Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[OH:40][C@@H:41]([C:45]([CH3:48])([CH3:47])[CH3:46])[C:42](O)=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:42](=[O:43])[C@@H:41]([OH:40])[C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
A solution of the product of Example 2C (0.020 g, 0.038 mmol) in tetrahydrofuran (0.40 mL) was treated with (s)-(−)-2-hydroxy-3,3-dimethylbutyric acid (0.006 g, 0.045 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 2 hours and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic layer was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (0.005 g, 21% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.70 (s, 9 H), 0.79 (s, 9 H), 1.42-1.54 (m, 2 H), 2.71-2.76 (m, 3 H), 3.42 (d, J=5.9 Hz, 1 H), 3.48 (s, 3 H), 3.61-3.67 (m, 1 H), 3.82 (d, J=9.9 Hz, 1 H), 4.10-4.21 (m, 2 H), 4.98 (d, J=5.5 Hz, 1 H), 5.33 (d, J=5.8 Hz, 1 H), 6.65 (d, J=9.6 Hz, 1 H), 7.09-7.24 (m, 9 H), 7.28-7.32 (m, 1 H), 7.80 (d, J=8.5 Hz, 1 H), 7.84-7.89 (m, 4 H), 8.62 (m, 1 H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1)=C.C[N+]1([O-])CC[O:25]CC1.S([O-])([O-])(=O)=S.[Na+].[Na+].I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.O=[Os](=O)(=O)=O>[CH:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]2[N:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][CH:13]=1)=[O:25]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1sc(C(=O)OC)cc1-c1cnc2cccnn12
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2cnc3cccnn23)c(C=O)s1
Reaction time: 5 h

Procedure:
To a stirred solution of methyl 5-ethenyl-4-(imidazo[1,2-b]pyridazin-3-yl)thiophene-2-carboxylate (160 mg, 0.56 mmol) in THF (1.9 mL) and water (0.95 mL) were added OsO4 (4% in water, 0.36 mL, 0.056 mmol) and NMO (79 mg, 0.67 mmol). The reaction mixture was left to stir for 5 h, treated with additional 0504 (4% in water, 0.36 mL, 0.056 mmol) and NMO (79 mg, 0.67 mmol), and left to stir overnight. Additional OsO4 (4% in water, 0.36 mL, 0.056 mmol) and NMO (79 mg, 0.67 mmol) were added and the resultant solution was left to stir for 1 d, treated with aqueous sodium thiosulfate, and left to stir for 2 h. The mixture was extracted with dichloromethane (×3). The combined organics were dried (sodium sulfate), and concentrated. The residue was dissolved in THF (6 mL) and water (3 mL), and treated with sodium periodate (143 mg, 0.67 mmol). The mixture was left to stir overnight, diluted with water, and extracted with dichloromethane (×3). The combined organics were dried (sodium sulfate), concentrated, and purified by flash chromatography to afford the title compound as a yellow solid. LRMS (APCI) calc'd for (C13H10N3O3S) [M+H]+, 288.0. found 288.0.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:16]([N:14]([CH3:15])[C@H:11]1[CH2:12][CH2:13][C@@H:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:18])[CH3:17]
Reactant: CC(C)N(C)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)[C@H]1CC[C@@H](N)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [cis-4-(isopropyl-methyl-amino)-cyclohexyl]-carbamic acid tert-butyl ester (0.16 g, 0.6 mmol) in CH2Cl2 (3 mL) was cooled to 0° C., charged with trifluoroacetic acid (1 mL), and stirred at RT for 1 h before being concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this was repeated to afford N-isopropyl-N-methyl-cis-cyclohexane-1,4-diamine. A portion (25 mg, 0.15 mmol) of this material was dissolved in DMF (1 mL). The resulting solution was charged with N,N-diethylisopropylamine (0.13 mL, 0.7 mmol), {2-[2-(3-isopropyl-ureido)-5-trifluoromethyl-benzoylamino]-acetic acid (56 mg, 0.16 mmol), and BOP (97 mg, 0.22 mmol) and stirred for 14 h at RT. The reaction was partitioned between water and EtOAc, and organic phase was washed successively with sat. NH4Cl, water, and brine before being dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse phase HPLC afforded the TFA salt of the title compound as a white powder after lyopholization. MS found: (M+H)+=500.3.
Reaction SMILES: [Mg].II.Br[CH2:5][CH:6]([CH3:8])[CH3:7].[C:9]([OH:12])(=[O:11])[CH3:10].[C:13]([OH:16])(=[O:15])[CH3:14].[C:17]([OH:20])(=[O:19])[CH3:18].[C:21]([OH:24])(=[O:23])[CH3:22].Br[C@@:26]1([O:35][C@H:34]([CH2:36][OH:37])[C@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]1[OH:29])[OH:27]>C(OCC)C.CC(O)=O.O>[C:9]([OH:12])(=[O:11])[CH3:10].[C:13]([OH:16])(=[O:15])[CH3:14].[C:17]([OH:20])(=[O:19])[CH3:18].[C:21]([OH:24])(=[O:23])[CH3:22].[CH2:5]([C@:26]1([O:35][C@H:34]([CH2:36][OH:37])[C@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]1[OH:29])[OH:27])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CBr
Reactant: OC[C@H]1O[C@@](O)(Br)[C@H](O)[C@@H](O)[C@H]1O
Agent: II
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)C[C@@]1(O)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 69 %

Procedure:
Magnesium turnings (4.2 g) were suspended in diethyl ether (45 mL) and then initiated with a crystal of I2. 1-Bromo-2-methylpropane (1.37 mL, 12 mmol) was then added to the magnesium suspension. The mixture turned a cloudy white after the flask was heated with α heat gun. A solution of 1-bromo-α-D-galactose tetraacetate 4 (4.307 g, 10.5 mmol) in diethyl ether (10 mL) was added dropwise into the Grignard reaction mixture. The reaction went to completion after the mixture was heated at reflux for 4 h. The mixture was slowly poured into water (300 mL). Glacial AcOH (11 mL) was added. The mixture was separated and the aqueous layer was concentrated. The residue was treated with acetic anhydride (150 ML) and pyridine (150 mL) overnight. The resulting mixture was diluted with water (300 mL), extracted with diethyl ether (3×250 mL), washed with water (2×150 mL), and dried with magnesium sulfate. The solvent was removed under reduced pressure. The product was purified by flash chromatography (silica gel, 2:3 ethyl acetate/hexane) to afford 5 as a white solid (2.80 g, 7.24 mmol, 69%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5])C.[CH:17]([C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[OH:12][CH:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:26]([C:23]3[CH:24]=[N:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=3)[CH2:14][CH2:13]2)[CH2:11][CH2:10]1
Reactant: CC(C)c1ccc(N)cn1
Reactant: CCOC(=O)C1(CCOC)CCC(O)CC1
Product: CC(C)c1ccc(N2CCC3(CCC(O)CC3)C2=O)cn1

Procedure:
The title compound was prepared in analogy to example 1, step 4 from 4-hydroxy-1-(2-methoxy-ethyl)-cyclohexanecarboxylic acid ethyl ester (obtained in example 2, step 3) by treatment with 6-isopropylpyridin-3-amine [CAS Reg. No. 405103-O2-8]. MS (m/e): 289.1 [MH+].
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:25])=O>[Cl-].C([N+](CC)(CC)CC)C.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:25])[CH:5]=[C:4]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(C2CCCC2)cc(=O)[nH]1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)cc(C2CCCC2)n1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 120.5 %

Procedure:
A suspension of 2-amino-6-cyclopentyl-3H-pyrimidin-4-one (1.52 g, 8.4 mmol), tetraethyl ammonium chloride (2.8 g 16.9 mmol) and dimethylaniline (1.1 mL, 8.4 mmol) in acetonitrile (16 mL) was treated with phosphorous oxychloride (4.7 mL, 51 mmol) and heated at 110° C. for 20 min. The resulting solution was cooled to rt and concentrated to minimum volume then diluted with CHCl3 and ice and stirred for 30 min. The layers were separated and the organic layer was washed with water (3×50 mL) and 5% NaHCO3, dried, and concentrated to yield 2.0 g of crude product that was used without purification.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[C:10]2[CH:11]=[CH:12][O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1>C(O)C.O1CCCC1.[Pt](=O)=O>[O:13]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:4][C:3]3[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=3[F:1])[C:10]=2[CH:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3occc23)c(F)c1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc(Oc2cccc3occc23)c(F)c1
Reaction time: 2 h

Procedure:
Under argon, 150 mg (0.55 mmol) of 4-(2-fluoro-4-nitrophenoxy)-1-benzofuran (from example XXII) are initially charged in 5 ml of ethanol/tetrahydrofuran (1:1), platinum(IV) oxide is added and the mixture is hydrogenated under atmospheric pressure for 2 hours. The suspension is filtered off through CELITE (diatomaceous earth), the filtercake is washed with ethanol and the filtrate is concentrated using a rotary evaporator.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: ClCc1ccc(COC2CCCCO2)cc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 947.1 %

Procedure:
p-Hydroxymethylbenzyl chloride (1.33 kg, 1 mole) in dichloromethane (6 liters) was charged to a 10 liter Morton flask. Addition of 3,4-dihydro-2H-pyran (925 g, 1.1 moles) to the flask was followed by cooling to 5° C. Pyridinium p-toluenesulfonate (1.25 g, 5 mmoles) was added as a catalyst. The contents were allowed to warm up to 20°-25° C. and stirred for 24 hours. The contents were washed with water followed by a sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The residue, after removal of solvent, was kept under high vacuum (1-2 mm Hg) for 24 hours and provided 2.28 kg (95% yield) of the desired product. 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ7.4 (s, 4H), 4.75 (t, 1H), 4.65 (AB quartet, 2H, J=13 Hz), 4.6 (s, 2H), 3.85 (m, 1H), 3.55 (m, 1H), 1.5-1.95 (m, 6H).
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:20])=[CH:11][C:12](=[O:19])[N:13]2[CH2:16][CH:17]=O)=[CH:8][CH:7]=1.[N:21]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:26][CH2:25][NH:24][CH:23]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C>[CH3:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH3:20])=[CH:11][C:12](=[O:19])[N:13]2[CH2:16][CH2:17][N:24]2[CH2:25][CH2:26][N:21]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:22][CH:23]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COc1ccc2c(C)cc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1CCn1c(=O)cc(C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 3 mL of a dichloromethane solution containing 0.10 g of (7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.12 g of 1-tert-butyl 3-ethyl piperazine-1,3-dicarboxylate, 30 μl of acetic acid and 0.14 g of sodium triacetoxyborohydride were added at room temperature, and the mixture was stirred at room temperature for 1 hour and 40 minutes. The reaction mixture was added with water and chloroform. The organic layer was separated, and the aqueous layer was extracted twice with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:acetone=100:1] to obtain a colorless foam, 1-tert-butyl 3-ethyl 4-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-1,3-dicarboxylate. (2) To 2.6 mL of a dichloromethane solution containing 1-tert-butyl 3-ethyl 4-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-1,3-dicarboxylate, 1.3 mL of trifluoroacetic acid was added, the mixture was stirred at room temperature for 2 hours, and the solvent was removed under reduced pressure. The residue thus obtained was added with ethyl acetate and water, and the resultant solution was adjusted to pH 1.0 with 6 mol/L hydrochloric acid. The aqueous layer was separated, and the organic layer was extracted twice with 20 mL of 0.1 mol/L hydrochloric acid. The aqueous layer and an extract were combined, thereto was added ethyl acetate, and the resultant solution was adjusted to pH 8.5 with a 5 mol/L aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was adjusted to pH 11.5 with a 5 mol/L aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 89 mg of a colorless foam, ethyl 1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperazine-2-carboxylate.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[C:5]=1[NH2:6])([CH3:3])[CH3:2].C[Al](C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:23]#[N:24].ClCCl.CO>C1(C)C=CC=CC=1.CCCCCC>[CH:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:23](=[NH:24])[C:22]1[CH:25]=[C:26]([CH3:28])[CH:27]=[C:20]([O:19][CH3:18])[CH:21]=1)([CH3:13])[CH3:12]
Reactant: COc1cc(C)cc(C#N)c1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(C)cc(C(=N)Nc2c(C(C)C)cccc2C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 500 mL 3-neck round bottom flask was added 2,6-diisopropylaniline (4.82 g, 27.2 mmol) and 100 mL toluene. The solution was cooled in an ice bath under nitrogen and trimethylaluminum (2.0 M in toluene, 19 mL, 38.1 mmol) was added dropwise via dropping funnel. The reaction mixture was stirred at room temperature for 2 hours. Next, 3-methoxy-5-methylbenzonitrile (5.20 g, 35.3 mmol) in 50 mL toluene was added and the reaction mixture was heated to 70° C. overnight under nitrogen. The reaction mixture was cooled in an ice bath and was poured onto a stirring slurry of silica gel in 2:1 dichloromethane/methanol (v/v). The silica gel was filtered off and washed with dichloromethane and methanol. The filtrate was evaporated leaving a solid. Hexane was added to the solvent and the solid was filtered off and washed with hexane (5.83 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:31]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:30])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:29])[C:20]=2[N:21]2[CH2:26][CH2:25][CH2:24][C:23]([F:28])([F:27])[CH2:22]2)[N:13]=1.Cl>CO.O1CCOCC1>[NH2:31][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:29])[C:20]=1[N:21]1[CH2:26][CH2:25][CH2:24][C:23]([F:27])([F:28])[CH2:22]1)=[O:30]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(F)(F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.8 %

Procedure:
To a solution of tert-butyl 2-(2,6-difluorophenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (57 mg, 0.1 mmol) in MeOH (2 mL) was added HCl in 1,4-dioxane (4 M, 5 mL). After stirring at room temperature for 18 hr the mixture was concentrated under reduced pressure. Purification via preparative HPLC gave 287 as a white solid (29 mg, 63%). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.65 (s, 1H), 7.37-7.28 (m, 1H), 7.06-6.99 (m, 2H), 6.13 (s, 2H), 3.75 (s, 3H), 3.32 (t, J=11.0 Hz, 2H), 3.17-3.12 (m, 2H), 2.08-1.95 (m, 2H), 1.92-1.84 (m, 2H). LCMS (ES+) m/z 455.0 (M+1).
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.C1C2C(=O)CCCCC=2C=CN=1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1>>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:14](=[O:16])[CH2:13][CH:3]3[CH2:4][CH2:5][CH2:6][C:7]4[CH:12]=[CH:11][N:10]=[CH:9][C:8]=4[C:2]3=[N:37]2)=[CH:32][CH:31]=1
Reactant: O=C(O)CC1CCCc2ccncc2C1=O
Reactant: NNc1ccc(Cl)cc1
Agent: O=C1CCCCc2ccncc21
Product: O=C1CC2CCCc3ccncc3C2=NN1c1ccc(Cl)cc1

Procedure:
Prepared according to the method described in Example 1 from 9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine-8-acetic acid (prepared by hydrolysis of the corresponding ketal, the latter being prepared from 5,6,7,8-tetrahydrocyclohepta[c]pyridine-9-one (Hicks et al, J. Chem. Soc. Perkin I (1984)2297) according to the method of Wu et al supra) and 4-chlorophenylhydrazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:19])[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([Cl:19])[CH:12]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: Cc1cnc(Cl)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cnc(Cl)nc1Nc1ccc(C#N)c(Cl)c1

Procedure:
To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-2-chlorobenzonitrile (217 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1×100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 26, was used for next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14](=[O:35])[C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:34])[C@H:21]([NH:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.S(Cl)(Cl)=O.[CH3:40][CH:41](O)[CH3:42]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14](=[O:35])[C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:34])[C@H:21]([NH:29][CH2:30][C:31]([O:33][CH:41]([CH3:42])[CH3:40])=[O:32])[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc2cc(CNC(=O)[C@@H]3CCCN3C(=O)[C@@H](CC3CCCCC3)NCC(=O)O)ccc12
Reactant: CC(C)O
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)CN[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1

Procedure:
To a stirred solution of 96 mg of N-(1-amino-isoquinolin-6-ylmethyl)1-(2-hydroxycarbonylmethylamino-2(R)-cyclohexylmethyl-acetyl)-prolinamide in 6mL of 2-propanol was added 0.03 mL of thionyl chloride and the reaction mixture was heated at refux temperature for two days. After this period the reaction mixture was concentrated, ethyl acetate added, washed with aqueous 5% sodium hydrogencarbonate and brine, dried over sodium sulphate and concentrated. The residue was dissolved in a t-butanol/water 1/1 (v/v) mixture lyophilisation yielded 56 mg of the title compound. MS ESI+: 524(M+H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([CH2:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=3[S:26]([NH:29]C(C)(C)C)(=[O:28])=[O:27])[CH:14]=[CH:15][CH:16]=2)[CH:2]=1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:53]([O:52][C:50]([NH:29][S:26]([C:18]1[S:19][C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:21][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[N:1]=[CH:2]2)[CH:12]=1)(=[O:28])=[O:27])=[O:51])[CH2:54][CH2:55][CH3:56]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3cnc4cccnc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2cnc3cccnc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-(3-imidazo[4,5-b]pyridin-3-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (53.6 mg, 0.111 mmol; see Example 8(a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (32.9 mg, 0.222 mmol) and butyl chloroformate (141.3 μL, 1.11 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (20-100% CH3CN in water) to give the title compound in 70% yield, over two steps, (41 mg, 0.078 mmol).