Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:9]1[CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[NH:6][C:7]2[C:15]([NH:16][S:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:14][CH:13]=[CH:12][C:8]1=2)(=[O:30])[CH3:29]
Reactant: COc1ccc(S(=O)(=O)Nc2cccc3c2Nc2ccccc2CN3)cc1
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(S(=O)(=O)Nc2cccc3c2Nc2ccccc2CN3C(C)=O)cc1

Procedure:
N-(10,11-Dihydro-5H-dibenzo(b,e)(1,4)diazepin-6-yl)-4-methoxybenzensulfonamide, which had been synthesized in the same manner as the one of Example 31, was reacted with acetic anhydride at room temperature. Then the obtained product was purified by silica gel column chromatography and thus the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[C:11]([CH2:30][OH:31])=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:26]([CH3:28])[CH3:27])[CH:22]=4)[C:17]3=[O:29])[CH:13]=[CH:14][CH:15]=2)[CH:3]=1.O=C1CCC(=O)N1[O:39][C:40](=O)[CH2:41][C:42]#[N:43]>O1CCOCC1.C(O)C.C(OC(=O)C)C>[C:42]([CH2:41][C:40]([NH:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([N:26]([CH3:27])[CH3:28])[CH:22]=4)[C:17]3=[O:29])[C:11]=2[CH2:30][OH:31])[CH:3]=1)=[O:39])#[N:43]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(N)c(=O)n(C)c3)c1CO)C2=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)c1ccc2c(c1)CCN(c1cccc(-c3cc(NC(=O)CC#N)c(=O)n(C)c3)c1CO)C2=O
Temperature: 55 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
2-[3-(5-Amino-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-2-hydroxymethyl-phenyl]-6-dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (40 mg, 0.095 mmol) was placed in a mixture of 1.5 ml dioxane and 0.5 ml of ethanol. To this mixture was added cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester, at first 1 equivalent (17.4 mg, 0.095 mmol), and then over a period of 3 days 5 more equivalents of this reagent at 2-4 hours intervals. During this time the reaction mixture was heated at 50-60° C. After cooling, the reaction mixture was diluted with ethylacetate, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by Prep TLC with 5% methanol in dichloromethylene to afford 12 mg (26% yield) of 2-Cyano-N-{5-[3-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl}-acetamide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([C:19]([OH:21])=O)=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[I-].ClC1C=CC=C[N+]=1C>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:18]2[C:13](=[C:14]([CH3:22])[C:15]([C:19]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])=[CH:16][CH:17]=2)[S:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccncc1
Reactant: Cc1c(C(=O)O)ccc2c1SCC[C@@H]2NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Product: Cc1c(C(=O)Nc2ccncc2)ccc2c1SCC[C@@H]2NC(=O)OC(C)(C)C
Yield: 75.3 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 53 using (S)-4-(tert-butoxycarbonylamino)-8-methylthiochromane-7-carboxylic acid (2.00 g), 4-aminopyridine (582 mg) and 2-chloro-1-methylpyridinium iodide (2.37 g), the objective (S)-4-(tert-butoxycarbonylamino)-8-methyl-N-(4-pyridyl)thiochromane-7-carboxamide (1.86 g) was obtained as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2.CC(C)=O.[CH2:16]1[S:20](=[O:22])(=[O:21])[O:19][CH2:18][CH2:17]1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:18][CH2:17][CH2:16][S:20]([OH:22])(=[O:21])=[O:19])[CH2:7][CH2:6][CH2:5]2
Reactant: O=S1(=O)CCCO1
Reactant: Brc1ccc2c(c1)CCCN2
Solvent: CC(C)=O
Solvent: CO
Product: O=S(=O)(O)CCCN1CCCc2cc(Br)ccc21

Procedure:
4.2 g of the 6-bromo-1,2,3,4-tetra-hydroquinoline obtained according to a) above were dissolved in 0 ml. acetone and, while stirring at 50° C., 2.44 g. molten propane-1,3-sultone, dissolved in 20 ml. acetone, were added dropwise within the course of 30 minutes. After boiling under reflux for 24 hours, a further 2.44 g. molten propanesultone, dissolved in 20 ml. acetone, were added dropwise under the same conditions. After boiling under reflux for 48 hours, the reaction mixture was subjected to column chromatography (silica gel; elution agent chloroform/methanol=1/1 v/v; 25 ml. fractions); fractions 6-10 were evaporated in a vacuum at 35° C., the 1.8 g. of red-brown residue obtained was stirred with about 20 ml. methanol and 1.05 g of sand-coloured crystals were obtained; m.p. 217° C. (decomp.).
Reaction SMILES: [CH2:1]1[N:11]2[C:12]3[C:8]([C@@H:9]4[CH2:16][NH:15][CH2:14][CH2:13][C@@H:10]42)=[CH:7][CH:6]=[CH:5][C:4]=3[O:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][C:21]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[NH:23][N:22]=1>>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:21]([CH2:20][CH2:19][CH2:18][N:15]3[CH2:14][CH2:13][C@@H:10]4[N:11]5[CH2:1][CH2:2][O:3][C:4]6[CH:5]=[CH:6][CH:7]=[C:8]([C:12]5=6)[C@@H:9]4[CH2:16]3)=[N:22][NH:23]2)=[CH:28][CH:27]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCO2
Reactant: Fc1ccc2c(CCCCl)n[nH]c2c1
Product: Fc1ccc2c(CCCN3CC[C@H]4[C@@H](C3)c3cccc5c3N4CCO5)n[nH]c2c1

Procedure:
The title compound was prepared by the method of Example 355 Step B as a yellow oil (60 mg, 63%) from (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino-[2,3,4-hi]pyrido[4,3-b]indole (63 mg, 0.29 mmol) and 3-(3-chloropropyl)-6-fluoroindazole (93 mg, 0.43 mmol). 1H NMR (CDCl3, 300 MHz) δ1.89-2.15 (m, 5H), 2.27-2.38 (m, 1H), 2.43-2.55 (m, 2H), 2.71-2.80 (m, 2H), 2.88-3.02 (m, 3H), 3.18-3.32 (m, 3H), 4.43 (dd, J=6.2, 1.8 Hz, 2H), 6.60-6.72 (m, 3H), 6.90 (dt, J=9.1, 2.2 Hz, 1H), 7.07 (dd, J=9.2, 1.9 Hz, 1H), 7.63 (dd, J=8.8, 5.1 Hz, 1H), 9.85-10.15 (br-s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]([C:10]1[S:11][C:12]([S:33][CH3:34])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([OH:31])=[CH:26][C:25]=3[CH3:32])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:42]([O:44][P:45]([CH2:50]OS(C(F)(F)F)(=O)=O)([O:47][CH2:48][CH3:49])=[O:46])[CH3:43]>CN(C=O)C>[CH2:42]([O:44][P:45]([CH2:50][O:31][C:27]1[CH:26]=[C:25]([CH3:32])[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]3[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])=[NH:9])[S:11][C:12]=3[S:33][CH3:34])(=[O:17])=[O:16])[CH:19]=2)=[C:29]([CH3:30])[CH:28]=1)(=[O:46])[O:47][CH2:48][CH3:49])[CH3:43]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(O)cc2C)c1
Reactant: CCOP(=O)(COS(=O)(=O)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOP(=O)(COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(C)c1)OCC
Reaction time: 18 h

Procedure:
To a flask containing {[4-(4′-hydroxy-2′,6′-dimethyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 224: step b) 233 mg, 0.42 mmol), Cs2CO3 (137 mg, 0.42 mmol), DMF (2 mL), and trifluoro-methanesulfonic acid diethoxy-phosphorylmethyl ester (200 mg, 0.67 mmol, (Xu, Y. et al J. Org. Chem. 61, 7697 (1996); Phillion, D. et al Tetrahedron Lett. 27, 1477 (1986)) were added and heated to 50 C. This mixture was heated and stirred for 18 h under an Ar atmosphere. DMF was removed under vacuum and the residue was taken in EtOAc and washed with water and saturated NaCl. The EtOAc layer was separated dried over Na2SO4 and evaporated under vacuum to give an oil. This was purified by preparative thin-layer chromatography (EtOAc/Hexane) to give 94 (33%) of {3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-2,6-dimethyl-biphenyl-4-yloxymethyl}-phosphonic acid diethyl ester as a white solid. This solid was dissolved in dichloromethane (2 mL), and cooled in an ice bath. To this iodotrimethylsilane (Aldrich Chemical Company, 60 μL) was added and the mixture was stirred for 1 h at which time the dichloromethane was removed and the residue was taken in MeOH and treated with 6N HCl. This mixture was stirred for 3 h and the solvents were removed under high vacuum. To this residue a 50% solution of TFA in dichloromethane was added and the mixture was stirred for 1 h. TFA and dichloromethane were removed under vacuum and the residue was purified by preparative HPLC (Rev. Phase acetonitrile/water) which yielded the title compound as a white solid (30 mg, 33%). 1H-NMR (CD3OD): δ 7.8–7.7 (m, 2H), 7.62 (s, 1H), 7.5–7.3 (m, 2H), 6.7 (s, 2H), 3.77 (d, 2H, J=9.8 Hz), 2.44 (s, 3H), 1.74 (s, 6 H). ESI-MS (m/z): Calcd. for C21H23N2O6PS3: 527.1 (M+H); found: 527.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](C#N)[CH2:9][CH2:10][C:11]([CH2:13]CC(C#N)C2C(C)=NC=CC=2)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(CCC(C1C(C)=NC=CC=1)=O)#[N:28].BrCCCC#N>N.[Ni]>[CH3:1][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH:8]1[NH:28][CH2:13][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1ncccc1C(=O)CCC#N
Reactant: Cc1ncccc1C(C#N)CCC(=O)CCC(C#N)c1cccnc1C
Agent: [Ni]
Agent: N
Agent: N#CCCCBr
Product: Cc1ncccc1C1CCCCN1
Reaction time: 20 h
Yield: 89 %

Procedure:
The preparation of 2-methyl-3-pyridyl-3-cyanopropyl ketone was carried out using the procedure described for the synthesis of 2-methyl-3-pyridyl 2-cyanomethyl ketone (Preparation III) except that 4-bromobutyronitrile was used instead of 3 bromopiopionitrile. A solution of 2.8 g of the ketone in 150 ml ammonia saturated ethanol was prepared and 10 g of freshly prepared Raney nickel was added. The mixture was hydrogenated for 20 hours in a Parr apparatus at 67 psi. The reaction mixture was worked up as in Example 2. The product was isolated by distillation (108°-112°/0.2 mm Hg) to give 2.2 g (89%) of 2-methylanabasine.
Reaction SMILES: I[C:2]1[C:3]([CH3:19])=[N:4][N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:6]=1[CH3:7].C1COCC1.C([Mg]Cl)(C)C.CO[B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1>>[CH3:19][C:3]1[C:2]([B:32]2[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]2)=[C:6]([CH3:7])[N:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)[N:4]=1
Reactant: COB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(I)c2C)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@H](n2nc(C)c(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl trans-4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)cyclohexane-carboxylate (100.0 mg, 0.2658 mmol) in THF (5 mL, 60 mmol) was added 2 M isopropylmagnesium chloride in THF (0.5316 mL, 1.063 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.2178 mL, 1.329 mmol) was added, and the mixture stirred at rt overnight. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]2[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1.[CH3:17][S:18]SC.O>CCCCCC.CCOCC>[Br:16][C:14]1[CH:13]=[CH:12][C:9]2[S:10][CH:11]=[C:7]([S:18][CH3:17])[C:8]=2[CH:15]=1
Reactant: CSSC
Reactant: Brc1ccc2scc(Br)c2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1csc2ccc(Br)cc12
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A solution of n-butyl-lithium in hexane (35 ml of 1.55M solution) was added dropwise to a stirred solution of 3,5-dibromobenzo[b]thiophene (14.6 g) in dry ether (600 ml) at -70° C. under dry nitrogen. The mixture was stirred at -70° C. for 30 minutes and then a solution of dimethyl disulphide (4.90 g) in 10 ml of dry ether was added with stirring over 5 minutes. The resulting mixture was stirred at -70° C. for 4 hours and then allowed to warm up to room temperature. Water (50 ml) was added and the organic layer was separated, washed with water and dried (Na2SO4). Evaporation of the ether gave an oil which was chromatographed on silica gel. Elution with petrol (b.p. 40°-60°) gave a small amount of impurity followed by pure product. The product-containing fractions were evaporated and the residue was distilled to give 5-bromo-3-methylthiobenzo[b]thiophene (10.36 g), b.p. 140°-144° @ 0.6 mm, m.p. 56°-57°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11]C)=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[N:5]=[C:4]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:3]=1.[OH-].[Na+]>CO>[CH3:1][C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=[O:10])=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:25]=2[N:24]=[CH:23][CH:22]=[CH:21]3)[N:5]=[C:4]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCCC2)nc1-c1cccc2cccnc12
Yield: 10.7 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-methyl-2-(piperidin-1-yl)-6-(quinolin-8-yl)pyrimidin-5-yl)pentanoate (0.057 g; 0.136 mmol), sodium hydroxide 10N solution (0.200 mL; 2.00 mmol) in methanol (2 mL) at 60° C. for 18 h. Purification by flash-chromatography on silica gel using a gradient of methanol (1-10%) in dichloromethane, followed by a purification by preperative HPLC (HPLC method 1) furnished 0.0059 g (9%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[C:6]([N:8]1[C@@H:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:10][CH2:11][CH2:12][C@@H:13]1[CH3:14])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: [BH3-]C#N
Reactant: CCCCCC1CCC=C(C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-6-methyl-2-n-pentyl-1,2,3,4-tetrahydropyridine (1.0 g, 3.55 mmol) in 240 mL of CH2Cl2 was added sodium cyanoborohydride (1.34 g, 21.3 mmol). After being stirred 15 minutes at room temperature, the heterogeneous solution was cooled to −42° C. and TFA (3.5 mL, 35.53 mmol) was added slowly dropwise. After being stirred for 4 h at −42° C., the cold bath was removed, and the reaction mixture was immediately quenched with 200 mL of a saturated aqueous NaHCO3/THF mixture (50:50). The aqueous phase was extracted with CH2Cl2 (2×70 mL) and the combined organic extracts were washed with water and brine. The organic phase was dried with K2CO3, filtered through Celite, and evaporated to give crude product. Column chromatography using 5% EtOAc in hexanes gave 0.54 g (54%) of the product which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ 3.99-3.82 (m, 1H), 3.79-3.74 (m, 1H), 1.91-1.15 (m, 28H), 0.92-0.83 (t, 3H); 13C NMR (75 Mhz) 155.6 (s), 78.6 (s), 51.6 (s), 46.9 (s) 34.34 (s), 31.9 (s), 29.3 (s), 28.5 (s), 27.1 (s), 26.9 (s), 23.1 (s), 22.6 (s), 20.8 (s), 14.0 (s), 13.7 (s) ppm.
Reaction SMILES: N[C:2]1[C:3]([CH2:20][CH3:21])=[C:4]([N:10]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[CH:11]2)[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1.[BrH:22].N([O-])=O.[Na+].N([O-])=O.NC(N)=O>O.[Cu](Br)Br.C(O)(=O)C>[Br:22][C:2]1[C:3]([CH2:20][CH3:21])=[C:4]([N:10]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:12]=[CH:11]2)[C:5]([CH2:8][CH3:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cncn1-c1c(CC)ccc(N)c1CC
Reactant: Br
Agent: Br[Cu]Br
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cncn1-c1c(CC)ccc(Br)c1CC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
20 g (0.07 mol) of ethyl 1-(3-amino-2,6-diethylphenyl)imidazole-5-carboxylate were added to a mixture of 30 ml of concentrated hydrobromic acid, 30 ml of glacial acetic acid and 30 ml of water, the mixture was cooled to 0° C., and a solution of 12.0 g (0.17 mol) of sodium nitrite in 15 ml of water was added dropwise at this temperature. After 30 minutes at 0° C., the excess nitrite was decomposed using urea, and the solution was added dropwise at 0° C. to a copper bromide solution (prepared by conventional processes from 24.9 g of copper sulfate, 15.5 g of sodium bromide, 6.3 g of sodium sulfite, 80 ml of water and 40 ml of concentrated hydrobromic acid). The reaction mixture was allowed to warm to room temperature and was neutralized, the product was extracted with methylene chloride, and the organic phase was washed with water, dried over sodium sulfate and evaporated. After chromatographic purification, 17.4 g (71% of theory) of ethyl 1-(3-bromo-2,6-diethylphenyl)-imidazole-5-carboxylate were obtained as a pale yellow oil. Identification was effected by 1H NMR spectroscopy.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH3:21][O:22][C:23]1[CH:34]=[CH:33][C:26]2[CH:27]=[C:28]([C:30](O)=[O:31])[O:29][C:25]=2[CH:24]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30]([C:28]1[O:29][C:25]2[CH:24]=[C:23]([O:22][CH3:21])[CH:34]=[CH:33][C:26]=2[CH:27]=1)=[O:31]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: COc1ccc2cc(C(=O)O)oc2c1
Product: COc1ccc2cc(C(=O)Nc3ccc(N4CCC(CN5CCCC5C)C4)cc3C)oc2c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 6-methoxy-benzofuran-2-carboxylic acid. MS: 448.5 (M+H).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].CC(O)C.B.C(N)(C)(C)C.[CH3:16][O:17][C:18](=[O:27])[CH:19]=[C:20]([NH2:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[S:1](=[O:3])(=[O:2])([OH:5])[OH:4].[CH3:25][O:24][C:22](=[O:23])[CH2:21][CH:20]([NH2:26])[CH2:19][C:18]([O:17][CH3:16])=[O:27]
Reactant: COC(=O)C=C(N)CC(=O)OC
Agent: B
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CC(C)(C)N
Product: COC(=O)CC(N)CC(=O)OC
Reaction time: 8 h
Yield: 96.6 %

Procedure:
A diluted alcoholic sulfuric acid solution is prepared by adding sulfuric acid (20.69 Kg) to i-PrOH (51.7 Kg) at 0-5° C. The resulting solution was slowly added to a solution of tert-butylamine borane (9.19 Kg) in THF (69.3 Kg), maintaining the temperature below −5° C. Dimethyl-3-aminoglutaconate (18.28 Kg) was slowly added to the resulting mixture, maintaining the temperature below 0° C. The resulting reaction mixture was stirred between 0° C. and 15° C. overnight, then quenched by slow addition to water (166 Kg) while maintaining the temperature below 10° C. and the pH between 5 and 7 by adding concentrated aqueous NaOH. The pH of the mixture was then adjusted to about 9-10 by adding concentrated aqueous NaOH at the end of the quenching process. The phases were separated and the aqueous phase was extracted with DCM. The combined organic extracts were washed with brine (20.6 Kg), filtered through a cotton cartridge and concentrated under reduced pressure to give 3-amino-pentanedioic acid dimethyl ester (17.87 Kg, 97% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:33]=[CH:32][C:12]([C:13]([NH:15][CH2:16][C:17]2[C:18]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[C:11]([NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)[N:10]=1)#[N:2].Cl>CO.O1CCOCC1>[NH2:24][CH2:23][C:18]1[C:17]([CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:32]=[CH:33][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[N:10][C:11]=2[NH:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)NCc1ncccc1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccccc1-c1ccc(C(=O)NCc2cccnc2CN)c(NCCc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of tert-butyl (3-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyridin-2-yl)methylcarbamate (737 mg, 1.27 mmol) in methanol (6 mL) at 0° C. was added a solution of 4M HCl in 1,4-dioxane (3 mL). The mixture was warmed to room temperature and stirred for 2 hrs. Concentration of the mixture followed by the purification on RP-HPLC using a mixture of acetonitrile and H2O gave N-((2-(aminomethyl)pyridin-3-yl)methyl)-6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamide as a pale yellow solid (545 mg, 89%). LRMS (M+H+) m/z 481.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[CH2:13]([O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1O

Procedure:
A mixture of methyl 2,4-dihydroxybenzoate (50 g), benzyl chloride (37 mL), tetrabutylammonium bromide (0.25 g), potassium carbonate (44.4 g) and potassium iodide (18.4 g) in acetone is stirred at reflux overnight. The reaction mixture is evaporated to dryness and the residue is partitioned between water (300 mL) and ethyl acetate (300 mL). The organic layer is washed with aqueous sodium hydrogen carbonate solution and water, dried and evaporated. Crystallisation of the residue from ethyl acetate gives methyl 4-benzyloxy-2-hydroxybenzoate (45.1 g), in the form of a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:31][CH:32]=O>>[CH3:20][C:21]1[C:29]2[CH2:28][O:27][C:26](=[O:30])[C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:31][CH2:32][N:6]1[CH2:5][CH2:4][N:3]([CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[C:2](=[O:1])[CH2:7]1
Reactant: Cc1c(CC=O)ccc2c1COC2=O
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Product: Cc1c(CCN2CCN(C3CCc4cc(C#N)ccc4C3)C(=O)C2)ccc2c1COC2=O

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and (4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 430 [M+1]+.