Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CS(O[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][C:33]4=[O:37])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCN1CCCC1=O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCN1CCn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 443 mg; 1.30 mmol), 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate (Intermediate 43; 400 mg; 1.93 mmol), Cs2CO3 (1.30 g; 3.99 mmol) in DMF (10 mL) was stirred at 90° C. overnight. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 285 mg (48%) of the title compound as a brown solid, which was used directly used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@@H:13]3[CH2:15][C@@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.[NH2:19][C@@H:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:21][OH:22]>>[OH:22][CH2:21][C@@H:20]([NH:19][C:16]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:15][C@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared as described in Method G using Intermediate 2 and (S)-2-amino-3,3-dimethylbutan-1-ol. LCMS m/z=342.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.41 (td, J=4.4 and 3.3 Hz, 1H), 0.93 (s, 9H), 1.23-1.28 (m, 1H), 2.25-2.34 (m, 1H), 2.69-2.74 (m, 1H), 2.75 (d, J=16.0 Hz, 1H), 2.90 (dd, J=16.2 and 6.4 Hz, 1H), 3.50-3.58 (m, 1H), 3.62-3.67 (m, 1H), 3.76-3.82 (m, 1H), 4.52 (t, J=5.0 Hz, 1H), 7.54 (d, J=9.8 Hz, 1H), 8.58 (dd, J=2.5 and 1.5 Hz, 1H), 8.64 (d, J=2.6 Hz, 1H), 9.39 (d, J=1.4 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:10]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([OH:18])[C:8](=[O:19])[O:7]1)=O)C.[Li+].[BH4-].O.Cl>O1CCCC1>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:10]1[C:6]([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)([CH2:4][OH:3])[O:7][C:8](=[O:19])[C:9]=1[OH:18]
Reactant: CCOC(=O)C1(CSCc2ccco2)OC(=O)C(O)=C1SCc1ccco1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(CO)(CSCc2ccco2)C(SCc2ccco2)=C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of 4-hydroxy-5-oxo-3-(2-furanylmethylsulfanyl)-2-[(2-furanylmethylsulfanyl)-methyl]-2,5-dihydrofuran-2-carboxylic acid ethyl ester (0.5 g, 1.219 mmol) in anhydrous tetrahydrofuran (THF, 30 mL) was added a THF solution of LiBH4 (2 mL, 4 mmol) at 0-5° C. under argon atmosphere. The mixture was stirred overnight at room temperature and water (1 mL) was slowly added. The mixture was stirred for 5 min and concentrated hydrochloric acid (1 mL) was added. The solution was mixed with water (150 mL) and extracted with methylene chloride (2×100 mL). The combined organic solution was washed with water (50 mL), dried and evaporated. The residue was purified by column chromatography, eluted with a mixed solvent of hexane and ethyl acetate (3:1 to 2:1, v/v) affording 55.6 mg of 4-(furan-2-ylmethylsulfanyl)-5-(furan-2-ylmethylsulfanylmethyl)-3-hydroxy-5-hydroxymethyl-5H-furan-2-one as a cream oil. 1H NMR (CD3OD, 300.16 MHz) δ (ppm): 7.45-7.42 (m, 2H), 6.35-6.22 (m, 4H), 4.50-3.71 (m, 5H), 3.48 (d, J=12.2 Hz, 1H), 2.97 (d, J=14.8 Hz, 1H) and 2.64 (d, J=14.8 Hz, 1H). 13C NMR (CD3OD, 75.48 MHz) δ (ppm): 167.70, 151.21, 150.45, 143.03, 142.38, 142.19, 125.61, 110.33, 110.00, 108.44, 107.81, 88.79, 64.19, 34.07, 28.87 and 26.83. MS (ESI, rel. int.) m/z: 369 (M+H+, 3), 391 (M+Na+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=1>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cnc3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-dichloro-9H-purine (16 mmol) is dissolved in DMF (50 mL) and potassium carbonate (50 mmol) is added. α-Bromo-p-tolunitrile (22 mmol) is then added and the mixture is stirred at ambient temperature for 16 hours. After filtration to remove insoluble inorganic salts, the filtrate is poured into water (1500 mL) and extracted with ethyl acetate (2×400 mL), dried over magnesium sulfate and evaporated to yield a residue which is subjected to flash silica gel chromatography using 1:2:10 ethyl acetate/acetone/hexanes. Yield 3.33 g (69%). UV, NMR and MS were consistent with structure assignment.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH2:27][CH2:28][CH2:29][CH2:30][N:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>>[N:31]1([CH2:30][CH2:29][CH2:28][NH:27][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH:14]=3)=[O:26])=[C:2]([Cl:1])[CH:3]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NCCCn1ccnc1
Product: O=C(NCCCn1ccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-(3-aminopropyl)imidazole via Procedure G. The product was purified on reverse phase HPLC to yield N4-(3-(1H-imidazol-1-yl)propyl)-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 495 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.O1CCC[CH2:21]1.O.Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH2:21])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(c1ccc(OC)cc1)c1ccc(N(C)C)cc1
Reaction time: 1 h

Procedure:
Separately, a solution was prepared by mixing 18.2 g of 4-methoxy-4'-dimethylaminobenzophenone (melting at 126°-127° C.) and 100 ml of tetrahydrofurane, and the solution was slowly added to the liquid reaction mixture and the whole matter was stirred for one hour at a temperature of 40° to 50° C. Then the whole matter was mixed with 400 ml of water and 300 ml of toluene and after making the mixture weakly acidic by dilute hydrochloric acid, the acidified mixture was stirred for a whole at 80° C. and separated into an aqueous layer and an organic layer (toluene layer). After adding activated carbon to the toluene layer and filtering the layer while hot, toluene was distilled off from the filtrate to obtain 17.1 g of 1-(p-methoxyphenyl)-1-(p-dimethylaminophenyl)ethylene of pale yellow in color, melting at 123°-125° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 58 °C
Yield: 96 %

Procedure:
3-bromophenylacetic acid (10000 mg, 46.50 mmol) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58° C. for 2 h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35% AcOEt/hexanes to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96%). GC-MS (MH+ 230 RT=9.34 min).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:31](I)([CH3:33])[CH3:32]>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:25][C:26]2[CH:27]=[N:28][N:29]([CH:31]([CH3:33])[CH3:32])[CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)cc1)CCC2
Reactant: CC(C)I
Product: COc1ccc2c(c1)C(C(=O)N(Cc1cnn(C(C)C)c1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 83 using N-(4-isopropylphenyl)-7-methoxy-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) and isopropyl iodide (0.11 mL) as starting materials, N-(4-isopropylphenyl)-N-[(1-isopropylpyrazol-4-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15])([O-:11])=[O:10].N1C=CC=CC=1>O1CCCC1>[Cl:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1cnccc1Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cnccc1Cl)c1ccccc1[N+](=O)[O-]

Procedure:
A solution of 3-amino-4-chloropyridine (5 g, 39 mmol), 2-nitrobenzoyl chloride (5.1 mL, 39 mmol) and pyridine (11 mL) in tetrahydrofuran (50 mL) was stirred for 20 hours. The reaction mixture was partitioned between water (200 mL) and dichloromethane (600 mL). The phases were separated and the organic phase was washed with water (150 mL) then brine (150 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10% ethyl acetate in dichloromethane). The N-(4-chloropyridin-3-yl)-2-nitrobenzamide was obtained as a brown solid (2.0 g). LCMS [M+H]: 279.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[C:21](Cl)=[N:20][CH:19]=[CH:18][N:17]=1.CN(C=O)C>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21]2[C:16]([Cl:15])=[N:17][CH:18]=[CH:19][N:20]=2)[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nccnc1Cl
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Solvent: O
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1Cl
Yield: 45 %

Procedure:
3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (5.0 g, 25 mmol), 2,3-dichloropyrazine (1.3 mL, 12.5 mmol), and DMF (5.0 mL) were combined and heated to 100 C overnight with stirring. The reaction mixture was poured into H2O and extracted with EtOAc (3×). The combined EtOAc extractions were washed with sat'd NaHCO3 (2×), sat's NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (4:1 hexanes:EtOAc) to give 1.76 g (45%) of 3′-chloro-2-methyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester. 1H NMR (CDCl3) 8.08 (d, 1H), 7.86 (d, 1H), 4.22-3.76 (complex m, 3H), 3.48-3.17 (complex m, 4H), 1.48 (s, 9H), 1.19 (d, 3H) ppm. LC-MS (MH+)=257 (-t-butyl).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][C:5]2[CH:17]=[CH:18][C:19]([C:21]#[C:22][C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)=[CH:20][C:4]=2[NH:3]1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31].CCN(CC)CC>C1COCC1>[CH3:31][C:30]([CH3:33])([CH3:32])[C:29]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]#[C:21][C:19]2[CH:18]=[CH:17][C:5]3[N:6]=[C:7]([C:9]4[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=4)[C:12]#[N:13])[CH2:8][C:2](=[O:1])[NH:3][C:4]=3[CH:20]=2)[CH2:28][CH2:27]1)=[O:34]
Reactant: N#Cc1cccc(C2=Nc3ccc(C#CC4=CCNCC4)cc3NC(=O)C2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CC=C(C#Cc2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)CC1
Yield: 38.5 %

Procedure:
Prepared from 3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile (Example 140) (55 mg, 0.15 mmol) by treatment with pivaloyl chloride (0.02 mL, 0.165 mmol) and Et3N (0.021 mL, 0.15 mmol) in THF (3 mL) at 23° C. for 19 h. Obtained as a sand solid (26 mg).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5]([CH3:36])([CH2:34][CH3:35])[CH2:6][C:7]1[N:8]=[C:9]([CH:18]([OH:33])[C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[CH:22][CH:21]=2)[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=1>O1CCCC1>[OH:33][CH:18]([C:9]1[N:10]([S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH:11]=[C:7]([CH2:6][C:5]([CH3:36])([CH3:4])[CH2:34][CH3:35])[N:8]=1)[C:19]([OH:32])([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:22][CH:21]=1)[CH3:1]
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C(=O)c2ccc(-c3ccccn3)cc2)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C(C)(O)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (28 μL, 0.09 mmol) was added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-[1-hydroxy-2-oxo-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (20 mg, 0.04 mmol) in tetrahydrofuran (2 mL). After stirring at 0° C. until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded 2-[1,2-dihydroxy-2-(4-pyridin-2-ylphenyl)propyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10])[CH3:2].[C:12]1(=O)[C:21]2[C:16]3[C:17](=[CH:22][CH:23]=[CH:24][C:15]=3[C:14](=[O:25])[O:13]1)[CH:18]=[CH:19][CH:20]=2>S(=O)(=O)(O)O>[CH2:1]([NH:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][C:9]=1[CH3:10])[C:12]([C:21]1[CH:20]=[CH:19][CH:18]=[C:17]3[C:16]=1[C:15]([C:14]([OH:13])=[O:25])=[CH:24][CH:23]=[CH:22]3)=[C:7]1[C:6](=[CH:5][C:4](=[N:3][CH2:1][CH3:2])[C:9]([CH3:10])=[CH:8]1)[O:11]2)[CH3:2]
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Reactant: CCNc1cc(O)ccc1C
Agent: O=S(=O)(O)O
Product: CCN=c1cc2oc3cc(NCC)c(C)cc3c(-c3cccc4cccc(C(=O)O)c34)c-2cc1C
Reaction time: 1 h
Yield: 10.8 %

Procedure:
3-Ethylamino-4-methyl-phenol (0.3 g, 2 mmol) and benzo[de]isochromene-1,3-dione (0.2 g, 1 mmol) in sulfuric acid (3 ml) was heated to 150° C. over a period of 6 h. The reaction mixture was pouring into crushed ice, allowed to stand over a period of 1 h and the precipitate was filtered. The filtrate was neutralized with concentrated ammonium hydroxide and concentrated to give a dark purple residue. Purification via preparatory layer chromatography (PLC, 1 mm silica gel, 9/1 DCM: MeOH, 2% AcOH) gave the title compound (50 mg). ABS λmax=527 nm (EtOH).
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.C=O.N1CCOCC1>CO>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Solvent: C1COCCN1
Solvent: CO
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
Biphenyl-4-ylmethyl-2-oxo-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (4a, R1=t-butoxycarbonyl, R4=hydroxyl) (3.95 g, 10.0 mmol) is dissolved in 10 mL of methanol, add paraformaldehyde (0.60 g, 20.0 mmol) and morpholine (1.05 g, 12.0 mmol), the mixture is heated to refluxed for 2 h under nitrogen atmosphere, cool to room temperature, evaporate the solvent under vacuum, the residue is dissolved in 50 mL of ethyl acetate, ish with 1% HCl(aq), 10% sodium hydrogen carbonate(aq) and brine, dry over anhydrous sodium sulfate and concentrate under vacuum to obtain (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1a, R1=t-butoxycarbonyl).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1.CCN(CC)CC>C(Cl)Cl>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[N:16]3[N:17]=[C:18]([O:25][CH2:26][C:27]4[N:32]=[CH:31][C:30]([CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:29][CH:28]=4)[C:19]4[C:24]([C:15]3=[N:14][N:13]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(CO)cn4)nn23)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(COS(C)(=O)=O)cn4)nn23)no1
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (1.07 ml, 13.9 mmol) was added to a stirred suspension of {6-[3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazin-6-yloxymethyl]pyridin-3-yl}methanol (2.78 mmol), Et3N (1.94 ml, 13.9 mmol) in CH2Cl2 (100 ml) under nitrogen. The reaction mixture was stirred overnight and then diluted with CH2Cl2. The resulting solution was washed with H2O (100 ml), 1 N HCl (100 ml), NaHCO3 (sat., 100 ml) and brine (100 ml). The solution was then dried MgSO4) and concentrated under reduced pressure. The resultant mesylate was used without further purification.
Reaction SMILES: C[N+]1([O-])CCOCC1.[CH3:9][C:10]([C@@H:14]1[C@:22]2([CH3:23])[C@H:17]([C@@H:18]([OH:24])[CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15]1)([CH3:13])[CH2:11][CH3:12]>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:13][C:10]([C@@H:14]1[C@:22]2([CH3:23])[C@H:17]([C:18](=[O:24])[CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15]1)([CH3:9])[CH2:11][CH3:12]
Reactant: CCC(C)(C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCC(C)(C)[C@H]1CC[C@H]2C(=O)CCC[C@]12C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
The solution of NMO (7.2 mg) and molecular sieves 4 Å (41 mg) in methylene chloride (0.3 mL) was stirred at room temperature for 15 min., then the solution of 7 (6 mg, 27 μmol) in methylene chloride (0.15 mL) was added followed by TPAP (0.8 mg). The resulted dark mixture was stirred for 30 min., diluted with methylene chloride and applied on a silica Sep-Pak (2 g). Elution with hexane/ethyl acetate (96:4) gave a pure ketone 8 (4.7 mg, 78%). 8: [α]24D−43° (c 0.18 CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.721 (3H, s, 18-H3), 0.825 (3H, t, J=7.3 Hz, 23-H3), 0.872 and 0.945 (3H and 3H, each s, 20-CH3 and 21-H3), 2.41 (1H, dd, J=11.0, 7.5 Hz, 14α-H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[O:19])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:36])(S(F)(=O)=O)C(O)=O>CC#N.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH:28]([F:36])[F:27])[CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[O:19])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(OC(F)F)CC1C(=O)OCC(=O)c1ccc(Br)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To 4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (500 mg) and Cu(I)I (45 mg) in MeCN (8 mL) at 45° C. was added 242 μl of difluoro-fluorosulfonyl-acetic acid in 2 mL of MeCN dropwise for 60 min. The reaction mixture was stirred at 45° C. for 60 min. and evaporated under reduced pressure, and resulting residue was taken up in ethyl acetate (100 mL). The organic phase was washed with brine (1×100 mL) and dried over sodium sulfate. After the solvent was removed, the resulting oil was subjected to silica gel chromatography using effluent of 10-50% ethyl acetate and hexanes. The fractions containing product were combined and the solvent was removed under reduced pressure to provide 4-Difluoromethoxy-pyrrolidine-1,2-dicarboxylic acid 2-[2-(4-bromo-phenyl)-2-oxo-ethyl]ester 1-tert-butyl ester (339 mg, 61%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33].C[O-].[Na+:37]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O-:34])=[O:33].[Na+:37]
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)[O-])CCO3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)-chroman-4-carboxylic acid (4.50 g, 8.64 mmol) was dissolved in 25 mL of MeOH and cooled to 0° C. A 0.5 M solution of sodium methoxide in methanol (17.3 mL, 8.64 mmol) was then added and the cooling bath removed. After stirring at ambient temperature for 1 hour, the solution was concentrated to a residue. The residue was mixed with 50 mL of hexanes and stirred for 1 hour. The resulting precipitates were collected by filtration and dried under high vacuum to provide the title compound. The hexane treatment was repeated and the resulting white powder was dried under high vacuum at 65° C. to give sodium 6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)-phenoxy)chroman-4-carboxylate (4.7 g, 100% yield). MS (apci) m/z=518 (M+2H-Na).