Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][OH:12])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][C:21]([C:23]1[CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[C:31]2[C:26](=[CH:27][CH:28]=[N:29][C:30]=2[O:43][CH:44]([CH3:46])[CH3:45])[NH:25][C:24]=1[CH3:47])=O)C1C=CC=CC=1.C(O)(=O)/C=C/C(O)=O.ClCCl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:9][N:8]([CH2:10][CH2:11][O:12][C:21]([C:23]1[CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:41])[F:40])[C:31]2[C:26](=[CH:27][CH:28]=[N:29][C:30]=2[O:43][CH:44]([CH3:45])[CH3:46])[NH:25][C:24]=1[CH3:47])=[O:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: CC1=C(C(=O)OCc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1=C(C(=O)OCCN(C)Cc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1

Procedure:
To a solution of 21.05 g 2-(N-benzyl-N-methylamino)-ethanol in 42 mL toluene are added under nitrogen 0.74 g sodium hydride (80%). After stirring for 30 minites a solution of 8.42 g (0.0174 mole) (-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid benzyl ester is added dropwise. The reaction mixture is stirred under nitrogen and the exclusion of moisture for 4 hours by heating to boiling temperature under reflux. The reaction mixture is subsequently extracted with 2×50 mL 2N acetic acid. The reaction mixture is subsequently dried over sodium sulfate and evaporated to dryness. The residue is purified over silica gel with toluene:ethyl acetate (7:3) as elution agent. After distilling off the elution agent there is obtained an oily product. The oil is dissolved with 1.28 g fumaric acid in 180 mL ethyl acetate under heating to reflux temperature. After filtration the reaction mixture is evaporated to about 20 mL. The precipitated product is filtered off with suction, dispersed in 14 mL toluene and stirred with 3 mL 1M aqueous ammonium hydroxide solution. The toluene phase is washed with 2×5 mL of water. The organic phase is after drying over sodium sulfate evaporated to dryness. There is obtained an oily product, yield 0.8 g (8.5% of theory); [α]D =-40.8° (c=1/dichloromethane).
Reaction SMILES: CS(C)=[O:3].[H-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22]Br>C(OCC)C>[C:21]([O-:3])(=[O:20])[CH3:22].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:15]#[N:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: CS(C)=O
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)[O-]
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 25 °C

Procedure:
Into a round-bottom flask under argon fitted with an addition funnel and thermometer was added anhydrous dimethylsulfoxide (60 mL) and sodium hydride (1.17 g, 48.8 mmol, 95%). Then a solution of (4-chlorophenyl)acetonitrile (3.37 g, 22.2 mmol) and 2-bromoethyl ether (90%, 3.41 mL, 24.4 mmol) in diethyl ether (15 mL) was added slowly, while maintaining the reaction temperature at 20-30° C. The reaction mixture was maintained at room temperature for overnight. The reaction mixture was carefully quenched with water (50 mL) and then extracted with hexane (3×100 mL). The organic extracts were combined, washed with water (3×75 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give a pale yellow oil. The oil was purified by column chromatography on silica gel using hexane/ethyl:acetate (80:20) to give 4.7 g of 4-(4-chlorophenyl)tetrahydropyran-4-carbonitrile, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 2.00-2.15 (m, 4H); 3.89 (dt, 2H, J1=12.6 Hz, J2=3 Hz); 4.05-4.11 (m, 2H); 7.37-7.45 (m, 4H); 13C NMR (CDCl3, 300 MHz): δ 36.66 (2C), 41.51, 64.98 (2C), 121.40, 127.03, 129.37, 134.31, 138.46.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[C:18]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=5)[N:23](S(C5C=CC=CC=5)(=O)=O)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:15]=2)[C:10]([C:48]#[N:49])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.CO.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[C:18]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH:27]=5)[NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:15]=2)[C:10]([C:48]#[N:49])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4ccc5c(C#N)cn(Cc6ccccc6)c5c4)ncnc3n2S(=O)(=O)c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(-c4ccc5c(C#N)cn(Cc6ccccc6)c5c4)ncnc3[nH]2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of Example 22C (500 mg, 0.75 mmol) in tetrahydrofuran (5 mL) and methanol (3 mL) was added 1M sodium hydroxide (2.24 mL, 2.24 mmol) and the mixture was stirred at 50° C. overnight. The mixture was diluted with water, extracted with dichloromethane, dried over sodium sulfate, filtered, and concentrated to provide the title compound. LCMS: 531.2 (M+H)+.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][N+:13]([O-:1])=[N:12][C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=2)=[CH:8][CH:9]=1
Reactant: OO
Reactant: CS(=O)(=O)c1ccc(-c2nnccc2-c2ccc(Cl)cc2)cc1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2n[n+]([O-])ccc2-c2ccc(Cl)cc2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 44.1 %

Procedure:
Hydrogen peroxide solution (31%, 5.2 ml) was added to a solution of 4-(4-chlorophenyl)-3-[4-(methylsulfonyl)phenyl]pyridazine (2.6 g, 7.55 mmol) in acetic acid (30 ml), followed by stirring at 50° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and to the residue, an aqueous solution of potassium carbonate was added. The thus-obtained mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was separated and purified by chromatography on a silica gel column [silica gel 100 g, benzene/ethyl acetate (1/1)], whereby the title compound was obtained as a pale yellow amorphous solid (1.2 g, 44.1%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=1[C:38]1[N:43]=[C:42]([C:44](O)=[O:45])[CH:41]=[CH:40][C:39]=1[F:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:44]([C:42]3[CH:41]=[CH:40][C:39]([F:47])=[C:38]([C:32]4[C:31]([F:30])=[CH:36][CH:35]=[CH:34][C:33]=4[F:37])[N:43]=3)=[O:45])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (12.0 mg, 0.030 mmol), 6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.036 mmol), HATU (28.2 mg, 0.074 mmol) in DMF (0.07 mL) and DIPEA (11.5 mg, 0.089 mmol) was stirred at room temperature for 2 h. The reaction mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to afford the sub-title compound (11 mg, 58%). LCMS calc. for C33H37F3N5O5 (M+H)+: m/z=640.3. Found: 640.1.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([F:15])=[C:12]([OH:14])[CH:13]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[O:14][C:12]1[CH:13]=[C:8]([CH:9]=[CH:10][C:11]=1[F:15])[NH2:7]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Nc1ccc(F)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Oc3cc(N)ccc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred slurry of cesium carbonate (9.53 g, 29 mmol) in a mixture of THF/DMF (9/1, 200 mL) at rt, was added 5-amino-2-fluorophenol (2.10 g, 14.6 mmol) in one portion. After stirring for 30 min at rt, 4-chloro-6,7-dimethoxyquinazoline (3.61 g, 16 mmol) was added and the reaction mixture was heated at 50° C. for 30 h. The reaction was cooled to rt, then diluted with ethyl acetate. The solution was washed with 1 N sodium hydroxide solution, then brine, and dried over MgSO4. Filtration followed by concentration under reduced pressure gave a solid that was triturated with methanol. Filtration afforded 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline (3.10 g, 67%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.05 (dd, J=9.2, 9.2 Hz, 1H), 6.47-6.56 (m, 2H), 5.19 (brs, 2H), 4.00 (s, 3H), 3.99 (s, 3H); LC-MS (ESI) m/z 316 (M+H)+.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:6]1([CH2:4][N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)/[C:4](=[N:21]/[NH:20][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)/[C:2]2=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Product: O=C(N/N=C1\C(=O)N(CC2CCCCC2)c2ccccc21)c1ccccc1
Yield: 71.4 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 7 and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 71.4%. 1H NMR (DMSO-d6): δ 1.05-1.09 (m, 2H), 1.18-1.20 (m, 3H), 1.61-1.79 (m, 6H), 3.65 (d, J=7.5 Hz, 2H), 7.22 (t, J=8 Hz, 1H), 7.28 (d, J=8 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.66-7.70 (m, 3H), 7.75 (t, J=7 Hz, 1H), 7.96 (d, J=7 Hz, 2H), 13.97 (br s, 1H). 13C NMR (DMSO-d6): δ 25.68 (CH2), 26.26 (CH2), 30.71 (CH2), 36.40 (CH), 45.90 (CH2), 110.95 (CH), 119.57 (C), 121.19 (CH), 123.67 (CH), 127.87 (CH), 129.68 (CH), 132.19 (CH), 132.44 (C), 133.40 (CH), 137.70 (C), 143.94 (C═N), 161.90 (C═O), 163.42 (C═O). HRMS (ES+) calcd for C22H24N3O2 (M+H+), m/e, 362.1872; found, 362.1863.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([CH3:20])=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:13]=2)[CH:10]=1.[Cl-].[NH4+].O>C(O)C.C(OCC)(=O)C>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([C:11]([CH3:20])=[C:12]([NH:14][C:15]([CH:17]4[CH2:19][CH2:18]4)=[O:16])[N:13]=3)[CH:10]=2)=[C:2]([F:1])[CH:24]=1
Reactant: Cc1c(NC(=O)C2CC2)nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cn12
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1c(NC(=O)C2CC2)nc2ccc(Oc3ccc(N)cc3F)cn12
Yield: 81.6 %

Procedure:
A mixed solution of N-[6-(2-fluoro-4-nitrophenoxy)-3-methylimidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (80 mg, 0.216 mmol), reduced iron (64 mg, 1.08 mmol) and ammonium chloride (116 mg, 2.16 mmol) in ethanol (2 mL)/water (0.5 mL) was stirred at 80° C. for 3 hr. The reaction mixture was diluted with ethyl acetate and filtered through celite. Water was added to the filtrate, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure to give the title compound (60 mg, 82%) as a slightly yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][NH2:16])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[Cl:24][CH2:25][C:26](Cl)=[O:27]>O1CCCC1>[Cl:24][CH2:25][C:26]([NH:16][CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:27]
Reactant: CC1(CN)OCCc2c1[nH]c1ccccc21
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(CNC(=O)CCl)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.5 %

Procedure:
A mixture of 1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-methanamine(15 g, described in Example 3), triethylamine(7 g), chloroacetyl chloride (7.9 g) and tetrahydrofuran (300 ml) is stirred at 0° C. for 5 minutes and at 25° C. for 18 hours, filtered and evaporated. The residue is crystallized from chloroform-diethyl ether to obtain the title compound (13.7 g); mp 186°-187° C.; nmr (CDCl3) δ 3,41 (d), 3.61 (d), 3.89 (m), 4.09 (s), 6.75-7.50 (m) and 8.0 (t).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1.Cl.[NH2:15][NH:16][C:17]([NH2:19])=[O:18]>C(O)C.O>[Cl:1][CH2:2][C:3](=[N:15][NH:16][C:17]([NH2:19])=[O:18])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][N:7]=1
Reactant: O=C(CCl)COc1ccc(Cl)cn1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=O)NN=C(CCl)COc1ccc(Cl)cn1

Procedure:
1-Chloro-3-(5-chloropyrid-2-yloxy)propan-2-one (400 mg.) was dissolved in ethanol (4 ml.) with warming, and stirred while a solution of semicarbazide hydrochloride (223 mg.) in water (2 ml.) was added. The mixture was cooled in ice for 11/2 hours and filtered, and the filter cake was washed with a 1:1 v/v mixture of ethanol and water (1 ml.), then with water (3 × 1 ml.). The product was dried in a desiccator over silica gel to give 1-chloro-3-(5-chloropyrid-2-yloxy)-2-semicarbazonopropane, RF = 0.72 (5% v/v methanol in ethyl acetate), m.p. 115°-117° C.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>O>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Solvent: O
Product: CCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)-ethylamino]ethylene (seeExample 55(i)) with ethylamine by the procedure of Example 8(ii) gives the title product, m.p. 115°-116° (from water).
Reaction SMILES: [CH:1]1([C:6]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:18]([O-])([OH:20])=[O:19]>>[CH:1]1([C:6]([C:8]2([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=3)[CH2:10][CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(C1CCCC1)C1(c2ccc(Cl)cc2)CC1
Reactant: O=[N+]([O-])O
Product: O=C(C1CCCC1)C1(c2ccc(Cl)c([N+](=O)[O-])c2)CC1

Procedure:
Prepared analogously to Example 1a from 4-[1-(cyclopentylcarbonyl)cyclopropyl]-chlorobenzene and fuming nitric acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11]Br)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].C[N:25]([CH3:31])[CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>C1COCC1.CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:28]2[CH2:27][CH2:26][N:25]([CH3:31])[CH2:30][CH2:29]2)=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CN(C)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.5 %

Procedure:
To a solution of 4-bromomethyl-3-trifluoromethyl-benzoic acid ethyl ester 36 (120 mg, 0.386 mmol) in THF (4 mL) and DMF (1 mL) was added K2CO3 (80 mg, 0.579 mmol) and 3-(dimethylamino)pyrrolidine (0.043 mL, 38.6 mg, 0.386 mmol). The resulting mixture was stirred at rt for 4 h. The reaction mixture was poured out in water and extracted twice with ethyl acetate. The combined organic extracts were dried, filtered and concentrated in vacuo. The crude material was purified by chromatography CH2Cl2/MeOH (95/5) to give pure 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-benzoic acid ethyl ester 37 (21 mg, 16%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[C:28]([S:30][CH3:31])[CH:27]=[C:26]([CH:32]([CH3:34])[CH3:33])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[CH:32]([C:26]1[CH:27]=[C:28]([S:30][CH3:31])[CH:29]=[C:23]([CH:20]([CH3:22])[CH3:21])[C:24]=1[NH:25][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])([CH3:34])[CH3:33]
Reactant: CSc1cc(C(C)C)c(N)c(C(C)C)c1
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: CSc1cc(C(C)C)c(NC(=O)C2c3ccccc3COc3ccc(C)cc32)c(C(C)C)c1
Yield: 84 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.12 g of Compound A and 1.18 g of 2,6-diisopropyl-4-methylthioaniline in place of aniline to obtain 1.70 g of Compound 30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][C:16]([OH:18])=O.C(Cl)(=O)C(Cl)=O.ClCCl.CN(C=O)C>Cl[Ti](Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[CH:9]1[CH:10]([CH2:15][C:16]2=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccccc1C1CCCCC1CC(=O)O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1C1CCCCC1CC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
Combine [2-(2-methoxy-phenyl)-cyclohexyl]-acetic acid (0.300 g, 1.21 mmol), oxalyl chloride (0.13 mL, 1.45 mmol), and dichloromethane (6.0 mL) and catalytic DMF (0.1 mL) at room temperature. After 1 hour at 0° C. added TiCl4 (0.33 mL, 3.0 mmol) and reaction gradually warmed to room temperature. After 3 hours, quenched reaction with 5N HCl and added ethyl acetate. Separate layers, wash with brine, and dry over anhydrous sodium sulfate. Concentrate and flash chromatograph using 0 to 20% ethyl acetate/hexanes eluent to yield the titled compound (0.198 g, 72%). TLC Rf=0.4 in 20% ethyl acetate/hexanes. 1H NMR (CDCl3): 7.6 (d, 1H, J=7.0 Hz), 7.3 (m, 1H), 7.0 (m, 1H), 3.8 (s, 3H), 3.2 (m, 1H), 2.9 (m, 1H), 2.4 (m, 2H), 1.9 (m, 1H), 1.6 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][CH:6](C(O)=O)[C:7]([OH:9])=[O:8].C(=O)=O>CCOCC>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]([C:16]2[C:3]([O:2][CH3:1])=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:13]=[CH:14][CH:15]=2)=[O:25])=[CH:19][CH:20]=1
Reactant: COc1c(CC(C(=O)O)C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Agent: O=C=O
Solvent: CCOCC
Product: COc1c(CCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 67.2 %

Procedure:
96.2 g of 2-methoxy-3-(p-chlorobenzoyl)-benzylmalonic acid were heated at 170°-195°C under an argon atmosphere and after the evolution of carbon dioxide gas, the mixture was cooled and added to 1 liter of ether. The acid mixture was extracted several times with 600 ml of a solution of 10% potassium carbonate and 150 ml of water. The combined aqueous phases were acidified with concentrated hydrochloric acid and the acid precipitate formed was extracted with ether. The combined ether phases were washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from cyclohexane to obtain 56.8 g of 3-(3'-p-chlorobenzoyl-2'-methoxy-phenyl)-propionic acid in the form of colorless crystals.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12].[CH2:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[F:11][C:7]1[C:6]([CH3:12])=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:21]2[N:22]([CH:2]=1)[CH:23]=[CH:24][CH:25]=[CH:26]2
Reactant: Cc1c(F)cccc1CC(=O)CBr
Reactant: c1ccc(Cc2ccccn2)cc1
Solvent: CC(C)=O
Product: Cc1c(F)cccc1Cc1cn2ccccc2c1-c1ccccc1
Yield: 33.8 %

Procedure:
The compound of step 2 (1.50 g, 6.12 mmol) and 2-benzyl-pyridine (2.071 g, 12.24 mmol) were dissolved in acetone (30 ml) and the mixture was stirred under reflux overnight. The mixture was concentrated to dryness and the residue was purified by chromatography on silica gel (cyclohexane) to give 0.653 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:40][C@@H:41]2[NH:45][C:44](=[O:46])[CH2:43][CH2:42]2)(=O)=O)=CC=1.CCOCC>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][C@@H:41]1[NH:45][C:44](=[O:46])[CH2:43][CH2:42]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)C[C@H]2CCC(=O)N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.3 %

Procedure:
To a suspension of 7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (1.36 g, 4.24 mmol), (prepared as described in Example 49), in DMF (70 ml), was added potassium carbonate (2.34 g, 17.0 mmol, 4eq.) followed by (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.25 g, 4.66 mmol, 1.1 eq.), (prepared as described for the starting material in Example 317), and the resulting yellow suspension heated at reflux. After 4 hours, some starting material remained, and a further addition of (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (0.57 g, 2.12 mmol, 0.5eq.) was made. The reaction was heated at reflux for a further 2 hours resulting in consumption of starting material. The reaction was cooled to ambient temperature, the inorganic residue filtered off and the filtrate evaporated in vacuo to leave a brown oil which was purified by column chromatography (methylene chloride/methanol, (100/0 to 90/10)) to give a light brown oil. Trituration with ether afforded a thick oil, which upon chromatography eluting as above gave a yellow oil. Trituration of this oil with ether gave an initial crop of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (5 mg) as an off-white solid (ca. 90% pure by nmr). Chromatography of the residues (eluting as above) followed by ether trituration gave further crops of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline as a white solid (180 mg, >95% pure by nmr), as an off-white solid (800 mg, ca. 95% pure by nmr).