:2]=[CH2:1]
Reactant: O=C1CCCCCC1
Reactant: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C=CCBr
Solvent: O
Solvent: CCOCC
Product: C=CCC1CCCCCC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 32.1 %

Procedure:
To a mechanically stirred mixture of potassium t-butoxide (Aldrich, 67.0 g, 0.6 mol) in benzene (600 mL) cooled to 0° C. under a nitrogen atmosphere was added cycloheptanone (Aldrich, 56.1 g, 0.5 mol) dropwise over 15 minutes. Ten minutes after the addition was complete, allyl bromide (Aldrich, 61.6 g, 0.51 mol) was added dropwise over 20 minutes. The reaction was warmed to room temperature, refluxed or 7 hrs., stirred at room temperature for 18 hrs., and diluted with 0.5 N KHSO4 (300 mL). This mixture was further diluted with Et2O (600 mL), 3.5 N KHSO4 (200 mL) and H2O (200 mL) before the organic was separated, washed with H2O (200 mL) and brine (200 mL), dried (Na2SO4), filtered, and stripped of all solvent under reduced pressure. The crude product (76.1 g) was distilled to yield 24.4 g (32%) of the title material (bp=104-108° C., 25 mm of Hg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:36])[CH2:17][NH:18][C:19]([O:21][CH2:22][CH:23]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:29]3[C:24]2=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH:34]1[C:35]2[CH:23]([CH2:22][O:21][C:19]([NH:18][CH2:17][C:16]([NH:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:36])=[O:20])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]=2[CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 152.4 %

Procedure:
To 1-(tert-Butoxycarbonyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (3.17 g, 6.42 mmol) was added 4 N HCl in dioxane (50 mL). The solution was stirred at room temperature for 5 h. The reaction mixture was concentrated to give 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (3.85 g) as a white solid. The product was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[O:10][C:9](=[O:11])[CH2:8][NH:7][C:5]([O:4][C:2]([CH3:12])([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 99.9 %

Procedure:
N-(1,1-Dimethylethoxycarbonyl)glycine (6.12 9, 35 mmol) was stirred with 2,4,5-trichlorophenol (6.91 g, 35 mmol) and dicyclohexylcarbodiimide (7.22 g, 35 mmol) in ethyl acetate (100 mL) at 0° C. for 4 h. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate. The residue was dissolved in ethyl acetate. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate to give N-(1,1-dimethylethoxycarbonyl)glycine 2,4,5-trichlorophenyl ester (12.4 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH:6]=[CH:7][C:8](OC)=O)=[CH:4][CH:3]=1.[Na].[C:15]([NH:18][NH2:19])([NH2:17])=[NH:16].Cl>CO>[NH2:17][C:15]1[N:16]=[C:8]([CH:7]=[CH:6][C:5]2[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:19][N:18]=1
Reactant: COC(=O)C=Cc1ccc(Cl)cc1
Reactant: N=C(N)NN
Agent: Cl
Agent: [Na]
Solvent: CO
Product: Nc1n[nH]c(C=Cc2ccc(Cl)cc2)n1
Yield: 46 %

Procedure:
The synthesis method of Example 7-(2) was applied. The compound (9.66 g) obtained in (1) above, methanol (140 ml), metallic sodium (5.69 g) and aminoguanidine hydrochloride (27.3 g) were used as reagents to give 4.93 g of a pale-brown solid (yield 46%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:13]([F:14])=[C:12]([CH2:15][CH2:16][OH:17])[CH:11]=[CH:10][C:9]=1[OH:18].Br[CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24].O>CN(C=O)C>[CH2:23]([O:22][CH:21]([O:25][CH2:26][CH3:27])[CH2:20][O:18][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][OH:17])=[C:13]([F:14])[C:8]=1[F:7])[CH3:24]
Reactant: OCCc1ccc(O)c(F)c1F
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(CCO)c(F)c1F)OCC
Temperature: 90 °C

Procedure:
Cesium carbonate (0.99 g) was added to a solution of 2,3-difluoro-4-(2-hydroxyethyl)phenol (example 77, step b) (0.44 g) and 2-bromo-1,1-diethoxyethane (0.4 mL) in DMF (10 mL). The resulting suspension was heated at 90° C. for 18 h. The reaction was allowed to cool and poured into water (100 mL). The aqueous mixture was extracted with diethylether (3×100 mL). The combined organic solutions were washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by silica gel chromatography eluting with isohexane to 1:1 ethyl acetate:isohexane gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 0.49 g.
Reaction SMILES: [F:1][C:2]([S:5]([C:8]1[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=1)(=[O:7])=[O:6])([F:4])[F:3].[Cl:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[Cl:22].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:1][C:2]([F:4])([F:3])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:23][C:18]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1)C(F)(F)F
Temperature: 125 °C
Yield: 86.3 %

Procedure:
To a solution of 4.7 g (0.0192 mole) of 4-chlorophenyl trifluoromethyl sulfone prepared according to known procedures (see E. A. Nodiff et al., J. Org. Chem., 25, 60 (1959)) and 4.7 g (0.0288 mole) of 3,4-dichlorophenol dissolved in 150 ml of DMSO was added 4.0 g (0.0288 mole) of K2CO3. The reaction mixture was heated at 125° C. for 3.5 hrs and the product recovered (6.15 g, 86.3% yield) as described in Example 18. Recrystallization from ethanol afforded purified 4-(4-((trifluoromethyl)sulfonyl)phenoxy)-1,2-dichlorobenzene, mp 77°-78° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][CH:41]=[O:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].P([O-])(O)(O)=[O:44].[Na+].CC(=CC)C.C1COCC1.Cl([O-])=O.[Na+]>C(O)(C)(C)C.[Cl-].[Na+].O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:24]3[C:19]([CH:20]=[CH:21][CH:22]=[CH:23]3)=[C:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]=2[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[CH3:39])=[O:15])[CH2:10][C@@H:9]1[CH2:40][C:41]([OH:44])=[O:42])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC=O)C1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)O)C1
Temperature: 0 °C
Reaction time: 3.75 h
Yield: 40.2 %

Procedure:
The compound obtained in step 1 (0.960 g, 1.69 mmol) was suspended in 9.6 ml of tert-butanol and cooled to 0° C. A solution of sodium dihydrogenphosphate (0.607 g, 5.06 mmol) in 2.4 ml or water, a 2 M solution of 2-methyl-but-2-ene in THF (5.06 ml, 10.11 mmol) and sodium chlorite (0.286 g, 2.53 mmol) were then added and the mixture was stirred for 3.75 h. Brine (30 ml) was added and the mixture was extracted three times with EA. The combined organic phases were washed twice with 1 N hydrochloric acid and once with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (DCM/MOH, 100:0, then 96:4) to give 0.398 g of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[C:24]([N:36]3[CH2:41][CH2:40][CH:39]([N:42]([CH3:50])[C:43](=[O:49])[C@@H:44]4[CH2:48][CH2:47][CH2:46][NH:45]4)[CH2:38][CH2:37]3)[N:23]=2)=[C:17]([F:51])[CH:16]=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:8]([N:45]1[CH2:46][CH2:47][CH2:48][C@H:44]1[C:43]([N:42]([CH:39]1[CH2:38][CH2:37][N:36]([C:24]2[N:23]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][C:17]=3[F:51])[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=2)[CH2:41][CH2:40]1)[CH3:50])=[O:49])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: COc1cc2nc(N3CCC(N(C)C(=O)[C@@H]4CCCN4)CC3)nc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nc(N3CCC(N(C)C(=O)[C@@H]4CCCN4C(C)=O)CC3)nc(Nc3ccc(Cl)cc3F)c2cc1OC
Temperature: 25 °C

Procedure:
Triethylamine (175 μl) and acetyl chloride (32 μl) were added under ice-cooling to a dichloromethane (5 mL) solution of N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide dihydrochloride (250 mg), followed by stirring under ice-cooling for 2 hours and under room temperature for 20 hours. A saturated sodium bicarbonate aqueous solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated. By purifying the resulting residue by a silica gel column chromatography (chloroform-MeOH), 1-acetyl-N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide was obtained. This compound was dissolved in MeOH (3 mL), 4 M HCl/ethyl acetate solution (203 μl) was added thereto, and the solvent was evaporated. By crystallizing the resulting crude crystals from isopropanol-diisopropyl ether, 1-acetyl-N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide hydrochloride (167 mg) was obtained as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[Br:13]Br>C(Cl)Cl.C1COCC1>[Br:13][C:3]1[C:2]([CH3:1])=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: BrBr
Reactant: Cc1ccc2c(c1)NC(=O)CO2
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)OCC(=O)N2
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
To a suspension of 6-methyl-2H-1,4-benzoxazin-3(4H)-one (10.0 g, 61.3 mmol) in DCM (200 mL) and THF (200 mL) at 0° C. was added bromine (15.0 g, 93.7 mmol) dropwise. The reaction mixture was stirred at this temperature for 30 minutes, then filtered. The solid was washed with Et2O (200 mL) to give the title compound (11.95 g, 80%) as a white solid that was used without further purification. δH (CDCl3) 8.95 (1H, s), 7.16 (1H, s), 6.70 (1H, s), 4.59 (2H, s), 2.31 (3H, s).