Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH:44][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:7](=[O:24])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(=O)OCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 96 °C
Yield: 16.5 %

Procedure:
Acetic acid 8-cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl ester (0.80 g, 2.29 mmol), prepared as in Example 27, and 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.17 g, 4.20 mmol) were added to toluene (8 ml), heated to 96° C. for 6 hours. The reaction mixture was allowed to cool, then filtered and the residue washed with toluene. The resulting solid was dried in vacuo then recrystallized from chloroform/diethyl ether to provide 4-[6-(6-acetoxymethyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.213 g, 16.5%). MS (APCI) M++1; Calc'd, 564.2. Found, 564.3.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[O-]CC.[Na+].[CH:31]1([CH2:34]Br)[CH2:33][CH2:32]1>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:34][CH:31]3[CH2:33][CH2:32]3)[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: BrCC1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 1.4 g of sodium ethoxide, and the whole was stirred for 30 minutes at room temperature. To this was further added 4.1 g of cyclopropylmethyl bromide, and the mixture was reacted for 2 hours at room temperature. Then, the solvent was distilled off from the resulting mixture under reduced pressure to leave a residue, to which was added water to precipitate a crude product. Recrystallization of this product from methanol gave 3.1 g of 1-(m-nitrophenyl)-3-cyclopropylmethyl-quinazoline- 2,4(1H, 3H)-dione as colorless needles, melting, at 163°-164° C.
Reaction SMILES: C([O:3][C:4](=[O:50])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)[CH:25]=[C:24]([C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[CH:23]=2)[C:10]=1[CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])C.[OH-].[Na+]>>[O:38]1[C:37]2[CH:41]=[CH:42][C:34]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:50])=[O:3])=[CH:35][C:36]=2[O:40][CH2:39]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(-c3ccncn3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc4c(c3)OCO4)cc(-c3ccncn3)c2)c1CCC(=O)O
Yield: 25.3 %

Procedure:
A similar procedure as described in Example 12, step 9 was used, starting from 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-pyrimidin-4-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (26 mg, 0.12 mmol) and 1.0 N aqueous sodium hydroxide (3 mL) to afford 4-{3-[6-(3-benzo[1,3]dioxol-5-yl-5-pyrimidin-4-yl-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy}-butyric acid (19 mg, 79%) as an amorphous light yellow solid: ES(+)-HRMS m/e calculated for C36H38N2O8 (M+H)+ 627.2701, found 627.2696.
Reaction SMILES: Cl.N[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18](CC(OCC)=O)[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:27]1(=[O:34])[O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28]1>C1COCC1>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]3([CH2:20][CH2:19][N:18]([C:31](=[O:32])[CH2:30][CH2:29][CH2:28][C:27]([OH:33])=[O:34])[CH2:17][CH2:16]3)[O:13][N:12]=2)=[CH:7][CH:6]=1)#[N:3]
Reactant: O=C1CCCC(=O)O1
Reactant: CCOC(=O)CN1CCC2(CC1)CC(c1ccc(C=NN)cc1)=NO2
Agent: Cl
Solvent: C1CCOC1
Product: N#Cc1ccc(C2=NOC3(CCN(C(=O)CCCC(=O)O)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 1.5 g (6.22 mmol) of the intermediate from Example 5. Step B in 40 ml dry THF were added 0.71 g (6.22 mmol) glutaric anhydride and 76 mg 4-N,N-dimethylaminopyridine (DMAP). It was stirred for 1 h at room temperature followed by 2 h heating with reflux. The solvent was removed under reduced pressure, and the title compound was obtained by chromatography on silica gel with dichloromethane containing 4% ethanol. It was recrystallized from ethyl acetate/ether, and the crystals were collected by filteration and dried in vacuo.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:36])[NH:13][CH:14]([C:30](=[O:35])N(OC)C)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:36])[NH:13][CH:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)[CH:30]=[O:35])([CH3:10])([CH3:8])[CH3:9]
Reactant: CON(C)C(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
LiAlH4 (916 mg, 24.1 mmol) was added cautiously and portionwise during 15 min to a stirred solution of (RS)-[2-(4-Benzyloxy-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (10.00 g, 24.1 mmol) in THF (150 mL) at 0° C. under an atmosphere of argon. The ice-bath was removed and the mixture was stirred for 1 hr, then poured onto a mixture of ice and KHSO4 (1 M aq.). When the ice had melted the product was extracted into EtOAc. The combined extracts were washed with brine then dried (Na2SO4) and evaporated to give (RS)-[1-(4-Benzyloxy-benzyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (8.51 g, 99%), mp 100.3-101.7° C. 1H NMR (CDCl3) δ 1.44 (s, 9H), 3.07 (d, J=6.7 Hz, 2H), 4.40 (br s, 1H), 5.05 (s, 2H), 6.92 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 7.33-7.45 (m, 5H), 9.63 (s, 1H). 13C NMR (CDCl3) δ 199.6, 156.4, 144.4, 136.8, 130.4, 128.6, 128.5, 128.0, 127.9, 127.5, 115.1, 80.9, 70.0, 46.0, 34.6, 28.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([NH2:8])=[O:7].C(Cl)Cl.Cl[C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26]>C(N(CC)CC)C>[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([OH:11])[CH:3]=1)=[O:29])([OH:27])=[O:26]
Reactant: COC(=O)CCCCCCCCC(=O)Cl
Reactant: NC(=O)c1ccc(N)cc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1ccc(NC(=O)CCCCCCCCC(=O)O)cc1O
Reaction time: 48 h

Procedure:
4-aminosalicylamide (2 g) from Example 5 is charged with 20 mL of methylene chloride. To the solution, 3.3 g of methyl 10-chloro-10-oxodecanoate is added. The reaction is initiated by addition of 2.6 mL of triethylamine. The reaction mixture is allowed to stir at ambient conditions for 2 days. Solvent is removed and the residue is acidified using 1 N HCl. The precipitate is extracted into ethyl acetate. The organic layer is further extracted with 1 N NaOH and saturated NaCl solutions. After drying over anhydrous sodium sulfate, solvent is removed. The residue is reconstituted in tetrahydrofuran (10 mL) and 10 mL of 2 N NaOH is added. The solution is brought to gentle reflux for 2 hours. The disappearance of the methyl ester is followed by HPLC. When all ester is hydrolyzed, the solution is cooled and acidified and the product is extracted into ethyl acetate. The organic layer is washed with saturated NaCl and dried over anhydrous sodium sulfate. Solvent is removed under reduced pressure and the product is obtained as off-white powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[C:8]1([F:26])[C:12](Cl)([F:13])[O:11][C:10]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])([C:15]([F:18])([F:17])[F:16])[O:9]1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl>[F:13][C:12]1[O:11][C:10]([C:19]([F:24])([F:25])[C:20]([F:22])([F:23])[F:21])([C:15]([F:18])([F:17])[F:16])[O:9][C:8]=1[F:26]
Reactant: FC(F)(F)C(F)(F)C1(C(F)(F)F)OC(F)(Cl)C(F)(Cl)O1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: FC1=C(F)OC(C(F)(F)F)(C(F)(F)C(F)(F)F)O1
Yield: 38 %

Procedure:
This example was carried out as illustrated in Example 4 with lithium aluminum hydride (6.14 g, 0.162 mole), titanium (IV) chloride (7.67 g, 4.43 mL, 0.041 mole) and 4,5-dichloro-4,5-difluoro-2-pentafluoroethyl-2-trifluoromethyl-1,3-dioxolane (29.5 g, 0.081 mole) in tetrahydrofuran (100 mL). The pure desired product obtained after distillation and washing with ice-water, perfluoro-2-ethyl-2-methyl-1,3-dioxole, was 9.0 g (38% yield); boiling point 42°-43° C.
Reaction SMILES: [C:1](Cl)(=O)C.[O:5]=[C:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.C(=O)([O-])O.[Na+]>CO>[O:5]=[C:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([O:14][CH3:1])=[O:13])[CH2:8][CH2:7]1
Reactant: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCC(=O)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
Acetyl chloride (0.46 mL, 0.50 g, 6.4 mmol) was added to a solution of 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2, 0.94 g, 4.3 mmol) in methanol (5 mL) and the mixture was heated under reflux for 20 hours. The mixture was cooled, poured into aqueous sodium hydrogen carbonate (saturated, 100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), acetic acid (6 mL) and water (2 mL) were added and the mixture was stirred at 45° C. for 2 hours. The mixture was cooled, the solvent was evaporated under reduced pressure and aqueous sodium hydrogen carbonate (saturated, 100 mL) was added. The mixture was extracted with ethyl acetate (2×50 mL), the combined organic fractions were dried (Na2SO2) and the solvent was evaporated under reduced pressure to give the tide compound (0.98 g, 98%). 1H NMR (250 MHz, CDCl3) δ 7.45-7.26 (5H, m), 3.72 (3H, s), 2.77 (2H, m), 2.61-2.38 (4H, m), and 2.25 (2H, m).
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])=[CH:4][N:3]=1.[NH2:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CS(C)=O.O>[NH2:25][C@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:7])=[CH:4][N:3]=2)[CH2:27]1
Reactant: N[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(N2CC[C@H](N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A solution of compound 94 (1.00 g, 2.88 mmol) and 3-(S)(−)aminopyrrolidine (495 mg, 5.75 mmol) in DMSO (5 ml) was heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature and stirred for an additional 16 h and diluted with water. The aqueous solution was extracted with AcOEt/dichloromethane mixture, washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound 153 as an orange solid (981 mg, 86% yield). 1H NMR: (DMSO) δ (ppm): 8.76 (s, 2H), 4.26 (q, J=7.1 Hz, 2H), 3.70-3.53 (m, 4H), 3.26 (dd, J=11.3, 3.9 Hz, 1H), 2.07-1.98 (m, 1H), 1.75-1.67 (m, 3H), 1.29 (t, J=7.0 Hz, 3H). LRMS (ESI): (calc.) 397.2; (obt.) 398.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]([F:21])([F:20])[CH2:18][OH:19]>CN(C=O)C.O>[CH3:9][S:8][C:4]1[N:3]=[C:2]([O:19][CH2:18][C:17]([F:21])([F:20])[F:16])[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(Cl)n1
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc(OCC(F)(F)F)n1
Reaction time: 64 h
Yield: 103 %

Procedure:
To a solution of 4-chloro-2-methylthiopyrimidine (16.0 g) and potassium carbonate (27.6 g) in DMF (90 ml) at 0° C., was added with stirring a solution of 2,2,2-trifluoroethanol (10.0 g) in DMF (10 ml). Stirring was continued for 64 hours, then the reaction mixture was diluted with water and extracted with ether (3×150 ml). The combined extracts were washed with brine, dried and concentrated to give 2-methylthio-4-(2,2,2-trifluoroethoxy)pyrimidine (23.0 g, crude yield) as a clear pale orange oil, 1H NMR δ 2.57(3H,s); 4.79(2H,q); 6.54(1H,d); 8.33(1H,d) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:18](O)[CH3:19]>>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13][CH2:18][CH3:19])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1n[nH]c2cc(O)ccc12
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1n[nH]c2cc(O)ccc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Crude product of 6-hydroxyindazole-3-carboxylic acid (1.504 g) which can be prepared according to the method described in Reference example 16, etc. was dissolved in ethanol, cooled to 0° C., and then thionyl chloride (7.6 mL; manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise thereto. The reaction solution was stirred overnight at 60° C. After cooling to room temperature, disappearance of the reacting material and generation of the target compound was confirmed based on LCMS. The solvent was evaporated under reduced pressure. To the residue, ethanol (50 mL) was added, and to the residue which had been obtained by evaporation of the solvent under reduced pressure, THF (50 mL) was added and the solvent was removed again by evaporation under reduced pressure to obtain the target compound as a crude product (1.457 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[NH:4][C:5]1[S:6][C:7]([CH3:12])=[CH:8][C:9]=1[C:10]#[N:11].Cl.CC(C)=O.C.[CH3:23][N:24]1[CH2:29][CH2:28]N[CH2:26][CH2:25]1>>[CH3:12][C:7]1[S:6][C:5]2[NH:4][C:3]3[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=3[N:1]=[C:10]([N:11]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[C:9]=2[CH:8]=1
Reactant: Cc1cc(C#N)c(Nc2ccccc2N)s1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2-(2-Aminoanilino)-5-methylthiophene-3-carbonitrile (2.0 g) is taken in N-methyl-piperazine (12 ml) and N-methyl piperazine.HCl (4.6 g). The solution is heated at 120° C. until completion of reaction. The reaction mass is cooled to 70-75° C. and acetone and activated charcoal are added. The reaction mixture is stirred for 30 minutes and filtered. The water is added at 45-50° C., the mixture is cooled up to room temperature and the precipitated solid is filtered off and washed with acetone-water mixture.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:39][CH3:40])=[CH:29][C:30]=2[O:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:39][CH3:40])=[CH:29][C:30]=4[O:32][CH:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC2CCOCC2)c2c(Cl)ncnc2c1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: COc1cc(OC2CCOCC2)c2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2c1
Temperature: 60 °C
Yield: 22 %

Procedure:
According to the procedure described in Example 50, a mixture of the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-mercaptophenyl)urea described in Example 44A (0.204 g, 0.7 mmol), 4-chloro-7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazoline from Example 94A (0.212 g, 0.72 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (10 mL) was heated at 60° C. for 4 hours, to afford 1-(5-tert-butylisoxazol-3-yl)-3-{3-[7-methoxy-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-ylthio]phenyl}urea as solid (0.086 g, 22%). 1H NMR (300 MHz, CDCl3) δ 9.3 (s, 1H), 8.60 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.65 (d, 1H), 7.41 (t, 1H), 7.33 (d, 1H), 6.86 (d, 1H), 6.54 (d, 1H), 5.90 (s, 1H), 4.78 (m 1H), 4.18 (m, 2H), 3.94 (s, 3H), 3.69 (m, 2H), 2.19 (m, 2H), 2.11 (m, 2H), 1.33 (s, 9H); LC-MS (ESI) m/z 550 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.O=C1CCC(=O)N1[O:62][C:63](=O)[CH2:64][C:65]#[N:66]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:63](=[O:62])[CH2:64][C:65]#[N:66])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(=O)N1CCN(C(=O)COc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile as the starting materials in 60% yield. LCMS for C26H26ClN8O3 (M+H)+: m/z=533.0.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[NH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[CH3:18][N:19]1CCOCC1.Cl.CN>C(OCC)C>[CH3:18][NH:19][C:15]([C:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[NH:3][C:2](=[O:1])[C:11]=2[NH:12][CH:13]=1)=[O:17]
Reactant: CN1CCOCC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Agent: CN
Agent: Cl
Solvent: CCOCC
Product: CNC(=O)c1c[nH]c2c(=O)[nH]c3ccccc3c12
Yield: 7.3 %

Procedure:
This compound is prepared according to synthesis 79 from 37 mg (0.17 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 75), 108 μL (0.99 mmol) of N-methylmorpholine and 17 mg (0.25 mmol) of methylamine hydrochloride. After trituration in diethyl ether, 3 mg (7%) of N-(methyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxamide are obtained in the form of a light brown solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][CH2:22][N:21]=3)=[CH:16][C:15]=2[O:31][CH3:32])(=[O:12])=[O:11])=[CH:6][CH:5]=1>CN(C)C=O>[F:34][C:2]([F:1])([F:33])[O:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH:23]=[CH:22][N:21]=3)=[CH:16][C:15]=2[O:31][CH3:32])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: COc1cc(C2=NCCc3ccc(Cl)cc32)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Product: COc1cc(-c2nccc3ccc(Cl)cc23)ccc1NS(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.2 %

Procedure:
500 mg of 1-[4-(4-Trifluoromethoxybenzenesulfonamido)-3-methoxyphenyl]-7-chloro-3,4-dihydroisoquinoline (1a) are dissolved in 500 μl of of dimethylformamide. To this solution 560 mg of potassium tert.-butylate in 4000 μl of dimethylformamide are added under an atmosphere of oxygen. The reaction mixture is stirred at RT for 4 h and evaporated to dryness. The residue is dissolved in ethyl acetate/water and the organic layer is separated. The aqueous layer is extracted twice with ethyl acetate and the combined organic layers are dried and evaporated. The product is stirred out of diethylether to yield 215 mg of the title compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].CN(C)[CH:25]=[O:26]>CCCCCC.O1CCCC1.O.C(O)(=O)C>[F:13][C:14]1[C:21]([CH:25]=[O:26])=[C:20]([F:22])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1ccc(F)cc1F
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: N#Cc1ccc(F)c(C=O)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In an atmosphere of nitrogen gas, 66 ml of a 1.6 M solution of n-butyllithium in hexane was added to an ice-cold solution of 11.1 g of N,N-diisopropylamine in 100 ml tetrahydrofuran, and the mixture was stirred at the same temperature for 20 minutes. After cooling to −78° C., a solution of 13.9 g of 2,4-difluorobenzonitrile in 15 ml tetrahydrofuran was added dropwise. After stirring at the same temperature for 10 minutes, 8.6 ml of dimethylformamide was added dropwise and the mixture was stirred at the same temperature for 15 minutes. After adding 20 ml of glacial acetic acid to the reaction mixture, 200 ml of water was added and the mixture was extracted with diethyl ether for two times. The organic layer was sequentially washed with 0.2 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The resulting crude crystals were triturated with diethyl ether-n-hexane, to give 8.61 g of the title compound as bright yellow crystals.