Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[Cl-].C(N(CC)CC)C.Cl[S:28]([C:31]1[CH:43]=[CH:42][C:34]2[O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:33]=2[CH:32]=1)(=[O:30])=[O:29]>>[CH:32]1[C:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[O:35][C:34]=2[CH:42]=[CH:43][C:31]=1[S:28]([NH:1][C@@H:2]1[C@H:7]2[CH2:8][C@H:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc2oc3ccccc3c2c1
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1N
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
Methyl (Z)-7-[(1S,2R,3R,4R)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (II-1) (251 mg, 1.00 mmol) was dissolved inmethylene chloride (8 ml) and triethylamine (0.238 ml, 2.00 mmol) was added thereto under a nitrogen atmosphere. To the mixture was added 2-chlorosulfonyldibenzofuran (350 mg, 1.31 mmol) under ice-cooling, and the mixture was stirred for 30 min and allowed to warm up to room temperature. The reaction mixture was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:4)) and recrystallized from n-hexane (10 ml) to yield methyl (Z)-7-[(1S,2R,3R,4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (342 mg, 0.710 mmol). Yield 71 %, mp 115-116° C.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[OH:15].[C:16](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.CCOCC>[Br:3][C:4]1[CH:9]=[C:8]([O:10][C:11]([F:13])([F:14])[F:12])[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CCOCC
Product: COc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Iodomethane (14.94 mL, 0.24 mol) was added to a solution of 2-bromo-4-(trifluoromethoxy)phenol (Description 15, 7.2 g) and potassium carbonate (11.6 g, 0.084 mol) in dimethylformamide (60 mL) and the mixture was stirred at room temperature for 15 h. Water (400 mL) and ether (200 mL) were added and the layers were separated. The organic fraction was washed with water (4×200 mL), saturated aqueous sodium hydrogen carbonate (2×200 mL) and brine (200 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (100:0 increasing to 98:2), to give the title compound. 1H NMR (250 MHz, CDCl3) δ7.45 (1H, d, J 2.8 Hz), 7.16 (1H, dd, J 9.0, 2.8 Hz), 6.88 (1H, d, J 9.0 Hz), and 3.90 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[CH:7]([C:8]1[CH:9]=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]([OH:18])=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=1)[Br:24])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C

Procedure:
To a solution of Intermediate 18 (1.0314 g, 3.22 mmol) in 7.3 mL CCl4 was added N-bromosuccinimide (0.5827 g) and a catalytic amount of benzoyl peroxide. The reaction was heated to 60° C. overnight. The solvent was removed in vacuo. The residue was taken up in ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated to an orange oil (0.8654 g, 2.17 mmol), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([CH:24]=1)[CH2:7][N:8]1[C:12](=[O:13])[N:11]([CH:14]2[CH2:16][CH2:15]2)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[N:9]1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([CH2:7][N:8]2[C:12](=[O:13])[N:11]([CH:14]3[CH2:16][CH2:15]3)[C:10]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:9]2)[CH:24]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: O=c1n(Cc2cc(Br)ccc2F)nc(-c2ccc(Cl)cc2)n1C1CC1
Product: O=c1n(Cc2cc(-c3ccccc3Cl)ccc2F)nc(-c2ccc(Cl)cc2)n1C1CC1

Procedure:
Analogously to the preparation of Example 122, 89 mg (0.15 mmol) of the compound from Example 100A were reacted with 59 mg (0.23 mmol) of 2-chlorophenylboronic acid. This gave 51 mg (73% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[CH:27]=1.O>CN(C)C=O>[Cl:34][C:30]1[CH:29]=[C:28]([C:26]2[CH:25]=[N:24][CH:23]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[CH:27]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: ClCc1cncc(-c2cccc(Cl)c2)c1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cncc(-c3cccc(Cl)c3)c2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 3-Chloromethyl-5-(3-chloro-phenyl)-pyridine were added and stirred continued at r. t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. to give 131 mg (71%) of the title compound as white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[C:11]([N+:18]([O-])=O)=[CH:10][C:9]=2[CH3:21])[CH2:4][CH2:3]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:21][C:9]1[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[C:11]([CH:10]=1)[NH2:18]
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1N1CCN(C)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(N)c(OC(C)C)cc1N1CCN(C)CC1
Temperature: 80 °C
Yield: 191 %

Procedure:
Two 20 ml tubes each containing a mixture of 614 mg of 1-methyl-4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperazine, 185 mg of 10% Pd on carbon and 793 mg of ammonium formate in 10 ml of methanol are microwave-heated at 80° C. (P 6-7 bar) for 5 min. The content of the tubes is combined and filtered on Clarcel. The Clarcel is washed with methanol and the filtrate is concentrated under vacuum. The residue is taken up with 20 ml of ethyl acetate, 2 ml of water and 8 ml of a saturated sodium chloride solution. The aqueous phase is extracted three times with 10 ml of ethyl acetate. The combined organic phases are washed with 10 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum, so as to obtain 1.053 g of 5-methyl-4-(4-methylpiperazin-1-yl)-2-(propan-2-yloxy)aniline in the form of a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[CH3:34][NH:35][CH3:36]>>[Cl:33][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[OH:9])[CH:17]=2)[N:22]=[C:21]([N:35]([CH3:36])[CH3:34])[C:20]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CNC
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Product: CN(C)c1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1-c1ccccc1
Temperature: 85 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (124 mg, 0.251 mmol, Example 65) was treated with dimethylamine (2 M in MeOH, 2 mL, 4 mmol) and the resulting suspension was heated in a sealed tube in an 85° C. oil bath for 2 days. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography (Biotage NH column, 0-1% MeOH-DCM) to provide the title compound as a cream-colored foam. 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=2.20 Hz, 1H), 7.72 (d, J=8.80 Hz, 1H), 7.43-7.52 (m, 3H), 7.34-7.43 (m, 3H), 7.22-7.34 (m, 6H), 6.33 (s, 1H), 3.36 (s, 3H), 2.72 (s, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[C:10]([NH2:23])=[CH:11][C:12]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2].N1C=CC=CC=1.[CH:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([NH:8][C:9]1[C:10]([NH:23][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([CH:33]([CH3:34])[CH3:35])=[CH:37][CH:38]=2)=[CH:11][C:12]([O:15][Si:16]([CH3:21])([CH3:22])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:14]=1)=[O:7])#[N:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)c2cccc(C#N)c2)c(N)c1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)Nc2cc(O[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a mixture of N1-(3-cyanobenzoyl)-4-(dimethyl-t-butylsiloxy)-1,2-benzenediamine (2.63 g, 7.17 nmmol) and CH2Cl2 (45 mL) at 0° C. was added pyridine (0.65 mL, 8.0 mmol) followed by a solution of the 4-isopropyl benzoyl chloride (10.1 mmol) in CH2Cl2 (90 mL). The reaction was allowed to warm to room temperature and stirred for 10 m. The reaction was diluted with CH2Cl2 (200 mL) and washed with sat. aq. NH4Cl (2×50 mL). The organic layer was MgSO4 dried filtered, and concentrated. The residue was chromatographed (10% EtOAc/hexanes to 20% EtOAc/hexanes) to give the title compound as a solid (3.04 g, 83%); IR(CHCl3): 2962, 1656, 1610, 1513, 1473, 1295 cm−1; NMR(300 MHz, CDCl3): δ0.16 (s, 6H), 0.95 (s, 9H), 1.29 (s, 3H), 1.31 (s, 3H), 3.00 (m, 1H), 6.68 (d, 1H, J=9.0), 6.86 (s, 1H), 7.38 (d, 2H, J=8.1), 7.50 (d, 1H, J=9.0), 7.61 (m, 1H), 7.81 (d, 1H, J=6.3), 7.89 (d, 2H, J=7.1), 8.16 (d, 1H, J=9.3), 8.29 (s, 1H), 8.58 (br s, 1H), 9.40 (br s, 1H); MS(FD): 513.1.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([F:42])=[C:26]([CH:41]=1)[O:27][C:28]1[N:33]=[C:32]2[S:34][C:35]([NH:37][C:38](=[O:40])[CH3:39])=[N:36][C:31]2=[CH:30][CH:29]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:38]([NH:37][C:35]1[S:34][C:32]2[C:31]([N:36]=1)=[CH:30][CH:29]=[C:28]([O:27][C:26]1[CH:41]=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]4([C:14]#[N:15])[CH2:13][CH2:12]4)[C:2]=3[Cl:1])[CH:23]=[CH:24][C:25]=1[F:42])[N:33]=2)(=[O:40])[CH3:39]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(N)ccc3F)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)ccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (0.11 g, 0.5 mmol) produced in Example C62(ii) in oxalyl chloride (0.5 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and the solution was added dropwise to a solution of N-[5-(5-amino-2-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.11 g, 0.33 mmol) produced in Example C73(vi) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (50 mg, 29%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]([CH3:19])=[C:6]([CH:18]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][N:15]=[C:16]([I:17])[C:9]=12.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Cl[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1>O>[CH3:43][O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][N:14]2[C:10]3=[N:11][CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:18]=[C:2]([Cl:1])[C:3]([N+:20]([O-:22])=[O:21])=[CH:4][C:5]=4[CH3:19])=[C:9]3[C:16]([I:17])=[N:15]2)=[CH:37][CH:38]=1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Oc1ccnc2[nH]nc(I)c12
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2nc(I)c3c(Oc4cc(Cl)c([N+](=O)[O-])cc4C)ccnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(5-Chloro-2-methyl-4-nitrophenoxy)-3-iodo-1H-pyrazolo[3,4-b]pyridine (26.5 g, 61.5 mmol) was dissolved in stirring DMF (100 mL). K2CO3 (17.0 g, 123 mmol) and 1-(chloromethyl)-4-methoxybenzene (10.1 ml, 73.9 mmol) were added and the reaction mixture was stirred at ambient temperature under N2 for 18 hours. The mixture was diluted with water, and then the water was decanted. The gum washed a second time with water, and the water decanted. The residue was partitioned between EtOAc (250 mL) and brine (100 mL). The phases were separated, and the organic phase was dried (Na2SO4), filtered, and concentrated. The resulting solid was triturated with diethyl ether (100 mL), and the yellow powder (27.3 g, 80%) filtered. The product was a 9:1 mixture of pyrazole regioisomers as determined by 1H NMR: (400 MHz, CDCl3, major regioisomer reported) δ 8.43 (d, J=5 Hz, 1H), 7.95 (s, 1H), 7.38 (d, J=9 Hz, 2H), 7.19 (s, 1H), 6.84 (d, J=9 Hz, 2H), 6.35 (d, J=5 Hz, 1H), 5.64 (s, 2H), 3.77 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[N:9]=[C:8]([C:14]3[CH:19]=[CH:18]C=CN=3)[C:7]=2[CH:20]=1)#[N:2]>CN1CCCC1=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[N:9]=[C:8]([CH:14]3[CH2:19][CH2:18][N:9]([CH3:8])[C:10]3=[O:11])[C:7]=2[CH:20]=1)#[N:2]
Reactant: CC1(C)N=C(c2ccccn2)c2cc(C#N)ccc2O1
Solvent: CN1CCCC1=O
Product: CN1CCC(C2=NC(C)(C)Oc3ccc(C#N)cc32)C1=O

Procedure:
According to the same manner as that described in the preparation of Compound 1 in Example 1, 6-cyano-2,2-dimethyl-4-(1-methyl-2-oxopyrrolidin-3-yl)-2H-1,3-benzoxazine (Compound 15) was obtained except that N-methylpyrrolidone and a solution of 1.6M lithium diisopropylamide in a mixed solvent of tetrahydrofuran and hexane were used instead of 2-bromopyridine and the solution of 1.6M n-butyl lithium in hexane, respectively.
Reaction SMILES: COP([CH2:7][C:8](=[O:22])[CH:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[Si](OC(CCC)CC(=O)/C=[CH:35]/[C@H:36]1[C@H:40]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:39][C@@H:38]([Cl:48])[C@@H:37]1[CH2:49][CH2:50][CH2:51][C:52]1[S:56][C:55]([C:57]([O:59][CH3:60])=[O:58])=[CH:54][CH:53]=1)(C(C)(C)C)(C)C>>[Si:15]([O:14][CH:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:22])/[CH:7]=[CH:35]/[C@H:36]1[C@H:40]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:39][C@@H:38]([Cl:48])[C@@H:37]1[CH2:49][CH2:50][CH2:51][C:52]1[S:56][C:55]([C:57]([O:59][CH3:60])=[O:58])=[CH:54][CH:53]=1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: CCCC(CC(=O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)OC)s2)[C@H](Cl)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)CP(=O)(OC)OC
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)OC)s2)[C@H](Cl)C[C@H]1OC1CCCCO1
Yield: 86 %

Procedure:
Compound 15 (1.32 g) was prepared in 86% yield by employing dimethyl (3-((tert-butyldimethylsilyl)oxy)-2-oxoheptyl)phosphonate 6 and aldehyde 10 according to the procedures described for compound 11 (see Schemes 1 and 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[H-].[Na+].[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([CH3:25])=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1>C[Si](C)(C)N[Si](C)(C)C.O1CCOCC1>[Br:15][C:16]1[C:17]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=2)=[N:18][C:19]([CH3:25])=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cc1nc(Cl)c(Br)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
In a 50 mL single-necked round-bottomed flask, 0.13 ml of hexamethyldisilazane and 1.21 g of 4-chloro-3-trifluoromethyl-phenol are dissolved and stirred in 3.0 ml of dry dioxane under Argon atmosphere at ambient temperature. To this mixture, 270 mg of 55% sodium hydride suspension is added carefully (gas evolution) and stirring is continued for 30 minutes. After this, a solution of 1.55 g of 3-bromo-2-chloro-6-methyl-5-nitro-pyridine in 4.0 ml of dry dioxane is added dropwise by syringe and stirring is continued for 22 hours at ambient temperature. The reaction is then quenched by the addition of an excess of a dilute aqueous NaOH solution (pH=12 of water phase) and extraction carried out with cyclohexane. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo to obtain an orange oil. Purification by flash chromatography over a silica gel cartridge (50 g, 150 ml) using heptane/ethyl acetate 95:5 (v:v) as eluent gave 480 mg of the compound in the form of a wet solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27][C:26]=2[CH:33]=1.C(O)(C)C>Cl.O1CCOCC1.O>[Cl:20][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27][C:26]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: Nc1ccc2c(c1)CCC(=O)CC2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)CCC(=O)CC3)ncc1Cl
Yield: 90 %

Procedure:
Into a microwave vial was placed N-[(1R,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (50 mg, 0.0001 mol) and 2-amino-5,6,8,9-tetrahydro-benzocyclohepten-7-one (34 mg, 0.00019 mol) in isopropyl alcohol (5 mL, 0.06 mol) along with 3-4 drops of 4 M HCl in dioxane-water. The mixture was subjected microwaves at 130° C. for 10 minutes. The reaction mixture was resubjected to the same conditions for complete conversion of starting materials. The resulting solid was collected by filtration and washed with cold methylene chloride and dried in a vacuum oven at 50° C. overnight to give N-{(1R,2R)-2-[5-chloro-2-(7-oxo-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as an off-white solid (43 mg, 60%). MP: 146-153° C.; 1HNMR (400 MHz, DMSO-d6) δ 9.34 (broad s, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.44 (d, 1H, J=8.8 Hz), 7.18 (d, 1H, J=8 Hz), 7.14 (d, 1H, J=8 Hz), 6.99 (broad s, 1H), 3.85 (m, 1H), 3.57 (m, 1H), 2.94 (s, 3H), 2.84 (dd, 4H, J=7 Hz), 2.54 (m, 4H), 2.06 (m, 2H), 1.70 (d, 2H, J=11 Hz), 1.19-1.38 (m, 4H); MS (m/e) 478 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5]2[O:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:3]1=[O:23].[H][H]>[Pd].C(O)C>[NH:15]=[C:16]([C:4]1[C:3](=[O:23])[N:2]([CH3:1])[CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][C:5]=1[OH:14])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN1C(=O)c2c(-c3ccccc3)noc2CC1c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)C(C(=N)c2ccccc2)=C(O)CC1c1ccccc1

Procedure:
A mixture of 4 grams (0.013 mole) of 5-methyl-6,7-dihydro-3,6-diphenyl isoxazolo[4,5-c]pyridin-4(5H)-one, 0.44 grams palladium on carbon and 80 ml. ethanol is hydrogenated at 50 psi until the equivalent amount of hydrogen is absorbed. The catalyst is filtered and washed thoroughly with ethanol. The ethanol is evaporated in vacuo and the residue recrystallized to give 3-α-iminobenzyl-5,6-dihydro-4-hydroxy-1-methyl-6-phenyl-2(1H)-pyridone; m.p. 117° to 120° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[C:7]#[N:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(N(CC)CC)C>[CH3:9][S:10]([O:1][C@@H:2]1[CH2:6][O:5][CH2:4][C@H:3]1[C:7]#[N:8])(=[O:12])=[O:11]
Reactant: N#C[C@@H]1COC[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1COC[C@H]1C#N
Yield: 89.3 %

Procedure:
The title compound is prepared by the procedure of Example 178 using 0.367 g of product from Example 197, 0.394 g of triethylamine, and 0.446 g of methanesulfonyl chloride to give 0.554 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)N1CCOCC1
Reaction time: 4 h

Procedure:
To a mixture of (1R,2R)-4-oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester (10.0 mmol) in tetrahydrofuran (25 ml) was subsequently added morpholine (11 mmol) triethylamine (70 mmol), 1-hydroxybenzotriazole hydrate (20 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 20 mmol) and stirring was continued at 22° C. for 4 h. The mixture was partitioned between ethyl acetate and 1N aqueous HCl, the organic layer was washed with saturated aqueous Na2CO3, dried and evaporated to give the title compound as pale brown oil. MS: 270.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[O:13])[CH:6]=[CH:7][CH:8]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH2:44].[Cl-].[Na+].[OH2:47]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([CH2:10][C:11]([OH:28])([CH3:27])[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=2)=[O:13])(=[O:47])=[O:44])[CH:6]=[CH:7][CH:8]=1
Reactant: O
Reactant: COc1cccc(SCC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cccc(S(=O)(=O)CC(C)(O)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-methoxyphenylthio)-N-(4-Cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (29 mg, 0.07 mmol) in dichloromethane (0.18 mL) at −78° C. was added 30% hydrogen peroxide (16 μL, 0.57 mmol) followed by the slow addition of trifluoroacetic anhydride (60 μL, 0.45 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 19 mg of desired product. Production of PLM5 was confirmed by 1-H NMR, 13-C NMR, and mass spectral analysis.