Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[Sn](Cl)Cl.[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C([O-])(O)=O.[Na+].CC(O)=O>CCO>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[C:12]([NH2:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(C(=O)O)c(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Tin(II) Chloride hydrate (50 g, 0.29 mol) was added to a solution of 2,4-dichloro-5-nitrobenzoic acid 1-2 (10.0 g, 0.045 mol) in EtOH (200 mL). The mixture was stirred for 70° C. for 30 min, cooled and poured onto ice. The pH of the mixture was adjusted to 8 using saturated aqueous NaHCO3. The suspension was left to stir at room temperature for 5 h and re-acidified to pH 5 with glacial AcOH. The resulting white suspension was continuously washed with EtOAc, the extracts combined, washed with brine, dried over Na2SO4, filtered and concentrated to afford the desired amine 1-3 as an off-white solid (8.8 g, 96%). 1H NMR (400 MHz, CD3OD) δ7.27 (s, 1H), 7.30 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25](=[O:46])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([CH:43]([CH3:45])[CH3:44])=[N:41][N:42]=4)[CH:39]=3)=[CH:29][CH:28]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].F.F.F.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25](=[O:46])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([C:40]([CH:43]([CH3:44])[CH3:45])=[N:41][N:42]=4)[CH:39]=3)=[CH:29][CH:28]=2)[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2ccc(Sc3ccc(CC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O[Si](C)(C)C(C)(C)C)cc4)cc3)cn12
Agent: F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)c1nnc2ccc(Sc3ccc(CC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O)cc4)cc3)cn12
Yield: 68 %

Procedure:
A solution of Example 20 step a (80 mg, 0.12 mmol) and triethylamine trihydrofluoride (40 mg, 0.24 mmol) in THF (2 mL) was stirred at RT for 24 H, then diluted with EtOAc, washed with sat. aq. sodium bicarbonate, dried (Na2SO4), and evaporated. The residue was purified by FCC (DCM/MeOH 100/0 to 95/5), dissolved in EtOAc, washed with aq. citric acid and brine, dried (Na2SO4), evaporated and dried in vacuo at 40° C. to afford the title compound (45 mg, 68%) as a pink solid. LCMS (Method 7): Rt 11.15 min, m/z 541 [MH+]. 1H NMR (400 MHz, CDCl3): δ 8.23 (1 H, s), 7.91 (1 H, s), 7.74 (1 H, d, J 9.5), 7.25-7.14 (5 H, m), 7.05 (2 H, d, J 8.4), 6.85 (2 H, t, J 8.6), 6.51 (1 H, s), 3.64 (2 H, s), 3.47-3.38 (1 H, m), 1.55 (3 H, s), 1.53 (3 H, s), 1.31 (9 H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]>CN(C)C=O.N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:18]=1[C:19]#[N:20]
Reactant: N#Cc1c(CBr)cccc1[N+](=O)[O-]
Reactant: Oc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(COc2cccc(Cl)c2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
3-Chlorophenol (0.27 g, 2.07 mmol) and potassium carbonate were added to a cooled (0° C.) and stirred solution of 2-bromomethyl-6-nitrobenzonitrile [W. T. Ashton and J. B. Hynes, J. Med. Chem, 16, 1233 (1973)] (0.5 g, 2.07 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 1.5 hours, then diluted with pyridine (1.5 mL), water, stirred for 1 hour, filtered and dried. Purification by silica gel chromatography (1:1 dichloromethane in hexanes) yielded 185 mg of 2-(3-chlorophenoxymethyl)-6-nitrobenzonitrile.
Reaction SMILES: [CH2:1]([OH:12])[CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].Cl[CH2:16][C:17]([O-])=[O:18].[Na+].O>C(OCC)C>[CH2:3]([CH:2]1[O:11][C:17](=[O:18])[CH2:16][O:12][CH2:1]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C([O-])CCl
Reactant: CCCCCCCCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCC1COCC(=O)O1
Temperature: 55 °C
Reaction time: 1.75 h
Yield: 63 %

Procedure:
Powdered decane-1,2-diol (0.25 moles) is stirred at room temperature and very well powdered sodium hydroxide (0.25 moles) is added in portions. Gentle heating of the mixture to 55° C. gives a viscous yellow paste. Sodium chloroacetate (0.25 moles) is now added in portions over 10 minutes. The white mobile paste produced is stirred at 70°-60° C. for 1.75 h. After cooling to 20° C., 100 ml of petroleum ether is added followed by water. After separation of phases (aided by acetone) the aqueous phase is run off and acidified to pH 1.5 using 98% sulphuric acid. The oil produced is taken up into 2×375 ml diethyl ether which is then dried and evaporated to leave the title product as a clear oil (63%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23](I)=[CH:24][C:18]=2[N:17]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:34][Si:35]([C:38]#[CH:39])([CH3:37])[CH3:36].O>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:39]#[C:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2cc(I)ccc2[nH]1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.1 %

Procedure:
A solution of [(S)-1-(5-iodo-1H-benzoimidazol-2-yl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (100 mg, 0.216 mmol), copper (I) iodide (8 mg, 0.043 mmol) and dichlorobis(triphenylphosphine)palladium (II) (15 mg, 0.022 mmol) in N,N-dimethylformamide (7 mL) in a sealed tube apparatus was degassed with dry nitrogen. The yellow mixture was stirred at room temperature for an additional 5 minutes, then triethylamine (90 μL, 0.648 mmol) and trimethylsilylacetylene (92 μL, 0.648 mmol) were added, and the resulting solution was degassed once more After stirring the reaction mixture for 5 minutes at room temperature a deep red to black solution resulted. This mixture was left to stir overnight at room temperature then poured into a separatory funnel containing water (50 mL) and ethyl acetate (50 mL). The aqueous layer was separated and extracted twice with ethyl acetate (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was applied to a silica gel column using dichloromethane (10 mL) and gradient eluted from 10 to 100% v/v ethyl acetate in hexanes to give [(S)-2-phenyl-1-(6-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-ethyl]-carbamic acid tert-butyl ester (90 mg, 96%).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH2:38])[C:19]3=[O:39])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1([C:46]([NH:59][C:60]2[S:61][CH:62]=[C:63](/[C:65](=[N:69]/[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])/[C:66](O)=[O:67])[N:64]=2)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O1CCCC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:18]3[C@H:21]([S:22][CH2:23][C:24]=2[CH2:25][S:26][C:27]2[S:37][C:30]4=[N:31][C:32]([CH3:36])=[CH:33][C:34](=[O:35])[N:29]4[N:28]=2)[C@H:20]([NH:38][C:66](=[O:67])/[C:65](/[C:63]2[N:64]=[C:60]([NH:59][C:46]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[S:61][CH:62]=2)=[N:69]\[O:70][C:71]([O:74][CH3:75])([CH3:73])[CH3:72])[C:19]3=[O:39])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(C)(C)O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cc1cc(=O)n2nc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)[C@@H](N)[C@H]4SC3)sc2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nn4c(=O)cc(C)nc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The product obtained in Step 2 (3.25 g) and 2-(2-triphenylmethylamino-4-thiazolyl)-2-[Z-(1-methoxy-1-methylethyl)oxyimino]acetic acid (5.64 g) were dissolved in dichloromethane (93 ml) and tetrahydrofuran (93 ml) under a nitrogen stream, and the solution was cooled to 0° C. Dicyclohexylcarbodiimide (2.32 g) was added to this solution by small portions, and the mixture was stirred overnight at room temperature. After filtering off the insoluble matters, the filtrate was concentrated under reduced pressure. The residue was redissolved in ethyl acetate and the insoluble matters were filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, giving 2.5 g of the objective compound as yellow crystals.
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].ClC(Cl)(Cl)C(=N)O[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.FC(S(O)(=O)=O)(F)F>C(Cl)Cl>[CH2:15]([O:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)[C@@H](O)CC(C)C
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)OCc1ccccc1
Yield: 74.7 %

Procedure:
To a stirred solution of methyl (2S)-2-hydroxy-4-methylpentanoate (0.5 g, 3.4 mmol) in anhydrous CH2Cl2 (10 mL) at R.T. under Ar was added benzyl 2,2,2-trichloroacetimidate (1.4 ml, 6.8 mmol) and trifluoromethylsulfonic acid (25 μl). After 30 min the reaction mixture was taken up in CH2Cl2 (20 mL). The organic layer was washed with sat. NaCl (2×10 mL), 1N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (EA:H; 1:10) afforded methyl (2S)-2-benzoxy-4-methylpentanoate as an oil (0.6 g, 73.5%): 1H NMR (CDCl3, 300 MHz) δ 0.80-0.98 (m, 6 H), 1.40-1.58 (m, 1 H), 1.69-1.87 (m, 2 H), 3.74 (s, 3 H), 3.93-4.06 (m, 1 H), 4.42 (d, 1 H, J=12.0 Hz), 4.68-4.80 (m, 1 H), 7.14-7.32 (m, 5 H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.[Cl:17][CH2:18][C:19](Cl)=[O:20]>CC(O)C.CCCCCC>[Cl:17][CH2:18][C:19]([N:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:20]
Reactant: Cc1ccc(Nc2c(F)cccc2Cl)cc1
Reactant: O=C(Cl)CCl
Solvent: CC(C)O
Solvent: CCCCCC
Product: Cc1ccc(N(C(=O)CCl)c2c(F)cccc2Cl)cc1
Temperature: 37.5 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
20.4 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine are heated to about 80° C. and treated with 10.75 g of chloroacetylchlonde. The mixture is stirred for 2 hours and diluted with 10 ml of 2-propanol. The solution is cooled to 35-40° C. and seeded. The precipitated suspension is diluted with 30 ml of hexane, cooled to 0-5° C. and stirred for about 1 hour. The crystals are isolated by filtration, washed with a cold solution of 2-propanol/hexane ⅓. After drying, 22.7 g of 2-chloro-N-(2′-chloro-6′-fluorophenyl)-N-(4-methylphenyl)acetamide are obtained. HPLC purity: 99%. Melting point: 79-80° C. 1H-NMR(DMF-d7, 400 MHz, 393K) δ 2.44(s, 3H, CH3); 4.32 (s, 2H, CH2), 7.35[d, J=8.0 Hz, 2H, HC(3) and HC(5)], 7.43[ddd, J=8.0, 2.0 Hz, JH-F=8.0, 1H, HC(5′)], 7.48[d, J=8.0 Hz, 2H, HC(2) and HC(6)], 7.55[d, J=8.0 Hz, 1H, HC(3′)], 7.60[ddd, J=8.0 Hz, JH-F=5.5, 1H, HC(4′)].
Reaction SMILES: C(O)(=O)C.[CH3:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:36])([C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]=1[O:28][CH2:29][O:30][CH3:31])[CH2:23]N)[CH3:19]>C1(C)C=CC=CC=1>[CH3:35][C:32]([C:26]1[CH:25]=[C:22]([CH2:23][NH:16][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([S:6][CH3:5])=[CH:12][CH:11]=2)=[O:15])[CH:21]=[C:20]([C:18]([CH3:36])([CH3:19])[CH3:17])[C:27]=1[O:28][CH2:29][O:30][CH3:31])([CH3:33])[CH3:34]
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Reactant: CSc1ccc(NC(N)=O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCOc1c(C(C)(C)C)cc(CNC(=O)Nc2ccc(SC)cc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
Acetic acid (1.08 g; 18 mmol), 4.5 g (24.7 mmol) of the compound of Example 5 and 5.0 g (18 mmol) of the compound of Example 1 were dissolved in 180 ml of toluene. The resulting solution was heated to reflux, stirred at that temperature for 4 hours and then cooled to room temperature. The cooled solution was washed with a IN hydrochloric acid solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. The washed solution was then filtered to remove any solid particulates which had formed and the liltrate was concentrated to dryness to provide a residue. This residue was purified by column chromatography using a 20-40% ethyl acetate in hexane gradient as eluent. Fractions containing the above titled compound were combined and then concentrated to dryness to provide 3.14 g of title compound.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[O:2]1.[OH-:12].[K+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]1[O:11][C:10]2[C:3](=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]([OH:12])=[O:6])[O:2]1
Reactant: [OH-]
Reactant: O=Cc1cccc2c1OCO2
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1OCO2
Reaction time: 2 h

Procedure:
To a solution of 0.85 g (5.66 mmol) of 2,3-methylenedioxybenzaldehyde (Aldrich) in EtOH at 0° C. was added a solution of 2.12 g (12.45 mmol) of AgNO3 in 7.5 mL of H2O. To this was then added a solution of 1.74 g (31.4 mmol) of KOH in 12 mL of H2O. After 2 h, the reaction mixture was filtered and the filter was washed with EtOH. The filtrate was concentrated and the pH was adjusted to pH=2 to 3 with 6N HCl. The title compound precipitated out and was isolated by filtration to give the title compound. 1H NMR (CDCl3) δ6.16 (s, 2H), 6.92 (t, 1H, J=8 Hz), 7.04 (d, 1H, J=8 Hz), 7.48 (d, 1H, J=8 Hz);
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:49]([C:51]1[CH:52]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)[CH:54]=[CH:55][C:56]=1[F:57])#[N:50]>CN(C=O)C>[C:49]([C:51]1[CH:52]=[C:53]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=2)[CH:54]=[CH:55][C:56]=1[F:57])#[N:50]
Reactant: N#Cc1cc(-c2cccc(N)c2)ccc1F
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)ccc1F
Temperature: 25 °C
Yield: 42.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3′-cyano-4′-fluoro-biphenyl-3-ylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.011 g of product in 46% yield: LCMS (ESI) m/z 401 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:22])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(SCc2ccccn2)cc1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 37.8 %

Procedure:
A suspension of 2-(((4-chlorophenyl)thio)methyl)pyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated with a solution of m-chloroperoxybenzoic acid (1.7 g) in CH2Cl2 (25 ml). The mixture was allowed to warm to ambient temperature and was stirred for 5 hours. The solution was washed with saturated sodium carbonate solution and water, then dried (MgSO4). The residue was dissolved in acetone and converted into the hydrochloride with ethereal HCl. N.m.r. showed approximately 20% of starting material remaining so the material was suspended in methylene chloride (50 ml) and treated with further m-chloroperoxybenzoic acid (2×500 g). The solution was washed with saturated sodium carbonate solution and water, dried (MgSO4) evaporated and the residue was dissolved in acetone and the hydrochloride precipitated with ethereal HCl solution. Recrystallisation from acetone-ether gave the title compound as the hydrochloride (0.7 g) mp 170° C. decomp. (Found: C,49.2; H,3.8; N,4.5 C12H10ClNOS.HCl.1/4H2O requires C,49.2; H,4.0; N,4.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=[O:6].[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution at 0° C. of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzaldehyde (2.00 g, 5.34 mmol) in THF (50 mL) and MeOH (25 mL) was added sodium borohydride (0.188 mL, 5.34 mmol). The reaction mixture was allowed to warm up to ambient temperature. The crude reaction mixture, after 1 h, was concentrated in vacuo and purified by silica gel chromatography to afford (3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol. MS (ESI) m/z: calculated: 376.1: Observed: 377.0 (M++1).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:13]O)[CH2:9][CH2:8]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([NH2:13])[CH2:11][CH2:12]1
Reactant: ON=C1CCN(CC2CCCO2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC1CCN(CC2CCCO2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2-tetrahydrofurylmethyl)piperid-4-one oxime (42.5 g; 0.22 moles) in anhydrous tetrahydrofuran (700 ml) was added dropwise to a suspension of lithium aluminium hydride (24.4 g; 0.64 moles) in anhydrous tetrahydrofuran (300 ml). The reaction mixture was left with stirring at room temperature overnight and then, water (24.5 ml), 4N sodium hydroxide aqueous solution (24.5 ml) and water (73.5 ml) were successively added, filtered, the filtrates dried (Na2SO4) and brought to dryness in vacuo. The resulting oil (28 g) was distilled to give 1-(2-tetrahydrofurylmethyl)-4-aminopiperidine, boiling point 94°-98° C./0.2 mm Hg.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][NH2:33])([CH3:27])([CH3:26])[CH3:25].CC(O)=O>CCO>[C:24]([O:28][C:29](=[O:34])[NH:30][CH2:31][CH2:32][NH:33][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 80.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and (2-amino-ethyl)-carbamic acid tert-butyl ester (62 mg, 0.39 mmol) in EtOH (9 mL) was refluxed for 16 h. After cooling to r.t., AcOH (0.2 mL) was added, and the mixture was concentrated in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and washed with 0.1 M HCl and brine. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 113 mg of the title compound as an off-white solid. MS: (−) m/z 437.33 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[C:19]([CH2:21][NH:22][C:23](=O)[O:24]C(C)(C)C)[CH:18]=[CH:17][N:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=O)[C:42](C)([CH3:44])[CH3:43].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[C:19]([CH2:21][NH:22][C:23](=[O:24])[C:42]([CH3:44])([CH3:43])[CH3:41])[CH:18]=[CH:17][N:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)C(=O)NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a stirred solution of (4-(aminomethyl)pyridin-2-yl)(4-(4-chlorophenoxy)piperidin-1-yl)methanone (25 mg, 0.072 mmol. Example 321), N,N-diisopropylethylamine (0.038 mL, 0.22 mmol) in dichloromethane (1 mL) was added pivaloyl chloride (0.011 mL, 0.087 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into water (3 mL). This was extracted with ethyl acetate (4 mL) and washed with water (3 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 14.0 mg (45% yield) of the title compound.