Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCOCC4)CC3)n[nH]c12
Yield: 32.1 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-Chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and morpholine (97 uL, 1.11 mmol) to afford the title compound (37.73 mg, 32% for 2 steps).
Reaction SMILES: C(OC([N:8]1[C@H:13]([C:14]2[NH:15][C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]5[NH:39][C:38]([C@@H:40]6[CH2:45][C@@H:44]7[C@@H:42]([CH2:43]7)[N:41]6C(OC(C)(C)C)=O)=[N:37][CH:36]=5)=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)=[CH:17][N:18]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=O)(C)(C)C.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>C(Cl)Cl>[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54].[C@@H:9]12[CH2:10][C@@H:11]1[CH2:12][C@@H:13]([C:14]1[NH:18][CH:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]5[N:39]=[C:38]([C@@H:40]6[CH2:45][C@@H:44]7[C@@H:42]([CH2:43]7)[NH:41]6)[NH:37][CH:36]=5)=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)[N:15]=1)[NH:8]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2c[nH]c([C@@H]3C[C@H]4C[C@H]4N3)n2)ccc1-c1ccc2cc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of (1R,3S,5R)-tert-butyl 3-(5-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (275 mg) in DCM (10 mL) was added TFA (2 mL, 26.0 mmol). The mixture was stirred for 2 h at room temperature. The volatiles were removed under vacuum and the crude residue was purified by a reverse phase HPLC (water/MeOH/TFA) to afford a TFA salt of (1R,3S,5R)-3-(4-(4-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane (106 mg) as tan solid. LC-MS retention time 1.153 min; m/z 499.36 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.33 (s, 1H), 8.19 (s, 1H), 7.99-8.05 (m, 2H), 7.85-7.95 (m, 6H), 7.83 (s, 1H), 7.76 (s, 1H), 4.78 (q, J=9.4 Hz, 2H), 3.47-3.54 (m, 2H), 2.65-2.74 (m, 4H), 2.02-2.12 (m, 2H), 1.18-1.25 (m, 2H), 0.97-1.05 (m, 2H).
Reaction SMILES: [O:1]=[C:2]([CH:8]([CH2:14][CH2:15][Si:16]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])C(OCC)=O)[C:3]([O:5]CC)=[O:4].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O>[CH3:24][Si:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:17])[CH2:15][CH2:14][CH2:8][C:2](=[O:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(=O)C(CC[Si](C)(C)c1ccccc1)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [OH-]
Solvent: O
Product: C[Si](C)(CCCC(=O)C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 90.2 %

Procedure:
In a flask were placed 27.1 g (0.0773 mole) of diethyl 2-oxo-3-(3-methyl-3-phenyl-3-silabutyl)succinate, 301 g (0.464 mole) of 40 wt % tetrabutyl ammonium hydroxide, and 500 mL of water. This mixture was heated at reflux under a nitrogen atmosphere for 25 minutes after which it was cooled to ambient temperature. The reaction mixture was acidified with 50 mL of 12N hydrochloric acid and then extracted twice with 400 mL of diethyl ether. The extracts were combined and washed with 100 mL of 3N hydrochloric acid after which the solvent was evaporated under reduced pressure, yielding 17.45 g of 6-methyl-6-phenyl-2-oxo-6-silaheptanoic acid as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][O-:12].[Na+]>O>[CH2:9]([O:8][C:7]1[C:2]([O:12][CH3:11])=[N:3][CH:4]=[CH:5][CH:6]=1)[CH3:10]
Reactant: CCOc1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1cccnc1OC
Yield: 94.5 %

Procedure:
A solution of 2-chloro-3-ethoxy-pyridine (3.0 g, 19.0 mmol, 1.0 equiv) and sodium methoxide (8.8 mL, 47.5 mmol, 2.5 equiv, 5.4 M solution in methanol) was heated to 100° C. under microwave irradiation for 20 min. The crude reaction mixture was poured into water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic phases were dried over MgSO4 and the solvent removed by evaporation under reduced pressure to yield 2.75 g (95%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.40 (t, J=7.0 Hz, 3H), 3.94 (s, 3H), 4.02 (q, J=7.0 Hz, 2H), 6.75 (dd, J=7.8 Hz, J=5.0 Hz, 1H), 6.96 (dd, J=7.8 Hz, J=1.5 Hz, 1H), 7.65 (dd, J=5.0 Hz, 1=1.5 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 13.62, 52.53, 63.25, 115.69, 117.53, 136.13, 142.45, 153.84. MS (ISP): 153.8 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][C:15]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[CH:16][CH:17]=2)[N:12]=1.C(#N)C>O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:15]2[N:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([NH:10][C:1](=[O:9])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:12]3)=[CH:17][CH:16]=2)=[CH:23][CH:24]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1ccc(Oc2ccc3ccc(N)nc3n2)cc1
Solvent: CC#N
Solvent: O
Product: COc1ccc(Oc2ccc3ccc(NC(=O)c4ccccc4)nc3n2)cc1
Temperature: 4 °C
Yield: 73.8 %

Procedure:
The procedure is similar to that described in Example 1, but starting with benzoic acid (11 g), N,N'carbonyldiimidazole (16.2 g) and 2-amino-7-(4-methoxyphenoxy)-1,8-naphthyridine (26.7 g). The product produced by precipitation in water (30.8 g; m.p. approximately 110° C.) is dissolved in boiling acetonitrile (150 cc). After 3 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×5 cc) and dried at 50° C. under reduced pressure (0.067 kPa). N-[7-(4-methoxyphenoxy)-1,8-naphthyridin-2-yl]benzamide (24.7 g) is produced, m.p. 171° C. 2-Amino-7-(4-methoxyphenoxy)-1,8-naphthyridine can be prepared in the following manner:
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:16][O-].[Na+].C=O.[BH4-].[Na+]>CO>[CH3:16][NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:10]=1
Reactant: CCCCCCC#Cc1cccc(N)c1
Reactant: C[O-]
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCC#Cc1cccc(NC)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
To a solution of 3-(oct-1-ynyl)aniline (1.34 g, 6.67 mmol) in MeOH (35 mL) was added NaOMe (25% wt. in MeOH, 7.7 mL), followed by paraformaldehyde (1.0 g, 33.3 mmol). The resulting mixture was refluxed 2 h under argon. After cooling to 0° C., NaBH4 (1.27 g, 33.4 mmol) was added and the mixture was refluxed for 90 min. The reaction mixture was then cooled to rt, quenched with ice and extracted with dichloromethane (50 mL+30 mL). The combined extracts were washed with H2O and brine and dried (Na2SO4). Flash chromatography (eluent: EtOAc/Hex=1:10 to 1:6) gave N-methyl-3-(oct-1-ynyl)aniline as a light yellow oil (920 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.10 (t, 1H, J=7.8 Hz), 6.77 (d, 1H, J=7.2 Hz), 6.66 (s, 1H), 6.55 (d, 1H, J=8.4 Hz), 3.80 (s, br, 1H, NH), 2.84 (s, 3H), 2.40 (t, 3H, J=7.0 Hz), 1.61 (quint, 2H, J=7.4 Hz), 1.46 (quint, 2H, J=6.8 Hz), 1.38-1.25 (m, 4H), 0.92 (t, 3H, J=6.6 Hz).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([Cl:34])[C:26]([N:27]3[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28]3)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:35])(C)(C)C>>[Cl:34][C:25]1[C:26]([N:27]2[CH2:31][CH2:30][CH:29]([O:32][CH3:33])[CH2:28]2)=[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:20]2=[C:21]([CH:24]=1)[C:22](=[O:23])[N:13]([OH:12])[C:14]3=[O:35]
Reactant: COC1CCN(c2c(Cl)cc3c4c(cccc24)C(=O)N(OC(C)(C)C)C3=O)C1
Solvent: O=C(O)C(F)(F)F
Product: COC1CCN(c2c(Cl)cc3c4c(cccc24)C(=O)N(O)C3=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.5 %

Procedure:
Following the procedure from Example 62, TFA (1.0 mL) and 2-tert-butyloxy-5-chloro-6-[3-methoxypyrrolidin-1-yl]-benzo[de]isoquinoline-1,3-dione (0.2 g, 0.5 mmol from Example S2) was stirred at room temperature overnight, concentrated, and the solid recrystallized from ethanol/ether solution to give 0.02 g of the title compound, mp 136-142° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]C.C([Li])CCC.[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[CH3:31].[ClH:39].C(=O)(O)[O-].[Na+]>>[ClH:39].[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13]([C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH2:31])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: CC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li]C
Product: C=C(c1ccccc1)c1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.250 g, 0.664 mmol), MeLi (0.519 ml, 0.831 mmol), butyllithium (0.332 ml, 0.831 mmol), and acetophenone (0.0798 g, 0.664 mmol) were reacted according to the method of Example 7. 1M HCl was added and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was poured onto ice and saturated sodium bicarbonate and extracted twice with dichloromethane. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (5-10% EtOAc in hexane) to provide the title compound (0.125 g, 47.1% yield) after HCl salt formation. 1H NMR (DMSO-d6) δ 7.81 (d, 1H), 7.54 (m, 2H), 7.48 (m, 1H), 7.37 (m, 6H), 7.30 (m, 2H), 6.81 (s, 1H), 5.60 (s, 1H), 5.54 (s, 1H), 5.33 (s, 2H), 2.31 (s, 3H). Mass spectrum (apci) m/z=400.1 (M+H-HCl)
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[C@@H:20]([NH2:27])[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:27][C@@H:20]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:19]([F:18])([F:28])[F:29])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Product: O=C(N[C@@H](c1cccnc1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (S)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 336105-46-5) as starting materials, MS (EI): m/e=392.2 [M+H]+.
Reaction SMILES: [N+:1]([CH:4]([CH3:15])[CH:5]([OH:14])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-])=O>CO.[Pt]=O>[NH2:1][CH:4]([CH3:15])[CH:5]([OH:14])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C(O)COc1ccccc1)[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CO
Product: CC(N)C(O)COc1ccccc1
Yield: 28.2 %

Procedure:
3-Nitro-1-phenoxy-butan-2-ol (1.7 g, 8.0 mmol) in methanol (50 mL) was hydrogenated over platinum oxide (300 mg) at atmospheric pressure overnight. The mixture was filtered through celite and purified by semi-preparative HPLC (XBridge, C18, 5 μm, 19×50 mm, 12 min gradient of 5-20% acetonitrile in (water+2 mL NH3/L). Fractions containing the faster eluting peak were pooled and concentrated to give the subtitle compound (409 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][CH2:13][O:14][CH3:15])[CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)CC(C)C)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 40.4 %

Procedure:
4-(2-Methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (1 g) was dissolved in pyridine (15 ml) under an argon atmosphere at RT and 2-methyl-propane-1-sulfonyl chloride (0.728 g) was added and the mixture was stirred for 60 h at RT. The pyridine was evaporated off, the residue dissolved in AcOEt, washed with 0.05M HCl and brine. The layers were separated, the organic layer dried over sodium sulphate and concentrated. The crude product was purified by flash chromatography (AcOEt/heptane, gradient from 0 to 25%,) to give the desired 4-(2-methoxy-ethyl)-1-(2-methyl-propane-1-sulfonyl)-piperidine-4-carboxylic acid ethyl ester (0.63 g) as a yellow oil. MS (ESI): 336.18 (MH+).
Reaction SMILES: [OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13]1.C(N(CC)CC)C.[C:35](S(O)(=O)=O)([NH2:37])=[NH:36]>CN(C=O)C>[OH:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:37][C:35](=[NH:36])[N:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([CH2:18][NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13]1
Reactant: O=C(NC[C@@H]1CCCNC1)c1ccccc1
Reactant: N=C(N)S(=O)(=O)O
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)N1CCC[C@@H](CNC(=O)c2ccccc2)C1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
Bc) 19.3 g of the mandelic acid salt obtained under Bb) are suspended in 193 ml of DMF, treated with 21.7 ml of triethylamine and 7.75 g of formamidinesulfonic acid and stirred at room temperature. The reaction mixture is evaporated and the residue is chromatographed on RP-18 silica gel with a water-acetonitrile gradient. There are isolated 13.4 g of (S)-N-[1-(amino-imino-methyl)-piperidin-3-ylmethyl]-benzamide (R)-hydroxy-phenylacetate (1:1), MS (FAB): 218M-(H2N-CN).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([OH:46])[CH2:43][CH2:42][NH:41][CH2:40][C:39]2([CH3:45])[CH3:44])=[CH:34][C:33]=1[O:47][CH3:48].CCN(C(C)C)C(C)C>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2([OH:46])[CH2:43][CH2:42][N:41]([C:13](=[O:15])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:10]([CH3:11])[CH3:12])[CH2:40][C:39]2([CH3:44])[CH3:45])=[CH:34][C:33]=1[O:47][CH3:48]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(C2(O)CCNCC2(C)C)ccc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C2(O)CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)CC2(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
N-Boc-D-valine (85 mg, 0.39 mmol), EDC (75 mg, 0.39 mmol), HOBt (53 mg, 0.39 mmol) was dissolved in dichloromethane (2 mL). 4-(4-Chloro-3-methoxyphenyl)-3,3-dimethylpiperidin-4-ol hydrochloride (100 mg, 0.33 mmol) was added followed by DIPEA (136 μL, 0.78 mmol) and the solution was stirred at rt for 10 min. The reaction was concentrated and the resulting oily residue was purified via column chromatography (10% to 50% EtOAc/heptane) to furnish tert-butyl (2R)-1-(4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (153 mg, 99% yield) MS found: (M-Boc)+=396.3.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:16])C(=O)C1>CN(C=O)C>[Cl:16][C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(N)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6-methylpyridin-2-amine (10.80 g, 100 mmol) in 50 mL of dry DMF was added a solution of NCS (13.4 g, 100 mmol) in 60 mL of dry DMF dropwise at 0° C. over 20 min. The resulting brown yellow solution was stirred at 0° C. for 1 hour, and at room temperature for 3 hours, then poured to 300 mL of ice-water. The resulting mixture was extracted with EtOAc, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified via column chromatograph to afford 5-chloro-6-methylpyridin-2-amine.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[C:16]1[S:15][C:14]([C:20]3[O:24][N:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]=3[C:31]([F:34])([F:33])[F:32])=[N:13][C:12]=1[CH2:11][CH2:10]2)(=O)=O.[CH2:37]([Sn](CCCC)(CCCC)C=C)[CH2:38]CC.[Cl-].[Li+]>O1CCOCC1.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:25]1([C:22]2[C:21]([C:31]([F:33])([F:34])[F:32])=[C:20]([C:14]3[S:15][C:16]4[C:17]5[C:9](=[CH:8][C:7]([CH:37]=[CH2:38])=[CH:19][CH:18]=5)[CH2:10][CH2:11][C:12]=4[N:13]=3)[O:24][N:23]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S(=O)(Oc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[2,1-d]thiazol-7-yl trifluoromethanesulfonate (Preparation 56D, 0.451 g, 0.825 mmol), tributyl(vinyl)tin (0.265 mL, 0.908 mmol), and lithium chloride (0.105 g, 2.476 mmol) in dioxane (5.0 mL) was placed in a microwave reaction vessel. To this was added tetrakis(triphenylphosphine)palladium(0) (0.095 g, 0.083 mmol) and argon was bubbled into the mixture for 3 min. The vessel was capped and the reddish brown mixture was immersed in a 100° C. oil bath. After 6 h of stirring, the reaction mixture was cooled to room temperature. EtOAc was added and the contents were stirred for 30 min. It was then filtered through a plug of Celite. The filter cake was washed with EtOAc (2×). The combined organic layers were then concentrated in vacuo. The residue was suspended in ether and stirred vigorously for another 30 min., filtered through a plug of celite and the filter cake washed with ether (2×). The combined organic layers were concentrated and chromatographed. The product had an LC ret. time=3.996 min. (condition: Start % B=50, Final % B=100, Gradient Time=4 min, Flow Rate=4 ml/min, Wavelength=220, Solvent Pair=MeOH−H2O−TFA; Solvent A=10% MeOH—90% H2O−0.1% TFA; Solvent B=90% MeOH−10% H2O−0.1% TFA; Column 1=1: Waters Sunfire C18 4.6×50 mm (4 min. grad)); LC/MS M+1=425.07.
Reaction SMILES: [S:1]1(=[O:15])(=[O:14])[C:6]2[S:7][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:9][C:5]=2[CH:4]=[N:3][NH:2]1.[H-].[Na+].[CH3:18][CH:19]([CH3:22])[CH2:20]Br>CN(C=O)C.O>[CH3:18][CH:19]([CH3:22])[CH2:20][N:2]1[N:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([NH2:13])(=[O:11])=[O:12])[S:7][C:6]=2[S:1]1(=[O:14])=[O:15]
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)NN=C2
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CN1N=Cc2cc(S(N)(=O)=O)sc2S1(=O)=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
The product from step C (0.05 g, 0.18 mmol) was dissolved in DMF (1 mL). Sodium hydride (0.016 g, 40 mmol of a 60% suspension in mineral oil) was added slowly at room temperature. The mixture was stirred for 15 min and then 2-methylbromopropane (0.024 mL, 0.40 mmol) was added. The mixture was warmed to 60° C. and stirred for 12h. DMF was evaporated under high vacuum. The residue obtained was diluted with water (1 mL) and the mixture was extracted with ethyl acetate (3×1 mL). The combined extracts were dried over MgSO4 and evaporated to provide an oil which was purified by flash column chromatography (silica, hexane-ethyl acetate gradient) to give the desired compound as a white solid, crystallization in ethyl acetate-hexane gave 0.032 g (52%). mp:130°-132° C. 1HNMR (CDCl3):δ:0.96 (6H, d, 2CH3); 2.18 (1H, m, CH); 3.78 (2H, d, CH2); 5.27 (2H, s, NH2 exchangeable); 7.67 (1H, 1s, CH); 7.91 (1H, s, CH=N). Analysis calculated for C9H13N3O4S3 : C, 33.42; H, 4.05; N, 12.99. Found: C, 33.51; H, 4.04; N, 12.91.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:27](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[CH:47]=[CH:48][C:49]([N:51]([CH3:61])[C:52]([NH:54][CH:55]3[CH2:60][CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:53])=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C(Cl)Cl.CCOCC.CO>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[CH:47]=[CH:48][C:49]([N:51]([CH3:61])[C:52]([NH:54][CH:55]3[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60]3)=[O:53])=[CH:50][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(N(C)C(=O)NC3CCCCC3)ccc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCc1nc2cc(N(C)C(=O)NC3CCCCC3)ccc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared in analogous manner to Example 58b from 4'-[(2-n-butyl-5-(N-cyclohexylaminocarbonyl-methylamino)-benzimidazol-1-yl)-methyl]-2-(1-triphenylmethyl-tetrazol-5-yl)-biphenyl and hydrochloric acid in methylene chloride/ether/methanol.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:5][CH:4]=1)=[O:2].[OH-].[Na+].O1CCO[CH2:22][CH2:21]1>>[CH2:21]([CH2:15][C:8]([O:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:17][CH:16]=1)([CH3:14])[C:9]([OH:11])=[O:10])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Product: CCCC(C)(Oc1ccc(C=O)cc1)C(=O)O
Temperature: 25 °C
Yield: 99 %

Procedure:
The obtained Compound 97a (1.0 eq.) was dissolved in 1,4-dioxane, and 1 N NaOH (1.4 eq.) was added thereto. The reaction mixture was stirred at room temperature, and after a volatile material was evaporated, the residual was distributed between methylene chloride and water. An water layer was acidified by using a 12 N HCl and extracted by using methylene chloride. An organic layer was evaporated to obtain Compound 97c.