Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4cccnc4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
1-(β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene obtained in Example 19 was used and treated in a manner similar to Example 106-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 590/592 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-chloro-2-thienylmethyl)benzene and tri-n-butyl(3-pyridyl)tin were used and treated in a manner similar to Example 124 to give the target compound as colorless powder. APCI-Mass m/Z 448/450 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccccc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1Cl
Yield: 25 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-chlorophenylboronic acid (available from Combi-Blocks Inc.; 63 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (23 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ 13.04 (br s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.33-7.56 (m, 5H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([CH2:20][N:21]4[CH:25]=[CH:24][N:23]=[N:22]4)[O:17][C:16]3=[O:26])=[CH:10][C:9]=2[F:27])=[CH:4][CH2:3]1.N1C=CC=CC=1.[CH3:34][C:35]1([CH3:43])[O:39][C@H:38]([C:40](Cl)=[O:41])[CH2:37][O:36]1>ClCCl>[CH3:34][C:35]1([CH3:43])[O:39][C@H:38]([C:40]([N:2]2[CH2:7][CH2:6][C:5]([C:8]3[C:9]([F:27])=[CH:10][C:11]([N:15]4[CH2:19][C@H:18]([CH2:20][N:21]5[CH:25]=[CH:24][N:23]=[N:22]5)[O:17][C:16]4=[O:26])=[CH:12][C:13]=3[F:14])=[CH:4][CH2:3]2)=[O:41])[CH2:37][O:36]1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1cc(F)c(C2=CCNCC2)c(F)c1
Reactant: CC1(C)OC[C@@H](C(=O)Cl)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC[C@@H](C(=O)N2CC=C(c3c(F)cc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)CC2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
A solution of (5R)-3-(4-(1,2,5,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one hydrochloride (650 mg, 1.64 mM) in dry dichloromethane (20 ml) at 0–4°, was treated with pyridine (648 mg, 8.2 mM) followed by dropwise addition of (4S)-2,2-dimethyl-1,3-dioxolane-4-carbonyl chloride (430 mg, 2.64 mM). The solution was allowed to warm to ambient temperature and stir for 1 hour. The reaction mixture was washed with water and brine, dried (sodium sulfate) and evaporated to a gum which crystallised readily on trituration with diethyl ether to give the title compound (788 mg).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:8]=1[CH2:9][CH2:10][C:11]1[S:15][C:14]([SH:16])=[N:13][C:12]=12)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29](Br)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[S:16][C:14]2[S:15][C:11]3[CH2:10][CH2:9][C:8]4[C:17](=[CH:18][CH:19]=[CH:20][C:7]=4[O:6][CH2:5][C:4]([OH:3])=[O:21])[C:12]=3[N:13]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccc(F)cc3)c3ccc(F)cc3)nc1-2
Yield: 77 %

Procedure:
Using ethyl[(2-mercapto-4,5-dihydronaphtho[1,2-d]thiazol-6-yl)oxy]acetate and bis(4-fluorophenyl)methyl bromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 77%. Amorphous solid.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:5]([C:6]#[N:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.CN(C)[CH:18]=[O:19].C[O-].[Na+]>CO>[CH3:18][O:19][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:5]([C:6]#[N:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1
Reactant: CN(C)C=O
Reactant: N#Cc1c([N+](=O)[O-])cc(F)cc1[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(C#N)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To 1.92 g (9.11 mmol) of 4-fluoro-2,6-dinitrobenzonitrile dissolved in 20 mL methanol and 3 mL dimethylformamide at 0° C. was added 1.87 mL (1 eq., 4.87 M in methanol) sodium methoxide over 1 hour. The mixture was stirred an additional hour at 0° C., partitioned between ethyl acetate and water, dried over magnesium sulfate and concentrated under reduced pressure. Column chromatography, eluting with ethyl acetate/hexanes, provided 1.32 g of 4-methoxy-2,6-dinitrobenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][N:11]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: F[n+]1ccccc1
Reactant: Brc1cccc(-c2nn[nH]n2)c1
Agent: C[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: Brc1cccc(-c2nnn(-c3ccccn3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5-(3-Bromophenyl)-2H-tetrazole (448 mg, 2.0 mmol) was stirred in anhydrous MeOH (15 mL) under argon at ambient temperature. To this was added NaOMe (4 mL of 0.5M solution in MeOH, 2.0 mmol), and the reaction flask was cooled to −78° C. A solution of N-fluoropyridinium triflate (331 mg, 1.0 mmol) in anhydrous MeOH (2 mL) was then added dropwise via syringe. The resulting reaction mixture was stirred at −78° C. for 30 min, then warmed to ambient temperature and stirred for an additional 3 h. The reaction mixture was partitioned between EtOAc (150 mL) and 10% aqueous NaHCO3 (50 mL). The EtOAc layer was washed with additional 10% aqueous NaHCO3 (2×50 mL), and the combined aqueous layers were back extracted with EtOAc (100 mL). The EtOAc layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The crude material was then chromatographed on silica gel eluting with hexanes:EtOAc (3:1) to afford 2-[5-(3-bromophenyl)-2H-tetrazol-2-yl]pyridine as a white solid.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][C:8]([C:11]3[O:12][C:13]([CH3:16])=[N:14][N:15]=3)=[CH:9][CH:10]=[C:5]2[O:4][CH:3]=1.[CH2:17]([S:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)[CH3:18]>>[CH2:17]([S:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:6]3=[N:7][C:8]([C:11]4[O:12][C:13]([CH3:16])=[N:14][N:15]=4)=[CH:9][CH:10]=[C:5]3[O:4][CH:3]=2)=[CH:22][CH:21]=1)[CH3:18]
Reactant: Cc1nnc(-c2ccc3occ(Br)c3n2)o1
Reactant: CCSc1ccc(B(O)O)cc1
Product: CCSc1ccc(-c2coc3ccc(-c4nnc(C)o4)nc23)cc1
Yield: 12 %

Procedure:
In the same manner as in Example 132 and using 3-bromo-5-(5-methyl-1,3,4-oxadiazol-2-yl)furo[3,2-b]pyridine instead of 2-(3-bromo-1-benzofuran-5-yl)-5-methyl-1,3,4-oxadiazole, using [4-(ethylthio)phenyl]boronic acid instead of (4-fluorophenyl)boronic acid, and using [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex instead of tetrakis(triphenylphosphine)palladium(0), the title compound (yield 12%) was obtained as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13](O)=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[OH:22].C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([Cl:26])=[O:14])=[N:10][C:9]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[OH:22]
Reactant: O=C(O)c1nc(-c2ccncc2)c(-c2ccc(Cl)c(O)c2)[nH]1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1nc(-c2ccncc2)c(-c2ccc(Cl)c(O)c2)[nH]1
Yield: 119.7 %

Procedure:
A suspension of the product from Step 1 (1.24 g, 3.9 mmol) in dichloromethane (50 ml) was treated with oxalyl chloride (3.4 ml, 39 mmol) and 10 drops dimethylformamide. The suspension was then heated at reflux for 5 hours, cooled and concentrated under vacuum. The resultant residue was azeotroped with toluene then trituated with hexane to afford the title compound (1.56 g), which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].Cl[C:34]([O:36][CH3:37])=[O:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[O:36][CH3:37])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: COC(=O)Cl
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 0.034 mmol), methyl chloroformate (2.6 μL, 034 mmol) and diisopropylethyl amine (30 μL, 0.17 mmol) in anhydrous DMF (1.5 mL) was stirred under nitrogen at ambient temperature overnight. The crude reaction mixture was evaporated in vacuo and purified by reverse phase chromatography eluting with 10-90% aqueous CH3CN containing 0.1% formic acid to provide the product as a white solid: 1H NMR (CDCl3) δ 10.29 (2H, b), 8.57 (1H, s), 7.36 (1H, s), 7.13-7.18 (2H, m), 7.00-7.05 (2H, m), 5.60 (2H, b), 4.23 (2H, t, J=7 Hz), 4.13 (2H, s), 3.67 (3H, s), 3.63 (2H, b), 3.56 (2H, q, J=7 Hz), 3.11 (2H, b), 1.74-1.81 (2H, m), 1.24 (3H, t, J=7 Hz); ES+ MS: 501 (M+H+).
Reaction SMILES: [CH2:1]([N:8]([CH2:25][CH3:26])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Cl:34])C(=O)C1>CC(O)C>[CH2:1]([N:8]([CH2:25][CH3:26])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:11][C:10]=1[Cl:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCN(Cc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CC(C)O
Product: CCN(Cc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 10 h
Yield: 82.6 %

Procedure:
A solution of 20 mg (0.05 mmol) of 2-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 1.2) in 0.5 mL of 2-propanol was treated with 7 mg (0.05 mmol) of NCS. The mixture was stirred at 80° C. for 10 hours and the solvent was evaporated. Column chromatography on silicagel with n-heptane/EtOAc 9:1 yielded 17 mg (82%) of 2-[4-(benzyl-ethyl-amino)-3-chloro-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, colorless oil, MS: 412 (MH+, 1Cl).
Reaction SMILES: CCCCC(N([C@H](C(O)=O)C(C)C)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[C:21]2[NH:22]N=NN=2)=[CH:13][CH:14]=1)=O.BrCC1C=CC(C2C=CC=CC=2C#N)=CC=1.C([O-])(=[O:51])C.[Na+]>C(O)(=O)C>[C:21]([C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:12]1[CH:11]=[CH:10][C:9]([CH2:8][OH:51])=[CH:14][CH:13]=1)#[N:22]
Reactant: CC(=O)[O-]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Agent: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1ccc(CO)cc1

Procedure:
According to U.S. Pat. No. 5,399,578, the process for the preparation of Valsartan (I) involves the reaction of 4′-bromomethyl-2-cyanobiphenyl (II) with sodium acetate and glacial acetic acid to produce 2′-cyano-4-hydroxymethylbiphenyl (III), which is reacted with oxalyl chloride in dichloromethane and dimethyl sulfoxide to produce 2′-cyano-4-formylbiphenyl (IV), which is further reacted with (L)-valine methyl ester hydrochloride (V) and sodium cyanoborohydride to produce N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VI), followed by treatment with valeryl chloride to produce N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester (VII), which is treated with tri-n-butyltin azide followed by flash chromatography to produce Valsartan of formula (I).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][C:13]([CH3:15])=O.N1CCCC1.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:13]([CH3:15])([CH3:12])[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC(C)=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CC1(C)CC(=O)c2cc(Br)ccc2O1
Yield: 71 %

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)-ethanone (21.4 g, 0.1 mol), acetone (365 mL) and pyrrolidine (8.4 mL) in toluene (220 mL) was refluxed for 4 h. To the reaction mixture was added acetone (36.5 mL). The mixture was refluxed for 15 h. Then 1 N HCl (220 mL) was added, and the resulting mixture was extracted with ethyl acetate (200 mL, 3×). The combined organic layers were washed with water (150 mL), brine (150 mL), dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2,2-dimethyl-chroman-4-one (18.0 g, 71%). 1H-NMR (CDCl3): 1.45 (s, 6H), 2.71 (s, 2H), 6.82 (d, 1H), 7.52 (dd, 1H), 7.96 (d, 1H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]([F:17])([F:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C1COCC1>CCOCC.[Zn]>[F:16][C:10]([F:17])([CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: O=Cc1ccccc1
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A stirred suspension of zinc (0.981 g, 15.00 mmol) in a solution of benzaldehyde (0.531 g, 5 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.522 g, 7.50 mmol) in an. THF (10 mL) was sonicated for 4-5 h and then stirred at rt overnight. The reaction was cooled and diluted with ether and washed with 1 N HCl, water, brine and dried (MgSO4). Evaporation of solvents afforded a clear oil which was purified by silica gel FCC (0-10% EtOAc in DCM) to afford ethyl 2,2-difluoro-3-hydroxy-3-phenylpropanoate as a clear oil (619 mg, ˜54%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.49-7.44 (m, 2H), 7.43-7.39 (m, 3H), 5.23-5.12 (m, J=15.3, 8.0, 5.5 Hz, 1H), 4.32 (q, J=7.1 Hz, 2H), 2.87-2.76 (m, 1H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1F)[CH2:2][CH2:3][CH3:4].[SH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32].CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[CH2:1]([N:5]1[N:6]([CH3:28])[C:7]([C:24]([CH3:27])([CH3:25])[CH3:26])=[CH:8]/[C:9]/1=[N:10]\[C:11](=[O:23])[C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=1[S:29][CH2:30][C:31]([OH:33])([CH3:34])[CH3:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)cc(C(C)(C)C)n1C
Reactant: CC(C)(O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2SCC(C)(C)O)cc(C(C)(C)C)n1C
Yield: 25.7 %

Procedure:
A mixture of Example 81C (400 mg, 1 mmol), 1-mercapto-2-methylpropan-2-ol (213 mg, 2 mmol) and potassium tert-butoxide (225 mg, 2 mmol) in dimethylacetamide (10 mL) was heated at 100° C. for 12 hours. The mixture was then poured into water and extracted with ethyl acetate. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, eluant: EtOAc-MeOH 9:1) afforded 125 mg of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 0.90 (t, J=7.3 Hz, 3H), 1.25 (s, 6H), 1.31-1.42 (m, 11H), 1.58-1.81 (m, 2H), 2.95 (s, 2H), 3.87 (s, 3H), 4.30-4.43 (m, 2H), 4.70 (s, 1H), 6.84 (s, 1H), 7.40-7.65 (m, 2H), 8.21 (d, J=2.0 Hz, 1H). MS (ESI+) m/z 486 (M+H)+. Anal. calculated for C24H34F3N3O2S: C, 59.36; H, 7.06; N, 8.65. Found: C, 59.27; H, 6.74; N, 8.40.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1([Se][Br:40])C=CC=CC=1.BrC(Cl)(Cl)C(Cl)(Cl)Br>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:9]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18])[CH:10]=[C:11]([Br:40])[C:12]1=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Br[Se]c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC1CO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(=O)C(Br)=C[C@@H]1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A solution of 2-(tert-butyldimethylsilanyloxymethyl)-5-oxopyrrolidine-l-carboxylic acid tert-butyl ester (16.5 grams, 50 mmol) in tetrahydrofuran (800 mL) was cooled in bath at -78° C. A 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (100 mL, 100 mmol) was added slowly. After stirring for 2 hours, a solution of phenylselenylbromide (14.16 grams, 60 mmol) in tetrahydrofuran (100 mL) was added and, after 15 minutes, a solution of 1,2-dibromotetrachloroethane (19.5 grams, 60 mmol) in tetrahydrofuran (100 mL) was added. The reaction mixture was stirred for an additional 1.5 hours while cooling at -78° and was quenched by addition of saturated ammonium chloride solution. Water and diethyl ether were added. The aqueous phase was separated and extracted with diethyl ether. The combined organic layers were concentrated to an orange oil which was dissolved in methylene chloride (1000 mL). A 30% w/v aqueous solution of hydrogen peroxide (20 mL) was added and the mixture was stirred vigorously overnight. Water (50 mL) was added. The aqueous layer was separated and extracted with methylene chloride. The combined organic layers were dried over magnesium sulfate and concentrated to an orange oil. The title compound (12.0 grams, 59%) was isolated by flash chromatography on silica gel eluting first with a 1:1 mixture of hexane and methylene chloride and then with methylene chloride alone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C1NCCCCC1c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCCCC1c1cccc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 47.5 %

Procedure:
A solution of 3-(3-hydroxyphenyl)hexahydro-2H-azepin-2-one (2.05 g) in dry DMF was added dropwise to a suspension of sodium hydride (0.3 g). After 30 minutes at ambient temperature, benzyl chloride (1.3 g) was added. The mixture was stirred for a further 2 hours and then cooled, and treated with water. The resulting solution was extracted several times with toluene, and the combined toluene layers washed thoroughly with water. The solvent was evaporated to give an oil that crystallised from ethyl acetate to give the title compound as a white solid (1.4 g) m.p. 119°-122° C.
Reaction SMILES: CO.[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][OH:15].[CH3:16]C1C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][O:15][CH3:16]
Reactant: COC(=O)c1ccc(O)c(CO)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)OC)ccc1O
Temperature: 130 °C
Yield: 445.2 %

Procedure:
To MeOH (100 mL) was added methyl 4-hydroxy-3-(hydroxymethyl)benzoate (10 g; 54.89 mmol; 1 eq.) and PTSA (1.89 g; 10.98 mmol; 0.20 eq.). The resulting suspension was heated to 130° C. for 1 hour. The reaction mixture was concentrated giving a yellow solid. It was dissolved in EtOAc (400 mL), washed with a saturated aqueous solution of NaHCO3 (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as an orange solid (9.59 g, 89%). 1H NMR (DMSO-d6, 300 MHz) δ 10.48 (br s, 1H), 7.87-7.86 (d, J=2.11 Hz, 1H), 7.76-7.28 (dd, J=8.44 Hz, 2.31 Hz, 1H), 6.91-6.88 (d, J=8.48 Hz, 1H), 4.39 (s, 2H), 3.79 (s, 3H), 3.33 (s, 3H). LC/MS (Method B): 195.2 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[OH:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[CH2:11][C:12]#[N:13]>CN(C=O)C>[Si:5]([O:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[CH2:11][C:12]#[N:13])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: N#CCC(O)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CC#N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
TBDMS-Cl (2.7 g, 18.24 mmol) was added at 0° C. to a stirred solution of aniline 11 (3 g, 15.62 mmol) and TEA (1.73 g, 17.18 mmoles) in DMF and the reaction mixture was stirred at RT for 4 h. The reaction mixture was partitioned between EtOAc and water. Organic layer was washed with water 2×, dried over sodium sulfate and concentrated under reduced pressure to give 3-(tert-butyldimethylsilyloxy)-3-(3-nitrophenyl)propanenitrile as colorless liquid. Yield (4.0 g, 83%); 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.18 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 5.33 (t, J=5.6 Hz, 1H), 3.01-2.92 (m, 2H), 0.88 (s, 9H), 0.13 (s, 3H), −0.05 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: NC1=CC(=O)CCC1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNC1=CC(=O)CCC1)C(=O)OCC
Temperature: 130 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 3-amino-cyclohex-2-enone (3.3 g, 29.7 mmol) and diethyl 2-(ethoxymethylene)malonate (6.7 g, 31.2 mmol) was stirred at 130° C. for 4 h. The reaction mixture was concentrated under reduced pressure and the resulting oil was purified by column chromatography (silica gel, ethyl acetate) to give 2-[(3-oxo-cyclohex-1 -enylamino)-methylene]-malonic acid diethyl ester (7.5 g, 90%).