Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][N:27](S(C5C=CC(C)=CC=5)(=O)=O)[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CO>CO.O.C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCCCC(Nc2ncnc3[nH]ccc23)C1
Temperature: 80 °C
Yield: 66.7 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)-1-(3-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)azepan-1-yl)ethanone (800 mg, 1.36 mmol) in MeOH:H2O (4:1, 5 mL) was added K2CO3 (656 mg, 4.77 mmol) and the reaction mixture was heated at 80° C. for 4 h. The reaction mixture was concentrated in vacuo to give a residue which was triturated with 10% MeOH in EtOAc (20 mL), filtrated, the filtrate was evaporated in vacuo to give the crude compound that was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (393 mg, 66%) the titled compound. 1H NMR (DMSO-do, 400 MHz): 11.53 and 11.47 (2s, 1H), 8.15 and 8.07 (2s, 1H), 7.30 and 7.17 (2d, J=4 Hz, 1H), 7.07 (2t, d=2.4 Hz, 1H), 6.74 (s, 1H), 6.68 (m, 1H), 6.62 (s, 1H), 6.38-6.33 (m, 1H), 4.54-4.46 (m, 1H), 4.36-4.27 (m, 1H), 4.12-3.96 (m, 2H), 3.94-3.86 (m, 1H), 3.52-3.42 (m, 1H), 3.24-3.12 (m, 1H), 2.02-1.78 (m, 3H), 1.74-1.52 (m, 3H). LC-MS: m/z [M+1]=433.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:42])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([N:24]([CH3:42])[CH3:23])=[CH:30][CH:29]=1)[C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:40])[CH3:41])=[CH:35][CH:34]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)O)CCC2
Product: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 65.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.45 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.6 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.CCN(CC)CC.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1.C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][C:36](=[O:38])[CH3:37])[CH2:3][CH2:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)CCC3)s2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)NC1(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 92.4 %

Procedure:
To a solution of N-{3-[2-(1-aminocyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (Example 61B-1, 75 mg, 0.185 mmol) and Et3N (25.8 μL, 0.185 mmol) in THF (1000 μL), acetyl chloride (13.15 μL, 0.185 mmol) was added. The mixture was stirred at room temperature for 70 minutes. Additional acetyl chloride (6 μL) was added to drive the reaction to completion. The mixture was stirred for 10 additional minutes, then diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated to afford N-{1-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclobutyl}acetamide (80.8 mg, 0.171 mmol, 92%). MS ESI: [M+H]+ m/z 480.0. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.93 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.42 (s, 1H), 7.28 (d, J=4.9 Hz, 1H), 7.14 (s, 1H), 3.32-2.60 (m, 2H), 2.43-2.41 (m, 2H), 2.31 (s, 3H), 1.99-1.95 (m, 2H), 1.88 (s, 3H). rhSYK activity=+++
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[N:24][C:25]([N:28]3[CH2:33][CH2:32][N:31]([CH2:6][C:5]4[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=4[C:10]([F:13])([F:12])[F:11])[CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: Fc1ccc(CCl)c(C(F)(F)F)c1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(Cc3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 4-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (38% yield). 1H NMR (300 MHz, CDCl3) δ 7.96-8.04, 7.81, 7.36, 7.20-7.29, 6.96, 3.76, 3.68, 3.56, 2.61, 1.51, 0.68-0.84, 0.43-0.51, 0.06-0.13. MS (ES+) m/z 452 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:24])[CH3:2].[CH3:26][N:27](C=O)C>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:26]#[N:27])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:24])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(C#N)cc12
Temperature: 125 °C
Reaction time: 1 h

Procedure:
(2-Chloro-7-trifluoromethanesulfonyloxy-naphthalen-1-yl)-acetic acid ethyl ester (9.30 g, 23.43 mmol) is dissolved in DMF (80 ml) under an atmosphere of argon. Palladium(0) tetrakis(triphenylphosphane) (1.08 g, 0.9375 mmol) and zinc(II) cyanide (5.50 g, 46.87 mmol) are added. The reaction mixture is heated to 125° C. After 1 h, TLC analysis indicates complete consumption of starting material. The suspension is cooled to RT and poured onto water. After stirring for 15 minutes, filtration and concentration affords the crude reaction product. Purification by FCC (hexane/EtOAc 4:1) affords the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=8.8 Hz, 3H), 4.19 (q, J=8.8 Hz, 2H), 4.28 (s, 2H), 7.62-7.66 (m, 2H), 7.79 (d, J=9.9 Hz, 1H), 7.92 (d, J=9.9 Hz, 1H), 8.32 (s, 1H). ES+−MS; 274.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].Br[CH2:9][CH:10]=[CH:11][CH2:12][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>CO.C(N(CC)CC)C>[CH2:18]([O:17][P:13]([O:14][CH2:15][CH3:16])([CH2:12]/[CH:11]=[CH:10]/[CH2:9][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[O:20])[CH3:19]
Reactant: COC(=O)CN
Reactant: CCOP(=O)(CC=CCBr)OCC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOP(=O)(C/C=C/CNCC(=O)OC)OCC
Yield: 34 %

Procedure:
A solution of glycine methyl ester hydrochloride (1.6 g, 12.7 mmol) and diethyl (4-bromo-2-butenyl)phosphonate (Example E) (3.14 g, 11.6 mmol) in methanol and triethylamine (5 ml) is heated at reflux for 16 hours. The solvent is removed in vacuo and the residue dissolved in water and extracted with chloroform (2×70 ml). The organic layer is dried over magnesium sulfate, filtered and evaporated. The residue is purified over silica gel (0-2.5% methanol in chloroform as eluant) to give 1.1 g of a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:44][O:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][N:53]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54]2)=[C:48]([C:59]([F:62])([F:61])[F:60])[CH:47]=1>CN(C)C=O.CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:58][C:55]1[CH:56]=[CH:57][N:53]([CH2:52][C:49]2[CH:50]=[CH:51][C:46]([O:45][CH3:44])=[CH:47][C:48]=2[C:59]([F:61])([F:60])[F:62])[N:54]=1)=[O:10]
Reactant: O=C(O)c1ccncc1Cl
Reactant: COc1ccc(Cn2ccc(N)n2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ccc(NC(=O)c3ccncc3Cl)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-chloro-4-pyridinecarboxylic acid (103 mg, 0.654 mmol, Aldrich) in N,N-dimethylformamide (0.5 ml) was added HATU (250 mg, 0.657 mmol), DIPEA (0.27 ml, 1.55 mmol) and then 1-{[4-(methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-amine (for a preparation see Intermediate 52)(135 mg, 0.498 mmol). The resulting brown solution was stirred at ambient temperature for 30 min. The reaction mixture was diluted with methanol (1 ml) and purified by MDAP on an Xbridge column using Acetonitrile-Water with an ammonium carbonate modifier (Method E). The solvent was evaporated in vacuo to give the title compound as an orange foam (160 mg); LCMS (System 4) MH+=411, tRET=2.69 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[F:16][CH:17]([F:29])[O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH3:28])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([O:18][CH:17]([F:16])[F:29])=[CH:20][C:21]=2[CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cc(OC(F)F)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(OC(F)F)cc2C)Cc2ccccc2C1
Yield: 88.8 %

Procedure:
2-Amino-indane-2-carboxylic acid ethyl ester (2) (250 mg, 1.2 mmol), 4-difluoromethoxy-2-methyl-benzoic acid (242) (246 mg, 1.2 mmol) and HATU (555 mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen Anhydrous DMF (2 mL) is added and stirring is initiated. After few min, DIPEA (0.302 mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. Water (10 mL) is added, extracted with EtOAc (3×5 mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20-50% EtOAc in heptane as a gradient to afford 2-(4-difluoromethoxy-2-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (415 mg, 89%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.Cl>CO>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH2:10])[CH3:9])=[C:4]([C:20]([F:21])([F:22])[F:23])[CH:3]=1
Reactant: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: C[C@H](N)COc1ccc(F)cc1C(F)(F)F
Reaction time: 4 h

Procedure:
To a solution of tert-butyl {(2S)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl}carbamate (C6) (1.87 g, 5.54 mmol) in methanol (10 mL) was added a solution of hydrogen chloride (4 N in 1,4-dioxane, 5 mL). After 4 hours, the reaction mixture was concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0 to 20% methanol in ethyl acetate) afforded the title compound as a yellow liquid. Yield: 785 mg, 3.31 mmol, 60%. LCMS m/z 238.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J=6.5 Hz, 3H), 3.35-3.44 (m, 1H), 3.74 (dd, J=8.4, 7.4 Hz, 1H), 3.94 (dd, J=8.5, 4.0 Hz, 1H), 6.93 (dd, J=9.1, 4.2 Hz, 1H), 7.18 (br ddd, J=9, 8, 3 Hz, 1H), 7.30 (dd, J=8.4, 3.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]3)[C:12]=2[Cl:25])[C:9]#[N:10])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl[CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36].C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[C:22](=[O:23])[N:21]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:20](=[O:24])[CH:19]=[N:18]3)[C:12]=2[Cl:25])[C:9]#[N:10])=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: COCCOCCl
Reactant: N#CC(c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(-n2ncc(=O)[nH]c2=O)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COCCOCn1c(=O)cnn(-c2cccc(C(C#N)c3ccc(Cl)c(C(F)(F)F)c3)c2Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.5 %

Procedure:
A mixture of (±)-4-chloro-α-[2-chloro-3-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]-3-(trifluoromethyl)benzeneacetonitrile (0.00542 mol), 1-(chloromethoxy)-2-methoxyethane (0.006 mol) and triethylamine (0.0065 mol) in THF (15 ml) was stirred at RT for 2 hours. The mixture was poured out into water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.4 g of (±)-4-chloro-α-[2-chloro-3-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]phenyl]-3-(trifluoromethyl)benzeneacetonitrile (interm. 22).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]Cl)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[NH4+].[Cl-].[Zn]>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH3:15])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CCl)occ1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: Cc1cc(=O)c(OCc2ccccc2)co1
Temperature: 70 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
To a suspension of 5-(benzyloxy)-2-(chloromethyl)-4H-pyran-4-one (110 g, 0.44 mol) in saturated aqueous NH4Cl (1 L) was added Zn powder (58.5 g, 0.9 mol) at r.t. and the mixture was stirred at 70° C. for 2 h. The mixture was partitioned between water and EtOAc, the EtOAc phase was collected and water phase was extracted with EtOAc twice. The combined EtOAc layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography to give 40 g (42%) of 5-(benzyloxy)-2-methyl-4H-pyran-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]C#N)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:3][N:1]=[C:4]3[CH:9]=[CH:8][C:7]([C:10]4[N:14]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=5)[N:13]=[CH:12][CH:11]=4)=[CH:6][C:5]=23)=[CH:24][CH:23]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccn2)cc1
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccn4)cc23)cc1

Procedure:
The title compound, light green solid (65 mg, 49%), MS (ISP) m/z=357.1 [(M+H)+], mp 175° C., was prepared in accordance with the general method of example 1 from 2-[5-(4-Nitro-phenyl)-pyrazol-1-yl]-pyridine (intermediate K) (100 mg, 353 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]CC)=[O:12])=[C:6]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:6]([NH:16][C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)O
Reaction time: 1 h
Yield: 70.1 %

Procedure:
Ethyl (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetate (17.6 g) prepared by step e) and step f) was dissolved in ethanol (176 mL) and thereto was added at 0° C. 1M aqueous NaOH solution (132 mL), followed by stirring for 1 hour. To the reaction solution was added 2M hydrochloric acid (400 mL), and ethanol was removed in vacuo. The resulting solid was collected by filtration and washed with 2M hydrochloric acid, and dried in vacuo to give the object compound as a pale brown solid (11.2 g, 70%). Further the aqueous layer was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the solvent was removed in vacuo to give the object compound (3.58 g, 22%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C@@H:21]([OH:23])[CH3:22])=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:21]([C:3]1[C:2]([F:1])=[CH:7][N:6]=[CH:5][C:4]=1[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]2)(=[O:23])[CH3:22]
Reactant: C[C@H](O)c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a solution of 6-[5-fluoro-4-((S)-1-hydroxy-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (100 mg, 0.3 mmol, Compound 34, Example 16) in 5 mL of dichloromethane is added Dess-Martin periodinane (135 mg, 0.3 mmol, 1 eq.). The reaction is stirred at room temperature until the reaction is complete. The reaction mixture is filtered through diatomaceous earth and the filtrate is concentrated. The crude reaction product is purified by flash column chromatography to give 75 mg of the titled product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].CC([O-])(C)C.[K+].Cl[C:13]1[N:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:14]=1[C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]1)=[O:16]>C1COCC1.O>[Cl:32][C:30]1[CH:29]=[CH:28][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[CH2:20][CH2:19]2)=[O:16])=[C:13]([O:5][CH2:4][CH2:3][O:2][CH3:1])[N:31]=1
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1ccc(Cl)nc1Cl
Reactant: COCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1nc(Cl)ccc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1
Reaction time: 0.08 h

Procedure:
2-Methoxyethanol (550 μL, 6.94 mmol) is added at rt to KOtBu (750 mg, 6.35 mmol) in THF (30 mL) and it is stirred for 5 min. 2,6-Dichloro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (2.00 g, 5.86 mmol) is added to the reaction mixture and it is stirred for 10 min at rt. The reaction mixture is diluted with water, filtered and the filtrate is concentrated. The residue is treated with water, filtered off, washed with water and dried.
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.N([O-])=O.[Na+].O.[BrH:17]>CO>[Br:17][C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: Br
Reactant: COC(=O)c1nc(N)sc1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1nc(Br)sc1C

Procedure:
2.8 g of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate was dissolved in 30 ml methanol and 7 ml hydrobromic acid, followed by adding dropwise an aqueous solution of 1.2 g sodium nitrite thereinto under ice-cooling. After stirring the reaction solution under ice-cooling for 30 minutes, a solution, previously heated at 60° C., of 1.3 g cuprous bromide in 7 ml hydrobromic acid was added thereto, followed by stirring at 60° C. for 1 hour. The reaction solution was ice-cooled and water was-added, followed by extracting with diethyl ether. The organic layer was extracted with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.47 g of methyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[O:19]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:24])[N:18]1[CH2:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:6]([C:7]#[N:8])=[C:5]([O:12][CH3:13])[N:4]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1nc(CO)cc(C)c1C#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1nc(CN2C(=O)c3ccccc3C2=O)cc(C)c1C#N
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a stirred solution of 6-(hydroxymethyl)-2-methoxy-4-methylnicotinonitrile (1.50 g, 8.42 mmol), phthalimide (1.3 g, 8.84 mmol) and triphenylphosphine (2.3 g, 8.77 mmol) in Tetrahydrofuran (THF) (50 mL) at 0° C. in an ice bath was added dropwise DIAD (1.8 mL, 9.26 mmol). Within minutes a white suspension formed. Additional THF (˜50 mL) was added to allow stirring. The reaction was allowed to warm to RT and stirred for 3 h. LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum. The remaining solid was triturated with a small volume of EtOAc, filtered, washed with a small volume of EtOAc, then dried under vacuum to give the product 6-((1,3-dioxoisoindolin-2-yl)methyl)-2-methoxy-4-methylnicotinonitrile (2.12 g, 6.90 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.00-7.92 (m, 2H), 7.92-7.87 (m, 2H), 7.15 (s, 1H), 4.86 (s, 2H), 3.74 (s, 3H), 2.43 (s, 3H). MS(ES)+m/e 308.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=O)[CH:8]=1)=[O:4].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O.[CH:53]([NH:55][NH2:56])=O>C1(C)C=CC=CC=1>[CH3:29][C:2]([CH3:1])([CH3:28])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([C:22]2[N:24]([CH:25]([CH3:26])[CH3:27])[CH:53]=[N:55][N:56]=2)[CH:8]=1)=[O:4]
Reactant: NNC=O
Reactant: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)NC(C)C)c1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2-c2nncn2C(C)C)c1
Temperature: 120 °C
Yield: 52.2 %

Procedure:
To a room temperature solution of 29.3 (244 mg, 608 μmol) in toluene was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (369 mg, 912 μmol, Acros Organics). The mixture was heated at 120° C. for 1.0 hour, cooled to room temperature, treated with water, and then extracted with EtOAc. After removal of organic solvent under reduced pressure, the residue was dissolved in dioxane (4 mL). To the solution was added formohydrazide (208 mg, 3461 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and mercuric acetate (202 μL, 2076 μmol, Acros Organics). The resulting mixture was heated at 130° C. for 1.5 hours, cooled to room temperature, treated with water, and extracted with 30% IPA. After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-60% EtOAc/hexanes for elution gave 29.4 as a colorless oil (135 mg, 52%).