Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=3[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1cccc2cc(C(Cl)C3CCCCC3)oc12
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COc1cccc2cc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)oc12

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-7-methoxy-1-benzofuran (422 mg) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (357 mg) synthesized in Example 1(2) and in the same manner as in Example A7(3), the title object compound (64.3 mg, 9%) was obtained as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:11]=[CH:10][N:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=2)=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>CN(C)C=O>[Br:16][C:11]1[C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:8][N:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH:10]=1
Reactant: CC(C)Cn1ccc(-c2ccc(Cl)s2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)Cn1cc(Br)c(-c2ccc(Cl)s2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of 3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazole (1 eq, 0.045 mol) in dry N,N-dimethylformamide (130 mL) was added N-bromosuccinimide (1.1 eq, 0.05 mol) slowly and the resulting mixture was stirred at room temperature for 3 h. After completion reaction monitored by TLC, the reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organics layer were washed with water, brine, dried over anhydrous Na2SO4, filtered and evaporated to afford 12 g of 4-bromo-3-(5-chloro-2-thienyl)-1-isobutyl-1H-pyrazole (82% yield).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[N:20]=1>O1CCCC1>[CH:1]([NH:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[CH:22][N:23]=2)[N:20]=1)=[O:3]
Reactant: NCCSc1ccc2nccn2n1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNCCSc1ccc2nccn2n1
Reaction time: 1 h

Procedure:
On the other hand, 5.52 g of formic acid is added to 12.25 g of acetic anhydride at room temperature and the mixture is stirred at 45°-50° C. for 1 hour. After cooling, 60 ml of tetrahydrofuran and 5.83 g of the above-prepared crystals of 6-(2-aminoethylthio)imidazo[1,2-b]pyridazine are added and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure and the residue made basic with a saturated aqueous solution of sodium hydrogen carbonate. The precipitated crystals are collected by filtration to give 2.83 g of 6-(2-formylaminoethylthio)imidazo[1,2-b]pyridazine as colorless crystals melting at 148° to 151° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].N12CCCN=C1CCCCC2>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1cc2nc(Cl)nc(NC3CCN(C(=O)OC(C)(C)C)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.9 %

Procedure:
To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (5.12 g, 19.8 mmol, 1.0 equiv) in THF (50 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.34 g, 21.7 mmol, 1.1 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.31 g, 3.25 mL, 21.7 mmol, 1.1 equiv) and the reaction mixture stirred at rt for 16 h. Additional 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 4.3 mmol, 0.2 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.66 g, 0.65 mL, 4.3 mmol, 0.2 equiv) were added and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the mixture dissolved in dichloromethane (100 mL). The solution washed with water (2×20 mL) and a sat. solution of NaCl (20 mL), the aqueous layers were combined and extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure to give an amber solid. The solid was crystallized from MeOH (500 mL) to afford 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.67 g, 22%) as a white solid. The mother liquours were evaporated and purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (1:1)→ethyl acetate and the fractions combined to afford additional 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 12%). 1H NMR (250 MHz, CDCl3): δ 1.49-1.51 (m, 2H), 1.61 (s, 9H), 2.30-2.48 (m, 2H), 2.89-3.10 (m, 2H), 4.04 (s, 3H), 4.09 (s, 3H), 4.29-4.48 (m, 2H), 4.75-4.50 (m, 1H), 5.61 (d, J=8.0 Hz, 1H), 6.87 (s, 1H), 7.18 (s, 1H). MS (ESP): 423.5 [M+H]+.
Reaction SMILES: [C:1]12([CH2:11][C:12]3[NH:13][C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][C:16]=3[C:17](O)=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C([O:33][C:34](=[O:42])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH2:41])[CH:36]=1)C1C=CC=CC=1.CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O.O1CCOCC1>O>[C:1]12([CH2:11][C:12]3[NH:13][C:14]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:15][C:16]=3[C:17]([NH:41][C:37]3[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=3)[C:34]([OH:33])=[O:42])=[O:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Nc1cccc(C(=O)OCc2ccccc2)c1
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]c1CC12CC3CC(CC(C3)C1)C2
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(NC(=O)c2cc(-c3ccccc3)[nH]c2CC23CC4CC(CC(C4)C2)C3)c1

Procedure:
The benzyl ester of the title compound was prepared by reacting 2-adamantan-1-ylmethyl-5-phenyl-1H-pyrrole-3-carboxylic acid (Example 1, step c) with 3-amino-benzoic acid benzyl ester according to the procedure of Example 1, step d. This was converted to the title compound using the procedure of Example 1, step e. 1H NMR (300 MHz, d6-DMSO) 11.19 (1H, s), 9.62 (1H, s), 8.37 (1H, s), 7.97 (1H, d) 7.66 (2H, d), 7.58 (1H, d), 7.39 (3H, m), 7.16 (2H, m), 2.84 (2H, s), 1.88 (3H, br s), 1.54 (12H, m). The product was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 62.82; H, 7.38; N, 5.82%; C36H47N3O8.2.0 H2O requires: C, 63.04; H, 7.50; N, 6.12%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].CS(O[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)(=O)=O>>[CH:27]1([CH2:26][N:8]2[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)=[N:9]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Reactant: CS(=O)(=O)OCC1CCCC1
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CCCC2)c1=O
Yield: 88.5 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and cyclopentylmethyl methanesulfonate as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 88.5%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.[Br:12]Br>ClCCl>[Br:12][C:6]1[C:7]([NH2:9])=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: BrBr
Solvent: ClCCl
Product: Nc1nc(C(F)(F)F)ccc1Br

Procedure:
A solution of 6-(trifluoromethyl)pyridin-2-amine (200 mg, 1.23 mmol) in dichlormethane (2.47 mL) was cooled to 0° C. and bromine (197 mg, 63.4 μL, 1.23 mmol) was slowly added within 30 minutes. After 25 hours at 0° C. the reaction mixture was extracted with saturated Na2S2O3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography over silica gel using CH2Cl2/MeOH (with 10% ammonia) as eluent. The title compound was obtained as a white solid (711 mg, 24%).
Reaction SMILES: Cl.[CH3:2][CH:3](NCCC(O)=O)[CH2:4][CH2:5][CH2:6]C.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.BrCCCCC.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)NCCC(=O)O
Reactant: CNCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCBr
Product: CCCCCN(C)Cc1ccccc1

Procedure:
The present invention provides an alternate process for the synthesis of 3-[N-(methylpentyl)amino]propionic acid (III) wherein N-methyl benzyl amine is condensed with 1-bromo pentane in presence of potassium carbonate, using acetone as solvent to give N-methyl N-pentyl benzyl amine. This is debenzylated using palladium on carbon as catalyst and alcohol as solvent. The resulting product N-methyl pentyl amine is condensed with methyl acrylate in toluene to get 3-[N-(methylpentyl)amino]propionate, which is further hydrolysed to obtain Intermediate III.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH2:27][CH2:28][CH3:29])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:33])(=O)=O>>[Cl:33][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH2:27][CH2:28][CH3:29])[N:14]2[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Product: CCCc1cc2c(Cl)c(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1

Procedure:
Synthesized as described in Example 22C from 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-2-propyl-1H-indole and sulfuryl chloride: MS (ES) m/z 441 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>>[Cl:32][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCc1ccc(CCl)cc1

Procedure:
(4-Propylphenyl)methanol (4.93 g) synthesized in Reference Example 36 was dissolved in carbon tetrachloride (65 mL), triphenylphosphine (9.5 g) was added thereto, and the mixture was heated under reflux for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in hexane. The insoluble material was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent; hexane) to give the title compound (2.24 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([OH:14])=O)[C:7]1=[O:15].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:58][CH:59]([C:63]1[S:64][CH:65]=[CH:66][CH:67]=1)[C:60]([OH:62])=[O:61]>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:58][CH:59]([C:63]2[S:64][CH:65]=[CH:66][CH:67]=2)[C:60]([OH:62])=[O:61])=[O:14])[C:7]1=[O:15]
Reactant: NC(C(=O)O)c1cccs1
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(C(=O)O)c1cccs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (0.23 g, 0.00088 mol;) was dissolved in N,N-Dimethylformamide (9 mL, 0.1 mol;) and N,N-Diisopropylethylamine (800 uL, 0.004 mol;), and N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.37 g, 0.00097 mol;) were added. After 5 minutes preactivation Amino-thiophen-2-yl-acetic acid (0.266 g, 0.00169 mol;) was added. Workup consisted of rinsing with 5% citric acid then brine after dissolving the crude in ethyl acetate. The organic layer was then dried with magnesium sulfate and concentrated. The crude material was brought on directly to the next step. ES (+) MS m/e=404.81
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:11][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[C:8](=[O:10])[CH3:9]
Reactant: BrCCOCCBr
Reactant: CC(=O)c1cc(N)ccc1F
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(N2CCOCC2)ccc1F
Yield: 73.3 %

Procedure:
A mixture of 1-(5-amino-2-fluoro-phenyl)-ethanone (3.5 g), bromoethyl ether (5.929 g), and i-Pr2NEt (7.121 g) in toluene (20 mL) was refluxed for 16 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (25% ethyl acetate in hexane) to give 3.74 g of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][C:14]=2[C:23](=[O:25])[NH2:24]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cl
Reaction time: 0.05 h
Yield: 53.8 %

Procedure:
40% Methanolic Triton B (0.15 mL, 0.34 mM) was added to a solution of the 9-[(2-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (80 mg, 0.23 mM) in 5 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (182 mg, 0.91 mM) was added and the resultant mixture stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 57 mg (53%) of the {9-[(2-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-6.9 (m, 9H), 6.55 (d, 1H, J=8 Hz), 6.35 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.75 (s, 2H), and 1.45 (s, 9H). IR (KBr, cm−1) 1753 and 1678. MS (FD) m/e 464.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25]1([CH3:36])[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][S:32](Cl)(=[O:34])=[O:33]>>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:32]([CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[CH3:36])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Cc1ccccc1CS(=O)(=O)Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Product: Cc1ccccc1CS(=O)(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 37 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and o-tolyl-methanesulfonyl chloride, the title compound (yield 37%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1.O[C@@H]1CCNC1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:31]5[CH2:32][CH2:33][CH:29]([OH:28])[CH2:30]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OC1CCNC1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Agent: O[C@@H]1CCNC1
Product: OC1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)C1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (R)-3-hydroxypyrrolidine. A yellow solid 116 was obtained (0.0353 g, 75%). 1H-NMR (CDCl3, 400 MHz) δ 2.15–2.23 (m, 1H), 2.25–2.31 (m, 1H), 3.78–3.84 (m, 2H), 3.87–3.95 (m, 2H), 4.28–4.34 (m, 4H), 4.72–4.76 (m, 1H), 6.77 (s, 1H), 6.91 (dd, J=1.1 Hz, 6.6 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H), 7.05 (dd, J=2.1 Hz, 8.1 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.54 (dd, J=1.4 Hz, 8.5 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H), 8.15 (d, J=6.6 Hz, 1H); MS (APCI) m/z 475 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C1COCC1.C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reaction time: 1 h

Procedure:
A solution of Ethyl 2-(3-hydroxy-4-nitrophenyl)propanoate (900 mg, 3.76 mmol) in THF/ethanol (1:1, 30 mL) was slowly added 10% Pd/C (93 mg) at room temperature. The mixture was hydrogenated for 1 hour at 46 psi and then filtered with celite pad and washed with EtOAc. The filtrate was concentrated in vacuo. The residue was purified by column chromatography eluting with n-Hexane/EtOAc=2/1.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[N:9][CH:10]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([C:15]([O:17][CH3:18])=[O:16])=[CH:7][C:8]([C:11]([O:13][CH3:14])=[O:12])=[N:9][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(C(=O)OC)c(CCCO)cn1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(C(=O)OC)c(CCCCl)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
370 mg of dimethyl 5-(3- hydroxypropyl)-pyridine-2,4-dicarboxylate (from Example 16) are dissolved in 10 ml of chloroform, the solution is cooled to 0° C. and 0.18 ml of thionyl chloride in 2 ml of chloroform are slowly added. The mixture is subsequently stirred at room temperature for one hour and then at 60° C. for one hour. After cooling, the mixture is evaporated and the residue is taken up in chloroform and water; the phases are separated and the organic phase is washed with sodium sulfate solution, dried over magnesium sulfate and evaporated. After chromatography on silica gel, 286 mg of a yellow oil remain.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:13]Br)=[C:6]([CH:12]=1)[C:7]([O:9]CC)=O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>C(O)C>[Br:1][C:2]1[CH:12]=[C:6]2[C:5]([CH2:13][N:15]([C:16]3[CH:17]=[CH:18][C:19]([CH:22]([CH3:30])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=3)[C:7]2=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(Br)ccc1CBr
Reactant: CC(C(=O)OC(C)(C)C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C(=O)OC(C)(C)C)c1ccc(N2Cc3ccc(Br)cc3C2=O)cc1
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A mixture of ethyl 5-bromo-2-(bromomethyl)benzoate (4.00 g, 12.4 mmol), tert-butyl 2-(4-aminophenyl)propanoate (3.4 g, 15.4 mmol) and N,N-diisopropylethylamine (1.98 g, 15.4 mmol) in ethanol (120 mL) was heated in a sealed tube at 100° C. overnight. After this time, the mixture was cooled with an ice bath and the solids collected by filtration to afford tert-butyl 2-(4-(6-bromo-1-oxoisoindolin-2-yl)phenyl)propanoate (2.00 g, 39%) as a white solid: mp 164-165° C.: 1H NMR (300 MHz, CDCl3) δ 8.06 (d, J=1.7 Hz, 1H), 7.81-7.77 (m, 2H), 7.71 (dd, J=8.0, 1.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 7.38-7.34 (m, 2H), 4.81 (s, 2H), 3.63 (q, J=7.1 Hz, 1H), 1.46 (d, J=7.2 Hz, 3H), 1.41 (s, 9H); ESI MS m/z 448 [M+H+CH3OH]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21]([NH2:25])=[N:20][CH:19]=[CH:18]3)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc3c(N)nccc3c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nccc2cc(NC3CCCNC3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a degassed solution of 1-amino-6-bromoisoquinolin (554 mg), prepared as described in WO 98/47876 (Akzo Nobel N.V.), 3-aminopiperidine-1-carboxylic acid tert-butyl ester (823 mg), 2-(di-tert-butylphosphino)biphenyl and sodium tert-butoxide (367 mg) in dioxane (10 ml) under argon, was added tris(dibenzylidene-acetone)dipalladium(0). The mixture was further degassed with argon then heated at 120° C. for 90 minutes. The mixture was cooled to room temperature then diluted with methanol. The crude mixture was loaded onto a pre-acidified SCX column and the basic products eluted with 2M ammonia in methanol to give a crude residue (700 mg). The residue was purified by preparative HPLC to give 3-(1-aminoisoquinolin-6-ylamino)piperidin-1-carboxylic acid tert-butyl ester. A mixture of the 3-(1-aminoisoquinolin-6-ylamino)-piperidin-1-carboxylic acid tert-butyl ester in dichloromethane (6 ml) and trifluoroacetic acid (3 ml) were stirred at ambient temperature for 3 h. The mixture was concentrated then purified by preparative HPLC followed by loading onto a pre-acidified SCX column and the free base eluted with 2M ammonia in methanol to give 6-(piperidin-3-ylamino)-isoquinolin-1-ylamine, El-MS: m/z=243.7 [M+H]+.
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9]>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][CH:3]([OH:4])[C:2]([OH:6])=[O:5])=[CH:11][CH:12]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: O=CC(=O)O
Solvent: O
Product: O=C(CC(O)C(=O)O)c1ccc(Cl)cc1

Procedure:
A mixture of glyoxylic acid monohydrate (4.6 g, 50 mmol) and 4-chloroacetophenone (15.4 g, 0.1 mol) are heated at +95° C. under reduced pressure (50 mbar) for 3 hours. During this time, water is continually removed. After cooling, the reaction mixture is taken up in aqueous sodium carbonate solution and extracted with diethyl ether. The aqueous layer is acidified with 15% hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and evaporated, the residue is crystallized from ethyl acetate/hexane to obtain 4-(4-chloro-phenyl)-2-hydroxy-4-oxo-butyric acid.