Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH2:17][O:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:16][CH2:17][O:18][CH2:19][CH3:20])[CH:3]=1
Reactant: CCOCCBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1cccc(Br)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
In DMF (120 ml) was dissolved 3-bromophenol (12 g). To the mixture was added potassium carbonate (12.5 g) and then was added 2-bromoethylethyl ether (9.1 ml), and the mixture was stirred at 70° C. for 16 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=12/1) to give 1-bromo-3-(2-ethoxyethoxy)benzene (12.1 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C-:20]#[C-:21].[Na+].[Na+]>C#C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=2)([OH:7])[C:20]#[CH:21])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCCO)cc1
Reactant: [C-]#[C-]
Agent: C#C
Agent: [Na+]
Product: C#CC(O)(c1ccc(F)cc1)c1ccc(OCCO)cc1
Temperature: 25 °C

Procedure:
A photochromic group initiator (represented by structure 1.3 in Table 1 above) was prepared as follows. Step 1: 4-fluoro-4′-(2-hydroxyethoxy)-benzophenone from Part A, Step 1 of Example 7 (below) (7-974) (43.3 grams) and acetylene saturated N,N-dimethylformamide (130 mL) were combined in a reaction flask. Reaction flask was cooled in an ice bath. Sodium acetylide solution (9% by weight in toluene, 221 grams) was added to the cooled reaction mixture dropwise over 30 minutes. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was poured into ice water (450 mL) and diethyl ether (300 mL) was added to it. The layers were phase separated and the aqueous layer was extracted one time with diethyl ether (300 mL) and twice with ethyl acetate (300 mL each). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation. The resulting residue was purified by column chromatography on silica gel (600 grams) eluting with a mixture of 45% ethyl acetate in hexanes. The fractions containing pure desired product were combined and concentrated by rotary evaporation to yield 30.1 grams of 1-(4-fluorophenyl)-1-(4′-(2-hydroxyethoxy)phenyl)-2-propyn-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)nc(Cl)c1
Yield: 76.5 %

Procedure:
2,6-Dichloro-4-pyridinamine (10 g, 61.3 mmol) (Aldrich) and triethylamine (10.69 ml, 77 mmol) were combined in dichloromethane (DCM) (75 ml) and cooled in an ice-bath. 2,2-dimethylpropanoyl chloride (8.30 ml, 67.5 mmol) (Aldrich) in DCM (15 ml) was added drop wise and the mixture stirred whilst allowing to warm up overnight producing a clear dark orange solution. LCMS showed good conversion to product. The solution was washed with water and sat. NaHCO3 (100 ml each), dried with Na2SO4, filtered and concentrated to yield a dark orange solid. The crude product was taken up in the minimum of DCM and applied to a 320 g Companion XL silica column and eluted with 0% EtOAc in cyclohexane for 2 CVs then 0-15% EtOAc in cyclohexane over 12 CVs then held at 15% for 2 CV. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (11.59 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1c(O)ccc(Br)c1Oc1ccccc1
Reactant: O=C(CO)c1ccccc1
Product: O=C(COc1ccc(Br)c(Oc2ccccc2)c1[N+](=O)[O-])c1ccccc1

Procedure:
This compound was synthesized according to the procedure of Example 76, Step 5, using 4-bromo-2-nitro-3-phenoxyphenol and 2-hydroxy-1-phenylethanone as the starting materials. LCMS calculated for C20H15BrNO5 (M+H)+: m/z=428.0, 430.0. found: 427.9, 429.9.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][O:13][C:14](=[O:37])[C@@H:15]([NH2:36])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:13][C:14](=[O:37])[C@@H:15]([NH:36][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1])[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1cc(Cl)ccc1N

Procedure:
(S)-2-(2-amino-5-chloro-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester was prepared following Procedure A using 2-amino-5-chloro-benzoic acid (1.23 g, 7 mmol), (S)-2-amino-3-(4′-phenoxy-biphenyl-4-yl)propionic acid methyl ester (2.43 g, 7 mmol), HBTU (3.19 g, 8.4 mmol) and DIEA (2.46 mL, 14 mmol) in DMF (35 mL). Purification by flash chromatography (ethyl acetate/hexanes 1:3, 1:2) gave the title compound as yellow solid (3.25 g, 6.49 mmol,).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN(C)C=O>O>[CH2:41]([O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (165 mg), benzyl bromide (205 mg), and N,N-dimethylformamide (10 ml) was stirred at 80° C. for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-benzyloxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (385 mg, yield: 64%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH:1]1([N:4]2[CH2:8][CH2:7][NH:6][S:5]2(=[O:10])=[O:9])[CH2:3][CH2:2]1.F[C:12]1[C:21]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:26])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>CN(C=O)C>[CH:1]1([N:4]2[S:5](=[O:10])(=[O:9])[N:6]([C:12]3[C:21]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:26])[CH:13]=3)[CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1C
Reactant: O=S1(=O)NCCN1C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N2CCN(C3CC3)S2(=O)=O)cc1C
Yield: 47.3 %

Procedure:
203 mg of 2-cyclopropyl-[1,2,5]thiadiazolidine 1,1-dioxide, 308 mg of methyl 4-fluoro-5-methanesulfonyl-2-methylbenzoate and 2.44 g of Cs2CO3 were stirred in 25 ml of anhydrous DMF at 80° C. for 5 hours. Standing at RT for 2 days was followed by dilution with 200 ml of EA and washing 3 times with 20 ml of water each time. After drying over Na2SO4, the solvent was removed in vacuo. Chromatography on silica gel with DIP afforded 230 mg of an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][N:6]=1)=[O:4].[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:31]=[C:30]([OH:32])[C:24]3[CH2:25][C:26]([CH3:29])([CH3:28])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:32][C:30]2[C:24]3[CH2:25][C:26]([CH3:28])([CH3:29])[O:27][C:23]=3[CH:22]=[C:21]([C:19](=[O:20])[NH:18][C:15]3[CH:16]=[CH:17][N:13]([CH3:12])[N:14]=3)[CH:31]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: COC(=O)c1ccc(F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cn1
Temperature: 160 °C
Yield: 56.4 %

Procedure:
A mixture of 5-fluoro-pyridine-2-carboxylic acid methyl ester (179a) (342 mg, 2.20 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (633 mg, 2.20 mmol), and Cs2CO3 (1.44 g, 4.40 mmol) in DMF was heated to 160° C. in a microwave for 30 min, cooled to room temperature, quenched with H2O, and extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried over Na2SO4 and concentrated. The residue was purified by Biotage column chromatography with 75-90% EtOAc in hexanes to give a white solid (524 mg, 56% yield). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=3.03 Hz, 2 H) 8.13 (d, J=8.59 Hz, 1 H) 7.22-7.36 (m, 2 H) 7.06 (d, J=5.05 Hz, 2 H) 6.77 (d, J=2.27 Hz, 1 H) 4.01 (s, 3 H) 3.78 (s, 3 H) 2.89 (s, 2 H) 1.49 (s, 6 H); LCMS for C22H22N4O6 m/z 423.20 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH3:36][O:37][C:38](=[O:41])[CH2:39][NH2:40]>>[CH3:36][O:37][C:38](=[O:41])[CH2:39][NH:40][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:34])[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)=[CH:10][C:2]=1[Cl:1]
Reactant: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Reactant: COC(=O)CN
Agent: Cl
Product: COC(=O)CNC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Yield: 39 %

Procedure:
The title compound was prepared in analogy to Example 29, from 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid and glycine methyl ester hydrochloride (commercially available, CAS RN 5680-79-5). The compound was purified on a preparative HPLC system (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5), to give 44 mg (39%) of the title compound as a light yellow solid. MS (ESI): m/z=569.136 [M+H]+.
Reaction SMILES: [CH3:1][Mg]I.[C:4]1([C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([C:13]4=[O:20])[CH2:11]2)[CH2:17]3)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCOCC.C1COCC1>[CH3:1][C:13]1([OH:20])[CH:12]2[CH2:18][CH:16]3[CH2:17][C:10]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)([CH2:19][CH:14]1[CH2:15]3)[CH2:11]2
Reactant: O=C1C2CC3CC1CC(c1ccccc1)(C3)C2
Reactant: C[Mg]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)C2CC3CC1CC(c1ccccc1)(C3)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Freshly prepared methylmagnesium iodide in ether (1 M, 85 mL), was added through a canola to 5-phenyladamantan-2-one (9.6 g, 42.5 mmol) obtained in step II, in THF (85 mL) at 0° C. After stirring at 0° C. for 0.5 h, the reaction mixture was quenched by adding sat. aq. NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with diisopropylether. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 2-methyl-5-phenyl-adamantan-2-ol (9.9 g) as an off-white solid in 97% yield. M.R: 98-100.4° C. m/z (M+23) 265; 1H NMR (CDCl3) 300 MHz δ 7.42-7.28 (m, 4H), 7.24-7.18 (m, 1H), 2.47-2.26 (m, 2H), 2.14-2.09 (m, 3H), 1.96-1.70 (m, 6H), 1.61-1.57 (m, 2H), 1.42 (s, 3H). 13C NMR (CDCl3) 75 MHz δ 150.0, 128.1 (2C), 125.7, 124.8 (2C), 73.3, 44.0 (2C), 40.5 (2C), 39.6 (2C), 35.9, 32.0, 27.6.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12.C=O.[C:29]([BH3-])#N.[Na+].C(O)(=O)C>CO>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH:18]4[CH2:19][CH2:20][N:21]([CH3:29])[CH2:22][CH2:23]4)[NH:13][C:12]4=[N:24][NH:25][CH:26]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: [BH3-]C#N
Reactant: N#CC1=C(C2CCNCC2)Nc2n[nH]cc2C1c1cccc2nonc12
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(C2=C(C#N)C(c3cccc4nonc34)c3c[nH]nc3N2)CC1
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a solution of 4-(2,1,3-Benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(piperidin-4-yl)-2H-pyrazolo[3,4-b]pyridine (0.7 g) in MeOH (200 mL) was added 37% formaldehyde (0.18 g), sodium cyanoborohydride (0.19 g) and acetic acid (0.36 g) at room temperature and the mixture was stirred overnight. After alkalification with sodium bicarbonate, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was washed with acetonitrile, and the precipitated crystals were collected by filtration to give the title compound (0.32 g) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(Cl)nc(NCc3cccc([N+](=O)[O-])c3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=1)[CH3:3].[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].CN(CCOC1C=CC(C(=O)C(F)(F)F)=CC=1)C>>[CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[CH:10]=[CH:11][CH:12]=1)[CH3:3]
Reactant: CN(C)CCOc1cccc(Br)c1
Reactant: CCOC(=O)C(F)(F)F
Agent: CN(C)CCOc1ccc(C(=O)C(F)(F)F)cc1
Product: CN(C)CCOc1cccc(C(=O)C(F)(F)F)c1
Yield: 43.8 %

Procedure:
N,N-Dimethyl-2-(3-bromophenoxy)ethylamine (2.87 g, 11.7 mmol) and ethyl trifluoroacetate (2.5 g, 17.6 mmol) were reacted by the general procedure as described in the preparation of [4-[2-(N,N-dimethylamino)ethoxy]phenyl]-2,2,2-trifluoroethanone. The residue was distilled under reduced pressure to afford the title compound (1.34 g, 44%) as a pale yellow liquid. Analytically pure sample was obtained by a second distillation under reduced pressure. Analysis for C12H14F3NO2.0.8H2O calcd. C 52.29%, H 5.70%, N 5.08%; Found: C 52.61%, H 5.53%, N 4.96%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19](=[O:20])[N:18]=[N:17][C:15]2=[O:16])=[CH:10][CH:9]=1.Cl>CC#N>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([N:17]2[C:15](=[O:16])[N:14]([C:11]3[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=3)[C:19](=[O:20])[NH:18]2)=[CH:3][CH:2]=1
Reactant: O=C1N=NC(=O)N1c1ccccc1
Reactant: Oc1ccccc1
Agent: Cl
Solvent: CC#N
Product: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
To a solution of phenol (11.3 mg, 0.120 mmol) in 100 mM pH 7.0 NaH2PO4/Na2HPO4 buffer (3.0 mL)-CH3CN (3.0 mL) was slowly dropped the 0.3 M solution of PTAD 17a (0.442 mL, 0.132 mmol) in CH3CN at room temperature. The resulting solution was stirred at room temperature for 30 minutes. The reaction mixture was acidified with 1M HCl and extracted with ethyl acetate twice. The organic layer was dried over Na2SO4 and concentrated in vacuo. The obtained crude material was purified by flash column chromatography (ethyl acetate) to give para-adduct 27 (4.8 mg, 15%) and para-ortho-di-adduct 27′ (10.1 mg, 19%) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 11.35 (br, 1H), 9.60 (s, 1H), 7.53-7.35 (m, 7H), 6.83 (m, 2H), 13C NMR (75 MHz, DMSO-d6): δ 156.11, 152.73, 150.41, 132.22, 129.22, 128.78, 128.66, 127.19, 122.99, 116.22. HRMS: calcd for C14H11N3O3 (MH+) 270.0873. found 270.0873.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(#N)C.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([C:4]1[NH:5][CH:6]=[C:2]([CH3:1])[N:3]=1)=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1c[nH]cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(C(=O)c2ccccc2F)n1
Temperature: 140 °C
Yield: 67.4 %

Procedure:
To a 350 mL pressure vessel was added 4-methylimidazole (12 g, 146 mmol, 1 eq.) and a stirbar. Acetonitrile (35 mL, 670 mmol, 4.6 eq.) was added. Triethylamine (59 mL, 424 mmol, 2.9 eq.) was added and the mixture was stirred until it became homogeneous. 2-fluorobenzoyl chloride (67.2 g, 424 mmol, 2.9 eq.) was added. Upon addition of the acyl chloride, the mixture became warm and viscous. The vessel was sealed and heated at 140° C. for 2 h with stirring. During heating, the mixture turned black in color. The vessel was removed from the heat, allowed to cool, and its contents were diluted with acetone (50 mL). The mixture was stirred and transferred to a 2 L round-bottomed flask containing 7% aqueous HCl (1000 mL). Charcoal was added to the flask and the mixture was heated at reflux for 1.5 h. The mixture was allowed to cool almost to room temperature and then was filtered through a Celite pad followed by a rinse with 1N HCl (˜100 mL). The filtrate was placed in an ice bath and was made alkaline with aqueous NH4OH (35%) whereupon a solid precipitate formed. The solid was filtered and washed with copious amounts of dilute NH4OH to remove triethylamine hydrochloride salts. The solid was collected and placed under high vacuum, yielding the desired ketone 1 as a brown solid (20.1 g, 67%). LC/MSD (HP Series 1100 MSD) Expected MW: 204.07, Observed M+H: 205.0, Retention time: 1.13. 1H NMR, CD3OD, Varian 400 MHz δ 7.70 (t, 1H), 7.59 (m, 1H), 7.30 (t, 1H), 7.25-6.96 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12]CC2C=CC(OC)=CC=2)[C@H:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:9]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.O>[N:1]([C@@H:4]1[C@@H:11]([OH:12])[C@H:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@@H:9]([CH2:30][O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+:2]=[N-:3]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](COCc3ccc(Cl)cc3)[C@H]2OCc2ccccc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CS[C@@H]1O[C@H](COCc2ccc(Cl)cc2)[C@@H](OCc2ccccc2)[C@H](O)[C@H]1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of methyl 2-azido-4-O-benzyl-6-O-(4-chlorobenzyl)-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D glucopyranoside (34) (580 mg, 1.01 mmol) and DDQ (270 mg, 1.2 mmol) in CH2Cl2—H2O 9:1 (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated NaHCO3 solution (3×15 ml), dried over MgSO4 and evaporated. The residue was purified by chromatography using CHCl3-Hexane-MeOH 30:20:0.5 as the mobile phase to give methyl 2-azido-4-O-benzyl-6-O-(4-chlorobenzyl)-2-deoxy-1-thio-β-D glucopyranoside (35) (300 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]C3C=CC=CC=3F)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([CH:44](Br)[CH3:45])=[CH:40][CH:39]=1>>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([CH:44]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH3:45])=[CH:40][CH:39]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccc3F)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Product: COC(=O)c1ccc(C(C)OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 34, from 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 34, intermediate) and 4-(1-bromo-ethyl)-benzoic acid methyl ester (CAS RN: 16281-97-3). The residue was purified by preparative HPLC chromatography (phenomenex gemini column) eluting with a gradient of water:acetonitrile (100:0 to 5:95). Light yellow foam (22%). MS (Turbo Spray): m/z=553.3 [M+H].
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:9])[CH2:3]1.C(Cl)Cl.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C1C=CN=CC=1)C.O>[F:1][C@H:2]1[C@H:6]([O:7][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[O:9])[CH2:3]1
Reactant: O=C(OCc1ccc2ccccc2c1)N1C[C@@H](O)[C@H](F)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OCc3ccc4ccccc4c3)C[C@H]2F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 44.1 %

Procedure:
A flask was charged with (trans)-naphthalen-2-ylmethyl 3-fluoro-4-hydroxypyrrolidine-1-carboxylate (237 mg, 0.819 mmol), TEA (0.343 ml, 2.458mmol) and DMAP (10.0 mg, 0.082 mmol) in DCM (4.3 ml, 0.86 mmol). The reaction mixture was cooled to 0° C., and 4-methylbenzene-1-sulfonyl chloride (234 mg, 1.23 mmol) was added. The reaction was warmed to ambient temperature and stirred for 3 hours. The reaction was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography, eluting with 0-5% MeOH in DCM to give the product as an oil (160 mg, 44% yield).