Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)(=[O:4])=[O:3].[N:13]#[C:14]Br>O>[NH2:13][C:14]1[NH:12][C:7]2[CH:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:10]=[CH:9][C:8]=2[N:11]=1
Reactant: CS(=O)(=O)c1ccc(N)c(N)c1
Reactant: N#CBr
Solvent: O
Product: CS(=O)(=O)c1ccc2nc(N)[nH]c2c1
Reaction time: 4 h

Procedure:
One mole, 186.1 g., of 4-methylsulfonyl-o-phenylenediamine was suspended in 1.2 l. of water with stirring. One mole, 106 g., of cyanogenbromide was added portionwise to the reaction mixture. The reaction mixture was stirred for 4 hours and then filtered. Sodium hydroxide, 39 g. (1 m.) in 500 ml. of water, was added to the filtrate. The aqueous mixture was cooled in an ice bath and the product crystallized. The product was collected and dried before crystallization from ethanol-ether; yield 200 g., m.p. 233°-238° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.ClCCl.C(Br)(Br)(Br)[Br:14]>C(#N)C>[Br:14][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cccc(O)c1
Solvent: CC#N
Solvent: ClCCl
Product: Oc1cccc(CBr)c1
Temperature: 2.5 °C

Procedure:
3-[(Hydroxy)methyl]phenol was dissolved in acetonitrile (300 ml) and dichloromethane (900 ml) and the resulting mixture was poured in the flask kept under argon; magnetic stirring was set on. The solution was then cooled with an ice bath and carbon tetrabromide and triphenilphosphine were added. The latter was added in small portions in order to maintain the temperature at ca. 2-3° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH:11](OCC)(OCC)OCC.[CH3:21][O:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:24]=1[NH2:25]>C(OC(C)C)(C)C>[CH3:21][O:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:24]=1[NH:25][CH:11]=[C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9]
Reactant: COc1ccc(N)c(OC)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(OCC)OCC
Solvent: CC(C)OC(C)C
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)c(OC)c1
Temperature: 85 °C
Yield: 87.8 %

Procedure:
In a three neck round-bottom flask equipped with a reflux condenser and a mechanical stirrer, a solution of 10.0 g (69.3 mmol) of 2,2-dimethyl-1,3-dioxan-4,6-dione (Meldrum's acid) and 46 mL (277 mmol) of triethyl orthoformate was treated with 11.1 g (72.7 mmol) of 2,4-dimethoxyaniline. The mixture was heated at 85° C. for two hours. Upon cooling to room temperature, the reaction mixture was diluted with isopropyl ether and filtered to furnish 18.7 g of 5-[(2,4-dimethoxyphenyl)aminomethylene]2,2-dimethyl-1,3-dioxan-4,6-dione as a bright orange solid. This solid was then added portionwise to 80 mL of a boiling solution of biphenyl and diphenyl ether/biphenyl, (Dowtherm, trademark). After the final addition heating was continued for just 5 minutes. After cooling to room temperature, the reaction mixture was stored in the refrigerator overnight, and then stirred with isopropyl ether for an hour. The solids were filtered and washed with isopropyl ether to afford 11.8 g (83%) of 6,8-dimethoxyquinolin-4-ol: m.p. 221°-224° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17](F)=[CH:18][CH:19]=2)[C:3]=1[CH3:21].Cl.[F:23][C:24]1([F:30])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([N:27]3[CH2:28][CH2:29][C:24]([F:30])([F:23])[CH2:25][CH2:26]3)=[CH:18][CH:19]=2)[C:3]=1[CH3:21]
Reactant: Cc1c(-c2ccc(F)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccc(N3CCC(F)(F)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 66.5 h

Procedure:
To a stirred solution of 4-chloro-5,7-difluoro-2-(6-fluoropyridin-3-yl)-3-methylquinoline (0.10 g, 0.32 mmol) in DMF (2 mL) was added 4,4-difluoropiperidine hydrochloride (0.056 g, 0.36 mmol) followed by potassium carbonate (0.090 g, 0.65 mmol). The reaction was stirred at 100° C. and stirring continued for 66.5 h. After which, the reaction mixture was cooled to rt and water was added. The crude reaction mixture was extracted with EtOAc and dried over magnesium sulfate and concd in vacuo. The crude material was purified on silica gel, eluting with 0-30% EtOAc in hexanes to provide 4-chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5,7-difluoro-3-methylquinoline as a brown solid. Mass Spectrum (ESI) m/e=410.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:28]4[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]4)[CH:20]=[CH:21][CH:22]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Reactant: O=C(O)C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1c(CCN2CCC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.7 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]acetaldehyde (D15) (73 mg) and 3-pyrrolidinecarboxylic acid (72.4 mg) in dichloromethane (DCM) (10 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (66.6 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, the residue was purified by Mass Directed AutoPrep to give 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]ethyl}-3-pyrrolidinecarboxylic acid (E12) (27 mg) as a TFA salt (off-white solid). δH (DMSO-d6, 400 MHz): 1.13 (3H, t), 1.35 (6H, d), 2.23 (1H, m), 2.86 (2H, m), 3.10 (2H, m), 3.22 (2H, m), 3.48 (4H, m), 3.72 (1H, m), 3.87 (1H, m), 4.84 (1H, m), 7.39 (2H, dd), 7.50 (2H, m), 7.96 (1H, dd), 8.10 (1H, d), 9.95 (1H, br s), 12.97 (1H, br s). δF (DMSO-d6, 376 MHz): −73.5. MS (ES): C26H30ClN3O3S requires 499. found 500.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:14])=[C:6]([C:8](=[O:13])[CH2:9]S(C)=O)[CH:7]=1.[C:15]([C:17]1[CH:26]=[CH:25][C:20]([CH:21]=[CH:22][CH:23]=O)=[CH:19][CH:18]=1)#[N:16].N1CCCCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:23]([CH:22]=[CH:21][C:20]3[CH:19]=[CH:18][C:17]([C:15]#[N:16])=[CH:26][CH:25]=3)=[CH:9][C:8](=[O:13])[C:6]=2[CH:7]=1
Reactant: CS(=O)CC(=O)c1cc(Br)ccc1O
Reactant: N#Cc1ccc(C=CC=O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: N#Cc1ccc(C=Cc2cc(=O)c3cc(Br)ccc3o2)cc1

Procedure:
A mixture of 3.9 g of 5'-bromo-2'-hydroxy-2-(methylsulfinyl)acetophenone, 2.2 g of p-cyanocinnamaldehyde, 50 ml of toluene and 0.1 ml of piperidine was refluxed for 4 hrs. The mixture was chilled, and the precipitate was filtered and recystallized from DMF, mp 275°-76° ; yield 1 g (20%); λ max mμ (ε) 223 (22,700), 273 (12,900), 330 (41,000); ν max 840 (m), 980 (m), 1280 (m), 1640 (m), 1660 (ms), 2240 (m) cm-1.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][O:7][C:8]1[N:13]=C(C=O)C=[CH:10][CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:3]([C:2]1[CH:1]=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[N:13]=1)=[CH2:4]
Reactant: [Li]CCCC
Reactant: COc1cccc(C=O)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cccc(OC)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 16 %

Procedure:
To a suspension of methyl(triphenyl)phosphonium bromide (7.07 g, 19.8 mmol, 1.1 eq) in dry THF (50 ml) at 0° C. is added n-butyl lithium (1.6M in cyclohexane, 12.5 ml, 19.8 mmol, 1.1 eq). After stirring at 0° C. for 20 minutes, a solution of 6-methoxypyridine-2-carbaldehyde a1-50 (2.5 g, 18 mmol, 1 eq) in dry THF (10 ml) is added dropwise to the mixture. The reaction mixture is warmed to room temperature for 30 minutes. The reaction mixture is quenched with 3 drops of water, and Rochelle salt is added (10 g). The mixture is filtered on Celite and MgSO4. The crude residue is distilled to afford 400 mg of pure 2-ethenyl-6-methoxypyridine a1-51.
Reaction SMILES: CS[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12](=[O:14])[CH:13]=2)=[CH:5][CH:4]=1.O[O:21][S:22]([O-:24])=O.[K+].[CH2:26]1COCC1>C(O)C.O>[CH3:26][S:22]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:12](=[O:14])[CH:13]=2)=[CH:5][CH:4]=1)(=[O:24])=[O:21]
Reactant: O=S([O-])OO
Reactant: C1CCOC1
Reactant: CSc1ccc(C2=CC(=O)C3(CCOCC3)O2)cc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C2=CC(=O)C3(CCOCC3)O2)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a stirred solution of 2-{4-(methylthio)phenyl}-1,8-dioxa-spiro[4,5]dec-2-en-4-one (0.6 g) in 10 ml THF and 10 ml ethanol, was added 2.67 g of OXONE dissolved in 5 ml water. The mixture was stirred for 26 hours at room temperature. After volatile solvent was evaporated in vacuo, the aqueous solution was extracted with dichloromethane. The organic layer was concentrated under reduced pressure and the resulting crude product was purified by recrystallization from hexane/dichloromethane to give 0.55 g of 2-{4-(methylsulfonyl)phenyl}-1,8-dioxa-spiro[4,5]dec-2-en-4-one. mp: 163-165° C. NMR: δ1.58-1.70 (m, 2H), 2.09-2.20 (m, 2H), 3.11 (s, 3H), 3.82-3.92 (m, 2H), 4.04-4.14 (m, 2H), 6.16 (s, 1H), 8.05 (d, J=8.7 Hz, 2H), 8.10 (d, J=8.7 Hz, 2H). IR (cm−1): 2862, 1694, 1314, 1152, 961.
Reaction SMILES: [C:1]([C:3](=[C:9](OC(=O)C(C)(C)C)[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[NH3:22]>C(#N)C>[NH2:22]/[C:9](/[CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[C:3](/[C:1]#[N:2])\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: N
Reactant: CCOC(=O)C(C#N)=C(OC(=O)C(C)(C)C)C(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C(C#N)=C(\N)C(CC)CC
Temperature: 10 °C
Reaction time: 3 h

Procedure:
118.2 g (0.4 mol) of ethyl 2-cyano-3-[(pivaloyl)oxy]-4-ethyl-2-hexenoate were dissolved in acetonitrile and cooled to 10° C. At 10-15° C., 112 g (0.8 mol) of 25% strength ammonia solution were then added dropwise, and the mixture was stirred at 15° C. for 3 h. The organic phases is [sic] washed, dried and concentrated. Recrystallization with diisopropyl ether gave 57.5 g (68% of theory) of the title compound (m.p. 87° C.).
Reaction SMILES: [N:1]#[C:2][NH2:3].[C:4]([O:8][C:9](=[O:24])[NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1)([CH3:7])([CH3:6])[CH3:5].CC(C)([O-])C.[K+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([F:43])[CH:36]=1)=[O:34]>C(#N)C.C(O)(C)(C)C.O>[C:4]([O:8][C:9](=[O:24])[NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]2[S:23][C:32]([C:33](=[O:34])[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[C:37]([F:43])[CH:36]=3)=[C:2]([NH2:3])[N:1]=2)=[CH:19][CH:20]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: N#CN
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(N=C=S)cc1
Reactant: COc1ccc(C(=O)CBr)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC#N
Product: COc1ccc(C(=O)c2sc(Nc3ccc(OCCCNC(=O)OC(C)(C)C)cc3)nc2N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of cyanamide (23.2 mg, 0.546 mmol) (Aldrich) in acetonitrile (2.5 mL) and tert-butanol (2.5 mL) was added [3-(4-Isothiocyanatophenoxy)-propyl]carbamic acid tert-butyl ester (from Example 64; 156.9 mg, 0.508 mmol) followed by a solution of potassium tert-butoxide (0.56 mL, 1 M in tert-BUOH). After 30 minutes at room temperature, 2-bromo-1-(3-fluoro-4-methoxy-phenyl)ethan-1-one (125.8 mg, 0.509 mmol) (Maybridge Chemical) was added. The reaction mixture was stirred at room temperature for 1 hour and then heated at 75° C. for 2 hours. The resulting mixture was poured into water (10 mL). The product was collected by filtration, washed with diethyl ether and dried in vacuo to provide (3-[4-[4-Amino-5-(3-fluoro-4-methoxy-benzoyl)-thiazol-2-ylamino]-phenoxy]-propyl)-carbamic acid tert-butyl ester (260.1 mg, 99% yield). HRMS, Observed: 517.1921; Calcd for M+H+:517.1916.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.CN(C=O)C.[H-].[Na+].Br[CH:31]([CH2:33][CH2:34][CH3:35])[CH3:32]>>[CH3:32][CH:31]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCC(C)Br
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.0002 mol) (see, Example 231, Step 1) was dissolved in DMF (2 mL, 0.02 mol) and cooled at 0° C. This solution was treated with sodium hydride (7.0 mg, 0.00029 mol) (60% in oil) and stirred for 15 min. The mixture was then treated with 2-bromopentane (40 mg, 0.0002 mol) and was stirred for 5 h. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product 4-[1-(1-methylbutyl)-1H-pyrazol-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine as an oil, LC/MS (M+H)+: 286.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH3:31]>>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH3:31])=[CH:9][C:8]([C:12]2[CH:17]=[CH:16][N:15]=[N:14][CH:13]=2)=[N:7]1)[CH3:20]
Reactant: CCOC(Cn1nc(-c2ccnnc2)cc1N)OCC
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Product: CCOC(Cn1nc(-c2ccnnc2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 4.5 g (16.2 mmol) of the compound of Example 79A and 3.86 g (17.8 mmol) of 2-bromo-4-nitrotoluene gave, after 3 h of heating under reflux, a crude product which was purified by chromatography on a Biotage system (100 g Snap column; mobile phase gradient ethyl acetate/0-8% methanol). This gave 5.52 g (82% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16](O)=[O:17])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([Cl:23])=[O:17])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(c1)CCc1c(cccc1C(=O)O)S2
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCc1c(cccc1C(=O)Cl)S2

Procedure:
An amount of 575 mg of 2-methoxy-9-carboxy-10,11-dihydrodibenzo[b,f]thiepin was dissolved in 10 ml of anhydrous benzene and to the mixture was added 1 ml of thionyl chloride. The resulting mixture was refluxed for 3 hours and freed of solvent under reduced pressure to obtain 614 mg of 2-methoxy-10,11-dihydrodibenzo[b,f]thiepin-9-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: C1CCNC1
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and pyrrolidine (4.3 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (7.1 mg). MS (pos) m/z 257.2 (M+H).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1.F[B:15]([C:25]1[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=1[CH3:33])[C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24]>CCCCCC.C1COCC1>[C:1]1([CH3:4])[CH:3]=[C:30]([CH3:29])[CH:25]=[C:26]([CH3:27])[C:2]=1[B:15]([C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([B:15]([C:25]2[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=2[CH3:33])[C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH:8]=1
Reactant: Brc1cccc(Br)c1
Reactant: [Li]C(C)(C)C
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(B(c2cccc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)c2)c2c(C)cc(C)cc2C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
25.9 ml (44 mmol) of a 1.7 M solution of tert-butyllithium in n-hexane was added dropwise to a well-stirred solution of 2.36 g (10 mmol) of 1,3-dibromobenzene in 200 ml of absolute THF which had been cooled to −78° C. over a period of 20 minutes at such a rate that the temperature of the reaction mixture did not exceed −65° C. The solution was stirred for another 1 hour at −78° C. and a solution of 6.44 g (24 mmol) of fluorodimesitylborane in 50 ml of absolute THF was then added dropwise over a period of 20 minutes at such a rate that the temperature of the reaction mixture did not exceed −65° C.
Reaction SMILES: CCN(CC)CC.O[C@@H:9]([CH3:28])[C@@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:16])[C:11]([OH:13])=[O:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:22]1([CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:15](=[O:16])[NH:14][C@H:10]2[C:11](=[O:13])[O:12][C@H:9]2[CH3:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
In a four necked round bottom flask, Et3N (5.5 mL, 39.4 mmol) was added to a solution of (2R,3S)-3-hydroxy-2-{[(4-phenylbutoxy)carbonyl]amino}butanoic acid (3.9 g, 13.1 mmol) in dry CH2Cl2 (170 mL) under argon. After cooling at 0° C., HBTU (7.5 g, 19.7 mmol) was added and the mixture stirred 3 h at 0° C., then 3.5 h at rt. The obtained solid was filtered-off and the solvent removed under vacuum. The crude was purified by typical silica gel automatic column chromatography, eluting with Cy/AcOEt (from 95:5 to 60:40). The resulting pale yellow oil (0.61 g) was further crystallized from cyclohexane to afford the pure title compound, (0.23 g, 6%), as white solid. MS (ESI) m/z: 276.24 [M−H]−. FTIR (cm−1): 3312, 3060, 3026, 2942, 2861, 1826, 1694, 1545, 1337, 1269, 1126, 1023. 1H NMR (CDCl3): δ 1.45 (d, 3H); 1.66-1.70 (m, 4H); 2.63-2.66 (m, 2H); 4.09-4.18 (m, 2H); 4.83-4.89 (m, 1H); 5.36 (br d, 1H); 5.45 (m, 1H); 7.16-7.31 (m, 5H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[CH2:9](N(CC)CC)C.F[C:17]1[C:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:19]([CH3:36])[C:20]([C:34]#[N:35])=[C:21]2[C:25]=1[O:24][C:23]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)(C)[NH:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:19]([CH3:36])[C:20]([C:34]#[N:35])=[C:21]3[C:25]=2[O:24][C:23]([N:27]([CH3:9])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:22]3)[CH2:4]1
Reactant: CCN(CC)CC
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(C#N)c2c(c(F)c1-c1ccccc1)OC(C)(Nc1ccccn1)N2
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(N(C)c3ccccn3)nc2c1C#N
Temperature: 95 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (63.2 μl, 0.498 mmol) and triethylamine (81.7 μl, 0.586 mmol) were added to a dimethyl sulfoxide (3 ml) solution of 7-fluoro-5-methyl-2-methylpyridin-2-ylamino-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-189) (105 mg, 0.293 mmol), followed by stirring in an oil bath at 95° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (50 ml), washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=20:1), and the obtained eluate was recrystallized from isopropanol to obtain the entitled compound (35.0 mg, 26.4%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)[C:19]=2C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45]CCOS(C)(=O)=O)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1.N1(C(OC(C)(C)C)=O)CCNCC1>>[CH:34]1([CH2:37][N:38]2[C:43](=[O:44])[C:42]([CH2:45][CH2:19][CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:41][C:40]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:39]2)[CH2:36][CH2:35]1
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CC(C)(C)OC(=O)N1CCNCC1
Product: COc1ccc(-c2cc(CCCN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 76.9 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reacted to yield the title compound as a yellow oil (yield: 76.9%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1.C(O)(=O)C>C1COCC1.C(OCC)C>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]([OH:19])[C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: C#CC(=O)OCC
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)C#CC(O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 64.7 %

Procedure:
To a cooled (−78° C.) solution of ethyl propiolate (8.96 mL, 88.4 mmol) in THF (100 mL) was added n-butyllithium (37.5 mL of 2.37M solution in hexane, 88.9 mmol) dropwise over 70 minutes so as to maintain the internal temperature below −70° C. Additional THF (5 mL) was used to rinse the addition funnel. A solution of 4-chloro-2-nitrobenzaldehyde (14.88 g, 80.2 mmol) in THF (30 mL) was transferred to the addition funnel and added dropwise over 47 minutes to maintain the reaction temperature below −70° C. Additional THF (5 mL) was used to rinse the addition funnel. The solution was stirred for 90 minutes at −70° C. and was then warmed to −60° C. glacial acetic acid (18.3 mL, 316 mmol) was quickly added. The solution was allowed to warm to 10° C. over 60 minutes and poured into diethyl ether (900 mL). The resulting solution was washed with saturated aqueous sodium carbonate (2×450 mL) and saturated aqueous sodium chloride (1×450 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator. This product was purified by flash chromatography eluting with ethyl acetate:hexanes (90:10) to give the title compound as red oil (14.73 g, 64.8%).