Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:9]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[CH3:8])[CH:10]=[CH:11]4)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Cc1ccccc1I
Product: Cc1ccccc1-n1ccc2cc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)ccc21

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-2-methylbenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]Br)=[C:6]([F:8])[CH:7]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1>C1COCC1.[Zn].C1COCC1.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>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:9][C:5]2[C:4]([F:11])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=2[F:8])[N:14]=1
Reactant: Brc1cccc(Br)n1
Reactant: Fc1cc(Br)cc(F)c1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(F)c1Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (from Step B above, 18.5 g, 65.17 mmol) in THF (400 mL) was added 100 mL of Zn/THF solution (5 g Zn/100 mL, 76.46 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes. To this reaction was added 2,6-dibromo pyridine (15.44 g, 65.17 mmol) and tetrakis(triphenylphosphine)palladium (7.51 g, 6.51 mmol), and heated to 90° C. for 1 hr. The reaction was monitor by LCMS. After cooling to room temperature, the reaction was quenched with aqueous NH4Cl, and diluted with EtOAc. The organic layer was washed with water (3×), brine (3×), dried over MgSO4, and condensed in vacuo to yield a yellow oil. The crude residue was purified via silica gel chromatography to give the title compound (16 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[CH:2]1.N1C=CN=C1.[CH3:13][C:14]([Si:17](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:16])[CH3:15]>CN(C=O)C>[Si:17]([O:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)([C:14]([CH3:16])([CH3:15])[CH3:13])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1c[nH]cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 97.1 %

Procedure:
A solution of (1H-imidazol-4-yl)methanol (14.6 g, 108 mmol) in DMF (100 mL) was treated with imidazole (22.16 g, 325 mmol) and TBDPSCl (29.8 g, 108 mmol) and the mixture was stirred and heated to 50° C. for 6 h. It was then allowed to cool to RT, poured onto H2O and extracted with DCM. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, DCM/MeOH 100:0 to 90:10) afforded the title compound (35.3 g). UPLC-MS: MS 337.2 (M+H+); UPLC rt 1.04 min.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]3[CH:34]=[C:33]([Br:35])[CH:32]=[CH:31][C:30]=3[Cl:36])=[CH:24][CH:23]=2)(=O)=O)=CC=1>O1CCCC1>[Br:35][C:33]1[CH:32]=[CH:31][C:30]([Cl:36])=[C:29]([CH2:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[CH:23][CH:24]=2)[CH:34]=1
Reactant: OC1CCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of cyclobutanol (260 mg, 3.6 mmol) in anhydrous tetrahydrofuran (4 mL) was added sodium hydride (138 mg, 5.7 mmol) in portions at 0° C. The mixture was stirred at 0° C. for 30 min, and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (300 mg, 0.6 mmol) was added in portions. The mixture was refluxed for 3 h, whereupon TLC showed the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate, washed with water and then with brine, dried over anhydrous sodium sulfate, and concentrated to a crude oil. The crude oil was purified by column chromatography (PE:EA=10:1) to get intermediate CL as an oil product (117 mg, yield: ˜49%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[CH:5][C:6]=1[SH:7].[CH2:9]([SH:14])[CH2:10][CH:11]([CH3:13])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].II>C(OCC)C.O>[CH3:1][C:2]1[O:3][C:4]([CH3:8])=[CH:5][C:6]=1[S:7][S:14][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CCS
Reactant: Cc1cc(S)c(C)o1
Agent: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1cc(SSCCC(C)C)c(C)o1

Procedure:
0.64 Grams (0.005 moles) of 2,5-dimethyl-3-furanthiol and 1.04 grams (0.01 moles) of isoamyl mercaptan are dissolved in 12 ml anhydrous diethyl ether. 0.8 Grams (0.0075 moles) of sodium carbonate dissolved in 8 ml water is added with stirring to the reaction mass. 1.9 Grams (0.0075 moles) of iodine dissolved in 6 ml anhydrous diethyl ether is then added dropwise to the reaction mass until the iodine color remains. The reaction mass is then stirred for a period of 30 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([Cl:23])=[O:19])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (0.400 g, 1.56 mmol) in CH2Cl2 (5 mL) at room temperature was added oxalyl chloride (0.86 mL, 1.7 mmol) followed by DMF (20 μL). Gas evolution was observed. After 30 minutes, the solution was concentrated in vacuo to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid chloride which was used without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]2=O>CN(C=O)C>[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:9]2[Cl:3]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(Br)cc2c1=O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(F)c(Br)cc2c1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
Thionyl chloride (150 mL, 2.08 mol) was added to a solution of ethyl 6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate (25 g, 79.59 mmol) in DMF (50 mL) and the solution stirred at 80° C. for 4 h. The mixture was concentrated under vacuum and quenched by the addition of ice/water. The reaction mixture was extracted with DCM (8×100 mL), the organic extracts combined and the mixture adjusted to pH=7 by the addition of 1.5M ammonium hydrogen carbonate. The resulting mixture was washed with water (3×100 mL), the organics dried over Na2SO4 and concentrated in vacuo to afford the desired material (20 g, 76%) as a light yellow solid which was used without further purification. NMR Spectrum: 1H NMR (400 MHz, CDCl3) δ 1.49-1.42 (3H, m), 4.54-4.82 (2H, q), 7.86 (1H, d), 8.69 (1H, d), 9.23 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=334.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:24][CH2:25][CH2:26][NH:27][C:28]2[C:29](=[O:45])[N:30]([C:41]([CH3:44])([CH3:43])[CH3:42])[S:31](=[O:40])(=[O:39])[C:32]=2[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=O)=O)=CC=1>>[C:41]([N:30]1[C:29](=[O:45])[C:28]([NH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[C:32]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[S:31]1(=[O:39])=[O:40])([CH3:42])([CH3:43])[CH3:44]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: COC(=O)Cc1cccc(O)c1
Product: COC(=O)Cc1cccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)c1
Yield: 66 %

Procedure:
The title compound was prepared as described for Example 12 from methyl (3-hydroxyphenyl)acetate and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 20-40% EtOAc in petroleum ether 40-60° C. as eluent. The product containing fractions were evaporated and the residue was dissolved in EtOAc, washed with aqueous K2CO3 (2M) and evaporated give the title compound (0.097 g, 66%). 1H NMR (500 MHz CDCl3): δ 7.55-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.26 (t, 1H), 6.90 (dd, 1H), 6.82-6.78 (m, 2H), 5.76 (t, 1H), 3.90 (t, 2H), 3.72 (s, 3H), 3.61 (s, 2H), 3.14-3.06 (m, 2H), 1.90-1.80 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 172.1, 159.8, 158.7, 135.7, 135.3, 131.8, 129.9, 129.8, 128.8, 125.3, 122.3, 115.5, 113.4, 107.2, 65.9, 61.7, 52.3, 42.4, 41.4, 29.0, 27.8; Mass Spectrum: M+H+ 487.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[NH:12][CH3:13])=[CH:4][C:3]=1[F:18].[OH:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1>N1C=CC=CC=1>[F:18][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:22]1[CH2:23][CH2:24][CH:20]([OH:19])[CH2:21]1)[N:9]([NH:12][CH3:13])[CH:8]=[C:7]([C:14]([OH:16])=[O:15])[C:6]2=[O:17]
Reactant: OC1CCNC1
Reactant: CNn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CNn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCC(O)C3)cc21

Procedure:
6-Fluoro-1,4-dihydro-7-(3-hydroxy-1-pyrrolidinyl)-1-methylamino-4-oxo-3-quinolinecarboxylic acid [I; R=CH3NH, R"=H, Z=N=3-hydroxy-1-pyrrolidinyl] was prepared from 7.7 g of 7-chloro-6-fluoro-1,4-dihydro-1-methylamino-4-oxo-3-quinolinecarboxylic acid (Preparation 4A) and 9.75 g of 3-hydroxypyrrolidine in 30 ml of pyridine according to the procedure of Example 1. There was obtained 4.7 g of product as a yellow powder, m.p. 319°-321° C. (decompn.) when recrystallized from dimethylformamide.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[C:6]([CH:12](O)[CH3:13])=[N:7]2.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[C:6]([CH:12]([N:51]1[C:47](=[O:57])[C:48]3[C:49](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:50]1=[O:52])[CH3:13])=[N:7]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethanol (0.08320 g, 0.2468 mmol) in tetrahydrofuran (2.468 mL, 0.2468 mmol) were added triphenylphosphine (0.07766 g, 0.2961 mmol), phthalimide (0.04357 g, 0.2961 mmol), and diisopropyl azodicarboxylate (0.05735 mL, 0.2961 mmol). The reaction mixture was stirred at room temperature. After 6 h, the mixture was concentrated under reduced pressure and partitioned between EtOAc (100 mL) and brine (100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 50% gradient of EtOAc in hexane over 20 min, then 50% isocratic of EtOAc for 3 min as eluent to give 2-(1-(5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)ethyl)isoindoline-1,3-dione as a tan solid: LC-MS (ESI) m/z 466.0 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:26][C:27]1[N:28]=[C:29]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[C:30]2[S:35][C:34](C=O)=[CH:33][C:31]=2[N:32]=1>>[CH2:19]([N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:6][C:34]2[S:35][C:30]3[C:29]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[N:28][C:27]([Cl:26])=[N:32][C:31]=3[CH:33]=2)[CH2:13][CH2:12]1)[CH2:15][CH2:16][O:17][CH3:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCCN(Cc1ccccc1)C1CCN(C(=O)OC(C)(C)C)CC1
Product: COCCN(Cc1ccccc1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 69.5 %

Procedure:
The reaction mixture was cooled and diluted with dichloromethane (30 ml), washed with water, brine and dried (MgSO4). The solvents were removed in vacuo to give a residue which was purified by silica flash chromatography to give 4-[benzyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (484 mg). 4-[Benzyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (442 mg), and 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (300 mg) were treated under standard reductive amination conditions to give benzyl-[1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-ylmethyl)-piperidin-4-yl]-(2-methoxy-ethyl)-amine (379 mg), as an oil which crystallized on standing.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([O:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].[H-].[Na+].[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([O:5][N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[S:27]([C:19]1[O:18][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1)(=[O:28])=[O:29])=[O:4]
Reactant: CC(C)(C)OC(=O)NOC(=O)C(C)(C)C
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(OC(=O)C(C)(C)C)S(=O)(=O)c1cc2ccccc2o1

Procedure:
N-[(tert-Butoxy)carbonyl]1-benzofuran-2-sulfonamido 2,2-dimethylpropanoate (55) is prepared from [(tert-butoxy)carbonyl]amino 2,2-dimethylpropanoate, sodium hydride and 1-benzofuran-2-sulfonyl chloride according to Scheme 2. (4.0 g, 87%), 1H NMR (250 MHz, DMSO-d6) δ ppm 8.06 (1H, d, 0.8 Hz), 7.92 (1H, d, 7.3 Hz), 7.81 (1H, dd, 8.5, 0.8 Hz), 7.64 (1H, ddd, 8.5, 7.2, 1.4 Hz), 7.42-7.53 (1H, m), 1.37 (9H, s), 1.28 (9H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(O)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:1][CH2:2][CH2:3][C:4]2[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCc1cccnc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(NCCc2cccnc2N)CC1
Yield: 42.2 %

Procedure:
A solution of 3-(2-aminoethyl)-2-aminopyridine (0.122 g, 0.88 mmol) and 1-t-butoxycarbonyl 4-piperidone (0.177 g, 0.88 mmol) in dichloroethane (3 mL) containing 2 drops of acetic acid was treated with sodium triacetoxyborohydride (0.28 g, 1.33 mmol) at 20-75° C. until starting material was no longer consumed. The reaction was worked up with saturated sodium bicarbonate and methylene chloride, and dried over sodium sulfate. The crude product was purified by chromatography (silica gel, 0-10% {0.1% ammonium hydroxide in methanol) in methylene chloride, gradient elution) to produce the title compound (0.119 g) as a yellow oil. MS 321 (M+1).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].Cl[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1.N12CCCN=C1CCCCC2>CN(C)C=O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1)=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCCC(=O)O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCCCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 36.5 %

Procedure:
The procedure is as in Example 24, but starting with 5-acetamidopentanoic acid (5 g) in dimethylformamide (66 cc), 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.7 cc). After recrystallization in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 5-acetamidopentanoate (3.3 g), m.p. 185° C., is obtained.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[CH2:16]([O:23][C:24]1[CH:29]=[C:28](F)[CH:27]=[C:26]([F:31])[C:25]=1[N+:32]([O-:34])=[O:33])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:23][C:24]1[C:25]([N+:32]([O-:34])=[O:33])=[C:26]([F:31])[CH:27]=[C:28]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(F)c([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 19.7 %

Procedure:
To a solution of tert-butyl ethyl malonate (10.0 g, 51.0 mmol) in DMF (200 ml) was added sodium hydride (60% in oil, 2.04 g, 51.0 mmol) at 0° C. under stirring. The reaction mixture was stirred at the same temperature for 30 minutes. A solution of 2-benzyloxy-4,6-difluoronitrobenzene (9.02 g, 34.0 mmol) in DMF (60 ml) was added dropwise to the reaction mixture at 0° C. The reaction mixture was then stirred at 80° C. for 18 hours. After cooling to room temperature, the reaction mixture was poured in ice-1N HCl to neutralize therewith, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, then distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from with ethyl acetate/hexane (1/5) eluate fractions, tert-butyl ethyl 5-benzyloxy-3-fluoro-4-nitrophenylmalonate (2.91 g, 17%) was obtained as a yellow oil.
Reaction SMILES: FC(F)(F)S(O[CH:7]1[CH:11]=[C:10]([O:12][CH3:13])[C:9](=[CH:14][C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:8]1)(=O)=O.C(OC([N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C>[CH3:13][O:12][CH:10]1[C:9](=[CH:14][C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:8][C:7]([C:34]2[NH:33][CH:37]=[CH:36][CH:35]=2)=[CH:11]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: COC1=CC(OS(=O)(=O)C(F)(F)F)NC1=Cc1cc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC1C=C(c2ccc[nH]2)NC1=Cc1cc2ccccc2[nH]1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The crude triflate 78 was mixed with about 3 equivalent of boronic acid 8, 8 equivalents of potassium carbonate and about 0.1 equivalent of tetrakistriphenylphosphine palladium under argon. Anhydrous 1,4-dioxane (10 mL) was added to the reaction mixture, and it was heated at 90° C. in a sand bath. After three hours, the mixture was cooled and added to ethyl acetate (100 mL). The organic layer was washed with brine (3×100 mL) and was then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude mixture was passed through a short column of neutral alumina using 50/50 hexanes/ethyl acetate as an eluent. The relevant fractions were combined and concentrated, and the resulting crude product was purified using a preparative plate of neutral alumina and eluted using 80/20 hexanes/ethyl acetate. The alumina band containing Compound 79 was washed with ethyl acetate and concentrated to provide the Compound 79 as a red dark solid (2 mg, 20%). (500 MHz, CD3OD) : δ (ppm), 7.55 (m, 2H); 7.20 (t, 1H); 7.13 (s, 1H); 7.03 (t, 1H); 6.90 (s, 1H), 6.88 (s, 1H); 6.85 (s, 1H); 6.32 (s, 1H), 6.17 (s, 1H); 3.97 (s, 3H). MS (M+H): 290.0.
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[F:19][C:20]([F:44])([F:43])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24].C(#N)C>O>[F:19][C:20]([F:43])([F:44])[CH2:21][NH:22][C:23]([C:25]1([CH2:38][CH2:39][CH2:40][CH2:41][N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][C:1]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)[C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc(-c2ccc(N3CCNCC3)cc2)cc1
Solvent: O
Solvent: CC#N
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc(-c4ccccc4)cc3)CC2)c2ccccc2-c2ccccc21

Procedure:
A solution of 0.4 g (1.678 mmol) of 1-biphenyl-4-yl-piperazine, 0.682 g (1.6 mmol) of 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide and 0.223 ml (1.6 mmol) of triethylaminein 20 ml acetonitrile is stirred for 14 hours at 60° C. and then diluted with water. It is extracted with ethyl acetate and the organic phase is dried over sodium sulphate. Purification is by column chromatography on silica gel (eluant: dichloromethane/ethanol=40:1).
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].[O:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1>>[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:31](=[O:32])[CH2:30][CH:27]2[CH2:28][CH2:29][O:24][CH2:25][CH2:26]2)[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: O=C(O)CC1CCOCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)CC3CCOCC3)c2c1N

Procedure:
Prepared as in Example Da from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example Db) and 2-(tetrahydro-2H-pyran-4-yl)acetic acid as a yellow solid (37%). 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.08 (m, 2H), 1.30-1.38 (m, 11H), 1.79 (m, 1H), 1.97 (d, J=4.0 Hz, 2H), 2.56 (s, 3H), 3.07 (t, J=8.0 Hz, 2H), 3.61 (d, J=8.0 Hz, 2H), 4.28-4.34 (m, 4H), 6.87 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.73 (s, 1H), 8.21 (s, 2H). MS 444 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:5][CH:4]=1)#[N:2].[ClH:16]>[Pd].O1CCCC1>[ClH:16].[O:15]=[C:11]1[NH:12][CH2:13][CH2:14][N:10]1[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(CN2CCNC2=O)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: NCc1ccc(CN2CCNC2=O)cc1
Yield: 81 %

Procedure:
Prepared analogously to Example 43b) from 1-[(4-cyanophenyl)methyl]imidazolidin-2-one by catalytic hydrogenation using palladium/activated charcoal and in the presence of 1 equivalent of 1N hydrochloric acid in a yield of 81% of theory. Colourless crystals, Mp. >250° C. (Tetrahydrofuran).