Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:24][CH3:25])[C:10]([S:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:26])[CH:3]=1.[NH3:27]>CO>[CH3:26][C:4]1[CH:3]=[C:2]([NH2:27])[N:7]2[N:8]=[C:9]([S:24][CH3:25])[C:10]([S:11]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc2ccccc2c1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-5-methyl-2-methylsulphanyl-3-(naphthalene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(naphthalene-2-sulphonyl)-pyrazolo[1,5-a]pyrimidine-7-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.O>CC(O)C>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]2[N:12]=[C:7]([C:4]3[O:3][C:2]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[N:6][CH:5]=3)[CH:8]=[CH:9][CH:10]=2)[CH:19]=1
Reactant: NCc1ccncc1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(Cl)o3)n2)c1
Solvent: O
Solvent: CC(C)O
Product: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Yield: 55 %

Procedure:
A solution of [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (50 mg, 0.174 mmol) in iPrOH (5 ml) was treated with 4-aminomethylpyridine (53 μl) and heated to reflux for 40 h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on Al2O3 (Brockman grade III, 7% H2O), eluting with 2% EtOH in DCM. Precipitation from DCM with n-pentane afforded the title compound as pale yellow solid (34 mg, 55%). 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.52 (d, J=4.6 Hz, 2H), 8.25 (t, J=5.8 Hz, 1H), 8.08 (d, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.36 (d, J=4.9 Hz, 2H), 7.29 (s, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.73 (d, J=5.0 Hz, 1H), 4.49 (d, J=5.7 Hz, 2H), 2.29 (s, 3H). (ESI+) m/z 359 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](=[O:23])[N:6]([CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[N:7]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][CH2:8][N:6]3[C:5](=[O:23])[CH:4]=[CH:3][C:2]([C:26]4[CH:27]=[CH:28][S:24][CH:25]=4)=[N:7]3)=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(OCCn3nc(Cl)ccc3=O)ccnc2c1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc2c(OCCn3nc(-c4ccsc4)ccc3=O)ccnc2c1
Temperature: 120 °C
Yield: 72.2 %

Procedure:
To a solution of 6-chloro-2-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridazin-3(2H)-one (0.090 g, 0.27 mmol) and 3-thiopheneboronic acid (0.069 g, 0.54 mmol) in 4 mL of dioxane was added 1 mL of 1N Na2CO3 followed by 30 mg of FibreCat, in a microwave vial. The reaction was heated to 120° C. for 30 minutes. The mixture was then diluted with 40 mL of NaHCO3 and 60 mL of EtOAc. The organic phase was separated, washed with 30 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtAOc to 10% MeOH/EtOAc) to give a white solid (0.074 g, 72% yield). MS (ESI pos. ion) m/z (MH+): 380.1. Calc'd Exact Mass for C20H17N3O3S: 379.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:35])C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([C:18]4[CH:23]=[CH:22][N+:21]([O-:35])=[CH:20][CH:19]=4)[CH2:14]3)=[O:12])[CH2:9][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(N1CC[C@@H](c2ccncc2)C1)C1(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: O=C(N1CC[C@@H](c2cc[n+]([O-])cc2)C1)C1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-((3S)-1-{[1-(4-Chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-yl)pyridine (20 mg 0.00006 mol, example 24) was dissolved in dichloromethane (1 mL, 0.02 mol) and to this solution was added m-chloroperbenzoic acid (44 mg, 0.00015 mol). The reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture then was concentrated and the residue was diluted with NaHCO3 and methanol. The crude product was purified by prep-HPLC. LCMS: m/z 343.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([NH2:43])([CH3:42])([CH3:41])[CH3:40]>CO>[C:39]([NH:43][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:16]1[CH:15]=[C:14]2[C:19]([C:20](=[O:22])[CH:21]=[C:12]([C:11]3[CH:28]=[C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)[O:13]2)=[CH:18][CH:17]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)N
Reactant: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Solvent: CO
Product: CC(C)(C)NCC(O)COc1ccc2c(=O)cc(-c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3)oc2c1

Procedure:
A solution of 3′,5′-dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 28 (2.5 g, 4.9 mmol) and tert-butyl amine (1.05 mL, 9.8 mmol) in dry methanol (150 mL) was stirred at reflux for 6 h. Reaction mixture was concentrated on rotavapor and crude product purified by column chromatography to afford 34. Yield 2.6 g (93%); mp 170-171° C.; MS (FAB) 580 (M++1); IR (KBr) 3428, 1648; 1H NMR (200 MHz, CDCl3) δ 8.02 (d, J=8.8 Hz, 1H), 7.59-7.33 (m, 10H), 7.13 (d, J=1.9 Hz, 2H), 7.07 (s, 1H), 7.01 (dd, J=9.8 Hz, 2.0 Hz, 1H), 6.76 (s, 1H), 6.71 (s, 1H), 5.12 (s, 4H), 4.57-4.54 (m, 1H), 4.27-4.16 (m, 2H), 3.24 (d, J=10.5 Hz, 1H), 3.05 (t, J=10.6 Hz, 1H), 1.45 (s, 9H); 13C NMR δ 178.3, 163.5, 163.2, 160.7, 158.1, 136.8, 133.9, 129.0, 128.6, 127.9, 127.5, 118.3, 115.2, 108.0, 105.9, 101.5, 72.9, 70.8, 67.5, 54.0, 45.3, 28.1. Analysis Calcd for C36H37NO6: C, 74.59; H, 6.43; N, 2.42. Found: C, 74.44; H, 6.35; N, 2.51.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)[C:28]=1[C:29]#[N:30]>C1COCC1>[NH2:30][C:29]1[C:28]2[C:27](=[CH:34][CH:33]=[CH:32][C:31]=2[N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:13][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:11]=1
Reactant: CCOC(=O)Cc1nc2cccnc2[nH]1
Reactant: C[C@@H]1CN(c2cccc(N)c2C#N)C[C@H](C)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2cccc3[nH]c(=O)c(-c4nc5cccnc5[nH]4)c(N)c23)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3.0 equivalents) was added to ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate (1.0 equivalent) in THF at −78° C. After 20 minutes, a solution of 2-amino-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]benzonitrile (1.1 equivalents) in THF was added. The resulting mixture was allowed to warm to room temperature, stirred for 2 hours, and then it was heated to 60° C. overnight. The mixture was cooled to 0° C. and quenched with an aqueous saturated NH4Cl solution. The aqueous phase was extracted with CH2Cl2 (5 times) and the organic extracts were collected, dried (Na2SO4), and concentrated. The crude product was purified by HPLC. LC/MS m/z 391.2 (MH+), Rt 2.35 minutes.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][C:6](=[O:8])[CH:5]([CH2:9][C:10](=O)[CH3:11])[C:4](=O)[CH2:3]1.C([O-])(=O)C.[NH4+:19].O>C(O)(=O)C>[CH3:11][C:10]1[NH:19][C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:7][C:6](=[O:8])[C:5]=2[CH:9]=1
Reactant: CC(=O)CC1C(=O)CC(C)(C)CC1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c([nH]1)CC(C)(C)CC2=O
Temperature: 65 °C

Procedure:
The crude tri-ketone from Example 37 was dissolved in 300 mL of acetic acid to which ammonium acetate (55 g, 0.714 mmol) was added. The reaction mixture was heated at 65° C. until all starting material had disappeared (2-3 h), cooled to RT, added to H2O, and washed with EtOAc. The organic layer was washed with saturated NaHCO3 (×3), brine (×1) and dried over MgSO4. Solvent was removed in vacuo and the oily residue was passed through a plug of silica. The appropriate fractions were collected and solvent was removed. The resulting solid was washed with EtOAc and hexanes (if too much hexanes is added the material crashing back out of solution after the addition of EtOAc will be gummy. To remedy this simply add a little EtOAc). The solid was filtered and washed with hexanes. More solid can be recovered by removing the solvent and repeating this procedure. LCMS m/z M+H=178.1. Approximately 5 g of a tan solid was collected and identified as 2,6,6-trimethyltetrahydroindol-4-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:22])[NH:9][CH2:10][C:11]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[O:22][C:11]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])=[CH:10][N:9]=1
Reactant: COC(=O)CCCCC(=O)NCC(=O)c1cc(Cl)ccc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCc1ncc(-c2cc(Cl)ccc2OC)o1
Reaction time: 17 h
Yield: 49.2 %

Procedure:
Dissolve 5-[2-(5-Chloro-2-methoxy-phenyl)-2-oxo-ethylcarbamoyl]-pentanoic acid methyl ester (9.39 g, 27.47 mmol) and 4-(dimethylamino)pyridine (6.54 g, 53.53 mmol) in 250 mL of CH2Cl2 and cool the reaction mixture in an ice bath. Add triphenylphosphinedibromide (22.54 g, 53.40 mmol) to the reaction portionwise over 15 minutes. Raise the reaction to ambient temperature and allow it to stir for 17 hours. Wash the reaction with water (1×) and brine (2×). Dry the organic layers with MgSO4. Filter off the drying agent and concentrate in vacuo to afford a crude residue. Purify the residue using silica gel chromotagraphy eluting with hexanes/ethyl acetate mixtures to afford 4.38 g of the titled product (49%): mass spectrum: m/z=324.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=O)[C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:3])[NH2:2].C(N(CC)CC)C.C[Si](Cl)(C)C>ClCCCl>[F:24][C:16]([F:25])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:15]1[N:2]=[C:1]([OH:3])[C:4]2[C:5](=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[N:14]=1
Reactant: COC(=O)c1ccc(C(N)=O)c(NC(=O)C(F)(F)c2ccc(F)cc2)c1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Temperature: 85 °C
Yield: 90.2 %

Procedure:
To a solution of methyl 4-carbamoyl-3-(2,2-difluoro-2-(4-fluorophenyl)acetamido)benzoate (1.3 g, 3.5 mmol) in DCE (20 mL) were added triethylamine (20 mL, 142 mmol) and trimethylsilyl chloride (6.7 mL, 53.2 mmol and the mixture was heated 85° C. overnight. The mixture was allowed to cool to rt, and then was concentrated under reduced pressure. The residue was partitioned between EtOAc (150 mL) and H2O (100 mL), and the separated aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with MeOH with sonication, and the solid was collected by filtration to afford methyl 2-(difluoro(4-fluorophenyl)methyl)-4-hydroxyquinazoline-7-carboxylate (1.1 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.39 (t, 2H), 7.78 (t, 2H), 8.06 (d, 1H), 8.16 (s, 1H), 8.27 (d, 1H), 13.34 (s, 1H); LC-MS (ESI) m/z 349 (M+H)−.
Reaction SMILES: C[O:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[C:8]#[N:9].[Al+3].[Cl-].[Cl-].[Cl-].CC(=O)OCC>C(Cl)Cl.Cl>[OH:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCOc1cc([N+](=O)[O-])c(C#N)cc1O
Yield: 35.3 %

Procedure:
To a solution of 5-methoxy-4-(2-methoxyethoxy)-2-nitrobenzonitrile (1.5 g) in anhydrous DCM (30 mL) was added anhydrous AlCl3 (6 g) at 0° C. The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was diluted with 1N aqueous HCl (50 mL) and exacted with EA (3×50 mL). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purification by silica chromatography to give 0.5 g of 5-hydroxy-4-(2-methoxyethoxy)-2-nitrobenzonitrile. 1H-NMR (400 MHz, CDCl3): δ: 7.85 (s, 1H), 7.33 (s, 1H), 4.32-4.30 (m, 2H), 3.87-3.84 (m, 2H), 3.50 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH:26][NH2:27])([CH3:25])[CH3:24]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:27][N:26]([CH:23]([CH3:25])[CH3:24])[C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Reactant: CC(C)NN
Product: CCc1nn(C(C)C)c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
4-(1-Benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1-isopropyl-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione and isopropylhydrazine in analogy to Example 190 b): light yellow viscous oil; MS (ISP): 337.3 ((M+H)+.).
Reaction SMILES: [C:1]([O:6][C:7]([C:10]12[CH2:19][C:14]3([O:20]COCCOC)[CH2:15][CH:16]([CH2:18][C:12]([O:27]COCCOC)([CH2:13]3)[CH2:11]1)[CH2:17]2)([CH3:9])[CH3:8])(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl.[Cl-].[NH4+]>CC(C)=O>[OH:20][C:14]12[CH2:19][C:10]3([C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([CH3:9])[CH3:8])[CH2:17][CH:16]([CH2:18][C:12]([OH:27])([CH2:11]3)[CH2:13]1)[CH2:15]2
Reactant: C=C(C)C(=O)OC(C)(C)C12CC3CC(OCOCCOC)(CC(OCOCCOC)(C3)C1)C2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: C=C(C)C(=O)OC(C)(C)C12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 10 mmole of the above-prepared 1-(1-methacryloyloxy-1-methylethyl)-3,5-bis(2-methoxyethoxymethoxy)adamantane, 1 mmole (in terms of HCl) of 6 N-HCl, and 40 ml of acetone was stirred at room temperature for 5 hours. An aqueous ammonium chloride solution was added to the reaction mixture; the resulting mixture was extracted with ethyl acetate; the organic layer was concentrated; and the concentrate was subjected to column chromatography on a silica gel to yield the title compound.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[F:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=4)[CH2:27][NH:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=3)[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:39][CH:38]=3)=[CH:17][CH:18]=2)=[O:24])=[O:9])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(O)Cn1cncn1
Reactant: Cc1cccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Product: Cc1cccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3cncn3)C2)c1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(3-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 171, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methylbenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.00 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.55 (d, 2H), 7.23-7.15 (m, 3H), 7.08-6.91 (m, 8H), 5.23 (q, 2H), 4.53-4.48 (m, 1H), 3.83-3.76 (m, 1H), 2.73-2.61 (m, 4H), 2.29 (s, 3H), 2.00-1.89 (m, 2H). MS (EI) for C29H28FN5O3. found 514.2 (MH+).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:3][CH:2]=1.C1C(=O)N([Br:29])C(=O)C1.O>C1COCC1>[Br:29][C:14]1[C:15]2[C:20]([C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=3)=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: Cc1ccc(-c2c3ccccc3cc3ccccc23)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
4 g (1 eq, 14.9 mmol) of 9-p-tolyl-anthracene, 5.3 g (2 eq, 29.8 mmol) of NBS were dissolved in 200 ml of THF in a 500-ml round-bottomed flask and stirred for 1 hour. 200 ml of water was added to the solution to obtain yellow crystals. The yellow crystals were filtered, dissolved in a small amount of toluene, and separated using column chromatography (silica and hexane) to obtain 4.6 g (89%) of yellow crystals.
Reaction SMILES: Cl.C([O:6][C:7](=[O:36])[CH2:8][N:9]([S:18]([C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:35])=[CH:26][N:27]=[C:28]2[NH:31][C:32]([NH2:34])=[NH:33])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])(C)(C)C>O1CCOCC1>[ClH:35].[C:7]([CH2:8][N:9]([S:18]([C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:35])=[CH:26][N:27]=[C:28]2[NH:31][C:32]([NH2:34])=[NH:33])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10][C:11]([OH:13])=[O:12])([OH:36])=[O:6]
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc12
Temperature: 23 °C
Reaction time: 18 h
Yield: 149.4 %

Procedure:
A solution of HCl (3 mL, 2 M, 6 mmol) was added to a solution of N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(t-butoxycarbonylmethyl)glycine t-butyl ester (90 mg, 0.17 mmol) in dioxane (4.0 mL). The mixture was stirred at 23° C. for 18 h and then heated at 70 ° C. The solvents were evaporated in vacuo and the residue dried to give N-(carboxymethyl)-N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]glycine hydrochloride (61 mg, 0.127 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH:35]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH3:18][C:14]1[CH:13]=[C:12]([C:10](=[O:11])[CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[O:41])[CH2:36][CH:35]=3)=[CH:3][CH:4]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:17]=[CH:16][N:15]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccccc2C)ccn1
Temperature: 85 °C
Yield: 96.6 %

Procedure:
A mixture of (R)-3-(4-bromophenyl)-1-(2-methylpyridin-4-yl)-3-o-tolylpropan-1-one (example 142, step 2; 300 mg, 761 μmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (353 mg, 1.14 mmol), [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (27.8 mg, 38.0 μmol) in 1,4-dioxane (7.5 mL), water (5 mL) and 2 M aq. sodium carbonate solution (1.14 mL, 2.28 mmol) was heated at 85° C. for 4 h, then after cooling partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (365 mg, 97%). White foam, MS (ESI+): m/z=497.4 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH2:5]2.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(Br)c2cc(Br)ccc21

Procedure:
To a solution of 1.2 g (5.0 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 20 ml of CCl4 was added 0.97 g (5.5 mmol) of N-bromosuccinimide followed by 20 mg (0.08 mmol ) of benzoylperoxide. The mixture was refluxed for 3 hours, filtered and the filtrate washed with water (5 ml). The organic phase was dried over MgSO4 and then concentrated in vacuo to yield the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1>C(O)C>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:10]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[CH:11][CH:12]=[N:13]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Solvent: CCO
Product: Oc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
4-Aminophenol (1.09 g, 10 mmol) and 4,7-dichloroquinoline (1.98 g, 1 eq) were refluxed in 50 mL of ethanol for 2 h. The reaction mixture was then cooled to room temperature and the precipitate was removed by filtration and washed successively with a saturated aqueous solution of NaHCO3, water, methanol and then petroleum ether to yield expected compound as a yellow powder (2.57 g, 95% yield). m/z (ESI) 271.1 [M+H]+.
Reaction SMILES: [C:1]([N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10]O)=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2].P(Br)(Br)[Br:15]>C(Cl)Cl>[C:1]([N:4]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Br:15])=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)c1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(=O)N(C)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 4-(N-acetyl-N-methylamino)benzyl alcohol (543.0 mg, 3.0 mmol), prepared as in step 2, dissolved. in dry CH2Cl2 (11.5 mL) was added dropwise 1M PBr3 in CH2Cl2 (3.6 mL, 3.6 mmol) at 0° C. The reaction was stirred at ambient temperature until TLC indicated complete reaction (~5 hours). The resulting solution was partitioned between ethyl acetate and brine. The combined organic layers were decolorized with charcoal, dried (MgSO4), filtered through celite and concentrated in vacuo. Purification by flash chromatography on silica gel (40% ethyl acetate / hexane) provided 4-(N-acetyl-N-methylamino)benzyl bromide as a colorless solid (595 mg, 81.0%). 1H NMR (300 MHz, CDCl3) δ7.46 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 4.50 (2H, s), 3.27 (3H, s), 1.88 (3H, br s). MS m/e 242 (M+H)+, 259/261 (M+NH4)+. Analysis calc'd for C10H12NOBr: C, 49.61; H, 5.00; N, 5.79. Found: C, 49.35; H, 4.97; N, 5.65.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:24]=[CH:23][C:17]([O:18][CH2:19][C@@H:20]([NH:22][C:27](=[O:29])[CH3:28])[CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H](N)COc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Product: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
(S)-2-[4-(4-Benzyloxyphenoxy)phenoxy]-1-methylethylamine (195 mg, 0.56 mmol) was reacted with acetic anhydride in analogy to example 2a. Yield: 218 mg (100%), M+H+: 392.18.