Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(O)C.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CCCNc1c(N)cnc2ccccc12
Reactant: CCOCC(=O)Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
A solution of ethoxyacetyl chloride (7.00 g, 57.1 mmol) in dichloromethane (10 mL) was added dropwise to a stirred solution of ethyl 4-(3-aminoquinolin-4-ylamino)butyrate (prepared as described in Steps 1-2 of Example 17, 12.5 g, 45.7 mmol) in dichloromethane (100 mL) at room temperature. After 1.5 hours, the reaction mixture was concentrated under reduced pressure to afford a solid to which was added ethanol (100 mL) and triethylamine (17.4 mL, 125 mmol). The solution was left at room temperature for 5 days, then was heated at reflux for 2 hours. The solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane (150 mL) and water (50 mL). The organic layer was washed with water (50 mL) and saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to yield 15.4 g of ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate as a brown oil that was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:31][S:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.C[Si](Cl)(C)C.O>C(O)CCC.C(OCC)(=O)C>[NH:28]1[C:29]2[C:25](=[CH:24][CH:23]=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:37][C:36]4[CH:38]=[CH:39][C:33]([S:32][CH3:31])=[CH:34][CH:35]=4)[N:3]=3)[CH:30]=2)[CH:26]=[N:27]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5cn[nH]c5c4)nc(Cl)nc32)cc1
Reactant: CSc1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CSc1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Temperature: 116 °C
Yield: 45.5 %

Procedure:
A mixture of 2-chloro-N-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (400 mg, 0.912 mmol), 4-(methylthio)aniline (0.227 mL, 1.83 mmol) and trimethylsilyl chloride (TMSCl) (0.231 mL, 1.83 mmol) in n-butyl alcohol (8 mL) was heated at 116° C. for 72 h. Water and ethyl acetate were then added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, and concentrated in vacuo. The residue was dissolved in CH3CN (20 mL), and water was added to induced precipitation. The solid was collected by filtration to give N4-(1H-indazol-6-yl)-N2-(4-(methylthio)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (225 mg). The filtrate was also purified by HPLC to give another portion of the desired product (127 mg).
Reaction SMILES: O[CH2:2][C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][N:4]=1.Cl.[NH2:13][CH2:14][CH2:15][SH:16]>>[NH2:13][CH2:14][CH2:15][S:16][CH2:2][C:3]1[N:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][N:4]=1
Reactant: NCCS
Reactant: OCc1ncc2n1CCCC2
Agent: Cl
Product: NCCSCc1ncc2n1CCCC2

Procedure:
Reacting 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine with cysteamine hydrochloride by the procedure of Example 1 gives 3-[(2-aminoethyl)thiomethyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([O:10]CC)=[CH2:9])=[CH:4][N:3]=1.C1C(=O)N([Br:20])C(=O)C1>C1COCC1.O.CCOC(C)=O.[F-].[K+]>[Br:20][CH2:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:9]
Reactant: C=C(OCC)c1cnc(Br)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cnc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a solution of 2-bromo-5-(1-ethoxyvinyl)pyrazine (0.65 g, 2.84 mmol) in THF and water was added NBS (0.505 g, 2.84 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, then diluted with EtOAc and aq. KF. The two phase mixture was stirred for 20 min at rt before being filtered through diatomaceous earth (Celite®). The filtrate was washed with sat. NaHCO3, sat. NaCl, dried over anhydrous Na2SO4, concentrated. The crude product was purified by silica gel chromatography (0-100% EtOAc in hexane) to yield 2-bromo-1-(5-bromopyrazin-2-yl)ethanone (0.38 g) as a yellow oil. LC/MS (Cond. N-1): [M+H]+ 280.91, RT=2.945 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl.[NH2:27][CH2:28][C:29]([NH2:31])=[O:30]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]=2[CH2:23][NH:27][CH2:28][C:29](=[O:30])[NH2:31])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NCC(N)=O
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: Cl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCC(N)=O)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and glycinamide hydrochloride.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:16].[CH2:17]([O:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH3:19].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:5]([CH2:4][CH2:3][CH2:2][N:24]1[CH2:25][CH2:26][CH:21]([O:20][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23]1)[C:6](=[O:16])[CH2:7][CH2:8]2
Reactant: Cc1ccc2c(c1)CCC(=O)N2CCCCl
Reactant: CCCOC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOC1CCN(CCCN2C(=O)CCc3cc(C)ccc32)CC1
Reaction time: 20 h
Yield: 58.2 %

Procedure:
A 4 mL vial was charged with 1-(3-Chloropropyl)-6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH14) (0.128 g), 4-propoxypiperidine (0.079 g, 0.54 mmol), KI (0.166 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) in MeCN (2 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH18-2) (0.108 g, total yield 50%). 1H NMR (CD3OD) δ 7.05-7.00 (m, 3H), 3.95 (t, J=7.2, CH2), 3.41-3.30 (m, 3H), 2.84-2.76 (m, 4H), 2.57-2.53 (m, 2H), 2.47-2.43 (m, 2H), 2.27 (s, 3H, CH3), 2.27-2.22 (m, 2H), 1.90-1.81 (m, 4H), 1.63-1.52 (m, 4H), 0.91 (t, J=7.4 Hz, CH3); 13C NMR (CD3OD) δ 172.4, 137.8, 134.0, 129.8, 129.0, 128.0, 116.2, 75.3, 70.7, 56.5, 51.9, 41.2, 32.8, 31.7, 26.2, 25.5, 24.3, 20.7, 11.0; HPLC-MS (ammonium acetate) [M+H+]=345.30.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[O:5][CH2:4][C@H:3]1[NH:10][C:11](=[O:19])[O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>ClCCl>[CH3:30][S:27]([O:1][C@H:2]1[C@H:3]([NH:10][C:11]([O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])=[O:19])[CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH2:7]1)(=[O:29])=[O:28]
Reactant: CC1(C)C[C@@H](O)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 119.7 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (3R,4R)-4-hydroxy-6,6-dimethyl-tetrahydro-2H-pyran-3-ylcarbamate (360 mg, 1.25 mmol) and triethylamine (378 mg, 3.75 mmol) in dichloromethane (5 mL) was dropwise added mesyl chloride (213 mg, 1.87 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, and then diluted with dichloromethane (100 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford the title compound (550 mg, crude) as a yellow oil, which was directly used in the next step without further purification.
Reaction SMILES: CC1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=5)[CH:23]=[C:22]([CH3:36])[N:21]=4)[N:15]=3)=[CH:10][CH:9]=2)C(C)=CC=1.Cl.NO.[OH-].[Na+].O>C(O)CC>[CH3:36][C:22]1[N:21]=[C:20]([C:16]2[N:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH2:3])=[N:13][CH:12]=3)[CH:19]=[CH:18][N:17]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:33])[F:35])=[CH:28][CH:27]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nccc(-c3ccc(-n4c(C)ccc4C)nc3)n2)n1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: O
Solvent: CCCO
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2nccc(-c3ccc(N)nc3)n2)n1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
Step 3) The title compound was prepared from the above described 4-[6-(2,5-dimethyl-pyrrol-1-yl)-pyridin-3-yl]-2-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (0.250 g, 1.29 mmol) by heating with hydroxylamine hydrochloride (259 mg, 3.86 mmol) in a mixture of aqueous NaOH (1.5 M, 0.86 mL, 1.29 mmol) in 1-propanol (2.5 mL) in a sealed tube at 120° C. for 4 h. Cooled to rt, added some water and extracted twice with AcOEt, dried over Na2SO4, filtered off and evaporated totally. The crude material was triturated with ether to give the title compound (0.140 g, 67%) as an off-white solid. MS (ISP) 408.3 [(M+H)+]; mp 258° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([B-](F)(F)F)=[CH2:12].[K+].C(N(CC)CC)C>C(O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:11]=[CH2:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=Cc1ccc([N+](=O)[O-])cn1
Temperature: 120 °C

Procedure:
To a 20 ml, microwave tube was added 2-bromo-5-nitropyridine (0.20 g, 0.98 mmol), potassium vinyltrifluoroborate (145 mg, 1.1 mmol), PdCl2(dppf)-CH2Cl2 complex (40 mg, 0.049 mmol), and a stir bar. The tube was sealed, and ethanol (6 mL) and triethylamine (0.41 mL, 3.0 mmol) was added via syringe. The mixture was purged three times with nitrogen and then heated to 120° C. for 30 minutes. LC at that point showed mostly product. The reaction was diluted with DCM, adsorbed onto silica gel, and purified by silica gel flash chromatography (Hexane:EtOAc). LC-MS (IE, m/z): 151 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O.[CH:15]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]>C1COCC1>[CH:15]([C:18]1[CH:19]=[C:20]([NH:24][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[CH:21]=[CH:22][CH:23]=1)([CH3:17])[CH3:16]
Reactant: CC(C)c1cccc(N)c1
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-3-nitro-benzoyl chloride (2.00 g, 0.010 mol) in THF (30 mL), in a water bath-cooled 100 mL RBF, was added 3-isopropyl-phenylamine (1.35 g, 0.010 mol) dropwise. The reaction was allowed to stir at room temperature for 1 hour before being concentrated. The mixture was taken up in EtOAc and washed with NaHCO3 (aq., conc.) and then brine. The solution was dried over MgSO4, filtered, and concentrated to yield N-(3-isopropyl-phenyl)-4-methyl-3-nitro-benzamide as an orange oil that solidifies upon standing. MS m/z 299=[M+H]+. Calc'd for C17H18N2O3: 298.34.
Reaction SMILES: [K].[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15](=[O:40])[CH:16]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][C:19]=2[CH2:28][CH2:29][CH3:30])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[OH-].[K+].C(Cl)Cl.CO.[NH4+].[OH-]>CO.O>[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15](=[O:40])[CH:16]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][C:19]=2[CH2:28][CH2:29][CH3:30])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: [K+]
Agent: [K]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 60 °C
Yield: 91.3 %

Procedure:
A mixture of 205 g (0.345 mol) of the product of Example 6, 425 mL of 1.0N KOH in methanol and 500 mL of water was stirred at 60° C. under a nitrogen atmosphere. After 1.75 hours TLC analysis (90:10:1 CH2Cl2 -MeOH-NH4OH) indicated that ester hydrolysis was complete. The reaction mixture was cooled slightly, then concentrated on a rotary evaporator. The concentrate was acidified with 400 mL of 2N HCl and extracted first with 6 L of ether-EtOAc-CH2Cl2 4:1:1, then with 3 L of 1:2 EtOAc-CH2Cl2. The organic layers were washed with 250 mL of 2N HCl, then with 3×500 mL of water, dried with magnesium sulfate, filtered, and concentrated, during which, the product began to crystallize. The solution was concentrated to a white sluury of ca. 750 mL, diluted with 1 L of hexanes, cooled to 0° C., aged 1 hr then filtered. The product was air dried affording 170.0 g (91% yield) of the title compound as a white crystalline solid.
Reaction SMILES: CC([O-])=O.[Na+].N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][C:19](=O)[OH:20])=O)C)=O)C.[NH2:35]C1C=C2C(C(C)=CC(=O)O2)=CC=1>>[NH2:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][C:19](=[O:20])[NH2:35]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)O
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Product: NC(=O)C[C@H](N)C(=O)O
Reaction time: 0.33 h

Procedure:
To a AEP (100 ng/well) in assay buffer (50 mM NaOAc, 300 mM NaCL, pH 4.5, 50 μL) was added 10 μL of the inhibitors (in PBS). The plate was then incubated at room temperature for 20 minutes. ZAla-Ala-Asp-MEC was then added (100 μM, Bachem, 60 μL) and 7-amino-4-methylcoumarin release was measured by fluorescence spectroscopy over time. Initial rates were plotted against inhibitor concentration.10
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[P:20]([O-:37])([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O.C(O)C.C(Cl)(Cl)(Cl)Cl>[CH2:22]([O:21][P:20]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:37])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)[C@H](Cc1ccccc1)NP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A solution of 8.2 g of L-phenylalanine and 25 ml of triethylamine in 15 ml of water and 10 ml of ethanol under argon is chilled to 0° C. To this stirred solution is added dropwise 13.1 g of dibenzyl phosphite in 20 ml of carbon tetrachloride. After the addition, the mixture is stirred at room temperature for 3 hours and the mixture is concentrated under vacuum, diluted with ethyl acetate (100 ml), cooled to 0° C. and 50 ml of 3N hydrochloric acid added dropwise. The organic layer is separated and the aqueous layer extracted twice with 100 ml of ethyl acetate. The organic layer and extracts are combined, dried (Na2SO4) and the solvent removed. The residue is dried under vacuum to give 20.7 g of a yellow gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)C.CO>[C:1]([O:5][C:6](=[O:9])[NH:7][N:8]1[CH:12]=[CH:16][CH:15]=[CH:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1CCC(OC)O1
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)Nn1cccc1
Temperature: 90 °C
Yield: 43.6 %

Procedure:
A flask (fitted with a Dean-Stark trap) containing a stirred solution of tert-butylcarbazate (100, 0.757 mol), 2,5-dimethoxytetrahydrofuran (108 g, 0.832 mol) and 2N HCl (10 mL) in 1,4-dioxane (700 mL) was heated under nitrogen at 90° C. As the reaction progressed over several hours, the solution changed from pale yellow to orange and began to reflux. The reaction was monitored by the amount of distillate collected in the Dean-Stark trap (primarily CH3OH, 2 moles/1 mole reagent). As methanol collection approached the theoretical amount (50 mL), a sample was analyzed by TLC (silica gel, 1:3 EtOAc/hexane, ninhydrin stain) to confirm reaction completion. Heating was shut off and the reaction was allowed to cool somewhat before adding saturated, aq sodium bicarbonate solution (˜25 mL) to neutralize the hydrochloric acid. The quenched mixture was filtered through a sintered-glass funnel and concentrated in vacuo to leave an orange, semi-solid residue. The residue was suspended in diethyl ether (minimum volume) and the nearly colorless solids were collected by suction filtration, washed with hexane and air-dried to afford 60.2 g (40%) of product. A second crop (yellow-tan solids) from the mother liquors was isolated: 29.0 g (19%). 1H-NMR (CD3OD): δ10.23 (br s, 1H), 6.66 (t, 2H, J=2.2 Hz), 5.94 (t, 2H, J=2.2), 1.42 (s, 9H); MS: GC/MS (+esi): m/z=182.9 [MH]+
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:31][S:32]([O-:34])=[O:33].[Na+].CNCCNC>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([O:20][CH3:21])=[C:18]([O:22][C:23]3[CH:28]=[CH:27][C:26]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: COc1c(Oc2ccc(Br)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(Oc2ccc(S(C)(=O)=O)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 120 °C
Yield: 41.5 %

Procedure:
A mixture of 4-[6-(4-bromo-2-fluoro-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (0.543 g, 1.21 mmol), sodium methane sulfinate (774.2 mg, 7.58 mmol), and N,N′-dimethyl-ethylene diamine (50.31 μL, 0.44 mmol) and copper (I) trifluoromethane sulfonate benzene complex (384.9 mg, 0.759 mmol) in 20 mL DMSO was heated in microwave for 7 minutes at 120° C. The mixture was purified by HPLC to give compound 4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound 76) as an oil (242.7 mg, 42%). 1HNMR (DMSO-d6, 400 MHz) δ 1.19-1.21 (d, 6H), 1.68-1.72 (m, 2H), 1.97-2.02 (m, 2H), 3.30-3.33 (m, 2H), 3.33 (s, 3H), 3.65-3.71 (m, 2H), 3.90 (s, 3H), 4.78-4.81 (m, 1H), 5.28-5.37 (m, 1H), 7.69-7.73 (m, 1H), 7.84-7.87 (m, 1H), 8.00-8.03 (m, 1H), 8.16 (s, 1H). Exact mass calculated for C21H26FN3O7S 483.15 found 484.2 (MH+).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:25]=[CH:26][C:27]([S:29]([N:32]3[CH:36]=[C:35]([CH:37]=[O:38])[CH:34]=[N:33]3)(=[O:31])=[O:30])=[CH:28][C:13]=2[N:12]=1)([CH3:10])([CH3:9])[CH3:8]>CN(C=O)C>[C:7]([C:11]1[N:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19][CH2:18]2)[C:14]2[CH:25]=[CH:26][C:27]([S:29]([N:32]3[CH:36]=[C:35]([C:37]([OH:1])=[O:38])[CH:34]=[N:33]3)(=[O:31])=[O:30])=[CH:28][C:13]=2[N:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCC(F)(F)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxone® (0.60 g, 0.97 mmol) was added to a solution of 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-1H-pyrazole-4-carbaldehyde (0.41 g, 0.88 mmol) in DMF (15 mL). The reaction mixture was stirred overnight at ambient temperature and the solvent was concentrated. The product was recovered in DCM, washed with 10% HCl solution, brine and dried over anhydrous Na2SO4, The solvent was concentrated to provide the pure title compound as white solid. Yield: 0.38 g (89%); 1H NMR (400 MHz, CDCl3) δ 1.42-1.53 (m, 2 H), 1.56 (s, 9 H), 1.59-1.75 (m, 4 H), 2.02-2.20 (m, 3 H), 4.25 (d, J=7.42 Hz, 2 H), 7.46 (d, J=8.59 Hz, 1 H), 7.99 (dd, J=8.69, 1.86 Hz, 1 H), 8.01-8.08 (m, 2 H), 8.47 (d, J=1.56 Hz, 1 H), 8.68 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=481.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28]([NH:30][CH3:31])=[O:29])=[C:11]([Br:27])[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:14](=[O:26])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.Br[CH2:48][CH:49]=[C:50]([CH3:52])[CH3:51]>CN(C=O)C>[CH3:51][C:50]([CH3:52])=[CH:49][CH2:48][N:30]([CH3:31])[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]2[C:14](=[O:26])[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:16][CH2:17][N:12]2[C:11]=1[Br:27])=[O:29]
Reactant: CC(C)=CCBr
Reactant: CNC(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)=CCN(C)C(=O)c1c(OCc2ccccc2)c2n(c1Br)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cold (0° C.) solution of 8-(benzyloxy)-6-bromo-2-(4-fluorobenzyl)-N-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazine-7-carboxamide (0.24 g, 0.50 mmol) in anhydrous DMF (10 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 0.55 mmol) was added. The reaction mixture was stirred at 0° C. for 15 minutes and treated with 4-bromo-2-methyl-2-butene (0.15 mL, 1.5 mmol; passed through activated basic alumina). The reaction mixture was stirred at rt for 40 minutes and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate. Collection and concentration of appropriate fractions provided the titled product. ES MS M+1=486,488 (1:1)