Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[N:59]1[CH:64]=[CH:63][C:62]([CH2:65][CH2:66][NH2:67])=[CH:61][CH:60]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([NH:67][CH2:66][CH2:65][C:62]3[CH:63]=[CH:64][N:59]=[CH:60][CH:61]=3)=[O:26])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1
Reactant: NCCc1ccncc1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccncc1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (390 mg, 0.982 mmol), 1-hydroxybenzotriazole (221 mg, 1.637 mmol) and EDCI (314 mg, 1.637 mmol) were dissolved in DCM (Volume: 4.0 ml). The suspension was stirred at room temperature for 10 minutes where it turned clear. Hunig's Base (0.286 ml, 1.637 mmol) and 2-(pyridin-4-yl)ethanamine (0.098 ml, 0.819 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was concentrated and triturated with ethyl acetate to afford the product as a white solid. Yield: 328 mg (White solid) 1H-NMR (500 MHz, DMSO-d6) 8.46, 7.91, 7.63, 7.55, 7.34, 7.25-7.18, 7.14-7.06, 6.72, 5.49, 4.54-3.80, 3.32, 3.07-2.77, 2.73, 2.37-2.28, 1.77-1.18.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:10][CH2:11][CH2:12]Cl)=[O:9].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:10][CH2:11][CH2:12][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1)=[O:9]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=S(CCCCl)c1ccccc1Br
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCS(=O)c3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-bromo-2-[(3-chloropropyl)sulfinyl]benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: Anal. Calcd for C24H31BrN2O2S+0.3CHCl3: ESMS m/e: 491.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][C:18]=1F)[C:11](OCC)=[O:12]>>[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]([OH:12])[N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: CCOC(=O)c1ccc(F)c(F)c1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1C(O)c1cccc(F)c1

Procedure:
Prepared from 2-methylimidazole and ethyl 3,4-difluorobenzoate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH2:19][C:20]([CH3:30])([C:26]([O:28][CH3:29])=[O:27])[CH2:21]2.O>N1C=CC=CC=1>[CH3:30][C:20]1([C:26]([O:28][CH3:29])=[O:27])[CH2:21][C:22]2[C:18](=[CH:17][CH:25]=[CH:24][C:23]=2[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:19]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C1(C)Cc2cccc(O)c2C1
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)C1(C)Cc2cccc(OS(=O)(=O)C(F)(F)F)c2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At −15° C., 1.5 ml (8.7 mmol) of trifluoromethanesulfonic anhydride were slowly added dropwise to a solution of 897 mg (4.35 mmol) of methyl 4-hydroxy-2-methyl-2,3-dihydro-1H-indene-2-carboxylate in 20 ml of pyridine. After warming to room temperature, the reaction mixture was stirred for another 2 h. 20 ml of water were then added and, after phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by flash chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 1100 mg (3.25 mmol, 75% of theory) of a colorless oil.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].N[CH2:14][CH2:15][SH:16].Cl>O.C(O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:16][CH2:15][CH2:14][N:12]=2)=[N:9][CH:10]=1)([OH:4])=[O:3]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C2=NCCS2)nc1

Procedure:
Sodium (11 mmol) is added to a flask containing 75 ml of ethanol. As soon as the sodium has dissolved, 10 mmol of 5-carboxy-2-cyanopyridine and 11 mmol of 2-amino-ethanethiol are added and the solution is refluxed for 24 h. The solution is then diluted with 25 ml of water, made acidic (pH=5) with 2N HCl and evaporated. The residue is dissolved in 100 ml of hot chloroform, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. 234°-235° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][N:39]([CH2:2][CH2:3][O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([NH:15][C:16](=[O:30])[C:17]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:20]=[C:19]([F:29])[CH:18]=3)=[CH:7][CH:6]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1CCNCC1
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Product: CCOC(=O)C1CCN(CCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CC1

Procedure:
Compound is prepared from N-[4-(2-chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and piperidine-4-carboxylic acid ethyl ester according to conditions described in general procedure N. 1H NMR 300 MHz (CDCl3) 8.31 (dd, 1H, J=1.2 and 8.4 Hz), 7.88 (s, 1H), 7.83 (d, 1H, J=7.5 Hz), 7.73 (d, 1H, J=8.1Hz), 7.54 (m, 2H), 7.31 (s, 1H), 6.98 (d, 1H, J=7.8 Hz), 6.84 (d, 1H, J=8.4 Hz), 6.76 (d, 1H, J=11.7 Hz), 4.31 (t, 2H, J=5.7 Hz), 4.14 (q, 2H, J=6.9 Hz), 3.28 (m, 4H), 3.05 (m, 2H), 2.97 (t, 2H, J=5.7 Hz), 2.24-2.32 (m, 3H), 1.64-1.97 (m, 10H), 1.25 (t, 3H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:7]([C:8](O)=[O:9])[CH:6]=1)[CH3:2].C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:7]([C:8]([Cl:21])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
To a solution of 5-nitroisophtalic acid monoethyl ester (80 g) in DCM (700 ml) at 25° C. was added 2M oxalyl chloride solution in DCM (63 ml), and DMF (5 ml). The reaction was stirred for 2 h and then concentrated in vacuum. The residue was triturated with toluene and again concentrated in vacuum leaving the title compound (60 g). Rt=1.40 min for derivatised methylester (method D).
Reaction SMILES: [C:1]([NH:5][C:6]([C@@H:8]1[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][NH2:19]>C(O)C>[NH2:19][C@@H:18]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:6]([OH:7])[CH2:8][N:9]1[C@H:8]([C:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:17][C@H:16]2[C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:10]1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: CN
Solvent: CCO
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(A)(ii) A suspension of 26.55 g of N-tert.butyl-2-[2(R) -hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (prepared as described in Example 1) in 100 ml of ethanol was treated with 25 ml of a 30% solution of methylamine in ethanol at room temperature for 1 hour. The mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 250 ml of ethanol, treated with 250 ml of a saturated solution of hydrogen chloride in ethyl acetate and stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous phase was separated, made basic with solid sodium carbonate and then extracted with dichloromethane. The dichloromethane extract was washed with sodium chloride solution and evaporated to dryness. The residue was triturated with diethyl etcher and, after filtration, there were obtained 17.48 g of 2-[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N -tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 402 [M+H]+.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[F:10][C:11]([F:25])([F:24])[C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:15]Br.C(O)C>O>[F:10][C:11]([F:24])([F:25])[C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1)[CH2:15][N:5]1[C:6](=[O:8])[CH2:7][S:3][C:4]1=[O:9]
Reactant: O=C1CSC(=O)N1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1CSC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
5N Aqueous sodium hydroxide (0.5 mL) was added to a mixture of 2,4-thiazolidinedione (198.7 mg, 1.69 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.50 g, 1.63 mmol) and ethanol (5 mL), and the mixture was refluxed for 4 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (405.6 mg, 72.5%) as a white crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[C:24]([CH3:31])[CH:23]=3)[CH2:18]2)[CH:13]=[C:14]([Cl:16])[CH:15]=1>N1C=CC=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([C:19]3[CH2:18][C:17]([C:12]4[CH:13]=[C:14]([Cl:16])[CH:15]=[C:10]([Cl:9])[CH:11]=4)([C:32]([F:35])([F:34])[F:33])[O:21][N:20]=3)=[CH:23][C:24]=2[CH3:31])=[N:7][CH:6]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Cl
Reactant: Nc1ncc(Br)cn1
Solvent: c1ccncc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncc(Br)cn1
Yield: 70 %

Procedure:
In a solution of 2.87 g of 2-amino-5-bromopyrimidine in 40 mL of pyridine, 6.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl-chloride synthesized in Step 4 of Synthetic Example 1 was added at room temperature with stirring, and stirred at the same temperature for 2 days. The solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of 1,4-dioxane, a solution of 3.09 g of potassium hydroxide in 30 mL of water was added and stirred at room temperature for 3 hours. After the completion of the reaction, 20 mL of hydrochloric acid was added in the reaction mixture under cooling with ice and with stirring, extracted with ethyl acetate (50 mL×1), the organic phase was washed with 50 mL of 3N hydrochloric acid, and dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with neutral alumina column chromatography that was eluated with chloroform to obtain 5.52 g of the aimed product as white crystal.
Reaction SMILES: C1(C)C=CC=CC=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]#[N:18])=[CH:11][CH:10]=1.[C:19](OCC)(=[O:22])[CH2:20][CH3:21]>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([C:19](=[O:22])[CH2:20][CH3:21])[C:17]#[N:18])=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC
Reactant: N#CCCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(=O)C(C#N)Cc1ccc(Br)cc1
Reaction time: 0.33 h

Procedure:
A 1.7 M solution of potassium tert. pentylate in toluene (81 ml, 139 mmol) was added dropwise to a solution of 3-(4-bromo-phenyl)-propionitrile (9.70 g, 46.2 mmol) in 200 ml of THF at rt, followed by addition of ethyl propionate (18.9 ml, 185 mmol). Stirring was continued for 20 min. The reaction mixture was quenched by careful addition of 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2 SO4 and evaporated. The residue was purified by column chromatography (silica gel, EtOAc/n-hexane 3:7) to yield 1 as a yellow oil.
Reaction SMILES: I[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([S:12][CH3:13])[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:13][S:12][C:4]1[N:3]=[C:2]([C:34]#[C:33][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CSc1ncc(C(F)(F)F)c(I)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccccc1C#Cc1nc(SC)ncc1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 68.7 %

Procedure:
4-Iodo-2-(methylthio)-5-(trifluoromethyl)pyrimidine (I14) (2.00 g, 6.24 mmol), PdCl2(PPh3)2 (438 mg, 625 μmol), CuI (119 mg, 625 μmol) and triphenylphosphine (164 mg, 625 μmol) were placed into an oven dried microwave reaction vial under nitrogen. Methyl 2-(2-ethynylphenyl)acetate (I4) (1.31 g, 7.49 mmol), THF (20 mL) and TEA (10 mL) were added and the resulting mixture was stirred at 100° C. under microwave irradiation for 10 minutes. The volatiles were evaporated under reduced pressure then the residue was adsorbed onto silica from DCM. The pre-adsorbed material was chromatographed on silica gel (0-25% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I64) (1.571 g, 69%) as an orange solid; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J=0.8 Hz, 1H), 7.68 (dd, J=7.7, 1.1 Hz, 1H), 7.50-7.29 (m, 3H), 3.93 (s, 2H), 3.71 (d, J=3.4 Hz, 3H), 2.62 (d, J=3.4 Hz, 3H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.O>CN(C)C=O>[Br:3][C:4]1[C:9]([O:10][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: BrC1CCCC1
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ncccc1OC1CCCC1
Yield: 60 %

Procedure:
Sodium hydride (160 mg) was dissolved in dimethylformamide (5 ml) and 2-bromo-3-pyridinol (500 mg) dissolved in dimethylformamide is slowly added dropwise. Then, bromocyclopentane (0.63 ml) was added to the solution and reacted for 5 hours at room temperature. Water was added to the suspension to dilute and extracted with ethyl acetate to separate an organic layer. The separated organic layer was dried with anhydrous magnesium sulfate and distilled under reduced pressure. As a result, 2-bromo-3-cyclopentyloxy pyridine (480 mg, yield: 60%) was obtained as an oil phase.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:47])[N:5]1[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:32][CH3:33])=[N:14][C:13]3[N:34]([S:37]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)(=[O:39])=[O:38])[CH:35]=[CH:36][C:12]=3[C:6]1=[N:7]2.[OH-].[NH4+:49]>O1CCCC1.CCOC(C)=O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:7][C:6]2[C:12]3[CH:36]=[CH:35][N:34]([S:37]([C:40]4[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=4)(=[O:38])=[O:39])[C:13]=3[N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]([CH3:31])[CH3:30])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[O:32][CH3:33])[N:5]=2)[C:3]=1[C:4]([NH2:49])=[O:47]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c2nc3cccc(F)c3c(=O)n12
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cccc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Reaction time: 24 h
Yield: 80 %

Procedure:
To a solution of 8-fluoro-5-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (7.6 g, 11.6 mmol) in tetrahydrofuran (350 mL) was added 27% ammonium hydroxide (500 mL). The resulting biphasic mixture, was rapidly stirred for 24 hours, at which time no starting material was evident by TLC/LCMS. Three such reactions were combined, diluted with EtOAc, and the organic layers washed with saturated sodium chloride, dried over sodium sulfate, and taken to a residue under reduced pressure to give 2-fluoro-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (19.3 g, 28.7 mmol, 80% Yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.36 (s, 1 H), 8.04 (d, J=8.2 Hz, 1 H), 7.87-7.99 (m, 4 H), 7.79 (br. s., 2 H), 7.26-7.47 (m, 4 H), 6.87-7.06 (m, 1 H), 6.63 (d, J=2.4 Hz, 1 H), 6.47-6.58 (m, 2 H), 3.70-3.85 (m, 3 H), 3.05-3.19 (m, 4 H), 2.66 (quin, J=6.5 Hz, 1 H), 2.54-2.63 (m, 4 H), 2.32 (s, 3 H), 1.00 (d, J=6.6 Hz, 6 H). ESIMS (M+H)+=673.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=2[C:28]2[CH:29]=[C:30]([C:33]([F:35])([F:36])[F:34])[CH:31]=[CH:32][C:27]=2[F:26])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Reactant: OB(O)c1cc(C(F)(F)F)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 53 %

Procedure:
To a stirred solution of 66.61 (0.7595 g, 2.007 mmol) in DMF (5 mL) at 23° C. was added 2-fluoro-5-(trifluoromethyl)phenylboronic acid (commercially available from Aldrich Chemical Company, Inc.) (0.8352 g, 4.017 mmol) and potassium carbonate (0.8357 g, 6.047 mmol) followed by tetrakis(triphenylphosphine)palladium (0.2364 g, 0.2046 mmol). The mixture was heated to 90° C. After 17 hours, LCMS-showed that the reaction was complete. The mixture was cooled to room temperature and then diluted with water. After extracting three times with EtOAc, the mixture was concentrated in vacuo and then purified on silica gel (0%-10% EtOAc/hexane) to afford 66.53A as a clear oil that was used without further purification (414.2 mg, 53% yield).
Reaction SMILES: F[C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C@@H:14]2[CH2:16][C@@H:15]2[F:17])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([NH:29][C:30]1([C@@H:34]2[CH2:38][CH2:37][NH:36][CH2:35]2)[CH2:33][CH2:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C>CS(C)=O>[C:22]([O:26][C:27]([NH:29][C:30]1([C@@H:34]2[CH2:38][CH2:37][N:36]([C:2]3[C:11]([O:12][CH3:13])=[C:10]4[C:5]([C:6](=[O:21])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]4[C@@H:14]4[CH2:16][C@@H:15]4[F:17])=[CH:4][CH:3]=3)[CH2:35]2)[CH2:31][CH2:32][CH2:33]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CCC1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CCC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 80 °C
Reaction time: 112 h

Procedure:
A mixture of 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (290 mg, 0.98 mmol), 3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidine (283 mg, 1.18 mmol), triethylamine (0.409 ml, 2.94 mmol), and dimethyl sulfoxide (5 ml) was stirred for 112 hours while heating in an oil bath at 80° C. under an argon-replaced atmosphere. After evaporating the solvent, the residue was partitioned in chloroform (50 ml) and 10% aqueous citric acid solution (30 ml), and after separating the organic layer, the organic layer was washed with saturated saline solution (30 ml). The organic layer obtained was then dried over anhydrous sodium sulfate, and after removing the drying agent by filtration, the solvent was evaporated under a reduced pressure. The residue was subject to a silica gel chromatography and a crude 7-{3-(R)-[1-(tert-butoxycarbonylamino)cyclobutyl]pyrrolidin-1-yl}-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was thereby obtained from a chloroform:methanol=20:1 eluate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14](O)[CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[N:17]1([CH:14]2[C:15]3[C:10](=[N:9][C:8]4[C:3]([C:2]=3[NH2:1])=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:11][CH2:12][CH2:13]2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: Nc1c2c(nc3ccccc13)CCCC2O
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: Nc1c2c(nc3ccccc13)CCCC2N1CCOCC1
Reaction time: 8 h

Procedure:
9-Amino-1,2,3,4-tetrahydroacridin-1-ol (15.0 g) was refluxed in 1000 ml of toluene that contained 12.18 g of morpholine and 9.285 g of benzaldehyde that had been freshly washed in K2CO3. The reaction mixture wasrefluxed overnight and allowed to cool. It was then filtered off and the crude product was purified by flash chromatography (20% PrOH/EtOAc) to give 2.20 g of analytically pure product after recrystallization from benzene/pentane, m.p. 215°-217°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([NH:7][NH2:8])=[O:6].C(Cl)Cl.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=S)=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]2[O:6][C:5]([C:4]3[CH:3]=[C:2]([NH2:1])[C:11]([NH2:12])=[CH:10][CH:9]=3)=[N:7][N:8]=2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1ccc(N=C=S)cc1
Reactant: NNC(=O)c1ccc(N)c(N)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccc(-c2nnc(Nc3ccc(C(F)(F)F)cc3)o2)cc1N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a 30 mL vial was added 0.5 g (3.01 mmol) of 3,4-diaminobenzhydrazide, 25 mL of DCM, and 0.61 g (3.01 mmol) of 4-trifluoromethyl-phenyl isothiocyanate. Allowed to stir at r.t. for 72 h. The pink suspension was concentrated in vacuo and used directly in the next reaction. MS (m/z) 370.0 M (+1), tR=1.10, Meth 10. To 20 mL scint vial was added 1.03 g (2.61 mmol) of the crude, 10 mL of DMF, and 0.55 g (2.87 mmol) of EDCI. Allowed to stir at 60° C., for 3 h. Added water, and filtered off solid. Used directly in next reaction. MS (m/z) 336.0 M (+1), tR=1.24, Meth 10