Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:25]=[CH:24][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=3[OH:23])[N:8]=[C:4]2[CH:3]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>CN(C)C=O>[C:26]1([S:32][C:2]2[CH:25]=[CH:24][C:5]3=[N:6][N:7]([C:9]4[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:10]=4[OH:23])[N:8]=[C:4]3[CH:3]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Into a two-liter three-necked flask equipped with stirrer, thermometer, distillation set-up and nitrogen supply are charged 268.4 g (0.75 mole) of 5-chloro-2-(2-hydroxy-3,5-di-tert-butylphenyl)-2H-benzotriazole, 93.7 g (0.825 mole) of thiophenol and 400 mL of N,N-dimethylformamide (DMF). The reactor is evacuated and filled with nitrogen three times to establish an inert atmosphere. To the slurry is added 66.0 g (0.825 mole) of 50% aqueous sodium hydroxide solution and the mixture heated to reflux. At this point water distills off as an azeotrope until the head-temperature reaches 132° C. and a reaction temperature of 150° C. After 18 hours there is no residual starting benzotriazole compound observed (TLC). At reduced pressure most of the DMF is distilled off at 80° C. To the residue is then charged 500 mL of toluene and 200 mL of water. After slow stirring for a few minutes at 80° C. the lower aqueous phase is drained off. The addition of 200 mL of water is repeated twice more, the second time with addition of 1 mL of acetic acid. Any residual water is azeotroped off until a clear solution is obtained. Approximately 300 mL of toluene is removed under partial vacuum at 90° C. and to the concentrate is added 800 mL of isopropanol, resulting in rapid crystallization. The reaction mixture is cooled to 20° C. and filtered. The light yellow crystals are washed with 250 ml of isopropanol and dried to give 317 g (97.9% of theory) of the title compound, mp. 132°-134° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C1(=O)[NH:28]C(=O)C2=CC=CC=C12.[K].O.NN>CN(C=O)C.CCOC(C)=O>[NH2:28][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOc1ccc(N(C)c2nc(CCl)nc3ccccc23)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: NN
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Reaction time: 8 h
Yield: 31 %

Procedure:
A mixture (2-chloromethyl-quinazolin-4-yl)-(4-ethoxy-phenyl)-methyl-amine (73 mg, 0.22 mmol) and potassium phthalimide (57 mg, 0.31 mmol) in DMF (1 mL) was heated at 70° C. for 2 h. The reaction was diluted with EtOAc and washed with H2O. The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine, filtered through Na2SO4 and concentrated. The intermediate was dissolved in EtOH (5 mL), treated with hydrazine monohydrate (81 mg, 1.62 mmol) and stirred overnight. The reaction mixture was quenched with H2O and diluted with EtOAc. The aqueous and organic phases were separated and the aqueous phase extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine, filtered over Na2SO4 and concentrated. Purification by gradient MPLC (SiO2, MeOH/CH2Cl2 w/0.1% NH4OH, 0-20%) provided 21 mg (31%) of the title compound. 1H NMR (CDCl3) δ 7.75 (d, 1H), 7.53 (ddd, 1H), 7.10 (d, 2H), 7.0 (m, 2H), 6.9 (d, 2H), 4.06 (s, 2H), 4.04 (q, 2H), 3.6 (s, 3H), 2.07 (s(br), 2H), 1.45 (t, 3H); LC-MS (ESI+; 309 ([M+H]+)).
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:27]=1)[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([C:22]1[CH:25]=[C:26]([C:2]2[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:27]=[C:20]([F:19])[CH:21]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1cc(F)cc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
To solution of tert-butyl 2-(2-bromo-4-formylphenoxy)acetate (1) (120 g, 0.38 mol) in dioxane/H2O (4:1, 700 mL) was added 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (20) (158 g in 60% purity, 0.38 mol), Na2CO3 (81 g, 0.76 mol) and Pd(PPh3)4 (22 g, 19 mmol) under N2. The mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the mixture was concentrated in vacuo and purified by column chromatography (PE:EA=10:1 v/v) to give 90 g of t-butyl 2-(2-(3-cyano-5-fluorophenyl)-4-formylphenoxy)acetate (21) (90 g, 67%).
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:25]([O-])=O.[Na+].O>C(O)(=O)C.CN(C=O)C>[C:1]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11](=[O:22])[CH:12]([C:14]2[CH:19]=[CH:18][C:17]3[NH:20][N:25]=[N:21][C:16]=3[CH:15]=2)[CH3:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc(N)c(N)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C(=O)NCc1ccc(C(C)(C)C)cc1)c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N-(4-tert-Butyl-benzyl)-2-(3,4-diamino-phenyl)-propionamide (110 mg, 0.338 mmol) in 5% aq. acetic acid (3 mL) and DMF (2.5 mL) was added sodium nitrite (30 mg, 0.435 mmol) at 0° C. The reaction mixture was stirred for 14 hours at room temperature. The mixture was added water (20 mL) and extracted with methylene chloride. The organic layer was dried with MgSO4 and filtered. Methylene chloride was removed by evaporation. The residue was purified by column chromatography eluting with CH2Cl2/MeOH=10/1.
Reaction SMILES: C(Cl)CCl.[OH:5][CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[CH:17]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=2[CH:31]=[O:32])[CH2:19][CH2:18]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:17]1([CH2:20][O:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([O:5][CH2:6][C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])=[O:27])=[CH:24][C:23]=2[CH:31]=[O:32])[CH2:19][CH2:18]1
Reactant: O=C(CO)OCc1ccccc1
Reactant: O=Cc1cc(C(=O)O)ccc1OCC1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=Cc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (2.52 g, 13.16 mmol) was added to a solution of compound benzyl 2-hydroxyacetate (2.02 g, 12.15 mmol), 4-(cyclopropylmethoxy)-3-formylbenzoic acid (2.23 g, 10.13 mmol), and DMAP (247 mg, 2.03 mmol) in DCM (20 ml) at RT under nitrogen atmosphere. The mixture was stirred at RT overnight. The mixture was then diluted with DCM and washed with NaHCO3 sat. sol., HCl 0.1M and brine. The organic phase was dried over Na2SO4, and the solvent was evaporated. 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-formylbenzoate was obtained (3.73 g, quantitative yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:16][C:17]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)#[N:2].[C:28]([Si](Cl)(C)C)(C)(C)C.N1C=CN=C1.CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[C:5]([N:16]([CH3:28])[C:17]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]1)#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N1CCC(O)CC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc2ccccc2s1)c1ccc(N2CCC(O)CC2)c(C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
N-[3-Cyano-4-(4-hydroxypiperidin-1-yl)phenyl]benzo[b]thiophene-2-carboxamide (2.0 g) obtained in Example 12, tertiary butyldimethylsilyl chloride (0.9 g) and imidazole (0.4 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 12 hr. Then the reaction mixture was treated with water and the organic layer was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in dimethylformamide. Under ice-cooling, sodium hydride (60% contained, 0.2 g) (was added and the mixture was stirred for 1 hr and methyl iodide (0.6 g) was added. The mixture was further stirred for 1 hr. The reaction mixture was treated with water and the organic layer was extracted with toluene. The extract was washed with water and the solvent was evaporated under reduced pressure. To the residue were added tetrabutylammonium fluoride (0.93 g) and tetrahydrofuran(15 ml) and the mixture was stirred at 60° C. for 4.5 hr. Then the solvent was evaporated and the residue was separated and purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (0.8 g). melting point: 211-212° C.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[NH2:53][CH:54]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C.C(OCC)C>[CH:54]([NH:53][C:12]([C@@H:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])([C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.51 g, 2.0 mmol, Example 1, Step B) was dissolved in dry DMF (6 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (1.0 mL, 5.7 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.74 g, 2.0 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; aminodiphenylmethane hydrochloride (0.43 g, 2.0 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc-hexanes afforded 0.67 g (82%) of the pure titled compound as a white solid: mp 180-181° C. APCI-MS m/z 422.3 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].[Br:13][C:14]1[C:15](F)=[C:16]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH:17]=O.O>CC#N>[Br:13][C:14]1[C:15]2[S:9][C:8]([C:7]([O:11][CH3:12])=[O:10])=[CH:17][C:16]=2[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(Br)c1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cc2cc(C(F)(F)F)cc(Br)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium carbonate (1.44 g, 10.42 mmol) then methyl thioglycolate (0.487 g, 4.59 mmol) were added to a degassed solution of 3-bromo-2-fluoro-5-(trifluoromethyl)benzaldehyde (1.13 g, 4.17 mmol) in CH3CN (11 mL). The mixture was stirred at room temperature for 30 minutes then refluxed at 100° C. overnight. The mixture was allowed to cool to room temperature, then water (20 mL) was added. The resulting light yellow solid was collected by vacuum filtration, washed with water, then dried in vacuo. The resulting ester was used directly for the following step. 1H NMR (500 MHz, CDCl3) δ 8.24 (br s, 1H); 8.15 (br s, 1H); 7.86 (br s, 1H); 4.02 (br s, 3H). LC1: 4.00 min. Compound does not ionize.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:17]=2[CH:18]=1)[CH3:13]>C(Cl)Cl>[C:12]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:17]=2[CH:18]=1)(=[O:11])[CH3:13]
Reactant: COC(=O)c1ccc2cc(C(C)O)oc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(C(C)=O)oc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Oxalyl chloride (0.1 ml, 1.15 mmol) is dissolved in CH2Cl2 (2 ml) in a dry flask under nitrogen and cooled to −78° C. DMSO (0.16 ml, 2.3 mmol) is added drop-wise, and the mixture stirred for 30 min, while maintaining the temperature. Methyl 2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate (220 mg, 1.0 mmol) is dissolved in CH2Cl2 (2 ml) and added drop-wise to the mixture, and the solution stirred for 1 h at −78° C. TEA (0.69 ml, 5.0 mmol), is added drop-wise and the reaction is stirred for an additional 30 min. The reaction is then warmed to 0° C. and stirred for another 30 min. The reaction is washed with saturated NaHCO3 (40 ml), and the organics are dried (K2CO3), filtered, and concentrated to a yellow solid. The crude material is chromatographed over 25 g slurry-packed silica gel, eluting with 20% EtOAc/hexane. The appropriate fractions are collected and concentrated to afford 174 mg (80%) of methyl 2-acetyl-1-benzofuran-6-carboxylate as a pale yellow solid. HRMS (FAB) calcd for C12H10O4+H: 219.0657, found 219.0667 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[N:3]=1.C(O)CCCCC.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>>[CH2:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCOc1cncc(Cl)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCO
Product: CCCCCCOc1cncc(N2CCNCC2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-(n-hexyloxy)pyrazine (1.54 g, 7.17 mmol; obtained according to the procedure of example 50, step 1, starting from n-hexanol), piperazine (1.90 g, 22.1 mmol) and K2CO3 (0.99 g, 7.16 mmol). The yield of the title compound was 1.21 g (64%) which was obtained as a colorless oil. HRMS m/z calcd for C14H24N4O (M)+ 264.1950, found 264.1953. Anal. (C14H24N4O) C, H, N.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9]O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.S(Cl)([Cl:13])=O>ClCCl.CN(C)C=O>[ClH:13].[Cl:13][CH2:9][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=1
Reactant: OCc1ncc(F)cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cl
Product: Fc1cnc(CCl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of (3,5-difluoropyridin-2-yl)methanol (Almedia et al., WO 08/117,050) (2.15 g, 14.8 mmol) in dichloromethane (20 mL) at 0° C. was added N,N-dimethylformamide (2 drops) and thionyl chloride (2.0 mL, 27 mmol). The solution was stirred at ambient temperature for 1 h and concentrated in vacuo to afford 2-(chloromethyl)-3,5-difluoropyridine hydrochloride (2.31 g, 78%) as a brown oil: Rf=0.71 (EtOAc/Hexanes, 1/1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH:7]1[O:15][CH:6]21)#[N:2].[OH:16][C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][N:18]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O>O1CCOCC1.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[C@@H:7]([OH:15])[C@@H:6]2[N:18]1[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:17]1=[O:16])#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Oc1ccnc(O)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2ccc(O)cc2=O)[C@@H]1O
Yield: 18.3 %

Procedure:
3 g of 6-cyano-2,2-dimethyl-3,4-epoxychromane are refluxed for 20 hours with 1.8 g of 2,4-dihydroxypyridine in 30 ml of dioxane and 20 ml of dimethylformamide, in the presence of 0.6 ml of a methanolic solution containing 35% of benzyltrimethylammonium hydroxide. The solvents are evaporated off under vacuum and the residue is then crystallized by the addition of isopropyl ether. The crystals obtained are taken up with water, filtered off and then washed with acetone to give 850 mg of the expected product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[F:17])=[N:4][CH:3]=1.[C:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)(=[O:25])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:27]3[C:26]([S:23]([NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:24])=[O:25])=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:12][C:11]=2[F:17])=[N:4][CH:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: N#Cc1nc(N)cnc1-c1ccc(Br)cc1F
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2ncc(N)nc2C#N)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 6-amino-3-(4-bromo-2-fluorophenyl)pyrazine-2-carbonitrile and (2-(N-(tert-butyl)sulfamoyl)phenyl)boronic acid. MS (ESI): mass calcd. for O21H20FN5O2S, 425.13; m/z found, 426.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.25 (s, 1H), 8.19 (dd, J=8.0, 1.4, 1H), 7.64-7.56 (m, 2H), 7.54-7.49 (m, 1H), 7.47 (dd, J=7.9, 1.7, 1H), 7.40-7.33 (m, 2H), 1.04 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[NH:16][CH2:17][C:18]#[N:19].FC1C=CC=C(OC)C=1C1C=CN=CC=1N(CC(F)(F)F)[C:38](=[O:53])[C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[C:41]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:40]=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>C(Cl)Cl>[C:18]([CH2:17][N:16]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:10]=1[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[O:3][C:2]([F:1])([F:20])[F:21])[C:38](=[O:53])[C:39]1[CH:44]=[C:43]([C:45]([F:48])([F:46])[F:47])[CH:42]=[C:41]([S:49]([CH3:52])(=[O:51])=[O:50])[CH:40]=1)#[N:19]
Reactant: COc1cccc(F)c1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: N#CCNc1cnccc1-c1ccccc1OC(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cc(C(=O)N(CC#N)c2cnccc2-c2ccccc2OC(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(4-(2-(trifluoromethoxy)phenyl)pyridin-3-ylamino)acetonitrile (0.07 g, 239 μmol) in CH2Cl2 (2 mL) were added 3-(methylsulfonyl)-5-(trifluoromethyl)benzoyl chloride (137 mg, 477 μmol, example 223, intermediate d) and DIPEA (123 mg, 167 μL, 955 μmol) and the clear, yellow solution was stirred at room temperature for 18 hours. The reaction mixture was poured on saturated aqueous NH4Cl solution and CH2Cl2 and the layers were separated. The aqueous layer was extracted three times with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless solid (0.085 g; 65%). MS (ESI): m/z=544.08 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([Si](C)(C)C)[C:19]#N)=[CH:14][CH:13]=1.[CH3:25][S:26][C:27]1[CH:32]=[CH:31][C:30](CCl)=[CH:29][CH:28]=1.Cl.[O:36]1CCCC1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:36])[CH2:19][C:30]2[CH:31]=[CH:32][C:27]([S:26][CH3:25])=[CH:28][CH:29]=2)=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)C(C#N)c1ccc(F)cc1
Reactant: CSc1ccc(CCl)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Product: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 321 ml of a 1.0M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (containing 321 mMol, 1.1 eqs) along with an additional 200 ml of dry tetrahydrofuran stirring at -70° C., was added dropwise a solution of 65.1 g (292 mMol) of (4-fluorophenyl)-2-trimethylsilyl-ethanenitrile from Step 1 in 100 ml of tetrahydrofuran. After stirring for 1 hour, a solution of 50.5 g (292 mMol, 1.0 eq) of (4-methylthiophenyl)chloromethane from Step 2 in 100 ml of tetrahydrofuran. The mixture was stirred overnight while warming to room temperature. To the mixture was then added 300 ml of 3N aqueous hydrochloric acid, and the resulting two phase mixture was stirred for 6 hours. The layers were separated, and the organic layer evaporated. The residue was taken up in 400 ml of dichloromethane, 250 ml of 2N aqueous sodium hydroxide was added, and the resulting two phase mixture was stirred rapidly overnight. The organic layer was separated and 100 ml of dimethylformamide were added. The solution was dried over sodium sulfate, filtered, and evaporated to give a yellow solid. Crystallization of the crude intermediate from ethyl acetate/toluene gave 1-(4-fluorophenyl)-2-(4-methylthiophenyl)ethan-1-one as white plates (25.8 g). Concentration of the filtrate followed by trituration of the residue gave an additional 15.7 g of white crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]12([C:24](Cl)=[O:25])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>C1COCC1.C(OCC)(=O)C>[C:14]12([C:24]([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])=[O:25])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)=CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)=CCOC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 78.9 %

Procedure:
A flask was charged with 2.6 g (0.03 mol) of 3-methyl-2-buten-1-ol, 3.1 g (0.025 mol) of triethylamine and 20 ml of THF to prepare a solution. While stirring the solution, a solution of 5.0 g (0.025 mol) of 1-adamantanecarbonyl chloride in 40 ml of THF was added dropwise over 1 hour, followed by stirring further for 5 hours. After salts formed were removed by filtration from the reaction mixture, the filtrate was concentrated. The thus-obtained crude product was dissolved in 70 ml of ethyl acetate, and the solution was washed each 3 times with a 5% aqueous solution of sodium hydrogencarbonate and saturated saline and dried over magnesium sulfate. The solvent was then distilled off to obtain 4.9 g of 3-methyl-2-butenyl 1-adamantanecarboxylate [the formula (61)].