Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:24])[CH:16]([CH3:23])[CH2:17][C:18]([O:20]CC)=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:24])[CH:16]([CH3:23])[CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CC(=O)O)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A mixture of the product of STEP 1 (45 g), ethanol (15 mL) and 15% aqueous NaOH (70 mL) was stirred at 23° C. for 30 minutes. The volatiles were removed in vacuo and the residue was acidified to pH=3. The precipitated solid was filtered and dried to give the above product as a white solid (40 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].N#N>CN(C=O)C.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.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]=1[C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[F:21]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(Cl)c1
Temperature: 100 °C

Procedure:
A mixture of ethyl 3-chloro-4-(trifluoromethylsulfonyloxy)benzoate T2.4 (3.00 g, 9.02 mmol), 2-fluoro-5-methoxyphenylboronic acid (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (1.84 g, 10.8 mmol), tetrakis(triphenylphosphine)palladium (0.521 g, 0.451 mmol) and potassium carbonate (2.49 g, 18.0 mmol) in DMF (20 mL), was purged with N2 three times and then heated at 100° C. for 4 hours. The reaction was cooled to room temperature, and EtOAc (130 mL) was added. The mixture was then washed with brine (30×4 mL). The organic layer was dried over MgSO4. The residue was purified by CombiFlash® silica gel column chromatography (eluent with hexane/EtOAc; 85/15) to give T2.5. 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, 1H), 7.90 (d, 1H), 7.33 (dd, 1H), 6.96-7.02 (m, 1H), 6.82-6.85 (m, 1H), 6.74 (d, 1H), 4.33 (q, 2H), 4.31 (s, 3H), 1.34 (t, 3H). MS ESI (pos.) m/e: 309.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12]Cl)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:32]2[S:33][CH:34]=[CH:35][C:36]=2[CH3:37])[CH2:27][C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(C)=O>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([CH2:12][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH:26]([C:32]4[S:33][CH:34]=[CH:35][C:36]=4[CH3:37])[CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)CC(c1ccc(O)cc1)c1sccc1C
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1ccsc1C(CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Benzyl chloride 2.3 (113 mg, 0.434 mmol) and phenol 54.1 (100 mg, 0.362 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50° C. for 16 h, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% to 60% ethyl acetate in hexanes). Eluant containing desired compound was concentrated and dissolved in a THF/MeOH/2N LiOH(aq) (1:1:1) solution (2 mL). The mixture was stirred at room temperature for 90 min., the solution was poured into 0.65 N HCl(aq.) (2 mL). The aqueous phase was extracted with dichloromethane (3×10 mL) and the combined organic phases were dried over Na2SO4. After filtration and drying, 154 mg (0.311 mmol) of carboxylic acid 54 was obtained. 1H NMR (400 MHz) (CDCl3) δ 7.43-7.70 (m, 8H), 7.21 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=5.0 Hz), 6.92 (d, 2H, J=8.6 Hz), 6.76 (d, 1H, 5.0 Hz), 5.09 (s, 2H), 4.74 (t, 1H, J=7.8 Hz), 3.05 (d, 2H, J=7.8 Hz), 2.15 (s, 3H).
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4](=[CH2:9])[C:5]([O:7][CH3:8])=[O:6]>CO>[CH3:9][CH:4]([CH2:3][NH:2][CH3:1])[C:5]([O:7][CH3:8])=[O:6]
Reactant: CN
Reactant: C=C(C)C(=O)OC
Solvent: CO
Product: CNCC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 72 h

Procedure:
To a solution of 12.4 g of methylamine in 45 ml of methanol was added with stirring and ice-water cooling a solution of 60.2 g of methyl 2-methylacrylate in 40 ml of methanol over a period of 1 hour. The mixture was allowed to stand at room temperature for 3 days, was evaporated and the residue was distilled at aspirator pressure to give the methyl 2-methyl-3-methylaminopropionate, bp. 57°-59° C./15 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Br[C:12]1[N:16]2[N:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[N:20][C:15]2=[N:14][CH:13]=1>>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:18]=[N:17][N:16]2[C:12]([C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=3)=[CH:13][N:14]=[C:15]2[N:20]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Product: Nc1cccc(-c2cnc3nc(C(F)(F)F)cnn23)c1
Yield: 40.4 %

Procedure:
This reaction was carried out as in Example 6, step b, using a mixture of 3-aminophenylboronic acid (290 mg, 1.87 mmol) and 7-bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (250 mg, 0.93 mmol). The residue was purified by flash chromatography (silica gel, 35% EtOAc/isohexane) to give 105 mg (41%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 3.87 (2H, br s), 6.80 (1H, ddd, J 7.9, 2.4, 0.8 Hz), 7.34 (1H, t, J 7.9 Hz), 7.46-7.43 (2H, m), 8.57 (1H, s), 8.77 (1H, s); MS (ES+) m/z 280 [M+H]+.
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7](Cl)[CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([CH3:3])[CH3:2].[C:15]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([C:22]3[CH:23]=[CH:24][C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=3)[CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: CC(C)C1Cc2cccc(Cl)c2C1=O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: CC(C)C1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Temperature: 80 °C
Yield: 97.3 %

Procedure:
28.0 g of 2-isopropyl-7-chloro-1-indanone, 28.64 g of 4-tert-butylphenylboronic acid, 35.56 g of sodium carbonate, 302 ml of ethylene glycol and 21.6 ml of water are placed in a reaction vessel. The mixture is degassed a number of times by careful application of an oil pump vacuum and subsequent admission of argon, and thus saturated with argon. It is heated to 80° C. and a freshly prepared catalyst solution comprising 60.23 mg of palladium acetate and 1.79 ml of an aqueous TPPTS solution (0.6 molar) in 25 ml of water is then added while stirring vigorously and the reaction mixture is refluxed for 5 hours with further stirring until completely reacted. After cooling to room temperature, 300 ml of water are added. After renewed cooling to room temperature, the ethylene glycol phase is washed 6 times with a total of 900 ml of toluene. The combined toluene phases are washed twice with a total of 250 ml of sodium chloride solution and dried over 150 g of sodium sulfate. Removal of the solvent on a rotary evaporator, drying of the residue and subsequent distillation in an oil pump vacuum gives 40 g (97%) of 2-isopropyl-7-(4′-tert-butylphenyl)-1-indanone as an orange-brown, viscous oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:13]([CH:14](O)[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:12][CH:11]=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:66]=[N+:67]=[N-:68])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:66]([CH:14]([C:13]1[N:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:10]=[CH:11][CH:12]=1)[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:67]=[N-:68]
Reactant: CCC(CC)C(O)c1ccnn1OCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1ccnn1OCc1ccccc1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To a stirred mixture of 1-[1-(benzyloxy)-1H-pyrazol-5-yl]-2-ethylbutan-1-ol (0.492 g, 1.79 mmol) in THF (17 mL) at 0° C. under a nitrogen atmosphere was added triphenyl phosphine (0.705 g, 2.69 mmol) followed by diethyl azodicarboxylate (0.42 mL, 2.7 mmol). Diphenyl phosphoryl azide (0.58 mL, 2.7 mmol) was then added over 4 min. The mixture was allowed to attain ambient temperature and stirred for 16 h. The solvent was then evaporated in vacuo producing a crude oil which was purified on a Biotage column (hexane/ethyl acetate, 9:1). This afforded the product as a clear colorless oil (0.36 g, 67%). Mass Spectrum (+ESI): 300 (M+H)+.
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:37]([O:39][CH3:40])=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(OCC1C=CC=CC=1)=O)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O>CO>[NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:18]([NH:20][C@H:21]([C:37]([O:39][CH3:40])=[O:38])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 145.8 %

Procedure:
Dilysine 10 (7.43 g, 0.0113 mol) was dissolved in MeOH (100 mL). After being purged with nitrogen, 10% Pd/C (0.30 g) was added. The flask was then purged with hydrogen and the reaction mixture was stirred for overnight. The Pd/C was removed by filtration through a pad of celite. Trifluoroacetic acid (TFA, 1.8 mL, 0.023 mol) was added into the filtrate and then the solvent was removed in vacuo to give viscous oil. A white gluey substance was obtained by triturating with 20 mL diethyl ether. The resulting substance was dried in vacuo to give the glassy solid product 11 (6.4 g, 92%): 1H NMR (500 MHz, d6 DMSO) δ 8.19 (d, J=7.5, 1 H), 7.90 (br s, 6H), 6.82 (d, J=8.0, 1 H), 4.23 (m, 1H), 3.91 (m, 1H), 3.61 (s, 3H), 2.75 (m, 4H), 1.36-1.61 (m, 21H); 13C NMR (125 MHz, d6 DMSO) δ 172.4 (2), 158.4 (q, 2), 155.3, 117.2 (q, 2), 78.0, 53.9, 51.6, 38.7, 38.6, 31.2, 30.3, 28.1 (3), 26.7, 26.5, 22.3, 22.2; HRMS (FAB) m/z calcd for C22H38F6N4O9 (M+H)+ 389.2764, found 389.2767.
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([CH2:10]P(=O)(OCC)OCC)#[N:9].[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[C:29]([CH:44]=O)=[CH:30][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:32][CH:33]=1>O>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=2)=[CH:30][C:29]=1[CH:44]=[CH:10][C:8]#[N:9]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=CC#N)c2)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under a nitrogen atmosphere, to a mixture of sodium hydride (60%, 133 mg) and THF (20 mL) was added diethyl cyanomethylphosphonate (0.54 mL) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the reaction mixture was added 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)biphenyl-2-carbaldehyde (1.03 g) obtained in Example 93, step 2, and the mixture was stirred at 50° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give a crude product of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:18][C:17](/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>>[CH:20]1([C:19]2[N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[N:16]=[C:17](/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29])[CH:18]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)/C=C/c1cc(C2CCCCC2)n(-c2ccc(OCc3ccccc3)cc2)n1
Agent: ClB(Cl)Cl
Product: COC(=O)/C=C/c1cc(C2CCCCC2)n(-c2ccc(O)cc2)n1
Yield: 89.4 %

Procedure:
According to the procedure for preparation of 3.1, debenzylation of 9.5 (100 mg, 0.240 mmol) with BCl3 (1.20 mmol) to yielded 70 mg (90%) of 9.7. MS (ESI) 653.7 (2MH+); (2M+Na+).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:30])[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccnc2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(c2cccnc2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535.0 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonic acid amide (1.7 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A19. A solution of 4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (231.2 mg, 0.82 mmol) and 1,1′-carbonyldiimidazole (442.0 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B19. Solution B19 was added to Solution A19 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid (4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-amide (94.7 mg, 30%) as a white solid: MS (ESI) M+1=386.2.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N:23]([CH3:25])[CH3:24])[CH:20]=3)[C:15]2=[O:26])=[CH:10][CH:9]=1)C.[OH-].[Na+].Cl>C(O)C>[CH3:25][N:23]([CH3:24])[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:26])[N:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3])=[CH:9][CH:10]=1)[CH2:22]2
Reactant: CCOC(=O)CCCc1ccc(N2Cc3cc(N(C)C)ccc3C2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc2c(c1)CN(c1ccc(CCCC(=O)O)cc1)C2=O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 4-[4-(5-dimethylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid ethyl ester (0.13 g, 0.35 mmol) obtained in Example 33 in ethanol (15 ml) was added with 0.5 M NaOH aq. (3.3 ml), and the mixture was stirred at room temperature for 10 hours. The reaction solution was made acidic by adding 10% hydrochloric acid, and then extracted with chloroform. The chloroform layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1) and recrystallization (ethanol) to obtain 4-[4-(5-dimethylamino-1-oxo-1,3-dihydro-isoindol-2-yl)-phenyl]-butyric acid (Compound 16) as a pale brown powdery substance (79.4 mg, yield: 66.7%).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:17][CH3:18])(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[N:6]([CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[Cl:19])[C:5]=1[CH2:17][CH3:18])(=[O:3])[CH3:2]
Reactant: Clc1ccccc1CBr
Reactant: CCc1[nH]c2cc(C(=O)OC)ccc2c1C(C)=O
Product: CCc1c(C(C)=O)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl

Procedure:
Methyl 3-acetyl-1-(2-chlorobenzyl)-2-ethylindole-6-carboxylate (170 mg) was prepared from methyl 3-acetyl-2-ethylindole-6-carboxylate (100 mg) and 2-chlorobenzyl bromide (0.06 ml) in a similar manner to that of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:25])[N:16]4[CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:12]([C:26]([O:28]CC)=[O:27])[N:11]=3)[C:6]=2[CH:31]=1>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:25])[N:16]4[CH:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:12]([C:26]([OH:28])=[O:27])[N:11]=3)[C:6]=2[CH:31]=1
Reactant: CCOC(=O)c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1
Agent: Cl
Product: O=C(O)c1nc(-n2cnc3ccc(F)cc32)nc2c1[nH]c(=O)n2C1CCOCC1

Procedure:
A solution of ethyl 2-(6-fluoro-1H-benzo[d]imidazol-1-yl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxylate (600 mg, 1.41 mmol) in concentrated aqueous HCl (15 mL) was heated at 100° C. for 6 h. The mixture was concentrated and the residue triturated with diethyl ether. The solid formed was filtered and dried to give 7 as an off white solid. Yield: 410 mg, 73%. 1H NMR (400 MHz, DMSO-d6) δ, ppm: 11.84 (s, 1H), 9.20 (s, 1H), 8.47 (dd, J=2.4, 2.4 Hz, 1H), 7.82 (dd, J=5.2, 4.8 Hz, 1H), 7.26 (m, 1H), 4.63 (m, 1H), 4.04 (q, J=3.6 Hz, 2H), 3.51 (t, J=11.6 Hz, 2H), 2.60-2.54 (m, 2H), 1.80 (d, J=9.8 Hz, 2H); LCMS (EI) m/z 399 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[CH2:15]O)[N:3]=1.CCN(S(F)(F)[F:23])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[CH2:15][F:23])[N:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCC1COCCN1Cc1nccc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCC1COCCN1Cc1nccc(Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
{4-[(4-Chloropyrimidin-2-yl)methyl]morpholin-3-yl}methanol (200 mg, 0.821 mmol) was taken up in DCM (4 mL) and cooled to 0° C. DAST (0.119 mL, 0.903 mmol) was added and the resulting mixture stirred at 0° C. for 90 minutes. Saturated NaHCO3 was added and the products extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by silica gel chromatography (12-100% EtOAc-hexanes) followed by HPLC (10-40% MeCN—H2O) gave the title compound as a pale yellow gum.
Reaction SMILES: [NH2:1][CH:2]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)[CH2:3][CH3:4].Cl[C:16]1[C:21]([Cl:22])=[C:20]([CH2:23][CH3:24])[N:19]=[CH:18][N:17]=1.C(N(CC)CC)C>C(O)(C)C>[Cl:22][C:21]1[C:16]([NH:1][CH:2]([CH:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6]2)[CH2:3][CH3:4])=[N:17][CH:18]=[N:19][C:20]=1[CH2:23][CH3:24]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: CCC(N)C1CCc2ccccc2N1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCc1ncnc(NC(CC)C2CCc3ccccc3N2)c1Cl
Temperature: 80 °C
Yield: 70.8 %

Procedure:
Example P-1:1.3 g of 2-(1-aminopropyl)-1,2,3,4-tetrahydro-quinoline, 1.4 g of 4,5-dichloro-6-ethylpyrimidine and 0.85 g of triethylamine in 60 ml of absolute isopropanol are placed in a sulfonation flask at room temperature. The internal temperature of the flask is increased to 80° C. and the reaction mixture is stirred under reflux for 12 hours. The solvent is then removed under a water-jet vacuum, the residue is taken up in a mixture of 200 ml of ethyl acetate and 70 ml of water andthe mixture is shaken well. The organic phase is removed and the aqueous phase is further extracted twice, each time with 100 ml of ethyl acetate. The organic phase is dried over Na2SO4 and the solvent is removed under a water-jet vacuum. The crude product which remains can thenbe further purified by flash chromatography on silica gel (eluant: ethyl acetate/n-hexane 1:3) to yield 1.6 g of 2-[1-(5-chloro-6-ethylpyrimidin-4-ylamino)propyl]-1,2,3,4-tetrahydro-quinoline in the form of a red oil (nD50 =1.5822).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[CH:23]([CH3:25])[CH3:24].[CH3:26][NH:27][CH2:28][CH3:29]>>[CH2:28]([N:27]([CH3:26])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([CH:23]([CH3:25])[CH3:24])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:29]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(C(C)C)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(C(C)C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-6-isopropyl-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-methylethanamine in step E. MS (ESI): predicted mass calcd. for C18H20FN5O2, 357.2
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.Br[C:42]1[CH:47]=[C:46]([N+:48]([O-:50])=[O:49])[CH:45]=[CH:44][C:43]=1[O:51][CH3:52].[CH3:53][NH:54][CH2:55][CH2:56][N:57]([CH3:59])[CH3:58]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:52][O:51][C:43]1[CH:44]=[CH:45][C:46]([N+:48]([O-:50])=[O:49])=[CH:47][C:42]=1[N:54]([CH3:53])[CH2:55][CH2:56][N:57]([CH3:59])[CH3:58]
Reactant: CNCCN(C)C
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1N(C)CCN(C)C
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.8 %

Procedure:
An oven-dried flask was charged with cesium carbonate (2.28 g, 7 mmol, 1.4 eq), Pd(OAc)2 (79 mg, 0.35 mmol, 0.07 eq), and X-phos (238 mg, 0.5 mmol, 0.1 eq) under nitrogen. 2-bromo-1-methoxy-4-nitrobenzene (1.16 g, 5 mmol, 1 eq), N1, N2, N2-trimethylethane-1,2-diamine (613 mg, 6 mmol, 1.2 eq) and toluene (20 mL, 0.25 M) were added, and the mixture was heated to 100° C. with stirring overnight. The reaction mixture was cooled to room temperature and concentrated. The crude product was then purified by flash chromatography on silica gel to give N1-(2-methoxy-5-nitrophenyl)-N1, N2, N2-trimethylethane-1,2-diamine (2) (340 mg, 1.34 mmol, 27%).