Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=3)[CH2:8]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:35][CH:36]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]([O:39][C:37]([N:34]1[CH2:33][CH:32]=[C:31]([C:2]2[CH:22]=[CH:21][C:5]([CH2:6][N:7]3[CH2:16][CH2:15][C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[CH:13]=4)[CH2:8]3)=[CH:4][CH:3]=2)[CH2:36][CH2:35]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1ccc2c(c1)CCN(Cc1ccc(Br)cc1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCN(Cc1ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc1)C2
Temperature: 80 °C
Yield: 82.1 %

Procedure:
A solution of methyl 2-(4-bromobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (200.0 mg, 0.600 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (188.8 mg, 0.6107 mmol) in DME (5.15 mL) was treated with Na2CO3 (2.00 M in water, 0.83 mL, 1.66 mmol). The mixture was degassed and Pd(Ph3P)4 (13 mg, 0.011 mmol) was added. The reaction mixture was heated under argon at 80° C. overnight. The mixture was then cooled to room temperature and diluted with water. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 10-50% EtOAc in hexanes) to give methyl 2-{4-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]benzyl}-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (228 mg, 89%). LC-MS: (FA) ES+ 263.
Reaction SMILES: OCCS(CCN[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)(=O)=O.[C:48]([O:52][C:53]([NH:55][CH2:56][CH2:57][NH:58][C@:59]12[CH2:94][CH2:93][C@@H:92]([C:95]([CH3:97])=[CH2:96])[C@@H:60]1[C@@H:61]1[C@@:74]([CH3:77])([CH2:75][CH2:76]2)[C@@:73]2([CH3:78])[C@@H:64]([C@:65]3([CH3:91])[C@@H:70]([CH2:71][CH2:72]2)[C:69]([CH3:80])([CH3:79])[C:68]([C:81]2[CH:90]=[CH:89][C:84]([C:85]([O:87]C)=[O:86])=[CH:83][CH:82]=2)=[CH:67][CH2:66]3)[CH2:63][CH2:62]1)=[O:54])([CH3:51])([CH3:50])[CH3:49]>>[C:48]([O:52][C:53]([NH:55][CH2:56][CH2:57][NH:58][C@:59]12[CH2:94][CH2:93][C@@H:92]([C:95]([CH3:97])=[CH2:96])[C@@H:60]1[C@@H:61]1[C@@:74]([CH3:77])([CH2:75][CH2:76]2)[C@@:73]2([CH3:78])[C@@H:64]([C@:65]3([CH3:91])[C@@H:70]([CH2:71][CH2:72]2)[C:69]([CH3:80])([CH3:79])[C:68]([C:81]2[CH:90]=[CH:89][C:84]([C:85]([OH:87])=[O:86])=[CH:83][CH:82]=2)=[CH:67][CH2:66]3)[CH2:63][CH2:62]1)=[O:54])([CH3:49])([CH3:50])[CH3:51]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCCS(=O)(=O)CCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCNC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the hydrolysis method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(2-hydroxyethylsulfonyl)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(tert-butoxycarbonylamino)ethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (10 mg, 0.015 mmol) as starting material. The title compound was isolated as a white solid (4 mg, 39%). LCMS: m/e 673.45 (M+H)+, 2.65 min (method 10). 1H NMR (500 MHz, Acetic acid d4) δ ppm 8.04 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.55 Hz, 2H), 5.51-5.32 (m, 1H), 4.87 (s, 1H), 4.75 (s, 1H), 3.82-3.53 (m, 1H), 3.53-3.24 (m, 3H), 3.04-2.83 (m, 1H), 2.37-1.15 (m, 22H), 1.77 (s, 3H), 1.53-1.49 (m, 9H), 1.27 (s, 3H), 1.14 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H), 1.00 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:18]([Cl:33])=[CH:17][N:16]=1>>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[C:27]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: CS(=O)(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CS(=O)(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
Title compound was prepared from 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(2-fluoro-6-methanesulfonyl-phenyl)-amine in an analogous manner to Example 1221d. Product isolated as an off-white solid (52 mg, 41%). MP=242-245, LCMS 478.05 (M+H), HPLC purity 93%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 9.19 (s, 1H), 8.89 (s, 1H), 8.20 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.75-7.72 (m, 1H), 7.67-7.64 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.84 (d, J=8.0 Hz, 1H), 3.21 (s, 3H), 2.55-2.51 (m, 2H), 2.07-2.04 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1COc1ccc(F)cc1
Reaction time: 3 h
Yield: 62.7 %

Procedure:
2-Bromomethyl-3-nitropyridine (100 mg, 0.456 mmol) prepared in Step 2 was added at room temperature to a solution of 4-fluorophenol (56 mg, 0.502 mmol) and potassium carbonate (189 mg, 1.37 mmol) in N,N-dimethylformamide (3 ml) and then stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (10 ml), washed with a saturated sodium bicarbonate solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 71 mg of the titled compound as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[Li]CCCC.Cl.C[CH2:19][O:20]C(C)=O>C1COCC1>[F:1][C:2]1[C:3]([CH:19]=[O:20])=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(F)cc1OC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(F)c(C=O)c1OC
Temperature: -78 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a cold (−78° C.) solution of 4-fluoro-1,2-dimethoxybenzene (15.00 g, 96.05 mmol) in anhydrous THF (150 mL) was added n-BuLi (84.5 mL, 211.32 mmol, 2.5 M solution in hexanes) under nitrogen and stirred it for 3 h at −78° C. Quenched the reaction with DMF (75 mL) at −65° C., added 2N HCl (300 mL) dropwise and further stirred for 30 min. Two layers separation was observed. Aqueous layer was extracted with EtOAc. Combined organic layers were washed with water, brine and dried over MgSO4. Filtered the ethyl acetate layer and concentrated it in vacuo. The title compound was purified by flash column chromatography using pure hexanes then 10 and 20% EtOAc in hexanes which provided 14.40 g (78.19 mmol, 82%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 7.36 (dd, J=9.0, 5.1 Hz, 1H), 7.03 (t, J=9.6 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ ppm −131.68-−131.66 (m, 1F).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:18]=2)O)=[CH:13][CH:12]=[CH:11][C:10]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)C1C=CC=CC=1>C(#N)C.[PH2](O)=O>[C:29]1([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:18]=2)[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:9]=2[OH:8])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: OC(c1ccccc1)(c1cccc(-c2ccccn2)c1)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: O=[PH2]O
Solvent: CC#N
Product: Oc1c(-c2ccccc2)cccc1C(c1ccccc1)c1cccc(-c2ccccn2)c1
Yield: 37 %

Procedure:
A solution of 2(0.95 g, 1.83 mmol) in acetonitrile (24 mL) and 50% aqueous hypophosphorous acid (22 mL) was kept at reflux for 64 hr. The acetonitrile was removed in vacuo, the residue was diluted with ethyl acetate (200 mL) and water (100 mL). Phases were separated. The organic phase was washed with saturated sodium bicarbonate (2×80 mL) and water (2×80 mL) dried over sodium sulfate and filtered. The solvent was removed on a rotary evaporator. The crude product was purified by chromatography on silica (80 g) with 10% ethyl acetate in hexane (3 L) to yield slightly impure A1 (0.28 g, total yield: 52%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:10][N:11]1[C:16](=O)[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[C:12]1=O)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C@H:9]([CH:38]1[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)[CH2:10][N:11]1[CH2:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=2[F:26])=[C:14]([CH3:27])[N:13]([CH2:28][C:29]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=2[F:36])[CH2:12]1
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C2=C(C)N(Cc3c(F)cccc3F)CN(C[C@H](N)C3CCCCC3)C2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To compound 11c (300 mg, 0.5 mmol) in dichloromethane (2 mL) was added TFA (2 mL) and the reaction mixture was stirred at ambient temperature for 1 hour. Volatiles were evaporated and the residue was partitioned between saturated NaHCO3/water and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by reverse phase HPLC (C-18 column, 15–75% ACN/water) to give compound 11d. MS (CI) m/z 502.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Cl.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:35](=[O:44])/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:19][C:20]([N:22]2[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23]2)=[O:21])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:35](=[O:44])/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:19][C:20]([N:22]2[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23]2)=[O:21])=[CH:14][CH:13]=1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
3,4-Dichlorobenzyl chloride (15 μL) was added to a mixture of [(S)-1-(2-{(4-hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]carbamic acid, tert-butyl ester 14 (50 mg, 0.11 mmol), cesium carbonate (52 mg, 0.16 mmol) and TBAI (40 mg, 0.11 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed with 10% hydrochloric acid (×2) and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petrol (2:1), to afford the title compound as a colourless foam (46 mg, 68%). 1HNMR (300 MHz) (CDCl3) δ 1.41 (9H, s), 1.7-2.2 (2H, m), 3.35-3.8 (4H, m), 4.15-4.35 (2H, m), 4.5 (1H, m), 4.7-4.9 (1H, m), 5.01 (2H, s), 6.35 (1H, d, J=16 Hz), 6.93 (2H, d), 7.2-7.3 (6H, m), 7.37 (2H, d), 7.44 (1H, d), 7.52 (1H, br s) and 7.64 (1H, d, J=16 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:15]=[C:16]([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH3:15][C:16]([O:10][C:9](=[O:11])[CH2:8][CH2:7][CH2:6][O:5][C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=1)([CH3:18])[CH3:17]
Reactant: O=C(O)CCCOc1cccc(Br)c1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCOc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.3 g of 4-(3-bromophenoxy)butanoic acid, 8 ml of liquid isobutene and 2 drops of sulfuric acid are placed in a pressure-resistant reactor. The reactor is closed and stirred at room temperature for 16 hours. The residual pressure is released gently and the product is taken up with ethyl acetate and sodium bicarbonate solution. The organic phase is washed with water and then dried and concentrated under reduced pressure to give the expected ester in the form of a colorless liquid (yield=94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1.O=[C:20]1[CH2:25][CH2:24][N:23]([C@H:26]([CH3:30])[CH2:27][C:28]#[N:29])[CH2:22][CH2:21]1.[C-]#N.[Na+]>O.CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH:20]3[CH2:25][CH2:24][N:23]([C@H:26]([CH3:30])[CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Oc2ccc(N)cc2)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(NC3CCN([C@H](C)CCN)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Using general procedure A with 4-(4-amino-phenoxy)-benzoic acid methyl ester (see EXAMPLE 96) (300 mg, 1.2 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (225 mg, 1.4 mmol) followed by general procedure J gave a green oil, which was subsequently treated with a solution of NaCN (175 mg) in H2O (5 mL) and MeOH (5 mL). The mixture was stirred at room temperature for 20 minutes to afford 4-{4-[1-((R)-3-amino-1-methyl-propyl)-piperidin-4-ylamino]-phenoxy}-benzoic acid methyl ester as a white solid (238 mg, 48% over 2 steps) following work-up and purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:16]=[N:17][N:18]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=2)=[CH:5][CH:4]=1.[CH2:39]([C:43]1[NH:44][C:45]([CH:49]=[O:50])=[C:46]([Cl:48])[N:47]=1)[CH2:40][CH2:41][CH3:42].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+]>CN(C)C(=O)C>[CH2:39]([C:43]1[N:44]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][N:18]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:19]=3)=[CH:5][CH:4]=2)[C:45]([CH2:49][OH:50])=[C:46]([Cl:48])[N:47]=1)[CH2:40][CH2:41][CH3:42]
Reactant: BrCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-2-triphenylmethyl-2H-tetrazole (0.102 m=63.1 g), 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.113 m=21.1) and anhydrous potassium carbonate (0.135 m=18.6 g) in 251 g of N,N-dimethylacetamide was stirred at 0°-5° C. for 8 hours and the temperature of the reaction was raised to 25° C. for an additional 4 hours. Normally the product of this step was not isolated but reduced with sodium borohydride to give 2-n-butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl) -1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-methanol. The title compound can be isolated by extraction into toluene from aqueous N,N-dimethylacetamide, concentration of the toluene solution, and crystallization from ethyl acetate or ethanol, mp 145°-147° C. (dec.)
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([I:11])[CH:5]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:12])=[C:6]([I:11])[CH:5]=1
Reactant: Oc1ccc(Br)cc1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Iodomethane (103 μL, 1.65 mmol) was added to a solution of 4-bromo-2-iodophenol (450 mg, 1.51 mmol) and potassium carbonate (271 mg, 1.96 mmol) in acetone (10 mL). The resulting mixture was stirred at room temperature for 16 hours.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:30]3[CH:35]=[CH:34][N:33]=[C:32](SC)[N:31]=3)[C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[C:49]1([C@@H:55]([NH2:57])[CH3:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([NH:57][C@H:55]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[CH3:56])[N:31]=3)[C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc32)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@H](Nc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc32)n1)c1ccccc1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
2-(4-Fluorophenyl)-1-(2-methylthio-4-pyrimidinyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine (106 mg, 0.2 mmol) is dissolved in CH2Cl2/HOAc 1:1 (10 ml), combined with mCPBA (113 mg 70%, 0.24 mmol) and stirred for 15 min. The reaction mixture is poured on water and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4. filtered and evaporated to dryness to yield the crude sulfoxide (100 mg), which is dissolved in 1-(S)-phenylethylamine (0.2 ml) and heated to 120° C. for 1 h. Purification over SiO2 (acetone/hexanes 1:1) yielded the title compound as colorless foam (45 mg 35%)
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:13])[C:4]=1[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[CH3:2]>CO.C1COCC1.[Pd]>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([OH:13])[C:4]=1[C:14]([OH:16])=[O:15])[CH3:2]
Reactant: CCc1c(C(=O)OCc2ccccc2)c(O)nc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)c(O)nc2ccccc12
Temperature: 40 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
Benzyl 4-ethyl-2-hydroxyquinoline-3-carboxylate (1.2 g) was suspended in methanol (12 mL) and THF (6 mL), followed by addition of 5% Pd—C (120 mg), and the mixture was stirred at 40° C. for 1 day. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain 4-ethyl-2-hydroxyquinoline-3-carboxylic acid (0.85 g). This compound was used in the subsequent step without purification.
Reaction SMILES: O.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:28]=[C:29]([N:43]1[CH2:48][CH2:47][N:46]2[C:49]([C:52]([F:55])([F:54])[F:53])=[N:50][N:51]=[C:45]2[CH2:44]1)[CH2:30][CH:31]([NH2:42])[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41].C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.O=C(N1CCN2C(C(F)(F)F)=NN=C2C1)C[C@H](N)CC1C=C(F)C(F)=CC=1F>CO.CC(O)C>[O:28]=[C:29]([N:43]1[CH2:48][CH2:47][N:46]2[C:49]([C:52]([F:55])([F:54])[F:53])=[N:50][N:51]=[C:45]2[CH2:44]1)[CH2:30][C@@H:31]([NH2:42])[CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 0.33 h

Procedure:
In a 50 mL three neck flask IPA (5 mL) and Dibenzoyl-L-tartaric acid monohydrate (1.84 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-70%) dissolved in methanol (6 mL) was added into reaction mixture at 60-65° C. After 20 min. Dibenzoyl-L-tartaric acid salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (20 mg, % Chiral purity by HPLC of R-isomer 99.6%) was added as a seeding. It was stirred for 60 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature over a period of 2-3 h. The salt was filtered and washed with a mixture of IPA: MeOH (2:1). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of a mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-0.742 g, % Y-19.2%, Purity by HPLC-99.0%, % Chiral purity by HPLC of R-isomer 78.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:7]([N+:9]([O-])=O)[CH:8]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: COc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)cc(-c2ccccc2)c1
Yield: 90.6 %

Procedure:
3-Methoxy-5-nitro-biphenyl (176 mg, 0.77 mmol) are hydrogenated in ethanol (5 ml) using palladium on carbon (10%, 17 mg) at atmospheric pressure for 2 h. The calalyst is filtered off and the solvent removed in vacuo. Flash chromatography (silica, eluent ethyl acetate/cyclohexane 1:1) affords the product (139 mg, 91%) as a bown oil. MS: m/e=199 (M+).