Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(#N)C.O>[Br:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[F:1])[O:9][CH2:8][CH2:7][CH2:6]2
Reactant: Fc1ccc2c(c1)OCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O
Product: Fc1cc2c(cc1Br)CCCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 7-fluorochroman (4.42 g, 29.0 mmol) in acetonitrile (40 mL) at 0° C. was treated with NBS ((5.16 g, 29 mmol)) and the mixture was stirred at ambient temperature for 2 hours. The reaction was diluted with water, stirred for 1 hour and then extracted with ethyl acetate, dried over sodium sulfte and concentrated under reduced pressure give a 6-bromo-7-fluorochroman as the major product in a 3:1 mixture of regioisomers as a colorless oil (4.05 g). This material was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.19 (d, J=7.8 Hz, 1 H), 6.59 (d, J=10.0 Hz, 1 H), 4.19-4.16 (m, 2 H), 2.74 (t, J=6.5 Hz, 2 H), 2.04-1.95 (m, 2 H); LCMS (m/z) ES+=230 (M−1).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: NCCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1cc(-c2cc3cc(CNCCc4ccccn4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 70.6 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with 2-(2-aminoethyl)pyridine (0.239 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (127 mg, 0.599 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=4/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-(1-(tert-butoxycarbonyl)-5-[(2-(pyridin-2-yl)ethyl)aminomethyl]indol-2-yl)isoindolinone (85.7 mg, yield 71%).
Reaction SMILES: [CH2:1]([O:15][C:16]1[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:24](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.CO>CC(C)=O>[CH3:24][O:22][C:21]([C:19]1[S:20][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1)=[O:23]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)s1
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OC)s1

Procedure:
A mixture of 10.6 g of (0.031 mole) of 5-tetradecyloxy-2-thiophene carboxylic acid, 200 ml of acetone, and 4.3 g (0.031 mole) of potassium carbonate is stirred at room temparature after which 3.9 g (0.031 mole) of dimethyl sulfate is added. The mixture is stirred with heating for about 21/2 hours during which time 10 ml of methanol is added. The mixture is then diluted with 100 ml of acetone and filtered. The filtrate is evaporated to dryness to give 5-tetradecyloxy-2-thiophene carboxylic acid methyl ester.
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[CH2:6]([OH:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].N1[CH:24]=[CH:23][CH:22]=[CH:21]C=1.O>CCCCC>[CH2:21]1[CH:23]([CH2:24][CH2:5][C:4]([O:18][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:3])[CH2:22]1
Reactant: CCOCC
Reactant: CCCCCCCCCCCCO
Reactant: c1ccncc1
Solvent: O
Solvent: CCCCC
Product: CCCCCCCCCCCCOC(=O)CCC1CC1
Reaction time: 8 h

Procedure:
To the acid chloride, thus prepared, is added 40 mls. of anhydrous ether and 1.49 g. of 1-dodecanol, followed, at 0°, by 0.8 mls. of pyridine (d20 = 0.982). A white precipitate forms immediately. The mixture is stirred at 24° overnight and then water, ether, and pentane are added to the reaction mixture, the organic layer separated, washed with 3N sulfuric acid, aqueous 15% potassium carbonate, water, and brine, dried over calcium sulfate, and the solvent removed to yield dodecyl 3-cyclopropanepropionate, boiling point 116° at 0.05 mm.
Reaction SMILES: [Na].[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13](OCC)(=[O:15])[CH3:14].Cl>O>[C:2]1([CH2:8][CH2:9][C:10](=[O:12])[CH2:11][C:13](=[O:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(=O)CC(=O)CCc1ccccc1

Procedure:
Sodium (23 g) was added in small portions to a solution of 4-phenyl-2-butanone (148 g, 1 mol) and ethyl acetate (264 g) at 20°-60° C. with stirring under nitrogen and then the reaction mixture was refluxed for 2 h with stirring. After cooling, the mixture was taken up in H2O (1l), neutralized with hydrochloric acid, the organic layer was separated, washed with H2O, dried over anhydrous Na2SO4 and then evaporated. The resultant residue (171 g) was distilled under reduced pressure to give the title compound as a colorless oil; yield: 73.4 g; bp 128°-133° C./3-4 mmHg (Lit. bp 133°-136° C./5 mmHg; C. R. Hauser, T. M. Harris, J. Am. Chem. Soc., 80, 6360 (1958)).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]1(=O)[O:15][C:13](=[O:14])[CH:12]=[CH:11]1>C(O)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13](=[O:14])[CH:12]=[CH:11][C:10]2=[O:15])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: Cc1cc(N2C(=O)C=CC2=O)ccc1Br
Temperature: 115 °C
Reaction time: 0.42 h
Yield: 74.4 %

Procedure:
4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898 g, 9.16 mmol) were dissolved in acetic acid (10 mL) and heated at 115° C. for 12 h. The reaction was then cooled to 25° C. and the acetic acid was removed in vacuo. The resulting residue was suspended in 5% K2CO3 (100 mL), stirred for 25 minutes followed by filtering and rinsing with water. The material was then dried in vacuo to give compound 13B as a light brown solid (1.65 g). HPLC: 100% at 2.96 min (retention time) (YMC S5 ODS column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:17]=[CH:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.[O:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.ClCCl>[ClH:27].[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH:34]6[CH2:35][CH2:36][O:31][CH2:32][CH2:33]6)[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH:17]=[CH:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CNC1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(-n2ccc3nc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC1CN(C2CCOCC2)C1
Product: Cl
Yield: 165.4 %

Procedure:
Suspend 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-5H-thiazolo[5,4-c]pyridin-4-one (50 mg, 0.11 mmol) in MeOH (5.68 mL). Add tetrahydro-4H-pyran-4-one (15.7 μL, 0.17 mmol) and acetic acid (9.8 μL, 0.17 mmol) and stir at room temperature for 10 min. Add sodium cyanoborohydride (7.1 mg, 0.11 mmol) and stir at room temperature for 6 h. Add dichloromethane to the reaction mixture to dissolve the solid material. Pour onto a 2 g SCX2 ion exchange column wet with MeOH and elute under gravity. Elute SCX cartridge with MeOH (approximately 3 volumes) under reduced pressure and discard. Elute SCX cartridge with 7N NH3 in MeOH:dichloromethane (1:1) (approximately 5 volumes) under reduced pressure and then concentrate in vacuo. Dissolve the resultant solid in dichloromethane (5 mL) and add 4 N HCl in dioxane solution (25 μL). Evaporate the solvent and suspend the solid in water. Freeze-dry to give (51 mg, 83%) of the title compound as a white solid. ES/MS m/z (35Cl) 524 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]([CH3:17])[CH2:13][CH:12]=1.[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH2:29].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]([C:2]1[CH:3]=[C:4]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)=[CH2:29]
Reactant: CN1C=CC(c2c[nH]c3c(Br)cc(OS(=O)(=O)c4ccccc4)cc23)=CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1cc(OS(=O)(=O)c2ccccc2)cc2c(C3CCN(C)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of benzenesulfonic acid 7-bromo-3-(1-methylpyridin-4-yl)-1H-indol-5-yl ester and Pd (PPh3)4 (0.2 eq.) in dry toluene was degassed and then treated with vinyl tributyltin (1.1 eq.). Heat the reaction mixture to reflux. After 5 hours, cool to room temperature, pour into ethyl acetate, wash with brine, dry the organic layer over Na2SO4, and concentrate. Purify to give the title compound.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:18]2[C:17]([O:19][CH3:20])=[CH:16][CH:15]=[C:14]([CH:21]=O)[C:13]=2[CH2:12][CH2:11][C:10]1=[O:23])=[O:7])(C)(C)C.[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].N1C=CC=CC1>C1(C)C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[C:6]([CH2:8][N:9]1[C:18]2[C:13](=[C:14]([CH2:21][CH:28]3[S:24][C:25](=[O:30])[NH:26][C:27]3=[O:29])[CH:15]=[CH:16][C:17]=2[O:19][CH3:20])[CH2:12][CH2:11][C:10]1=[O:23])([OH:5])=[O:7]
Reactant: COc1ccc(C=O)c2c1N(CC(=O)OC(C)(C)C)C(=O)CC2
Reactant: O=C1CSC(=O)N1
Agent: C1=CCNC=C1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COc1ccc(CC2SC(=O)NC2=O)c2c1N(CC(=O)O)C(=O)CC2
Yield: 44.9 %

Procedure:
4.16 g of 1-tert-butoxycarbonylmethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-carboxaldehyde and 1.66 g of 2,4-thiazolidinedione (1.00 eq.) were suspended in 40 ml of toluene, and two drops of acetic acid and two drops of piperidine were added, followed by heating and refluxing for 13 hours using a Dean Stark trap. After cooling, crystals were separated by filtration and washed with toluene. The crystals obtained were suspended in 3.15 g of silica gel, 2.09 g of dihydropyridine, and 60 ml of toluene, followed by heating and refluxing overnight. 3.15 g of silica gel was added, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1), and recrystallized from ethyl acetate-hexane, giving 2.13 g (38% yield) of 5-(1-carboxymethyl-8-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl)thiazolidine-2,4-dione as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](O)(=[O:27])[CH2:25][CH3:26]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:16])([NH:17][C:24](=[O:27])[CH2:25][CH3:26])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: CCC(=O)O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CC)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b) and propionic acid as a pale-yellow solid (23%). MS 374 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]([C@H:14](C)[CH2:15][CH3:16])[CH2:6][CH:7](C(O)=O)C(O)=O)=[O:4].C([O-])(=[O:20])C.[Na+].C(OC(=O)C)(=O)C>>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:6]([CH3:7])[CH2:16][C:15](=[O:20])[CH2:14]1)=[O:4]
Reactant: CC(=O)[O-]
Reactant: CC[C@@H](C)[C@H](CC(C(=O)O)C(=O)O)C(=O)OC
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)[C@H]1CC(=O)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.5 %

Procedure:
3.8 g of (3S, 4R)-3-methoxycarbonyl-4-methylhexane dicarboxylic acid and 1.1 g of sodium acetate were added to 18 ml of acetic anhydride, and the mixture was refluxed for one hour. The reaction mixture was cooled down to room temperature, and then allowed to stand for one hour at 5° C. The resulting precipitate was filtered off, and the filtrate was concentrated. To the residue was added ethyl acetate, and after the insoluble material was filtered off, the filtrate was concentrated. The residue was purified by distillation under a reduced pressure, and thus 2.23 g of the titled compound was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=[O:11])[C:6]=1[CH3:15].[OH-].[Na+].Cl.O>C1COCC1.CO>[CH3:1][C:2]([CH3:17])([CH3:16])[C:3]#[C:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[CH3:15]
Reactant: CCOC(=O)c1noc(C#CC(C)(C)C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)noc1C#CC(C)(C)C

Procedure:
Ethyl 5-(3,3-dimethylbut-1-yn-1-yl)-4-methylisoxazole-3-carboxylate (101 mg, 0.429 mmol) in THF (3 mL) and MeOH (1.800 mL) was treated at room temperature with 2M NaOH (aq) (0.429 mL, 0.859 mmol) for 1 hour. 2M HCl (aq) (0.6 mL) and water were added and the aqueous was extracted with EtOAc. The combined organic extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[C:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:22]2[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:24][CH2:23]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
A mixture of 17 mmol methyl-5-chloropyrazine-2-carboxylate, 18 mmol of N-BOC-piperazine and 20 mmol of K2CO3 in 20 ml of acetonitrile was heated under reflux for 3 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The title compound was recrystallized from ethyl acetate to yield a colorless solid. MS (m/e): 323.4 (MH+, 100%)
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>CN(C)C=O.CN(C1C=CN=CC=1)C>[C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([C:22](=[O:24])[CH3:23])[C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC(=O)N1C(=O)Cc2ccccc21)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)C1C(=O)N(C(=O)NC(=O)c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a stirred slurry of 841 mg (3.0 mmole) of N-benzoyl-2-oxindole-1-carboxamide in 5 ml of N,N-dimethylformamide was added 806 mg (6.6 mmole) of 4-(N,N-dimethylamino)pyridine. Stirring was continued for a few minutes, and then the slurry was cooled in an ice-bath and a solution of 337 mg (3.3 mmole) of acetic anhydride in 2 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for 1 hour, and then the reaction mixture was poured onto a mixture of 65-70 ml. of ice-water and 2.2 ml of 3 N hydrochloric acid. The solid which precipitated was recovered by filtration. It was recrystallized from ethanol to give 385 mg of the title compound as tan crystals, mp 198° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7]O.C(P(CCCC)CCCC)CCC.[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([OH:40])=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl.CCOCC>[ClH:22].[Cl:22][C:23]1[CH:42]=[CH:41][C:26]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:40][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:35]([O:38][CH3:39])[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[C:25]([F:43])[CH:24]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: COCCOCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCCOc1cc2ncnc(Nc3ccc(Cl)cc3F)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A solution of 2-(2-methoxyethoxy)ethanol (90 mg, 0.75 mmol) in methylene chloride (1 ml) was added to tributylphosphine (320 mg, 1.58 mmol) and 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (200 mg, 0.63 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (6 ml) at 0° C. under argon. To the resulting mixture 1,1′-(azodicarbonyl)dipiperidine (400 mg, 1.6 mmol) was added in portions. The mixture was allowed to warm to ambient temperature and stirred under argon for 2 hours. Ether (5 ml) was added, and the precipitated solids were removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was purified by column chromatography eluting with methylene chloride/methanol (90/10). The resulting partially purified product was dissolved in acetone, and ethereal hydrogen chloride (0.6 ml of a 1M solution, 0.6 mmol) added. The resulting precipitated product was collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-methoxyethoxy)ethoxy)quinazoline hydrochloride (128 mg, 44%).
Reaction SMILES: Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[NH2:44])[N:40]([C:45](=[O:52])[C@@H:46]1[CH2:50][CH2:49][CH2:48][N:47]1[CH3:51])[CH2:39][CH2:38][CH2:37]2.[CH3:53][NH2:54].[OH-].[K+]>C1COCC1.C(OCC)(=O)C>[F:18][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][C:7]2[N:16]=[C:3]([NH:44][C:43]3[CH:42]=[C:41]4[C:36]([CH2:37][CH2:38][CH2:39][N:40]4[C:45](=[O:52])[C@@H:46]4[CH2:50][CH2:49][CH2:48][N:47]4[CH3:51])=[CH:35][C:34]=3[O:33][CH3:32])[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]=23)[C:14]=1[C:15]([NH:54][CH3:53])=[O:17]
Reactant: COc1cc2c(cc1N)N(C(=O)[C@@H]1CCCN1C)CCC2
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2nc(Cl)n2c(=O)c4c(F)cccc4nc32)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)[C@@H]2CCCN2C)[nH]c2nccc1-2
Temperature: 65 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (300 mg, 0.63 mmol) and 6-(methyloxy)-1-(1-methyl-L-prolyl)-1,2,3,4-tetrahydro-7-quinolinamine 217 mg, 0.75 mmol) in THF (50 ml) was heated at 65° C. for 4 hrs. The reaction was diluted with ethyl acetate (200 ml) and washed with saturated NaHCO3 (300 ml). Organic layer was removed, concentrated by rotary evaporation, solids triturated from ethyl acetate/hexanes, and dried under house vacuum prior to next step. The solids were then added to THF (50 ml) followed by a solution of methylamine (2M in THF, 7.40 ml, 3.7 mmol) and the resulting mixture was stirred at rt overnight. Next, the crude reaction was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM over 30 min). ESIMS (M+H)+=727. The isolated pure amide was redissolved in 1,4-dioxane (10 ml), potassium hydroxide (2.497 ml, 12.49 mmol) added and the reaction was heated in the microwave at 120° C. for 20 min. The resulting solution was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM) to afford 2-fluoro-N-methyl-6-[(2-{[6-(methyloxy)-1-(1-methyl-L-prolyl)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (0.1 g, 28% over three steps). ESIMS (M+H)+=573; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.98 (m, 6 H) 2.06 (s, 3 H) 2.11-2.20 (m, 1 H) 2.58-2.73 (m, 2 H) 2.78 (d, J=4.41 Hz, 3 H) 2.85-2.97 (m, 1 H) 3.41-3.52 (m, 2 H) 3.88 (s, 3 H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:34])[CH2:30][N+:31]([O-:33])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1.CC(C)=O.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:34])[CH2:30][N+:31]([O-:33])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)C[N+](=O)[O-])cn3C2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: O=C(C[N+](=O)[O-])c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reaction time: 0.17 h
Yield: 87 %

Procedure:
4.7 g of 1-cyclopropyl-6-fluoro-7-(4-t-butoxycarbonylpiperazin-1-yl)-3-(2-nitroacetyl)-1,4-dihydro-4-oxoquinoline obtained from Example 3 was dissolved in 20 ml of trifluoroacetic acid and then stirred for 10 minutes. The solvent was removed, and the solid formed after addition of 50 ml of acetone was filtered and then dried to obtain 4.25 g of the object compound
Reaction SMILES: Cl.[CH2:2]([N:4]=C=NCCCN(C)C)C.[CH:13]([C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([OH:23])=O)[C:16]=1[CH3:24])=[O:14].O[N:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34]C=2N=N1.N1CCC(NC)CC1>O.CN(C=O)C.C(N(CC)CC)C>[NH:26]1[CH2:30][CH2:31][CH:32]([CH2:2][NH:4][C:21]([C:17]2[C:16]([CH3:24])=[C:15]([CH:13]=[O:14])[NH:19][C:18]=2[CH3:20])=[O:23])[CH2:33][CH2:34]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: On1nnc2ccccc21
Agent: CNC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCC1CCNCC1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
1-Ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (268.1 g, 1.4 mol), triethylamine (280.0 mL), 5-formyl-2,4-dimethyl-1H-pyrrole-3-formic acid (167.0 g, 1.0 mol) and 1-hydroxybenzotriazole (189.2 g, 1.4 mol) were added to DMF (500 mL) with stirring at about 0° C. and stirred for 1.5 hrs, then piperidin-4-yl-methylamine (1.2 mol) was added. The reaction was stirred at room temperature until completion was indicated by thin layer chromatography (TLC). 120 mL of water and 100 mL of saturated salt water were added, and the mixture was extracted with 10% methanol/dichloromethane (300 mL×3), the combined organic phase was washed with saturated salt water (300 mL×3), dried over anhydrous Na2SO4, and the solvent was distilled off under reduced pressure. The residue was then chromatographed on silica gel (eluted with methanol/ethyl acetate=1/1) to give 158.3 g (602 mmol) of N-[(piperidin-4-yl)methyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-formamide as an off-white solid. Yield 60.2%.