Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@H:19]1[CH2:23][N:22]([CH3:24])[C@H:21]([CH2:25][OH:26])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[Si:11]([O:18][C@H:19]1[CH2:23][N:22]([CH3:24])[C@H:21]([CH:25]=[O:26])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CN1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.6 %

Procedure:
Dimethyl sulfoxide (174 μL, 2.45 mmol) was dissolved in 20 mL of dichloromethane in a dry ice bath. After the system temperature was stable, oxalyl chloride (156 μL, 1.80 mmol) was added dropwise slowly. After stirring for 30 minutes, a solution of [(2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidin-2-yl]methanol 3d (300 mg, 1.20 mmol) in 2 mL of dichloromethane was added dropwise. After stirring for 45 minutes, the reaction mixture was added with triethylamine (510 μL, 3.67 mmol), and stirred for 10 minutes, then warmed up to room temperature and stirred for 1 hour. The reaction mixture was diluted with 100 mL of dichloromethane, washed with saturated sodium bicarbonate (20 mL), saturated ammonium chloride (20 mL) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carbaldehyde 3e (320 mg) crude product as a yellow oil, which was directly used in the next step.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([F:18])[CH:17]=2)[C:12]([NH2:14])=[O:13])=[C:6]([CH2:19][CH3:20])[N:5]([CH2:21][CH2:22]O)[N:4]=1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(=O)[NH:47]C(=O)C2=CC=CC=C12.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O.NN>O1CCCC1>[NH3:4].[NH2:47][CH2:22][CH2:21][N:5]1[C:6]([CH2:19][CH3:20])=[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([F:18])[CH:17]=2)[C:12]([NH2:14])=[O:13])[C:3]([CH2:1][CH3:2])=[N:4]1
Reactant: CCc1nn(CCO)c(CC)c1Oc1cc(F)cc(C(N)=O)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn(CCN)c(CC)c1Oc1cc(F)cc(C(N)=O)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.1 %

Procedure:
The alcohol from Example 163 (142 mg, 0.44 mmol), triphenylphosphine (346 mg, 1.32 mmol) and phthalimide (194 mg, 1.32 mmol) were dissolved in tetrahydrofuran (8 ml) at 0° C. under nitrogen and diisopropylazodicarboxylate (260 μl, 1.32 mmol) dissolved in tetrahydrofuran (1 ml) was added over 10 minutes. The reaction was allowed to warm to room temperature and was stirred for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in ethanol (9 ml) and hydrazine hydrate (107 μl, 2.2 mmol) was added. The slurry was stirred for 4 hours at 45° C. under nitrogen, concentrated under reduced pressure and the residue was dissolved in methanol. The solution was then passed through a polymer supported sulphonic acid column eluting with methanol to remove impurities, then 2M methanolic ammonia solution to elute the product. The product was then purified by flash chromatography on alumina eluting with dichloromethane:methanol:0.88 ammonia (90:10:1, by volume) to provide the title compound (60 mg) as an oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].Br[CH2:28][C:29]1([CH:36]=[CH:35][CH:34]=[CH:33][CH:32]1[C:37]([F:40])([F:39])[F:38])CBr>C1COCC1.CS(C)=O>[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]([F:38])([F:39])[F:40])[N:18]=1)=[O:15]
Reactant: FC(F)(F)C1C=CC=CC1(CBr)CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: O=C(Nc1ccn(Cc2ccccc2C(F)(F)F)n1)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2,6-dichloro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 44)(26 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 1-(bromomethyl)-2-(trifluoromethyl)benzyl bromide (24.7 mg, 0.1 mmol, Apollo Scientific Limited) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using the Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 4) MH+=415, tRET=3.11 min.
Reaction SMILES: [C:1]([C:3]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19]2)[CH2:5][CH2:4]1)#[N:2].[N-:24]=[N+:25]=[N-:26].[Na+].Cl.C(N(CC)CC)C>[N+](C1C=CC=CC=1)([O-])=O.C(OCC)C>[NH:2]1[C:1]([C:3]2([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]3([C:21]([OH:23])=[O:22])[CH2:19][CH2:20]3)[CH2:4][CH2:5]2)=[N:26][N:25]=[N:24]1
Reactant: N#CC1(CCCCCCCCCCCCC2(C(=O)O)CC2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(O)C1(CCCCCCCCCCCCC2(c3nnn[nH]3)CC2)CC1
Temperature: 130 °C
Reaction time: 24 h
Yield: 18.4 %

Procedure:
To a solution of Step 3 product of Example 19 (0.38 g, 1.8 mmol) in nitrobenzene (4 mL) were added sodium azide (0.46 g, 7.1 mmol) and triethyl amine hydrochloride (0.98 g, 7.1 mmol) at room temperature. The reaction mixture was allowed to stir at 130° C. over a period of 24 h. The reaction mixture was diluted with diethyl ether (50 mL) and extracted with 2% NaOH solution (50 mL×2). The combined aqueous layer was acidified to PH=5 (1N HCl), extracted with ethyl acetate (50 mL×2), dried over sodium sulphate. The residue obtained upon evaporation of the solvent was purified through silica gel (230-400) column (50% ethyl acetate in petroleum ether) to give product as Off-white solid 120 mg (27%). mp −133.2° C.-135.0° C.
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH:3]=O.[Br-].[CH2:8]([O:15][C:16]([CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1C(CC)C1>[OH:5][CH:2]([CH2:1][OH:6])[CH:3]=[CH:18][C:16]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:17]
Reactant: O=CC(O)CO
Reactant: O=C(C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Agent: CCC1CO1
Agent: [Br-]
Product: O=C(C=CC(O)CO)OCc1ccccc1

Procedure:
A mixture of DL-glycerinaldehyde (4.5 g, 50 mmole) and (benzyloxycarbonylmethyl)-triphenyl-phosphoniumbromide (24.57 g, 50 mmole) in 100 ml 1,2-epoxybutane was refluxed overnight. The mixture was evaporated under vacuum and the product was isolated by silica gel column chromatography.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][OH:3].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16]>CCOCC.CCCCCC>[C:15]([Si:19]([CH3:22])([CH3:21])[O:3][CH2:2][C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCOC(=O)CO
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCOC(=O)CO[Si](C)(C)C(C)(C)C

Procedure:
n-Butyl glycolate (231 g; 1.75 mol) and imidazole (345.1 g; 5.07 mol) were combined at 0° C. The suspension obtained was treated portionwise with t-butyldimethylchlorosilane (303 g; 2.01 mol) over 1.5 hours. After 20 hours at room temperature the reaction mixture was diluted with ether/n-hexane 1:1 (1 l) and suction filtered. The crystals were rinsed thoroughly with ether/n-hexane 1:1 (200 ml). The filtrate was washed in succession with water (2×700 ml) and saturated aqueous sodium chloride solution (500 ml), dried over magnesium sulphate and concentrated. The oil obtained was distilled over a Vigreux column (7.5 cm). Yield: 405 g (94%) as a colorless oil (b.p. 78° C./0.98 mm Hg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]([Cl:42])[CH:36]=1)=[O:34]>CN(C)C=O.O>[Cl:42][C:37]1[CH:36]=[C:35]([C:33](=[O:34])[CH3:32])[CH:40]=[CH:39][C:38]=1[O:41][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: CC(=O)c1ccc(O)c(Cl)c1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(Oc3ccc(C(C)=O)cc3Cl)n2)cc1Cl
Temperature: 80 °C
Yield: 19.9 %

Procedure:
A mixture of compound 133 (0.30 g, 0.78 mmol), potassium carbonate (0.54 g, 3.92 mmol) in dimethylformamide (10 mL) was added 3-chloro-4-hydroxyacetophenone (0.133 g, 0.78 mmol). It was heated to 80° C. for 12 hours with stirring under nitrogen atmosphere. The mixture was then cooled, diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulphate and concentrated under vacuum. The residue thus obtained was purified by column chromatography to afford the title compound as white solid (0.08 g, 67%). mp 186-196° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [mobile phase: 0.01 M KH2PO4: CH3CN (20:80)]; 212 nm, R, 12.33 min, 99.15% purity; MS (CI): m/z 516 (M+, 100).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][CH:30]=1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([C:29]4[CH:34]=[CH:33][C:32]([I:35])=[CH:31][CH:30]=4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(NO)c1ccc(I)cc1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccc(I)cc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-4-iodo-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.88 min; Mass spectrum (ESI+): m/z=582 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6](=[O:11])[C:7]([CH2:9]Br)=[CH2:8].[CH3:12][OH:13]>C(OCC)C>[CH3:4][O:5][C:6](=[O:11])[CH:7]([CH2:9][O:13][CH3:12])[CH2:8][O:2][CH3:1]
Reactant: C[O-]
Reactant: CO
Reactant: C=C(CBr)C(=O)OC
Agent: [Na+]
Solvent: CCOCC
Product: COCC(COC)C(=O)OC

Procedure:
Sodium methoxide (1.21 g) was added to a solution of 2-(bromomethyl)acrylic acid methyl ester (1.0 mL) in methanol (10 mL), and the mixture was heated under reflux for 26 hours. The reaction mixture was cooled, and was diluted with diethyl ether. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate hexane=1:4), to thereby give the title compound (726 mg).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:21]([CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=1)[CH2:11]2
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(CN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.6 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 4-methoxy-benzylamine (0.104 mL, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.084 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.78 (s, 3H), 4.14 (s, 2H), 4.74 (s, 2H), 6.84 (d, 2H), 7.14-7.40 (m, 4H), 7.91 (d, 1H). GC-MS: m/z 379 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[N:15][N:14]=2)[CH3:12])=[C:6]([CH:9]=1)[C:7]#N.C1(C)C=CC=CC=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:55].[Na+].[K+]>C(OCC)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C@H:11]([C:13]2[N:17]([CH3:18])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[N:15][N:14]=2)[CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:55]
Reactant: C[C@H](Oc1ccc(Cl)cc1C#N)c1nnc(-c2ccccc2C(F)(F)F)n1C
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc(Cl)cc1C=O)c1nnc(-c2ccccc2C(F)(F)F)n1C
Product: Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of 5-chloro-2-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy}benzonitrile (300 mg) and toluene (5 ml) was cooled to −78° C. under a nitrogen atmosphere and a 1M DIBAL/toluene solution (0.9 ml) was added dropwise thereto. After the dropwise addition was completed, it was stirred at the temperature for one hour and then further stirred at 0° C. for one hour. A saturated aqueous Rochelle salt solution was added thereto at 0° C., ethyl acetate was further added thereto, followed by stirring for 30 minutes, and it was then stood overnight. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5). The resulting formed precipitate was subjected to the same reaction and the residue was purified by silica gel column chromatography. The resulting residue was dissolved in ethyl acetate (1 ml), a 4M hydrogen chloride-ethyl acetate solution (100 μl) was added thereto, followed by stirring at room temperature, and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 5-chloro-2-[(1S)-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy]benzaldehyde monohydrochloride (31 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[S:14][C:13]=2[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[CH2:32][N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:26](Cl)=[O:27].[OH-].[Na+]>ClC1C=CC=CC=1.[Cl-].[Na+].O>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:26]([C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][C:13]=3[S:14][C:15]=2[N:17]([CH3:18])[CH3:19])=[O:27])[CH:29]=[CH:30][C:31]=1[CH2:32][N:33]1[CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COc1cc(C(=O)Cl)ccc1CN1CCCC1
Reactant: CN(C)c1cc2ccc(OCc3ccccc3)cc2s1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Yield: 84 %

Procedure:
A solution of 6-benzyloxy-2-(dimethylamino)benzo[b]thiophene (2.5 g, 8.8 mmol) and 3-methoxy-4-[(1-pyrrolidinyl)methyl]benzoyl chloride (3.0 g, 1.3 equiv) in chlorobenzene (30 mL) was heated at 135° C. under nitrogen for 2 h. The cooled reaction mixture was diluted with brine (100 mL), neutralized with NaOH solution (5.0 M), and extracted with dichloromethane (100 mL×3). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:EtOAc (5:95) afforded the product as a brown oil (3.7 g, 84%).
Reaction SMILES: [Cl-:1].[Al+3].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[Cl-].[Cl-].[Cl:14][C:15]1[C:23](Cl)=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=[O:18]>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:1])[C:16]=1[C:17](=[O:18])[C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[OH:11]
Reactant: [Cl-]
Reactant: COc1cccc(O)c1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: [Al+3]
Product: COc1ccc(C(=O)c2c(Cl)cccc2Cl)c(O)c1

Procedure:
2',3'-Dichloro-2-hydroxy-4-methoxybenxophenone is synthesized similarily from m-methoxyphenol aluminum chloride and 2,3-dichlorobenzoyl chloride.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl-].[Cl-].[Al+3].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:5][C:6]([C:16]1[CH:17]=[CH:18][C:13]([CH3:19])=[CH:14][CH:15]=1)=[O:7]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Add slowly tert-butylacetyl chloride (2 g, 14.858 mmol) to an ice-cold stirred solution of aluminum trichloride (2.972 g, 22.28 mmol) in anhydrous toluene (40 mL). Stir the reaction mixture at ambient temperature overnight. Add slowly ice-cold water and extract the mixture twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the desired intermediate (2.82 g, 100%) that was used without any further purification. GC-MS m/z: 190 (M4).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][O:14][CH3:15])[CH:3]=1.CS(C)=O.[CH2:20]([S-:22])[CH3:21].[Na+]>O>[CH2:20]([S:22][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:13][O:14][CH3:15])[CH:3]=1)[CH3:21]
Reactant: CC[S-]
Reactant: COCOc1cc(F)ccc1C(=O)OC
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1ccc(C(=O)OC)c(OCOC)c1
Reaction time: 19 h

Procedure:
To a solution of methyl 4-fluoro-2-(methoxymethoxy)benzoate (10.6 g, 50 mmol) and DMSO (20 mL), under nitrogen, was added sodium ethanethiolate (5.8 g, 55 mmol) in portions. The exothermic reaction was stirred for 19 h, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated; and the residue was dissolved in ether, filtered through diatomaceus earth, and concentrated to give intermediate methyl 4-(ethylthio)-2-(methoxymethoxy)benzoate.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22](OC)=[CH:21]C=3)[N:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:57]1C=CC=CC=1CO.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(O)(C(F)(F)F)=O.C1COCC1.ClCCl>[OH:1][CH:2]([C:7]1[N:12]([CH3:13])[C:11](=[O:14])[C:10]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:57]=3)[N:16]=[CH:17][C:9]=2[C:8]=1[C:27]1[C:28]([CH3:37])=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][CH2:32][CH2:31][CH2:30]2)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2cnn(Cc3ccc(OC)cc3)c2c(=O)n1C
Reactant: OCc1ccccn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)C(O)c1c(-c2ccc3c(c2C)CCCO3)c2cnn(Cc3ccccn3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 49.5 %

Procedure:
A solution of methyl 2-hydroxy-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridin-5-yl)acetate (100 mg, 0.2 mmol) in TFA (1 mL)/dichloromethane (1 mL) was stirred at 55° C. for 6 h and then concentrated. The residue was partitioned between EtOAc and saturated sodium bicarbonate/water. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in THF (2.5 mL) and to this solution triphenylphosphine (103 mg, 0.4 mmol) and pyridine-2-ylmethanol (43 mg, 0.4 mmol) was added followed by DIAD (0.076 mL, 0.4 mmol) and the mixture was stirred at ambient temperature for 2.5 h. The mixture was concentrated and purified on silica using EtOAc/hexanes 0-50% to provide the title compound (47 mg, 68%). 1H NMR (400 MHz, CDCl3) δ ppm 8.6 s (1H), 6.8-7.8 (m, 5H), 6.7 (d, 1H), 6.2-6.4 (m, 2H), 5.3 (s, 1H), 4.3 (broad s, 2H), 3.9 (s, 3H), 3.7 (s, 3H), 2.7 (broad s, 2H), 2.0 (s, 3H), 1.7 (broad s, 2H); ES-LCMS: 475.2 (M+1).
Reaction SMILES: [C@@H:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C[Si]([Br:14])(C)C.C(N(CC)C(C)C)(C)C.C1C=C(NS(C2C=CC(N/N=C3/C=CC(C(C(O)=O)=C/3)=O)=CC=2)(=O)=O)N=CC=1>CS(C)=O>[Br:14][C@@H:4]1[C@H:5]2[CH2:6][C@H:1]([C:7](=[O:9])[O:8]2)[CH2:2][CH2:3]1
Reactant: O=C(O)[C@H]1CC=CCC1
Reactant: C[Si](C)(C)Br
Agent: O=C(O)C1=C/C(=N\Nc2ccc(S(=O)(=O)Nc3ccccn3)cc2)C=CC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C1O[C@@H]2C[C@H]1CC[C@@H]2Br

Procedure:
(R)-Cyclohex-3-enecarboxylic acid, 98.2% e.e, (2.30 g, 18.2 mmol) [Schwartz et al, J. Am. Chem. Soc., 100, 5199, (1978)] was reacted with trimethylsilyl bromide (3.01 mL, 22.8 mmol), DMSO (1.62 mL) and N,N-diisopropylethylamine (3.97 mL, 22.8 mmol) [by the method of Iwata et al, Heterocycles., 31, 987 (1990)] to give a white solid, (2.13 g, 57%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10]O)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][CH:6]1[I:18])[CH2:2][CH2:3][CH3:4].O=S(Cl)Cl.[CH2:23]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH2:30])[CH3:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:5]1[C:9]([CH2:10][NH:30][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:23][CH3:24])[CH:27]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][CH:6]1[I:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(CO)=C(c2ccccc2)NC1I
Reactant: CCOc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCN1C(CNCc2cccc(OCC)c2)=C(c2ccccc2)NC1I
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(1-Butyl-2-iodo-4-phenyl-3H-imidazol-5-yl)-methanol (1.96 g), prepared by the method given in Example 2, step 2, is dissolved in 20 mL CH2Cl2. The solution is cooled to 0° C. and 3 equivalents of SOCl2 are added. The resulting solution is stirred at room temperature for 2 hours and then evaporated to dryness. The residue is dissolved in 5 mL of DMF and added to an ice cooled solution of 2 equivalents of 3-ethoxybenzylamine and 2 equivalents K2CO3 in 10 mL DMF. The mixture is stirred overnight at room temperature. The reaction is quenched with 20 mL water, extracted with EtOAc (3×30 mL), washed with water and brine, and dried over Na2SO4. Concentration and purification via silica gel chromatography provides (1-Butyl-2-iodo-4-phenyl-3H-imidazol-5-ylmethyl)-(3-ethoxy-benzyl)-amine.