Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[S:8][C:7]2[S:9][C:10]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:11][C:6]=2[CH:5]=1)(O)=O.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[S:9]1[C:7]2[S:8][CH:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[C:12]([C:14]1[CH:15]=[C:16]([CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: CCCCC(C(=O)O)c1cccc(C(=O)c2cc3cc(C(=O)O)sc3s2)c1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: CCCCC(C(=O)O)c1cccc(C(=O)c2cc3ccsc3s2)c1
Temperature: 165 °C
Yield: 106 %

Procedure:
2-{3-(5-Carboxy-thieno[2,3-b]thien-2-yl)carbonyl-phenyl}hexanoic acid (12.5 g) and copper powder (1 g) are suspended in quinoline (100 cc) and heated at 165° C. for 35 minutes. The reaction mixture is then heated to 190° C. over a period of 10 minutes, then cooled, poured into a mixture of 12N concentrated aqueous hydrochloric acid (120 cc) and distilled water (400 cc), and extracted three times with methylene chloride (total 300 cc). The combined methylene chloride phases are washed twice with a 2N aqueous solution of hydrogen chloride (total 60 cc), then three times with distilled water (total 90 cc), dried over anhydrous sodium sulphate in the presence of decolourizing charcoal (0.5 g), filtered and evaporated. Crude 2-{3-(thieno[2,3-b]thien-2-yl)carbonyl-phenyl}hexanoic acid (11.8 g) is thus obtained.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1-c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.153 mmol) and 2-methyl-phenylboronic acid (23 mg, 0.168 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.92 (dd, 1H), 8.19 (d, 1H), 8.13 (m, 3H), 8.00, (d, 2H), 7.86 (d, 1H), 7.49 (d, 2H), 7.36 (dd, 1H), 7.29 (m, 4H), 2.30 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24](Cl)=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1.[F-].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[C:1]([O:5][C:6](=[O:32])[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(COc3ccc(Cl)c(C(F)(F)F)c3)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCN1CCc2cc(COc3ccc(-c4ccccc4)c(C(F)(F)F)c3)ccc2C1
Temperature: 120 °C

Procedure:
A microwave vial is charged with 3-[6-(4-chloro-3-trifluoromethyl-phenoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid tert-butyl ester (56 mg, 0.119 mmol), phenylboronic acid (17 mg, 1.2 eq.), Pd(OAc)2 (1.3 mg, 5 mol %), (dicyclohexylphosphino)biphenyl (4.2 mg, 10 mol %), KF (21 mg, 3 eq.), and THF (0.25 mL). The resulting mixture is heated to 120° C. using microwave irradiation for 20 minutes. The mixture is filtered through celite. The celite is washed with EtOAc several times. The filtrate is then concentrated to give a dark oil. The mixture is purified by column chromatography (silica gel, EtOAc/Hexane, gradient) to give 3-[6-(2-trifluoromethyl-biphenyl-4-yloxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([O:13]CC)=[O:12].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1nc2ccccn2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)nc2ccccn12
Reaction time: 1 h

Procedure:
To a solution of compound 1-C (0.842 g, 4.12 mmol) in MeOH (10 mL) was added 3N NaOH (2.75 mL, 8.25 mmol) and the reaction mixture was refluxed for 18 h. The reaction mixture was cooled and the solvent evaporated under reduced pressure. The crude residue was dissolved in H2O and neutralized with 1N HCl to pH ˜7. The aqueous phase was evaporated to dryness under reduced pressure, and the resultant white solid was suspended in EtOH (20 mL) and stirred for 1 h. The solid was filtered and washed with EtOH. The solvent was evaporated under reduced pressure to afford compound 1-D as a white solid (0.793 g, 90%). 1H-NMR (CD3OD): δ 8.77-8.79 (t, 1H), 8.08-8.12 (m, 1H), 7.91-7.94 (m, 1H), 7.59-7.62 (m, 1H), 2.94 (s, 3H); MS: m/z 177.1 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([I:19])[C:3]=1[NH2:4].[Cl:20][C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].O>CN1C(=O)N(C)CC1>[Cl:20][C:21]1[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:4][C:3]1[C:2]([I:1])=[CH:8][C:7]([C:9]([F:18])([C:10]([F:13])([F:12])[F:11])[C:14]([F:15])([F:16])[F:17])=[CH:6][C:5]=1[I:19])=[O:24]
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1I
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1I)c1cccc([N+](=O)[O-])c1Cl
Temperature: 135 °C
Reaction time: 3 h
Yield: 103.5 %

Procedure:
To a solution of 40.0 g (78.0 mmol) of 2,6-diiodo-4-(heptafluoropropan-2-yl)aniline in 100 ml of DMI was added 20.6 g (94.0 mmol) of 2-chloro-3-nitrobenzoyl chloride, followed by stirring at 135° C. for 3 hours. After cooling to room temperature, the reaction mixture was poured into 1000 ml of water. After extraction with the addition of 1000 ml of ethyl acetate, the organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was washed with hexane to prepare 56.2 g (yield 99%) of a target compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([CH:18]([F:20])[F:19])[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>C(O)C>[C:7]([C:11]1[N:16]=[C:15]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:14]=[C:13]([CH:18]([F:19])[F:20])[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1nc(Cl)cc(C(F)F)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: CC(C)(C)c1nc(C(F)F)cc(N2CCNCC2)n1
Temperature: 78 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
6.3 g of piperazine (73.5 mmol) were dissolved in 50 ml of ethanol. 2.31 g of 2-tert-butyl-4-chloro-6-difluoromethyl-pyrimidine (10.5 mmol) were added and the mixture was stirred for 3 h at 78° C. The solvent was evaporated and the residue was added slowly to 100 ml of water. After cooling, the pH was adjusted to 12 with 2 N aqueous sodium hydroxide, and aqueos layer was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and the solvent was evaporated to yield 2.34 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21]>CN(C)C=O>[CH2:26]([O:25][C:23]([CH2:22][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[CH3:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:24])[CH3:27]
Reactant: CCOC(=O)CN=C=O
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)Nc1ccc(S(=O)(=O)Nc2onc(C)c2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
4-amino-N-(3,4-dimethyl-5-isoxazolyl)benzenesulfonamide (545 mg, 2.0 mmol) was dissolved in dry dimethylformamide (10 ml). Ethyl isocyanatoacetate (463 ml, 4.0 mmol) was added. The reaction was stirred at room temperature for 3 h and then heated at 80° C. for an additional 8 h. Dimethylformamide was removed under reduced pressure and the residue was recrystallized from acetonitrile/water to give 807 mg (90% yield) brownish solid, m.p. 115°-125° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].[ClH:19].[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH:22]([CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1)=[O:30])[CH2:21]2>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:19].[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH:22]([CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:34][CH:33]=1)=[O:30])[CH2:21]2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C(CC1CN2CCC1CC2)Nc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
61.3 mg (0.37 mmol) of 3-nitrophenylboronic acid, 0.5 ml (1.0 mmol) of 2M aqueous sodium carbonate solution and 12.2 mg (0.02 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride are added to a solution of 120 mg (0.33 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(4-bromophenyl)acetamide hydrochloride in 2 ml of DMF. The reaction mixture is stirred at 80° C. for 14 h, cooled, filtered through kieselguhr and then purified by preparative HPLC. The product fractions are concentrated, taken up in a 5:1 mixture of methanol and 1M hydrochloric acid and again concentrated. Drying under high vacuum results in 13 mg (9.7% of theory) of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10]O.CS(OS(C)(=O)=O)(=O)=O.CCN(C(C)C)C(C)C.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[F:30])[CH2:42][CH2:41]1
Reactant: OCc1cc2ccccc2s1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccccc1N1CCN(Cc2cc3ccccc3s2)CC1

Procedure:
The product from Example 8A (150 mg 0.9 mmol), methane sulfonic anhydride (159 mg, 0.9 mmol), and DIEA (475 μL 2.7 mmol) were combined. After stirring, 1-(2-fluorophenyl)piperazine (181 mg, 1.0 mmol) was also combined and processed as described in Example 8B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.63 (m, 4H) 3.04 (m, 4H) 3.86 (s, 2H) 7.04 (m, 6H) 7.32 (m, 2H) 7.77 (m, 1H). (ESI) m/z 327 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][NH:6][C:7](=[O:16])[CH2:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11]=[CH:10]1.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:4]=1[CH2:5][N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][C:12](=[O:15])[CH2:13]2)[CH2:8][C:7]1=[O:16]
Reactant: COc1ccc(CNC(=O)CC2C=CC(=O)CC2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CC3CCC(=O)CC32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a solution of N-(2,4-Dimethoxy-benzyl)-2-(4-oxo-cyclohex-2-enyl)-acetamide (469.8 mg, 1.549 mmol) in THF (15 mL) was added sodium hydride (60 wt % on mineral oil, 245 mg, 6.12 mmol). The reaction mixture was stirred at room temperature for one hour and then quenched with saturated aqueous ammonium chloride. The mixture was then extracted twice with dichloromethane, and the combined extracts dried over magnesium sulfate, filtered, and evaporated in vacuo. Purification by column chromatography on silica gel (gradient: 0 to 10% methanol in dichloromethane) yielded 365.0 mg (78%) of 1-(2,4-Dimethoxy-benzyl)-hexahydro-indole-2,6-dione. LCMS (Method E, ESI): RT=1.22 min, m+H=304.2; 1H NMR (400 MHz, CD3OD) δ: 7.11 (d, J=8.3 Hz, 1H), 6.53 (d, J=1.8 Hz, 1H), 6.48 (dd, J=8.3, 2.1 Hz, 1H), 4.72 (d, J=14.8 Hz, 1H), 4.04 (d, J=14.8 Hz, 1H), 3.88 (dd, J=13.3, 6.7 Hz, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 2.77-2.59 (m, 4H), 2.38-2.21 (m, 3H), 2.10 (dd, J=13.8, 7.8 Hz, 1H), 1.82 (dd, J=13.3, 6.2 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12])[CH2:6]Br.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[OH:23])[CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[CH:11]([CH3:13])[CH3:12]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: COc1cc(CBr)cc(OC)c1C(C)C
Product: COc1cc(CC(O)(c2ccccc2)c2ccccc2)cc(OC)c1C(C)C

Procedure:
This compound was prepared from 3,5-dimethoxy-4-i-propylbenzyl bromide obtained in example 6(b), Mg and benzophenone by the same procedure as described in example 1 (b). 1HNMR (CDCl3, ppm): δ 1.24 (d, J=7.1 Hz, 6H), 3.3-3.5 (m, 1H), 3.56 (s, 6H), 3.72 (d, J=15.4 Hz, 2H), 6.04 (s, 2H), 7.2-7.7 (m, 10H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(O)C>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[CH2:29][CH2:30]1
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(CCN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 150 °C

Procedure:
4-Methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (60 mg, 0.31 mmol, 1.2 mmol) and 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one (68 mg, 0.26 mmol, 1.0 eq) were suspended in ethanol (5 ml) in a microwave tube. The tube was capped, degassed under vacuum, and purged with nitrogen gas. The mixture was heated to 150° C. for 30 min under microwave irradiation. The mixture was then concentrated and purified by flash column chromatography (0-10% MeOH/DCM).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([CH3:15])[N:4]=1)[NH2:2].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=O)[CH3:25])=[CH:20][CH:19]=1>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24](=[N:2][NH:1][C:3]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]=[C:5]([CH3:15])[N:4]=2)[CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Solvent: CCO
Product: COc1ccc(C(C)=NNc2cc(-c3ccccc3)nc(C)n2)cc1

Procedure:
The title compound was prepared from 4-hydrazino-2-methyl-6-phenylpyrimidine (200 mg, 1.0 mmol) and 1-(4-methoxy-phenyl)-ethanone (150 mg, 1.0 mmol) in 10 mL of ethanol by a procedure similar to example 1, step 4 yielding 35 mg (11%) of a cream solid. HPLC Purity: 98%.
Reaction SMILES: C([NH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15]1[CH:24]=[C:23]3[C:18]([C:19](=[O:31])[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]3[CH:25]3[CH2:27][CH2:26]3)=[CH:17][C:16]=1[F:32])[CH2:9]2)(=O)C.[ClH:33].O>C(O)C>[ClH:33].[NH2:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][N:10]([C:15]1[CH:24]=[C:23]3[C:18]([C:19](=[O:31])[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]3[CH:25]3[CH2:27][CH2:26]3)=[CH:17][C:16]=1[F:32])[CH2:9]2
Reactant: CC(=O)NCc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: NCc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2

Procedure:
304 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro--4-oxoquinoline-3-carboxylic acid was added to a mixed solution of 12 ml of concentrated HCl, 2.5 ml of water, and 5 ml of ethanol, and the mixture was heated under reflux for 15 hours. After cooling under atmosphere, the crystals deposited were collected by filtration and washed with ethanol to obtain 264 mg of 7-(5-aminomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride.
Reaction SMILES: [Br-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[F:24][C:25]1([F:32])[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1>CCOCC>[F:24][C:25]1([F:32])[CH2:30][CH2:29][C:28](=[CH2:2])[CH2:27][CH2:26]1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(F)(F)CC1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: C=C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A methyl triphenyl phosphonium bromide/sodium amide mixture (MTP instant ylide, 0.49 g, 1.24 mmol) was suspended in anhydrous Et2O (3 mL) stirring for 1 h at r.t. Afterwards, the reaction mixture was cooled at 0° C. and a solution of 4,4-difluorocyclohexanone (0.145 g, 1.08 mmol) in 3 mL of Et2O was added dropwise into. Stirring at r.t. was maintained for 16 h, then the reaction mixture was filtered and the filtrate was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH:9]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N+:6]([O-:9])[CH:7]=1
Reactant: OO
Reactant: Oc1cncc(F)c1
Solvent: CC(=O)O
Product: [O-][n+]1cc(O)cc(F)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 54.3 %

Procedure:
A solution of 1.5 g (13.26 mmol) of 5-fluoro-3-pyridinol in 8 ml of acetic acid is heated to 70° C. and 1.25 ml (14.6 mmol) of 35% hydrogen peroxide are added gradually. The reaction mixture is stirred for 15 hours at 70° C. and then concentrated under reduced pressure; 50 ml of cold water are added to the evaporation residue and the mixture is stirred for 1 hour. The precipitate obtained is filtered off, rinsed with water and with a minimum amount of cold ethyl acetate on the filter and then dried to give 930 mg of the expected product in the form of a white powder (yield=55%).
Reaction SMILES: C([N:3](CC)CC)C.[NH:8]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@@H:9]([C:16](O)=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)(=O)OCC.N>C(Cl)(Cl)Cl>[NH:8]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@@H:9]([C:16]([NH2:3])=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(N[C@@H](C(=O)O)c1ccccc1)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@H](NC(=O)OCc1ccccc1)c1ccccc1
Yield: 49.4 %

Procedure:
11.6 ml (84 mmoles) of triethylamine are added to a solution of 24.0 g (84 mmoles) of Z-D-Phg-OH in 170 ml of chloroform, and 8.9 ml (84 mmoles) of ethyl chlorocarbonate are added dropwise to the mixture at -10° C. The solution of the mixed anhydride is stirred for additional 10 minutes at -10° C., thereafter cooling is stopped, and gaseous ammonia is introduced into the mixture for one hour. Next day the reaction mixture is evaporated in vacuo, and the solid residue is isolated with water. The crude product is crystallized from ethanol. 11.8 g (49.4%) of Z-D-Phg-NH2 are obtained; the chromatographically uniform substance melts at 171°-173° C. Rf4 : 0.75, [α]D =-76.8° (c=1.0, in dimethyl formamide).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].Br[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[O:20][CH3:21].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[C:13]([O:20][CH3:21])[CH:14]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: COc1cc(C#N)ccc1Br
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1CC(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 29 %

Procedure:
Combined (2-(tert-butoxy)-2-oxoethyl)zinc(II) chloride (4.24 mL, 2.122 mmol) and 4-bromo-3-methoxybenzonitrile (0.30 g, 1.42 mmol) in THF (4.29 mL), then 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (0.056 g, 0.141 mmol) and Pd(dba)2 (0.041 g, 0.071 mmol) were added and the reaction was refluxed at 100° C. overnight. The reaction mixture was concentrated down by rotary evaporation and purified on a silica gel column eluting with hexanes and EtOAc to give the title compound as a yellow oil (102 mg, 29%). MS m/z [M+H]+ 248.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[ClH:11].[N:12]([O-])=O.[Na+].N([O-])=O.C([O-])(=O)C.[NH4+]>CO.O.[Zn]>[ClH:11].[NH2:12][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH:2]1[CH3:1]
Reactant: O=N[O-]
Reactant: CC1Cc2ccccc2N1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC1Cc2ccccc2N1N
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
135.9 g of 2-methylindoline was dissolved in 750 ml of methanol and 100 ml of concentrated hydrochloric acid was added. The solution was cooled to 15° C. and a 33% solution of sodium nitrite in water was added slowly until the presence of excess nitrite was observed. This reaction mixture was stirred for 30 minutes followed by the addition of 100 g of ammonium acetate. The reaction mixture was cooled to 25°-30° C. and 160 g of zinc dust was added over a period of 20 minutes. Then 670 g of ammonium acetate was added in small portions over a period of 40 minutes. The mixture was stirred for about 60 minutes and then extracted four times with a total of 1 liter of toluene. To the combined toluene extract was added 100 ml of concentrated hydrochloric acid and 80 g of ice. The mixture was cooled and filtered to obtain a solid product. The solid product was washed with toluene and then with acetone and dried. The dried product melted at 272°-4° C. and showed one spot at Rf 0.58 on the Analtech Silica Gel plate, mobile phase hexane/ethylacetate/acetic acid - 7/3/1.
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][C@@H:7]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[I:20]I>C(Cl)Cl>[C:1]([Si:5]([O:6][C@@H:7]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)/[CH:8]=[CH:9]/[I:20])([CH3:18])[CH3:19])([CH3:3])([CH3:2])[CH3:4]
Reactant: C#C[C@H](CCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reactant: II
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](/C=C/I)CCc1ccccc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A flame dried Schlenk flask, evacuated and purged with nitrogen, was charged with alkyne 88 (1.50 g, 5.46 mmol, 1 eq.). Anhydrous CH2Cl2 (35 ml) was added and the reaction stirred at r.t. Zr(Cp)2HCl (2.82 g, 10.9 mmol, 2 eq.) was added as a solid, in portions. The yellow suspension was stirred at r.t. for 1 h. The resulting yellow solution was cooled to 0° C. and iodine (1.52 g, 6.01 mmol, 1.1 eq.) added as a solid, in one portion. The cooling bath was removed and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was poured into water (100 ml) and extracted with 40/60 petroleum ether (4×50 ml). The combined organic phases were washed with water (100 ml), saturated Na2S2O3 solution (2×100 ml) and brine (100 ml) before being dried (MgSO4), filtered, and concentrated to give the crude material. This was purified by flash chromatography, eluting with 40/60 petroleum ether. The fractions containing product were combined and washed with saturated Na2S2O3 solution (20 ml), dried (MgSO4), filtered, and concentrated to give the title compound 89 (1.98 g, 90%) as a clear, colourless oil. Analytical data consistent with the literature (Sato, F. et al., EP 1211241 A1, Taisho Pharmaceutical co., LTD (2002)).