Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:23]I.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH3:23])[C:12](=[O:13])[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:14]([N:9]1[CH2:8][CH2:7][CH:6]([CH3:4])[C:12](=[O:13])[CH2:11][CH2:10]1)(=[O:16])[CH3:23]
Reactant: CI
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(=O)C(C)CC1
Product: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 190.4 %
Yield: 95 %

Procedure:
A solution of compound racemic 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (2.5 g, 8.77 mmole) in 10 mL of DMF was added at 0° C. to a stirred suspension of NaH 60% dispersion in oil (355 mg, 8.77 mmole) in 10 mL of DMF. The reaction mixture was allowed to stir RT for one hour before being cooled to 0° C. Methyl iodide (1.37 mL, 21.92 mmole, 2.5 eqv) was added slowly and the reaction mixture was stirred at RT for 3 h before being poured into cold H2O and extracted with EtOAc (50 mL). The organic layer was washed with brine, dried, and evaporated to give 2.5 g of 4-methyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester desired compound (95% yield).
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH2:8]([C:10]1[C:19]([CH2:20][CH3:21])=[C:18]([O:22][CH3:23])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1O)[CH3:9].Cl.CN([CH:29]([CH3:33])[C:30]([OH:32])=[O:31])C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:6]([N:3]([CH2:33][CH2:29][C:30]([O:32][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]([O:22][CH3:23])=[C:19]([CH2:20][CH3:21])[C:10]=1[CH2:8][CH3:9])=[O:31])[CH2:4][CH3:5])[CH3:7]
Reactant: CCN(CC)CC
Reactant: CCc1c(CC)c(OC)c2ccccc2c1O
Reactant: CC(C(=O)O)N(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCc1c(CC)c(OC(=O)CCN(CC)CC)c2ccccc2c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.6 %

Procedure:
Dry methylene chloride (30 ml) and triethylamine (0.33 ml, 2.34 mmole) are added to a mixture of 2,3-diethyl-4-methoxynaphthol (180 mg, 0.78 mmole), dimethylamino propionic acid hydrochloride (2 eq, 283 mg, 1.56 mmole), dicyclohexylcarbodiimide (2 eq, 322 mg, 1.56 mmole) and 4-dimethylaminpyridine (1 eq, 95 mg, 0.78 mmole) at room temperature under argon, and the resulting suspension is stirred at room temperature under argon for two days. The white precipitate is removed by filtration, and the filtrate is concentrated. Thick layer chromatography (silica gel, 2000 micron) developed by a 9:1 mixture of ether and n-hexane isolates 144 mg (51.8% ) of 3-(N,N-diethylamino) propionic acid, 2,3-diethyl-4-methoxynaphth-1-yl ester as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[N:12]=[C:11]([N:20]3[CH2:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:32])(=[O:31])[CH2:22][CH2:21]3)[CH:10]=2)[CH2:6][O:5][CH2:4]1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[O:31]=[S:23]1(=[O:32])[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[CH2:26][N:20]([C:11]2[CH:10]=[C:9]([NH:8][CH2:7][C:3]3([CH2:2][NH:1][C:33](=[O:35])[CH3:34])[CH2:6][O:5][CH2:4]3)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[N:12]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)COC3)c2c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccc(C)cc23)COC1

Procedure:
The title compound was prepared in analogy to Example 63-1 in Scheme 25 by using N-{[3-(aminomethyl)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine (prepared in analogy to Example 3-50) and acetic anhydride. MS obsd. (ESI+) [(M+H)+] 495, 1H NMR (400 MHz, CD3OD) δ ppm 8.00 (d, J=7.6 Hz, 1 H), 7.89 (d, J=7.2 Hz, 1 H), 7.66 (t, 2 H), 7.46 (t, 2 H), 7.32-7.30 (m, 1 H), 6.22 (s, 1 H), 5.17 (s, 2 H), 4.56-4.51 (m, 6 H), 3.67 (d, 4 H), 3.60 (t, J=9.6 Hz, 2 H), 2.43 (s, 3 H), 2.06 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.N1[CH:16]=[CH:15]N=C1.C(Cl)(=O)C.Cl.[NH2:22][CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]1=[O:30].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(#N)C.O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:22]([CH:23]3[CH2:28][CH2:27][C:26](=[O:29])[NH:25][C:24]3=[O:30])[C:15]([CH3:16])=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: c1c[nH]cn1
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Cc1nc2cc(F)ccc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a stirred mixture of 2-amino-4-fluorobenzoic acid (2.5 g, 16 mmol) and imidazole (1.3 g, 19 mmol) in acetonitrile (25 mL), was added acetyl chloride (1.4 mL, 19 mmol) at room temperature. The mixture was stirred at room temperature overnight. To the mixture, was added 3-amino-piperidine-2,6-dione hydrogen chloride (2.7 g, 16 mmol), imidazole (2.4 g, 36 mmol) and triphenyl phosphite (5.1 mL, 19 mmol) and heated to reflux for 22 hours. To the mixture, was added water (60 mL). The suspension was tittered and washed with water (2×50 mL), ethyl acetate (2×50 mL), and water (50 mL) to give 3-(7-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a white solid (2.5 g, 52% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH3CN/0.1% H3PO4, 3.83 min (100%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 2.15-2.22 (m, 1H, CHH), 2.58-2.71 (m, 5H, CH3, 2CHH), 2.79-2.86 (m, 1H, CHH), 5.28 (dd, J=5, 11 Hz, 1H, NCH), 7.34-7.44 (m, 2H, Ar), 8.10 (dd, J=6, 9 Hz, 1H, Ar), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.89, 23.50, 30.58, 56.59, 111.62 (d, JC-F=22 Hz), 115.26 (d, JC-F=24 Hz), 117.32, 129.19 (d, JC-F=11 Hz), 148.97 (d, JC-F=13 Hz), 156.65, 159.77, 165.83 (d, JC-F=252 Hz), 169.41, 172.59; LCMS: MH=290; Anal Calcd for C14H12N3O3F: C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C, 58.09; H, 4.08; N, 14.42; F, 6.72.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([C:14]([N:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[NH:25][C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=1.[CH3:38][C:39]([CH3:43])([CH3:42])[CH:40]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:63]CCl>CO.O>[ClH:63].[ClH:63].[CH2:21]([N:16]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([NH:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:38][C:39]([CH3:43])([CH3:42])[CH3:40])[C:9]=2[CH:10]=1)=[O:15])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)(C)C=O
Reactant: COc1cc(Nc2nc3ccc(C(=O)N(CC(C)C)CC(C)C)cc3n2CCCN)cc(OC)c1OC
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(Nc2nc3ccc(C(=O)N(CC(C)C)CC(C)C)cc3n2CCCNCC(C)(C)C)cc(OC)c1OC
Product: Cl

Procedure:
A solution of 1-(3-aminopropyl)-N,N-diisobutyl-2-[(3,4,5-trimethoxyphenyl)amino]-1H-benzimidazole-6-carboxamide (100 mg, 1 eq) and trimethylacetaldehyde (25 mg, 1.5 eq) in dichloromethane (1 ml) is stirred for 4 hours at a temperature of approximately 20° C. The mixture is diluted with methanol (1 ml) then sodium triacetoxyborohydride is added (41 mg, 2 eq). After 1 hour at a temperature of approximately 20° C., dichloromethane (20 ml) and water saturated with sodium hydrogen carbonate (10 ml) are added to the mixture. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: 100% dichloromethane to dichloromethane/methanol 9:1) produces the expected compound in the form of a base. The corresponding hydrochloride salt is formed by adding a 1N solution of hydrochloric acid in ether. The precipitate obtained is filtered and dried in order to produce the expected dihydrochloride compound (83 mg, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]2[CH:14]=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:16]N1C(=O)CCC1=O.O>O1CCCC1>[Br:13][C:11]1[CH:10]=[C:9]([CH:14]=[O:15])[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:12]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1cc(Br)cn1-c1ncccc1Cl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc(Br)c(Cl)n1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.4 %

Procedure:
To a solution of 3.0 g of 3-chloro-2-(4-bromo-2-formyl-1H-pyrrol-1-yl)-pyridine in 30 ml of tetrahydrofuran was added 1.5 g of N-chlorosuccinimide. The resulting mixture was stirred at room temperature for 2 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.5 g of 4-bromo-5-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH:1]1([C:4]2[CH2:8][C:7](=[O:9])[NH:6][N:5]=2)[CH2:3][CH2:2]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][N+:11]=1[O-]>C(OC(=O)C)(=O)C>[CH:1]1([C:4]2=[N:5][NH:6][C:7](=[O:9])/[C:8]/2=[C:10]2\[NH:11][CH:12]=[CH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:3][CH2:2]1
Reactant: [O-][n+]1ccc2ccccc2c1
Reactant: O=C1CC(C2CC2)=NN1
Solvent: CC(=O)OC(C)=O
Product: O=C1NN=C(C2CC2)/C1=C1/NC=Cc2ccccc21

Procedure:
3-Cyclopropyl-1H-pyrazol-5(4H)-one (0.03 g, 0.27 mmol) and isoquinoline N-oxide (0.04 g, 0.27 mmol) were stirred in acetic anhydride (0.5 mL) for 30-40 minutes. The reaction mixture was concentrated and purified by LC-MS to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.78-0.86 (m, 4H) 1.77-1.86 (m, 1H) 7.91 (t, J=7.71 Hz, 1H) 8.10 (t, J=7.58 Hz, 1H) 8.26 (d, J=8.59 Hz, 3H) 8.58 (d, J=6.57 Hz, 1H); ESI-MS: m/z calc'd for C15H13N3O 251.28. found 252.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:52])[C:32]4[CH:37]=[C:36]([NH:38][C:39](=[O:50])[C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=5)[CH:35]=[CH:34][C:33]=4[Cl:51])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>C(Cl)Cl>[Cl:51][C:33]1[CH:34]=[CH:35][C:36]([NH:38][C:39](=[O:50])[C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=2)=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[N:25][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([S:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:16])=[O:15])=[CH:18][CH:19]=2)=[N:29][CH:28]=1)=[O:52].[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5cccc(C(F)(F)F)c5)ccc4Cl)cn3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc(Nc3ccc(S(=O)(=O)C4CCNCC4)cc3)nc2)c1)c1cccc(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
A stirred suspension of intermediate 14 (Example 21) (0.058 g, 0.076 mmol) in DCM (8 mL) was treated with TFA (0.100 mL) and stirred for 3 h. Solvents were then removed yielding desired product as TFA salt (0.05 g, 99%). 1H NMR (DMSO-d6): δ 1.62-1.70 (m, 2H), 2.01-2.08 (m, 4H), 2.8-2.9 (m, 2H), 3.3-3.6 (m, 2H), 3.45-3.49 (m, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.81 (t, J=15.7 Hz, J=7.8 Hz, 1H), 7.93 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H), 8.05 (d, J=8.9 Hz, 2H), 8.10 (d, J=2.5 Hz, 1H), 8.20-8.32 (m, 3H), 8.65-8.69 (m, 1H), 8.90 (s, 2H), 10.37 (s, 1H), 10.76 (s, 1H), 10.80 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8]#N)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[N:3]1.[OH-:21].[Na+].[OH2:23].C(O)C>>[CH3:1][N:2]1[C:6]([CH2:7][C:8]([OH:23])=[O:21])=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[N:3]1
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CC#N
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CC(=O)O

Procedure:
In analogy to the procedure described for example 9 c], [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetonitrile was treated with sodium hydroxide in water/ethanol 1/1 at 85° C. to give [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-acetic acid as off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:23]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:24][CH2:25]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Reaction time: 16 h
Yield: 40 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (100 mg, 0.24 mmol), DMF (1.5 mL), 1M Na2S2O4 (3 eq, 0.74 mmol, 0.74 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.05 eq, 0.26 mmol, 38 mg). After 16 h, filtration of the precipitate and trituaration with Et2O gave the product (50 mg, 40%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.43-1.51 (br s, 3H, CHCH3), 2.49-2.57 (2 m, 4H, piperazine N(CH2)2), 3.01 (s, 6H, N(CH3)2), 3.69 (br, 5H, piperazine N(CH2)2 & CHCH3), 6.82 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 7.48 (s, br, 2H, pyridine H-3 & H-5), 8.00 (d, J=8.7 Hz, 2H, N,N-dimethylaminophenyl), 8.16 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.61 (s, br, 2H, pyridine H-2 & H-6), 13.18 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C1C=CC=CC=1.C[N:23]([C:25]([O:29]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C[C@@H](N)CC1SC=CC=1>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6]([C:25]([NH2:23])=[O:29])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: CN(C)C[C@@H](N)Cc1cccs1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1-c1ccccc1
Reaction time: 2 h
Yield: 45 %

Procedure:
Biphenyl acid 10 (40 mg, 0.064 mmol, 1 eq) and HBTU (49 mg, 0.13 mmol, 2 eq) were dissolved in DMF (1 mL) followed by the addition of (S)—N1,N1-dimethyl-3-(thiophen-2-yl)propane-1,2-diamine (23 mg, 0.13 mmol, 2 eq). The reaction mixture was stirred for 2 h, diluted with EtOAc and quenched with a saturated aqueous NaHCO3 solution. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford an oil. The crude oil was purified by silica gel chromatography (2-5% MeOH/DCM, 0.1% Et3N) to afford 23 mg of biphenyl amide 251. Yield 45%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][O:13][CH3:14])[N:6]=[CH:7]2.C(N(CC)CC)C.[C:22](=S)=[S:23].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[N:1]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH2:12][O:13][CH3:14])[N:6]=[CH:7]2)=[C:22]=[S:23]
Reactant: COCc1cc2c(N)cccc2cn1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCc1cc2c(N=C=S)cccc2cn1
Reaction time: 4 h

Procedure:
A solution of 5-amino-3-methoxymethylisoquinoline (22.9 g) in pyridine (80 cc) is added dropwise, whilst stirring and at a temperature of about -10° C., to a solution of triethylamine (17 cc) and carbon disulphide (55 cc) in pyridine (80 cc). After 4 hours at -10° C., a solution of dicyclohexylcarbodiimide (25.2 g) in pyridine (80 cc) is added dropwise. Stirring is maintained for 3 hours at a temperature which changes from -10° to 20° C., and then for 20 hours at a temperature of about 20° C. The mixture is evaporated to dryness at 60° C. under reduced pressure (20 mm Hg), the residue is taken up in methylene chloride (800 cc), and insoluble material is removed by filtration and the filtrate is evaporated to dryness at 40° C. under reduced pressure (40 mm Hg). The residue is taken up in diisopropyl ether (1 liter; an insoluble material is removed by filtration and the filtrate is evaporated to dryness at 40° C. under reduced pressure (20 mm Hg). 5-Isothiocyanato-3-methoxymethylisoquinoline (18.5 g), m.p. 88° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:14])[N:8]([CH3:13])[C:9]=1[C:10]([OH:12])=O)=[O:4].[CH3:15][N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:25][CH2:26][NH2:27]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH3:14])[N:8]([CH3:13])[C:9]=1[C:10](=[O:12])[NH:27][CH2:26][CH2:25][C:17]1[N:16]([CH3:15])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)=[O:4]
Reactant: COC(=O)c1nc(C)n(C)c1C(=O)O
Reactant: Cn1c(CCN)nc2ccccc21
Product: COC(=O)c1nc(C)n(C)c1C(=O)NCCc1nc2ccccc2n1C

Procedure:
The product was obtained starting from 1,2-dimethyl-1H-imidazole-4,5-dicarboxylic acid 4-methyl ester (200 mg, 1.01 mmol) and 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanamine (195 mg, 1.11 mmol) according to the method described in example 7, step 5 after aqueous work-up and purification by flash chromatography (using silica gel amine phase and a MeOH/ethyl acetate gradient) as light red gum (98 mg, 276 μmol, 27.3%). MS: M=356.1 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(Cl)Cl.C(N(CC)CC)C.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>O>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][S:38]([C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:42])[F:43])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(NCCNc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
The operation is carried out as in Stage 1 of Example 10 starting from 280 mg of the product obtained in Stage 1 of Example 7, 3 ml of methylene chloride, 0.17 ml of triethylamine and 280 mg of 4-(trifluoromethyl)benzenesulphonic acid chloride in place of the 4-methyl-benzenesulphonic acid chloride, then the reaction medium is agitated at ambient temperature for approximately 30 min. Then 2 ml of water is added, followed by extracting with 3×5 ml of methylene chloride, washing with 5 ml of saturated sodium chloride, drying, evaporating, impasting in 5 ml of ether then in 5 ml of pentane, separating, and drying. In this way 375 mg of expected product is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[CH:24](N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH3:24][O:19][C:18]([C@@H:17]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1Cc2ccc(O)cc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 73.5 %

Procedure:
To a solution of (3S)-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester (1.47 g, 5.0 mmol) in dry DMF (25 mL) at ambient temperature, was added iodomethane (1.2 eq., 6.0 mmol, 0.37 mL) and diisopropylethylamine (1.5 eq. 7.5 mmol, 1.31 mL) in succession, and the reaction mixture was stirred at rt for 3-4 hours, at which point LC/MS analysis showed the presence of product. The reaction mixture was poured into 50 mL of water and extracted with DCM (3×50 mL) and the combined DCM extracts were washed with water (3×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica (ethyl acetate/hexanes) to afford (3S)-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (1.13 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([OH:9])=[O:8])[N:3]=[CH:2]1.[ClH:10].[CH3:11]O>O1CCOCC1>[ClH:10].[CH3:11][O:8][C:7](=[O:9])[CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)Cc1c[nH]cn1
Temperature: 60 °C

Procedure:
A solution of 4-imidazoleacetic acid (4.2 g, 26 mmol) in methanol (150 mL) is treated with HCl in dioxane (5 mL). The mixture is heated at 60° C. overnight. The solution is evaporated to give a white solid, which is then recrystallized from ether/hexane to yield 4-imidazoleacetic acid methyl ester hydrochloride. The yield is 4.5 g, 98%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][NH:5][C:4]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:3]1=2.N1C=CC=CC=1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25]>CN(C)C1C=CN=CC=1.ClCCCl>[N+:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][C:24]([N:5]2[CH2:6][CH2:7][CH2:8][C:2]([CH3:16])([CH3:1])[C:3]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:4]2=3)=[O:25])=[CH:32][CH:31]=1)([O-:35])=[O:34]
Reactant: CC1(C)CCCNc2cc([N+](=O)[O-])ccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC1(C)CCCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 41 h
Yield: 46 %

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.797 g, 3.62 mmol), Pyridine (6.310 mL, 3.83 mmol) and 4-Dimethylaminopyridine (21 mg, 0.17 mmol) were dissolved in anhydrous 1,2-Dichloroethane (5.0 mL) before adding p-Nitrophenyl Chloroformate (0.541 g, 2.68 mmol). The reaction was stirred at room temperature for 41 hours and then concentrated under reduced pressure. The residue was purified by normal phase chromatography to yield an off-white solid, 5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 4-nitro-phenyl ester (0.475 g, 46%). LCMS: m/z=386.07 (M+H+). 1H NMR (400 MHz, CDCl3) δ 8.21 (m, 4H), 7.65 (d, 1H, J=8.8 Hz), 7.42 (m, 1H), 7.23 (m, 1H), 4.53 (m, 1H), 2.87 (m, 1H), 2.32 (m, 1H), 1.69 (m, 5H), 1.34 (m, 4H).