Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH:9]=[CH:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].CO>C1COCC1.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: Cc1cccc(C)c1C=CCN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1CCCN1C(=O)c2ccccc2C1=O
Reaction time: 24 h

Procedure:
The title compound of Example 32 (10 g, 34 mmole) dissolved in 120 ml of THF and 100 ml of MeOH was reduced in a standard Parr hydrogenation apparatus using 1 g of 5% Pd/C as catalyst. The reaction was run at room temperature under a pressure of 5 psi for 24 hours. The residue after removing all solvent under reduced pressure was chromotographed to yield the pale yellow crystalline product which was recrystallized from Skelly B. The melting point was 92°-93.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O>[Cl:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 50 °C

Procedure:
To a stirred solution of 375.2 g (2 mole) of N-(4-chloro-2-fluorophenyl)acetamide in 600 mL of concentrated sulfuric acid and 400 mL of oleum (30%) was added 166 mL of a 1:1 mixture of nitric acid (100%) and concentrated sulfuric acid at 0° C. over a period of 1.5 hours. After the addition was complete, the reaction mixture was poured into 11 L of ice water. The precipitate was filtered and the filter cake suspended in 200 mL of water. The solid was redissolved by the addition of 2 L of ethyl acetate and neutralized with aqueous NaOH to pH 7. The two phase mixture was heated to 50° C. and separated. The organic layer was washed with 150 mL of water. 200 mL of ethyl acetate were distilled off and the remaining solution was treated with 12 g of Celite® at 70° C., filtered and washed with another 200 mL of ethyl acetate.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]([Cl:21])([Cl:20])[C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:21][C:12]([Cl:11])([Cl:20])[C:13]([C:15]1[NH:16][CH:17]=[C:18]([C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:19]=1)=[O:14]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h
Yield: 60 %

Procedure:
In a dry flask, phenylacetyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 1 in 60% yield. 1H NMR (CDCl3) δ 4.0 (s, 2H), 7.1-7.35 (m, 7H), 9.7 (br s, NH). HPLC using method B (as described below for Example 5) provided retention time of 4.9 minutes. LC/MS (M+1) 330.2, (M−1) 328.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.F[B-](F)(F)F.C[O+](C)C>ClCCl>[CH2:1]([O:8][C:9]([CH2:11][C@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:13][O:14][CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Reactant: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl (S)-1-((benzyloxy)carbonyl)-3-hydroxypropan-2-ylcarbamate (1 eq.) in dichloromethane was added 2,6-di-t-butyl 4-methylpyridine (2.5 eq.) and trimethyloxonium tetrafluoroborate (1.25 eq.) at 0° C. The reaction mixture was gradually warm to room temperature and stirred overnight. The reaction mixture was diluted with dichloromethane and washed with cold satd. sodium bicarbonate, water, and brine and dried over sodium sulfate. Purification by silica gel chromatography (25% EtOAc/Hexane) provide pure product as a colorless viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][S:18]([NH2:21])(=[O:20])=[O:19])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:35])([F:34])[F:33])[CH:26]=2)=[CH:4][CH:3]=1.IC.[C:40](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][S:18]([NH:21][CH3:40])(=[O:20])=[O:19])[C:12](=[O:22])[N:11]([CH3:23])[C:10]=3[N:9]=[C:8]2[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:34])([F:33])[F:35])[CH:26]=2)=[CH:36][CH:37]=1
Reactant: Cn1c(=O)n(CS(N)(=O)=O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNS(=O)(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)methanesulfonamide (0.1 g, 0.18 mmol, example 18) in DMF (3 mL) was added iodomethane (16 mg, 0.18 mmol) and potassium carbonate (36 mg, 0.26 mmol). The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by preparative-HPLC to give 1-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8 (3-(trifluoromethoxy)-phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-methylmethanesulfonamide (23 mg, 22.3% yield) as a white solid. 1H-NMR (DMSO-d6) δ 7.63(t, 1H), 7.50(d, 1H), 7.41-7.46(m, 4H), 7.34-7.37(m, 1H), 7.19-7.23(m, 1H), 5.45(s, 2H), 5.20(s, 2H), 3.31(s, 3H), 2.60(d, 3H). LCMS retention time 3.097 min; LCMS MH+ 574
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([N:27]1[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[N:28]1)[CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([C:29]2[CH:30]=[CH:31][N:27]([CH2:24][CH2:25][CH3:26])[N:28]=2)=[O:33])=[CH:18][C:17]=1[F:23]
Reactant: CCCn1ccc(C(=O)O)n1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Product: CCCn1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(F)c2)n1
Yield: 17 %

Procedure:
C1 was prepared from A2 and 1-propylpyrazole-3-carboxylic acid following the general procedure reported in Preparative Example 11. The residue was purified by reverse phase RP-HPLC (column: C18), using H2O and ACN as eluents. The desired fractions were lyophilized to yield the title compound C1 (46 mg, 0.10 mmol, 17%) as a white powder. 1H NMR (400 MHz, d6-DMSO, 300K) δ 0.85 (t, J=7.3 Hz, 3H), 1.86 (sext., J=7.3 Hz, 2H), 3.94 (s, 6H), 4.18 (t, J=7.3 Hz, 2H), 6.45 (d, J=5.1 Hz, 1H), 6.79 (d, J=2.3 Hz, 1H), 7.39 (s, 1H), 7.42 (t, J=9.0 Hz, 1H), 7.52 (s, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.90 (d, J=2.3 Hz, 1H), 8.05 (dd, J=13.4 Hz, J=2.3 Hz, 1H), 8.46 (d, J=5.2 Hz, 1H), 10.34 (s, 1H). MS (ES) C24H23FN4O4 requires: 450. Found: 451 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]=[O:9].O.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[N:3]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[C:5]([CH2:6][N:3]2[CH:7]=[CH:6][CH:5]=[C:4]2[CH:8]=[O:9])[CH:4]=1
Reactant: Cc1ccccc1
Reactant: O=Cc1ccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccn1Cc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A suspension of 60% NaH (3.28 g) in THF (400 ml) was cooled to 0° C. under nitrogen atmosphere, and thereto was added pyrrol-2-carbaldehyde (7.81 g) in portions. To the mixture was added a solution of the above crude bromo compound in toluene, and the mixture was stirred at room temperature for 0.5 hour, and stirred at 40° C. for one hour, and further stirred at 50° C. for 2 hours. The mixture was cooled to room temperature, and poured into water, and extracted with ethyl acetate. The extract was washed with a saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=3/1→2/1→1/1) to give 1-(3-quinolylmethyl)-1H-pyrrol-2-carbaldehyde (10.5 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:13].O>C(OCC)C>[Br:13][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCCCc1ccc(F)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(CCCBr)cc1

Procedure:
Compound 20-1 (9.39 g) was dissolved in diethyl ether (100 ml), phosphorus tribromide (8.58 ml) was added under ice-cooling, and the mixture was stirred under ice-cooling for 3.5 hr. To the reaction mixture was slowly added water, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (4.93 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.[NH2:18][C:19]([CH:23]([F:25])[F:24])=[CH:20][C:21]#[N:22]>CC(O)C.C(N(CC)CC)C>[F:24][CH:23]([F:25])[C:19]1[NH:18][C:15]([CH3:16])=[C:12]([C:13]#[N:14])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:20]=1[C:21]#[N:22]
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Reactant: N#CC=C(N)C(F)F
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)F)N1

Procedure:
A suspension of 3.42 g (15.2 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A) and 7.27 g (60.7 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in 2-propanol (20 ml) and triethylamine (0.21 ml) was stirred at reflux temperature overnight. After cooling, the precipitate was collected by filtration and washed twice with cold 2-propanol. The crude product was purified by silica gel chromatography (tert-butyl methyl ether/ethanol gradient, final mixture 94:6 v/v) to yield 0.36 g (7% of th.) of the racemic title compound as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:17])[CH3:16])([CH2:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:5][C:4](=[O:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:3]1[C:4](=[O:18])[O:5][C:6]([CH:15]([CH3:16])[CH3:17])([CH2:8][CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:7][C:2]=1[OH:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2ccsc2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccsc3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared as described in General Method 16a using 4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-20; 0.84 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.92 mmol), potassium carbonate (3.35 mmol) in DMF (4 mL). The product was purified via flash chromatography over silica gel eluting with 10:90 EtOAc:CH2Cl2, mp 63-70° C. MS (APCI): 475 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][OH:15])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][O:15][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)CC(=O)O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CO[Si](C)(C)C(C)(C)C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1 g of DL-3-tert-butoxycarbonylamino-4-hydroxy-butyric acid in a mixture of DMF/DCM 1:5, 1.24 g of imidazole and 1.7 g of tert-butyldimethylsilyl chloride were added. The solution was left stirring at room temperature overnight. The solution was extracted three times with 5% aq. NaHSO4 and the aqueous phases were washed twice with DCM. The organic extracts were dried over anh. sodium sulfate and the solvent evaporated under vacuum to provide 2.1 g of the title compound.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[CH:32]=[C:33]([C:37]2[CH:42]=[C:41]([NH:43][CH:44]3[CH2:46][CH2:45]3)[N:40]=[C:39]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:38]=2)[CH:34]=[N:35][CH:36]=1>COCCOC.C(Cl)Cl>[CH:44]1([NH:43][C:41]2[N:40]=[C:39]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:38]=[C:37]([C:33]3[CH:34]=[N:35][CH:36]=[C:31]([C:12]4[CH:11]=[CH:10][C:9]([C:7]([N:1]5[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]5)=[O:8])=[CH:14][CH:13]=4)[CH:32]=3)[CH:42]=2)[CH2:46][CH2:45]1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCNCC3)cc2)OC1(C)C
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: O=C(c1ccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)cc1)N1CCNCC1

Procedure:
To a solution of piperazin-1-yl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (1.2 eq, 0.163 mmol, 0.052 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (3 eq, 0.408 mmol, 0.2 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 0.050 g) and PdCl2dppf (0.1 eq, 0.0136 mmol, 0.001 g). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours 30. The reaction mixture is dissolved in DCM and washed with water. The organic layer is dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH and followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 477.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].Cl.[CH3:17][NH:18][CH3:19].CCN(CC)CC>C(#N)C>[CH3:17][N:18]([CH3:19])[CH:10]([C:3]1[N:4]([CH3:9])[CH:5]=[CH:6][C:7](=[O:8])[C:2]=1[OH:1])[C:11]([F:14])([F:13])[F:12]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: CNC
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(c1c(O)c(=O)ccn1C)C(F)(F)F
Reaction time: 2 h
Yield: 32 %

Procedure:
To a suspension of 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (5.00 g, 22.4 mmol) in 40 mL of acetonitrile at ice-water bath was added Vilsmeier's reagent (4.30 g, 33.6 mmol) portionwise. The resulting mixture was stirred for 2 h before being added to a suspension of dimethylamine hydrochloride (6.00 g, 73.6 mmol) and Et3N (15.0 mL, 107.6 mmol) in 30 mL of acetonitrile. The resulting suspension was stirred at RT for overnight. The solid was filtered off and the filtrate was concentrated to dryness. The residue was purified by flash chromatography on silica gel (10% MeOH in EtOAc as eluant) to afford title compound, Apo7041 (1.8 g). Yield=32%; 1H NMR (90 MHz, CD3OD-D4) δ (ppm): 7.63 (d, J=7.3 Hz, 1H), 6.41 (d, J=7.3 Hz, 1H), 4.78 (q, J=8.1 Hz, 1H), 3.99 (s, 3H), 2.41 (s, 6H); MS m/z 273 [M+Na]+, 251 [M+1]+, 206 (100%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(OCC)C>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)c(C)c1
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C(=O)Cl)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 60 ml of anhydrous ethyl ether, was suspended 6.2 g of 4-acetyloxy-2-methylbenzoic acid. To the suspension, was added 8.0 g of phosphorus pentachloride. The suspension was stirred for 3 hours at room temperature. The reaction mixture was freed from the solvent by distillation under reduced pressure, admixed again with ethyl ether, and freed from the solvent by distillation to obtain 4-acetyloxy-2-methylbenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][NH2:11])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:31])([CH3:30])[CH2:20][C@@H:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]2=[CH:14][C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1.Cl[C:40]1C=C(C(NO)=N)C=CC=1C1N=C2OC(C)(C)CC(NC(=O)C(C)(C)C)C2=CC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:40]=[N:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:31])([CH3:30])[CH2:20][C@@H:21]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[C:15]2=[CH:14][C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1
Reactant: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=N)NO)cc3Cl)nc2O1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2nc(-c3ccc(C(=O)NN)cc3Cl)c(-c3ccc(Cl)cc3)cc21
Product: CC(C)(C)OC(=O)N[C@@H]1CC(C)(C)Oc2nc(-c3ccc(-c4nnco4)cc3Cl)c(-c3ccc(Cl)cc3)cc21

Procedure:
The product was prepared using the procedures analogous to those described for Example 318 substituting tert-butyl [(4R)-7-[2-chloro-4-(hydrazinocarbonyl)phenyl]-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]carbamate for N-[7-{2-chloro-4-[(hydroxyamino)(imino)methyl]phenyl}-6-(4-chlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-2,2-dimethylpropanamide in Step B except without addition of boron trifluoride-diethyl etherate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[CH:12]1([CH:17]([OH:20])[CH:18]=[CH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:19][CH2:18][C:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:20])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: C=CC(O)C1CCCC1
Reactant: CCOc1cnc(Cl)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOc1cnc(Cl)cc1CCC(=O)C1CCCC1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
A mixture of 2-chloro-5-ethoxy-4-iodo-pyridine (1.5 g, 5.3 mmol), 1-cyclopentyl-2-propen-1-ol (0.83 g, 6.61 mmol), sodium acetate (0.54 g, 6.6 mmol), palladium (II) acetate (24 mg, 0.11 mmol) in DMAC (10 mL) was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the desired product (1.2 g, 58%). 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=7.0 Hz, 3H), 1.55-1.87 (m, 8 H), 2.75 (m, 2 H), 2.86 (m, 3 H), 4.11 (q, J=7.0 Hz, 2 H), 7.09 (s, 1 H), 7.89 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:41])[NH:39][CH3:40])[CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:42][CH3:43])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8].[H-].[Na+].I[CH3:53]>C1COCC1.O>[Cl:1][C:2]1[C:3]2[C:47]([F:48])=[CH:46][CH:45]=[C:44]([F:49])[C:4]=2[S:5][C:6]=1[C:7]([N:9]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38](=[O:41])[N:39]([CH3:53])[CH3:40])[CH:33]=2)[CH:29]=[CH:28][C:27]=1[O:42][CH3:43])[CH:10]1[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1)=[O:8]
Reactant: CI
Reactant: CNC(=O)c1cc(-c2ccc(OC)c(CN(C(=O)c3sc4c(F)ccc(F)c4c3Cl)C3CCC(N(C)C(=O)OC(C)(C)C)CC3)c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccnc(C(=O)N(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of amide 158 (125 mg, 0.175 mmol) in THF (5 mL) is treated with sodium hydride (11 mg, 0.26 mmol, 60% dispersion in mineral oil) at 0° C. After warming to RT and stirring 0.5 h, iodomethane (0.13 mL, 0.26 mmol, 2 M solution in TBME) is added via syringe and the reaction stirred 1 h. Analysis by LC/MS at this juncture revealed the reaction is only 75% complete. Hence more sodium hydride (11 mg, 0.26 mmol, 60% dispersion in mineral oil) is added, followed after 0.5 h by iodomethane (0.13 mL, 0.26 mmol, 2 M solution in TBME). After a further hour at RT, the reaction is diluted with water (10 mL) and extracted into EtOAc (3×20 mL). The combined EtOAc phases are dried (Na2SO4) and the solvent removed in vacuo. The title compound is obtained after chromatography (gradient elution—50-80% EtOAc in heptane with 0.5% triethylamine).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH:20]12[NH:27][CH:24]([CH2:25][CH2:26]1)[CH2:23][CH2:22][CH2:21]2>ClCCl.Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:24]23[NH:27][CH:20]([CH2:26][CH2:25]2)[CH2:21][CH2:22][CH2:23]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CC2CCC(C1)N2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)C23CCCC(CC2)N3)cc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A mixture of 4-nitrobenzenesulfonyl chloride (1.78 g, 8.0 mmol), pyridine (0.78 mL, 9.6 mmol), and 8-azabicyclo[3.2.1]octane (0.796 g, 8.02 mmol) in dichloromethane (22 mL) was stirred for 5 hrs at 0° C., diluted with 1N HCl, and extracted with dichloromethane. The isolated organic layer was dried (Na2SO4), filtered, concentrated, and triturated with diethyl ether to give 1-(4-nitro-benzenesulfonyl)-8-azabicyclo[3.2.1]octane as a brown solid. The solid was added to a mixture of HCO2NH4 (1.91 g, 30.3 mmol) and 10% Pd/C (catalytic amount) in methanol (20 mL) and ethyl acetate (4 mL), stirred overnight at about 25° C., filtered, concentrated, diluted with water, and extracted with dichloromethane. The isolated organic layer was dried (Na2SO4), filtered and concentrated to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.74 (d, 2H), 7.02 (d, 2H), 4.17 (brs, 2H), 1.42-1.86 (m, 10H).