Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]1[CH2:6][O:5][N:4]([CH3:7])[C:3]1=[O:8].[C:9]([C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[CH:16]=[O:17])([CH3:12])([CH3:11])[CH3:10].C(Cl)Cl.Cl>C1C=CC=CC=1.[Zn]>[C:22]([C:19]1[CH:18]=[C:15]([CH:16]([OH:17])[CH:2]2[CH2:6][O:5][N:4]([CH3:7])[C:3]2=[O:8])[CH:14]=[C:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:20]=1[OH:21])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CN1OCC(Br)C1=O
Agent: Cl
Agent: [Zn]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CN1OCC(C(O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 57 %

Procedure:
A mixture of 6 g (33.3 mmol) of 4-bromo-2-methyl-3-isoxazolidinone, 7 g (30 mmol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 3.25 g (50 mmol) of zinc dust in 125 ml of benzene was refluxed with stirring. One hour later another 3 g of zinc dust was added and, after refluxing for an additional 17 hours, the reaction mixture was stirred for five minutes with 200 ml of methylene chloride and 150 ml of 0.5N hydrochloric acid. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to yield 10 g of crude material. This material was chromatographed on silica gel with 80% ethyl acetatehexane and recrystallized from ether-hexane to afford 5.7 g (17.1 mmol, 57%) of 4-[(3,5-di-tert-butyl-4-hydroxyphenyl)hydroxymethyl]-2-methyl-3-isoxazolidinone, mp 137°-140° C.
Reaction SMILES: B.[CH3:2][C:3]1([CH3:11])[C@H:9]2[CH2:10][C@@H:4]1[CH2:5][CH2:6][C:7]2=[CH2:8].[OH-:12].[Na+].OO>ClCCl>[CH3:2][C:3]1([CH3:11])[C@H:9]2[CH2:10][C@@H:4]1[CH2:5][CH2:6][C@H:7]2[CH2:8][OH:12]
Reactant: C=C1CC[C@H]2C[C@@H]1C2(C)C
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)[C@H]2CC[C@@H](CO)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 192.6 %

Procedure:
A 6.0M borane adduct (9i) was dissolved in dichloromethane (12 ml) and (-)-β-pinene (5.0 g, 26 mmol), 91% ee was added at 0° C. The reaction was completed in 0.5 h, as indicated in 11B NMR. The mixture was maintained at room temperature for 1 h and oxidized by the addition of 3M sodium hydroxide (5.6 ml, 17 mmol) and 30% hydrogen peroxide (4.0 ml, 40 mmol), keeping the temperature during the addition below 30° C. and then stirring at room temperature overnight. The dichloromethane layer was separated and stirred with water (20 ml) for 0.5 h. The organic layer was separated, dried over anhydrous magnesium sulfate and distilled to give 5.05 g (91%) of pure product, bp 116°-118° C./15 mm Hg. α!20D=-19.4°.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]([CH2:18][C:19]([OH:21])=O)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1.[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:17]([CH2:18][C:19]([N:23]([CH3:22])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)=[CH:7][CH:8]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
Under nitrogen atmosphere, oxayl chloride (2.21 g, 0.0174 mole) was added slowly dropwise to a stirred and chilled (~10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in 75 ml of dimethylformamide. After the addition was complete, the reaction was heated at 60° C. for 5 hrs. This acylchloride solution was added dropwise to a stirred and cooled (~10° C.) solution of N-methylaniline (2.02 g, 0.019 mole), triethylamine (1.88 g, 0.019 mole), and 74 ml of dimethylformamide. The reaction was stirred at room temperature overnight. The reaction mixture was poured into 200 ml of water and diluted with water until the cloud point. The mixture was seeded and refrigerated overnight. The solid was collected by filtration and dried under high vacuum. The solid was suspended in dilute, sodium bicarbonate, collected by filtration, washed with water, and dried under high vacuum at 50° C. The solid was recrystallized from isopropyl alcohol-water, collected by filtration, washed with water, and dried under high vacuum first at 56° C., then at 98° C. for 2 days to give 3.0 g (45%) of crystals, mp 170°-171° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].C[Si](C)(C)N[Si](C)(C)C.[Li].Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1>C1COCC1>[C:1]([C:3](=[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][NH:23]1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C#N)=C1N=C(C(F)(F)F)C=CN1
Temperature: 50 °C
Yield: 79.7 %

Procedure:
tert-Butyl 2-cyanoacetate (97.45 g, 690 mmol) was dissolved in anhydrous THF (1 L), and cooled on an ice-bath for 90 min with stirring under nitrogen. A 1M solution of lithium hexamethyldisilazane in THF (690 mL, 690 mmol) was added dropwise. The mixture was stirred for an additional 1 hr, then 2-chloro-4-trifluoromethylpyrimidin (105 g, 590 mmol) was added dropwise. The mixture was then heated to 50° C. for 3 hr with stirring under nitrogen, allowed to cool, and the solvent removed under reduced pressure. Hydrochloric acid (1N) was added to the residue to achieve a pH of 1-2. The precipitated solids were collected by filtration and dried under vacuum to give tert-butyl 2-cyano-2-[4-trifluoromethylpyrimidin-2(1H)-ylidene]acetate (135 g, 82% yield) as a bright yellow solid, >98% pure by LC/MS. tert-Butyl 2-cyano-2-[4-trifluoromethylpyrimidin-2(1H)-ylidene]acetate (48 g; 166 mmol) was suspended in 4M hydrogen chloride in dioxane (415 mL, 1.66 mol) and the mixture stirred at room temperature for 6 hr, then concentrated under reduced pressure to give 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (31 g, 100% yield) as an orange oil, >98% pure by LC/MS. To a stirred solution of 2-(4-trifluoromethylpyrimidin-2-yl)acetonitrile (31.0 g; 166 mmol) in absolute ethanol (800 mL) was added potassium O-ethylxanthate (26.6 g; 166 mmol) followed by potassium carbonate (45.8 g; 332 mmol). The mixture was heated to 100° C. for 3 hr, cooled to room temperature, iodomethane (47.1 g; 332 mmol) added dropwise, and 1N hydrochloric acid (2 L) added. The resulting mixture was extracted with DCM (1.5 L), and the DCM layer was washed twice with brine (1 L each). The solvent was removed under reduced pressure to give 3,3-bis(methylthio)-2-(4-trifluoromethylpyrimidin-2-yl)acrylonitrile (36 g, 75% yield) as a light brown solid, >95% pure by LC/MS.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>CC(C)=O>[CH:12]1([C:10]([NH:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([O:1][S:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)(=[O:26])=[O:25])[CH:16]=[CH:15][C:5]=3[N:6]=2)=[O:11])[CH2:13][CH2:14]1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A solution of cyclopropanecarboxylic acid (6-hydroxybenzothiazol-2-yl)amide (intermediate 6) (1.81 g, 7.72 mmol), 4-fluorobenzenesulfonyl chloride (1.5 g, 7.72 mmol) and triethylamine (2.14 ml, 15.45 mmol) in 43 ml of acetone, in a 100 ml round-bottomed flask equipped with a magnetic bar, is stirred for 1 hour at room temperature. The precipitate obtained is filtered off and the filtrate is evaporated. The residue is washed with acetone and ethyl ether, to give 1.92 g of 4-fluorobenzenesulfonic acid 2-(cyclopropanecarbonylamino)-benzothiazol-6-yl ester (off-white powder) in a yield of 66%.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]3=[O:21])=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:31])/[CH:26]=[CH:27]/[O:28][CH2:29][CH3:30])[CH3:23].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO.[NH4+].[Cl-]>CN(C=O)C.O>[CH2:22]([O:24][C:25](=[O:31])[CH2:26][CH:27]([O:28][CH2:29][CH3:30])[N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:9]2[C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[S:7][CH:8]=2)[C:13]1=[O:21])[CH3:23]
Reactant: CCO/C=C/C(=O)OCC
Reactant: Cc1cccc2scc(Cn3c(=O)[nH]c4ccccc43)c12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCOC(=O)CC(OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 60 °C
Yield: 67.1 %

Procedure:
To a solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol) in dry DMF (0.7 mL) are added (E)-3-Ethoxy-acrylic acid ethyl ester (0.049 mL, 0.34 mmol) and 40% benzyltrimethyl ammonium hydroxide in MeOH (0.008 mL, 0.017 mmol). The resulting mixture is warmed up to 60° C. for 16 hr and then saturated NH4Cl solution (1 mL) is added followed by water (5 mL). The mixture is extracted with EtOAc (3×10 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography using EtOAc in hexane (from 0% to 30%) affords 50 mg (67%) of 3-Ethoxy-3-[3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-propionic acid ethyl ester.
Reaction SMILES: Br[C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH3:73][O:74][C:75]1[CH:80]=[CH:79][C:78]([CH2:81][SH:82])=[CH:77][CH:76]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:20][C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[C:6]([CH:11]=[C:2]([S:82][CH2:81][C:78]2[CH:79]=[CH:80][C:75]([O:74][CH3:73])=[CH:76][CH:77]=2)[C:3]=1[F:21])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of methyl 5-bromo-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.85 g, 35.6 mmol) in anhydrous 1,4-dioxane (30 mL) was added N,N-diisopropylethylamine (9.21 g, 71.2 mmol). Then Pd2(dba)3 (1.63 g, 1.78 mmol) followed by Xantphos (2.06 g, 3.56 mmol) and 4-methoxy-α-toluenethiol (5.48 g, 35.6 mmol) was added under nitrogen atmosphere. The mixture was stirred overnight at 100° C. under N2 atmosphere and then allowed to cool to ambient temperature. The reaction was quenched with water (150 mL) and extracted with ethyl acetate (200 mL×3). The combined organic extract was washed with water (200 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 50:1, v/v) to give the desired product (pale yellow solid, 12.64 g, 82% yield). 1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.78 (d, 1H), 7.06-7.44 (m, 6H), 6.82-6.88 (m, 2H), 4.03 (s, 2H), 3.90 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.F[C:13]1[N:18]=[C:17]([S:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([C:29]([NH:31][CH2:32][C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[O:30])=[CH:15][CH:14]=1.CCCCCC.CC(=O)OCC>CN(C=O)C>[C:23]1([CH2:22][CH2:21][CH2:20][S:19][C:17]2[C:16]([C:29]([NH:31][CH2:32][C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)=[O:30])=[CH:15][CH:14]=[C:13]([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[N:18]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCNC1
Reactant: O=C(NCc1cccs1)c1ccc(F)nc1SCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1cccs1)c1ccc(N2CCCC2)nc1SCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
153 mg of K2CO3 and 71 mg (1.0 mmol) of pyrrolidine were added to a solution of 387 mg (1.0 mmol) of 6-fluoro-2-(3-phenylpropylthio)-N-(thiophen-2-ylmethyl) -pyridine-3-carboxylic acid amide (exemplary compound 225) in DMF (10 ml), and the mixture was stirred for 2 h at RT. Dilution with water and extraction with EA were then carried out. The organic phase was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 308 mg (0.7 mmol, 71%) of 2-(3-phenyl-propylsulfanyl)-6-pyrrolidin-1-yl -N-(thiophen-2-yl-methyl)-pyridine-3-carboxylic acid amide. MS: m/z 438.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][C:7]([CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])([C:10]#[N:11])[C:8]#[N:9])[CH:5]=[CH:4][CH:3]=[N:2]1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:40]I>C(#N)C>[I:40][C:4]1[CH:3]=[N:2][N:1]([CH2:6][C:7]([CH2:12][CH2:13][C:14]([F:15])([F:16])[F:17])([C:10]#[N:11])[C:8]#[N:9])[CH:5]=1
Reactant: II
Reactant: N#CC(C#N)(CCC(F)(F)F)Cn1cccn1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 10 h
Yield: 115.6 %

Procedure:
1.21 g of [(1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl)malononitrile (the compound of the present invention (1)) was dissolved in 50 ml of acetonitrile. 2.19 g of ammonium cerium (IV) nitrate and 1.02 g of iodine were added to the solution, followed by stirring at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.71 g of [(4-iodo-1H-pyrazole-1-yl)methyl] (3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (42), hereinafter) shown by below formula.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@H:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:13][C:12]2=[O:28])[C@@H:7]1[C:29]([O:31][CH3:32])=[O:30].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[Na+].[Na+]>>[C:16]1([C:15]2[N:11]([C@H:8]3[C:9](=[O:10])[NH:6][C@H:7]3[C:29]([O:31][CH3:32])=[O:30])[C:12](=[O:28])[O:13][C:14]=2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@H]1[C@@H](n2c(-c3ccccc3)c(-c3ccccc3)oc2=O)C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Product: COC(=O)[C@@H]1NC(=O)[C@@H]1n1c(-c2ccccc2)c(-c2ccccc2)oc1=O

Procedure:
Methyl cis-1-(2,4-dimethoxybenzyl)-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine-2-carboxylate is treated with potassium persulfate and sodium monohydrogen phosphate as described in Preparation 5 to give methyl cis-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.C(S)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: SCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, benzyl mercaptan and DBU in DME. EI-MS m/e (%): 308 (M+, 68), 307 ([M—H]+, 48), 275 (24), 91 (100).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl-].[Ca+2].[Cl-].S(Cl)(Cl)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][C:21]=1[O:31][CH3:32]>O.CN(C)C=O>[CH3:32][O:31][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=1[O:19][CH3:18])[CH:26]=[CH:27][C:28]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:29]
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Reactant: Nc1ccccc1C(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Into 15 ml of dimethylformamide were dissolved with heating 2.0 g of anthranilic acid and 2.3 g of anhydrous calcium chloride. To 10 ml of dimethylformamide were added in order 0.78 ml of thionyl chloride and 2.08 g of 3',4'-dimethoxycinnamic acid, during which the reaction system was stirred and cooled with ice and water. The resulting mixture was added dropwise to the above solution, during which the reaction system was stirred and cooled with ice and water. After the completion of the dropping, the reaction mixture was stirred for 30 minutes at the same temperature and then for 1 hour at room temperature. After the completion of the reaction, 80 ml of ice-water mixture was added thereto. Then, air was introduced thereinto for 30 minutes, and crystals deposited were collected by filtration and recrystallized from ethanol-water (1:2) to give 2.35 g (yield: 71.8%) of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid. Melting point: 209°-211° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[NH:8][CH2:7][CH2:6]2.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=1)[N:8]([C:34](=[O:35])[C:33]1[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N2CCc3cc(OC)ccc3C2Cc2ccc(OCc3ccccc3)cc2)cc1
Yield: 72.6 %

Procedure:
The title compound was prepared as described in Example 24. A, using 6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.72 g, 2.0 mmol) and 4-methoxybenzoyl chloride (0.512 g, 3.0 mmol) to provide the title compound (0.717 g, 73% yield): ES-MS (m/z) 494 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH:31]3[CH2:33][CH2:32]3)[C:14]=2[N:15]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16]2)=[O:8])[N:6]=1.O.O.[F-].[K+].[F:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[C:48]=1B(O)O>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[C:38]([O:37][C:35]([NH:34][C:4]1[S:3][C:2]([C:48]2[C:47]([F:46])=[CH:52][CH:51]=[CH:50][C:49]=2[F:53])=[N:6][C:5]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][N:13]([CH:31]2[CH2:33][CH2:32]2)[C:14]=1[N:15]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16]1)=[O:8])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(C2CC2)c1N1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Reactant: OB(O)c1c(F)cccc1F
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 100 °C
Yield: 44.8 %

Procedure:
A mixture of tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate (191 mg, 0.29 mmol), potassium fluoride dihydrate (90 mg, 0.96 mmol) and 2,6-difluoro-phenylboronic acid (137 mg, 0.87 mmol) in THF (3 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. Tris(dibenzylideneacetone)dipalladium/tri-tert-butyl phosphonium tetrafluoroborate mixture (mole ratio: 1/1.2) (35 mg, 0.029 mmol) was then added and the mixture degassed was heated in a microwave at 100° C. for 2 hr. The solvent was removed under reduced pressure. Water (5 mL) was added and the mixture extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-60% EtOAc/isohexane) to give tert-butyl 4-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate as an orange solid (95 mg, 0.13 mmol) which was dissolved in a solution of HCl in 1,4-dioxane (4 M, 0.7 mL, 2.73 mmol) and MeOH (0.2 mL) and stirred at 70° C. for 48 hr. The solvent was removed under reduced pressure and the residue dissolved in MeOH/DCM and passed through an SCX cartridge washing with DCM and MeOH and eluting with 1 N ammonia in MeOH. Purification by silica gel column chromatography (0-10% MeOH/DCM) gave 145 as a beige solid (35 mg, 25% over two steps). 1H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 7.87 (s, 1H), 7.38-7.28 (m, 1H), 7.08-6.97 (m, 2H), 6.20 (s, 2H), 3.71-3.56 (m, 3H), 3.46-3.35 (m, 4H), 3.12-3.06 (m, 2H), 1.25-1.19 (m, 2H), 1.06-0.97 (m, 2H). Alkyl NH not observed. LCMS (ES+) m/z 496 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:19]2[CH2:18][C@H:17]3[N:20]([CH2:22][CH2:23][C@@:9]45[C@H:16]3[CH:15]=[CH:14][C@H:12]([OH:13])[C@@H:10]4[O:11][C:7]([C:8]=25)=[C:5]([OH:6])[CH:4]=1)[CH3:21].Br[CH2:25][CH2:26][CH2:27][N:28]1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38].II>O.CO>[C:29]1(=[O:38])[N:28]([CH2:27][CH2:26][CH2:25][O:6][C:5]2[CH:4]=[CH:3][C:19]3[CH2:18][C@H:17]4[N:20]([CH3:21])[CH2:22][CH2:23][C@:9]56[C:8]=3[C:7]=2[O:11][C@H:10]5[C@@H:12]([OH:13])[CH:14]=[CH:15][C@@H:16]46)[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: II
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1CC[C@]23c4c5ccc(OCCCN6C(=O)c7ccccc7C6=O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1.5 g (37.5 mmol) of NaH (60% dispersion in mineral oil) was rinsed with 2×25 mL of hexanes to remove the oil. To the reaction mixture was added 140 mL of anhydrous DMF followed by 10.1 g (35 mmol) of morphine. This mixture was allowed to stir at room temperature for 30 minutes under nitrogen atmosphere, and 14.5 g (53 mmol) of N-(3-bromopropyl) phthalimide was added. The reaction mixture was allowed to stir 18 h at room temperature. The reaction was monitored by thin layer chromatography (silica, 7:2:1:1, MeOH:EtAc:NH40H:H2O, I2 visualization), which showed that the reaction was incomplete. To the reaction mixture 0.15 g (3.75 mmol) of NaH (60% in oil) was added, and the mixture was allowed to stir for an additional 1.5 h. The mixture was poured into 350 mL of ice-water and extracted with 250 mL of ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with 2×250 mL of ethyl acetate. The organic layers were combined and washed with 2×150 mL of water, 150 mL of 1N NaOH and 2×150 mL of water. The organic layer was dried (Na2SO4) and concentrated. The residue was crystallized with diethyl ether to give 12.9 g (27.3 mmol, 77%) of the desired product 13 as a white solid.