Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][C:20]([NH:22][C:23]3[N:28]=[C:27]([NH:29][C:30]4[C:35]([C:36](=[O:39])[NH:37][CH3:38])=[CH:34][CH:33]=[CH:32][C:31]=4[F:40])[C:26]([Cl:41])=[CH:25][N:24]=3)=[CH:21][C:15]=2[NH:14][C:13](=[O:42])[CH2:12]1)=O)C1C=CC=CC=1>CSC.FC(F)(F)C(O)=O>[Cl:41][C:26]1[C:27]([NH:29][C:30]2[C:31]([F:40])=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]([NH:37][CH3:38])=[O:39])=[N:28][C:23]([NH:22][C:20]2[CH:19]=[CH:18][C:16]3[CH2:17][NH:11][CH2:12][C:13](=[O:42])[NH:14][C:15]=3[CH:21]=2)=[N:24][CH:25]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CN(C(=O)OCc2ccccc2)C3)ncc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CNC3)ncc1Cl
Yield: 67 %

Procedure:
A solution of 8-[5-chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid benzyl ester (0.21 g, 0.36 mmol) in methyl sulfide (3.5 mL) and trifluoroacetic acid (11 mL) was stirred at room temperature for 16 hours. Concentration and chromatography on a silica gel with methylene chloride and methanol (20:1) gave 0.11 g of 2-[5-chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (68% yield): 1H NMR (300 MHz, CD3OD) δ 8.18 (s, 1H), 7.45 (m, 4H), 7.27 (s, 2H), 4.24 (s, 2H), 3.65 (s, 2H), 2.84 (d, 3H); MS (m/e): 456.4 (M+1).
Reaction SMILES: C(Cl)Cl.[N+:4]([C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].[NH4+].[Cl-]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:16]([O:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N+:4]([O-:6])=[O:5])[CH:8]=1)(=[O:17])[C:15]([CH3:20])([CH3:19])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To 300 mL of CH2Cl2 was added 3-nitrophenol (structure 64 of Scheme XVII, where R1 =H, Y=O) (15 g, 0.11 mol), pyridine (20 mL) and DMAP (10 mg). To this cooled solution (0° C.) was slowly added trimethylacetyl chloride (18 mL, 146 mmol, 1.4 equivuiv). The solution was allowed to warm to rt and stirred for 3 h. To the amber colored solution was added sat'd NH4Cl (300 mL). The organic layer was washed with 1 N HCl (2×150 mL), 10% CuSO4. 5 H2O (2×100 mL), and brine (2×100 mL). The extract was dried (Na2SO4) and concentrated in vacuo to give 22.5 g (94%) of O-pivaloyl-3-nitrophenol as a white solid. Data for O-pivaloyl-3-nitrophenol: Rf 0.55 (silica gel, hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 8.11 (dd, J=4.2, 1.3, 1 H), 7.96 (t, J=2.2, 1 H), 7.56 (dd, J=8.4, 8.2, 1 H), 7.42 (dd, J=6.5, 1.3, 1 H), 1.35 (s, 9 H).
Reaction SMILES: [O:1]([CH2:8][CH:9]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([S-:34])#[N:33].[K+].BrBr>C(O)(=O)C>[O:1]([CH2:8][CH:9]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)[CH:10]([OH:11])[C:12]1[CH:17]=[CH:16][C:15]2[N:18]=[C:32]([NH2:33])[S:34][C:14]=2[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(C(O)C(COc2ccccc2)N2CCC(Cc3ccccc3)CC2)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(C(O)C(COc3ccccc3)N3CCC(Cc4ccccc4)CC3)cc2s1
Reaction time: 2 h

Procedure:
To a stirred solution of 1.5 g of (+) three 1-phenoxymethyl-1-(4-benzylpiperidin-1-yl)-2-p-aminophenyl-2-hydroxy-ethane and 1.43 g of KSCN in 20 ml of glacial acetic acid was added dropwise a solution of 0.58 g of Br2 in 5 ml of glacial acetic acid at room temperature. After stirring for 2 h., the yellow sospension was filtered and the solution was poured into 70 ml of concentrated ammonium solution. The cloudy basic solution was extracted with ethyl acetate dried and evaporated. The resulting yellow residue was chromatographed on silica gel eluting with ethylacetate/cycloexane ⅓, furnishing after crystallization from ethanol 0.9 g of the title compound, m.p. 210-214° C., [α]20D=−2.1±0.1
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:11]/[OH:12])/[CH3:10].[CH3:13][C:14](OC(C)=O)=[O:15]>>[C:14]([O:12]/[N:11]=[C:9](/[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[OH:1])\[CH3:10])(=[O:15])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: C/C(=N\O)c1cccc(C)c1O
Product: CC(=O)O/N=C(\C)c1cccc(C)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
(E)-1-(2-hydroxy-3-methylphenyl)ethanone oxime (Step 46.2) (5.5 g, 30 mmol) was added into Ac2O (48.1 mL, 509 mmol) under argon and the resulting mixture was stirred at RT for 1.5 hr. The reaction was concentrated to 10 mL volume under reduced pressure; the resulting suspension was diluted with cold water and stirred at RT until a fine precipitate occurred. The resulting solid was filtrated off, washed with water and dried to afford the title product (6.03 g, 28.8 mmol, 96% yield) as colorless solid. tR: 1.08 min (LC-MS 2); ESI-MS: 208 [M+H]+; Rf=0.60 (hexane/EtOAc 1:1).
Reaction SMILES: [C:1]([NH:9][C@@H:10]([C:16](O)=O)[CH2:11][CH2:12][C:13](O)=O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]C.[CH2:19](N(CC)CC)C.C(Br)C1C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH:10]1([NH:9][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][CH2:12][CH2:13][CH2:19][CH2:16]1
Reactant: CCCCCCC(=O)N[C@H](CCC(=O)O)C(=O)O
Reactant: CCN(CC)CC
Agent: BrCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C1CCC(NC2CCCCC2)CC1
Reaction time: 60 h
Yield: 64.5 %

Procedure:
A solution of 108.8 g (420 mmol) of N-heptanoyl-D-glutamic acid and 50.6 g (500 mmol) of triethylamine in 135 ml of dimethylformamide was treated with 85.7 g (500 mmol) of benzyl bromide and stirred under nitrogen atmosphere for 60 hours. The reaction was poured onto one liter of ethyl acetate and washed successively with two 500 ml portions each of dilute hydrochloric acid and water. The ethyl acetate was then washed with 500 ml of 1N sodium hydroxide. The basic aqueous layer was acidified with dilute acid and extracted with four 500 ml portions of ethyl acetate. The combined ethyl acetate extracts were treated with excess dicyclohexylamine and stirred 18 hours. The suspension was filtered, slurried in fresh ethyl acetate (400 ml) for two hours, refiltered and dried under vacuum to give 49.1 g of dicyclohexylamine salt. The resulting salt (14.0 g) was stirred in dilute hydrochloric acid, filtered and washed with ethyl acetate. The aqueous filtrate was extracted twice with ethyl acetate, and the organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting oil was triturated with hexane to give 7.9 g (86% from salt) of the title ester: mp 76°-79° C.; IR (Nujol) 3300, 2700-3100, 1730, 1700, 1645 cm-1 ; NMR (CDCl3) delta 7.35 (s, 5H), 5.20 (s, 2H), 4.70 (m, 1H), 1.85-2.50 (m, 6H), 1.55-1.70 (m, 2H), 1.10-1.40 (m, 6H), 0.75 (t, 3H); [alpha]D =27.6 (C=0.6, MeOH).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[CH3:18]I>O1CCCC1>[C:1]([NH:4][C:5]([CH3:18])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
To a solution of diethyl 2-acetylaminomalonate (2.17 g) in dry tetrahydrofuran is added sodium hydride (0.26 g), and the mixture is stirred at room temperature for one hour. After stirring, methyl iodide (1.60 g) is added dropwise thereto, and the mixture is stirred overnight. The reaction mixture is concentrated, and to the residue is added ethyl acetate and water. The organic layer is separated, dried and evaporated to remove the solvent. The residue is recrystallized from a mixture of isopropyl ether and n-hexane to give diethyl 2-acetylamino-2-methylmalonate (1.80 g), m.p. 89°-90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28][NH2:29]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([OH:26])[CH2:27][NH:29][CH3:28])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CN
Solvent: CCO
Product: CNCC(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 33% methylamine in ethanol, a mixture of regioisomers was obtained. This solution was evaporated and the isomers were separated by flash chromatography (SiO2, eluting with 5% to 20% methanol/DCM, containing 0.1% concentrated aqueous NH3), giving ABD789 as a light orange powder (165 mg). With further elution (increasing the polarity slowly to 40% methanol/DCM) ABD783 was obtained as an orange gum, which was triturated with ether to give the title compound as a light orange powder (330 mg). 1H NMR (400 MHz, DMSO-d6): δ 2.47 (3H, s), 2.70-2.76 (1H, t), 2.80-2.89 (1H, dd), 4.85 (1H, d, J=8 Hz), 6.95-7.15 (2H, m), 7.10-7.25 (3H, m), 7.40 (1H, t), 7.55-7.65 (1H, m), 7.66 (2H, d, J=8 Hz) and 7.84 (2H, d, J=8 Hz). MS, m/z: Calcd, 418.11. Found, 418.28 (M).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][CH:9]=2)[N:7]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>N1C=CC=CC=1>[C:23]([NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[N:7]=1)(=[O:25])[CH3:24]
Reactant: Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(-c2ccc(OCc3ccc(Cl)cc3)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In 30 ml of pyridine was dissolved 2.0 g hydrochloride of 2-amino-4-[4-(4-chlorobenzyloxy)phenyl]thiazole, and 1.0 ml of acetic anhydride was added to the solution, followed by stirring at room temperature for 2 hours. Water was added and, the precipitating crystals were recovered by filtration, thus yielding 1.9 g (95.0%) of 2-acetylamino-4-[4-(4-chlorobenzyloxy)phenyl]thiazole. m.p., 239°-240° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH3:5].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32]I)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][C:6]([CH2:3][CH2:4][CH3:5])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Reactant: ICCc1ccccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCc1ccccc1OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a suspension of sodium hydride (1.3 g) in dimethylformamide (15 ml), a solution of diethyl propylmalonate (6.6 g) in dimethylformamide (45 ml) was added under ice-cooling and the mixture was stirred at room temperature for an hour. To the solution was added a solution of 2-(2-benzyloxyphenyl)ethyl iodide (10 g) in dimethylformamide (30 ml), the mixture was stirred at the same temperature for an hour and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=8:1) to give the subject compound (10 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:11]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)=[N:12][C:13]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:14][C:15]=3[O:16]C)=[N:7][C:6]=2[CH:38]=1.Cl.O>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[C:15](=[O:16])[NH:14][C:13]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:12][C:11]=3[NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)=[N:7][C:6]=2[CH:38]=1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(Br)ccc2s1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: O=c1[nH]c(N2CCOCC2)nc(N[C@@H]2CCCNC2)c1-c1nc2cc(Br)ccc2s1
Reaction time: 0.08 h

Procedure:
Following the same procedure as in step 4 of Example 337 using tert-butyl (3R)-3-[[5-(5-bromo-1,3-benzothiazol-2-yl)-6-methoxy-2-(morpholin-4-yl)pyrimidin-4-yl]amino]piperidine-1-carboxylate (60.0 mg, 0.10 mmol, 1.00 equiv) and cone, hydrochloric acid (4.0 mL). The crude product (100 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm,; mobile phase, water with 50 mmol NH4HCO3 and CH3CN (38.0% CH3CN up to 53.0% in 7 min, up to 100.0% in 5 min, down to 38.0% in 1 min); Detector, Waters 2489 254&220 nm to afford the title compound as a white solid. 1H-NMR(400 MHz, DMSO-d6) δ ppm 1.54-1.72(m, 3H), 1.92-1.93(m, 1H), 2.65-2.75(m, 2H), 2.86(m, 1H), 3.10-3.13(m, 1H), 3.62-3.69(m, 8H), 4.17(m, 1H), 7.37-7.39(d, J=8.4 Hz, 1H), 7.89-7.94(m, 2H), 10.74-10.75(m, 1H); MS m/z [M+H]+ (ESI): 492. IRAK4 IC50=19 nM
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH3:10][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH3:10])=[CH:4][N:3]=1
Reactant: C[Mg]Br
Reactant: Cc1ncc(C=O)cn1
Solvent: C1CCOC1
Product: Cc1ncc(C(C)O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-methylpyrimidine-5-carbaldehyde (5.00 g, 38.9 mmol) in tetrahydrofuran (85 mL) was slowly added 33 mL of 1.4 M methylmagnesium bromide solution in tetrahydrofuran at 0° C. The mixture was stirred at room temperature for 1 hour and then quenched with water (50 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[CH3:11][C:12]1([CH3:24])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:23])([CH3:22])[CH2:14][CH2:13]1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][C:8]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[C:15]([CH3:23])([CH3:22])[CH2:14][CH2:13][C:12]2([CH3:24])[CH3:11])=[O:9]
Reactant: O=C(Cl)CCCl
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
73.5 g (0.55 mole) of anhydrous aluminum chloride were added a little at a time, at 0°-5° C., to a solution of 70 g (0.55 mole) of 3-chloropropionyl chloride in 200 ml of methylene chloride, after which a solution of 94 g (0.5 mole) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 200 ml of methylene chloride was added dropwise at the same temperature. The mixture was stirred overnight at room temperature, poured onto 1 l of ice/water and extracted with 3 times 300 ml of methylene chloride. The combined organic phases were washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated down. 138 g of 6-(3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene remained as an oil. The structure was determined by H-NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]([NH2:23])=O)=[N:11][N:10]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]#[N:23])=[N:11][N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C(N)=O)c2c1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(C#N)c2c1
Yield: 32.7 %

Procedure:
A solution of 4(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-phthalazine-1-carboxylic acid amide (1.06 g, 2.92 mmoles), prepared as described in example 109, in pyridine (80 ml) and trifluoroacetic anhydride (1.65 ml, 11.67 mmoles), under dry N2 at room temperature, was stirred for 3 hours, then dried, taken up in CH2Cl2, washed with citric acid, 5% NaOH and water. The organic phase was anhydrified and dried to give a solid which was flash chromatographed (eluent: CH2Cl2/CH3OH 99:1) to give 0.33 g of the title compound (yield: 33%).
Reaction SMILES: [Na].[C:2]([C:4]1[C:5]([S-:15])=[N:6][S:7][C:8]=1[NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:3].I[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH2:13]([O:12][C:10](=[O:11])[NH:9][C:8]1[S:7][N:6]=[C:5]([S:15][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=1[C:2]#[N:3])[CH3:14]
Reactant: CCCCCI
Reactant: CCOC(=O)Nc1snc([S-])c1C#N
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCSc1nsc(NC(=O)OCC)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.7 %

Procedure:
A mixture of sodium, 4-cyano-5-ethoxycarbonylamino-isothiazole-3-thiolate (5.0 g, 20 mmol), 1-iodopentane (4.0 g, 20 mmol) and tetrahydrofuran (20 mL) was stirred at ambient temperature for 16 hours. After concentration in vacuo, the residue was partitioned between ethyl acetate and brine. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was filtered through a pad of silica gel using 1:1 ethyl acetate-hexane as eluent. The filtrated was concentrated and the residue was recrystallized from cold aqueous methanol, affording 2.5 g (42%) (4-cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethyl ester as a colorless solid. An additional 0.5 g (8.4%) was obtained by concentration of the mother liquor and purification by radial chromatography (4 mm plate, 4:1 hexane-ethyl acetate). 1H NMR (400 MHz, acetone-d6) δ11.1 (bs, 1H), 4.32 (q, 2H, J=7.2 Hz), 3.21 (t, 2H, J=7.2 Hz), 1.73 (p, 2H, J=6.8 Hz), 1.44-1.28 (m, 7H), 0.90 (t, 3H, J=7.6 Hz) ppm; MS (APCI, m/z): 312 [M+Na]+.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[Li]CCCC.[C:14](Cl)(=[O:18])[CH:15]=[CH:16][CH3:17].[Li]CCCC.C(Cl)(=O)C=CC.C([O-])(O)=O.[Na+]>C1COCC1>[C:14]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C=C/C(=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of tert-butyl carbamate (1.0 g, 8.54 mmol) in THF (20 mL) at −78° C., were added nBuLi and 2-butenoyl chloride successively, in the following quantities (nBuLi/2-butenoyl chloride): 5.34/0.41, 2.67/0.21, 1.34/0.10, 0.67/0.05, 0.34/0.03 mL. Stirring was continued for 30 min, before the reaction mixture was poured into an ice-cooled solution of saturated aq. NaHCO3 (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and evaporated. The crude product was purified by flash chromatography (Et2O:pet. ether, 1:3, Rf 0.4) to give the product as a white solid. Yield 81% (1.28 g). m.pt. 138–139° C. 1H NMR: δ 1.49 (s, 9H, tBu); 1.92 (dd, 1H, CH3CH, 2JHH=6.8 Hz, 3JHH=1.5 Hz); 6.82 (dd, 1H, COCH, 2JHH=15.2 Hz, 3JHH=1.5 Hz); 7.05–7.15 (m, 1H, CH3CH); 7.31 (s, br, 1H, NH). 13C NMR: δ 15.9 (CH3CH), 27.9 (C(CH3)3), 82.3 (C(CH3)3), 121.2 (COCH), 145.5 (CH3CH), 150.5(CO2), 166.3 (COCH). m/z (HR-ESMS): Expected 185.1052 (M+), observed 185.1046. Anal. calcd for C9H15NO3: C, 58.36; H, 8.16; N, 7.56%. Found: C, 58.08; H, 8.05; N, 7.63%.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][C:7]=2[F:15])[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:19])=O>C1COCC1.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([Cl:19])=[O:11])=[CH:8][C:7]=2[F:15])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(OCC2CC2)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(OCC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-fluorobenzoic acid (1.57 g) in THF (50 mL) were added oxalyl dichloride (0.982 mL) and DMF (2 drops), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure to give 4-(cyclopropylmethoxy)-3-fluorobenzoyl chloride. This compound was used for the next reaction without further purification.
Reaction SMILES: [Na].[OH:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][N:11]=2)[NH:6][C:5](=[O:13])[C:4]=1[C:14]([O:16][CH3:17])=[O:15].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O.C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:18]([N:6]1[C:7]2[C:12](=[N:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]1=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(OCc2ccccc2)c2ncccc2n(Cc2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of the sodium salt of methyl 4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (2.0 g, 7.57 mmol) in water (50 mL) was added a solution of benzyl bromide (3.89 g, 22.72 mmol) in methylene chloride (50 mL). To the biphasic solution was then added tetrabutylammonium bromide (1.2 g, 3.79 mmol) and the reaction was sealed and heated to 50° C. After stirring overnight the reactions was cooled and the two layers were separated. The aqueous layer was extracted one time with methylene chloride and the combined organics were dried over sodium sulfate, filtered and concentrated. The crude mixture was separated by normal phase chromatography using an Isco 120 gram silica gel cartridge with a 50 minute gradient running at 40 mL/min. of 10% to 60% EtOAc/hexanes. The tubes containing the desired product were concentrated and taken on to the next step.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[C:23]([F:25])[N:22]=[C:21]([F:26])[CH:20]=2)[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:33]([NH2:35])[CH3:34])[CH:13]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:11][C:12]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:20]=[C:21]([F:26])[N:22]=[C:23]([F:25])[CH:24]=2)[C:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:14]([CH:33]([NH:35][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:34])[CH:13]=1
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2ccccc2)c1-c1cc(F)nc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2ccccc2)c1-c1cc(F)nc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (36 mg, 0.18 mmol), 1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanamine (60 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) in isopropyl alcohol (0.6 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C25H20ClF2N6 (M+H)+: m/z=477.1. found: 477.1.