Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2>>[NH:23]1[C:24]2[C:20](=[C:19]([NH:18][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:3]=3)[CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cccc2[nH]ccc12
Product: FC(F)(F)c1cc(Nc2cccc3[nH]ccc23)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-aminoindole (38 mg, 0.290 mmol) similar to Example 117 and isolated as a tan solid (6 mg, 9%). 1H NMR (CDCl3): 9.75-9.74 (m, 1H), 8.77-8.73 (m, 1H), 8.69 (dd, J=1.8, 5.1 Hz, 1H), 8.57 (s, 1H), 8.08 (s, 1H), 7.44-7.38 (m, 2H), 7.31-7.23 (m, 3H), 6.85 (s, 1H), 6.50-6.48 (m, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]12[O:13][C@:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=4)[CH:15]=3)([O:11][CH2:12]1)[C@H:9]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:8]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:7]2=[O:47])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[C:1]([O:4][CH2:5][C@:6]12[O:13][C@:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=4)[CH:15]=3)([O:11][CH2:12]1)[C@H:9]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:8]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:7]2[OH:47])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of [(1R,3R,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-oxo-6,8-dioxabicyclo[3.2.1]octan-1-yl]methyl acetate 28h (4.09 g, 6.2 mmol) in an anhydrous methanol/tetrahydrofuran mixture (v/v=3/1, 20 mL) was added sodium borohydride (278 mg, 7.5 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min, then quenched with water at 0° C. and adjusted with saturated aqueous ammonium chloride till pH becomes 7. The mixture was concentrated in vacuo to remove parts of the solvent. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (100 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 28i as pale yellow oil (4.08 g, 100%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.50 (m, 2H), 7.38 (d, 3H), 7.30 (m, 3H), 7.21 (m, 3H), 7.03 (d, 2H), 6.80 (d, 2H), 6.74 (d, 2H), 5.17 (d, 1H), 4.75 (d, 1H), 4.52 (d, 1H), 4.41 (d, 1H), 4.34 (d, 1H), 4.27 (d, 1H), 4.13 (d, 1H), 3.99 (m, 2H), 3.94 (m, 3H), 3.85 (m, 3H), 3.71 (d, 1H), 2.01 (s, 3H), 1.28 (t, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[N:9]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH3:25])[CH:13]=3)=[CH:11][C:4]=12.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH3:24][O:23][C:18]1[N:17]=[C:16]2[C:12]([C:10]3[N:9]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:5]4=[N:6][CH:7]=[CH:8][C:3]([CH2:2][NH:36][CH:37]5[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]5)=[C:4]4[CH:11]=3)=[CH:13][N:14]([CH3:25])[C:15]2=[CH:20][C:19]=1[O:21][CH3:22]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCN(C(=O)OC(C)(C)C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 40.6 %

Procedure:
The product is prepared by following the procedure described in example 52c, starting with 0.3 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine and 0.253 g of 4-amino-1-Boc-piperidine instead of the N-Boc-ethylenediamine used in example 52c. 0.161 g of tert-butyl 4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}piperidine-1-carboxylate is obtained with the following characteristics:
Reaction SMILES: [CH3:1][CH:2]([S-:4])[CH3:3].[Na+].[F:6][C:7]1[C:13](F)=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:8]=1[NH2:9]>CN(C=O)C.CCOC(C)=O>[F:6][C:7]1[C:13]([S:4][CH:2]([CH3:3])[CH3:1])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:8]=1[NH2:9]
Reactant: CC(C)[S-]
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Sc1ccc([N+](=O)[O-])c(N)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
Sodium 2-propanethiolate (5.66 g) was added to a solution of 2,3-difluoro-6-nitroaniline (10.04 g) in DMF (200 ml). The mixture was stirred at ambient temperature for 16 hours and then diluted with EtOAc (300 ml) and washed with brine (500 ml). The washing was extracted with EtOAc (300 ml). The organic phases were combined, washed with brine (500 ml), dried and volatile material was removed by evaporation to give the title compound (14.1 g) as a solid. NMR: 1.30 (d, 6H), 3.70 (septet, 1H), 6.70 (dd, 1H), 7.26 (s, 2H), 7.80 (dd, 1H); m/z 229.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([S:39]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)(=[O:41])=[O:40])[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(S(=O)(=O)c3ccccc3)CC2)cc1
Reaction time: 20 h
Yield: 71.8 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (41 mg, 0.12 mmol) and pyridine (0.05 mL) in methylene chloride (3 mL) was treated with benzenesulfonyl chloride (0.014 mL, 0.11 mmol). After 20 h, the mixture was treated with silica gel (3 cm3) and concentrated in vacuo. The residue was chromatographed (silica gel, 50% hexanes/50% ethyl acetate to 30% hexanes/70% ethyl acetate). Recrystallization of the residue from hexanes/ethyl acetate yielded 39 mg (68%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([NH:13][C:14]([NH2:16])=[S:15])[NH:11][N:12]=1.BrBr>CC(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[S:15][C:14]([NH2:16])=[N:13][C:10]=2[NH:11][N:12]=1
Reactant: NC(=S)Nc1cc(-c2ccccc2Br)n[nH]1
Agent: BrBr
Solvent: CC(=O)O
Product: Nc1nc2[nH]nc(-c3ccccc3Br)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
To a solution of [5-(2-bromo-phenyl)-2H-pyrazol-3-yl]-thiourea (1.6 g, 5.38 mmol) in glacial AcOH (200 mL) was added a 1.5 M solution of bromine in AcOH (3.59 mL, 5.38 mmol) dropwise under vigorous stirring. The resulting heterogeneous mixture was stirred at room temperature for 2 hours then at 80° C. for 1 hour. The reaction was cooled to room temperature and concentrated to dryness. Water was added followed by 1 N aqueous NaOH to neutralize to pH 7. The resulting precipitate was filtered, washed with water and dried in vacuo. The solid was then refluxed in MeOH for 2 hours, filtered and washed with MeOH to give 588 mg of pure 3-(2-bromo-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine as an off-white solid. The filtrate was further purified on silica gel with 0-10% MeOH in CH2Cl2 as eluent to provide another 460 mg of 3-(2-bromo-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine for a total of 1.408 g (88% yield). 1H-NMR (d6-DMSO) δ: 13.1 and 12.6 (2 broad s, 1H, NH+tautomer), 7.73 (d, 1H), 7.61 (broad m, 1H), 7.48 (m, 3H), 7.34 (t, 1H); HPLC/MS m/z: 294.9, 296.9 [MH]+.
Reaction SMILES: [F:1][C:2]1([F:23])[CH2:7][CH2:6][NH:5][C@@H:4]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH2:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>CC#N>[F:23][C:2]1([F:1])[CH2:7][CH2:6][N:5]([CH2:36][C:35]2[CH:34]=[CH:33][C:32]([C:31]([F:30])([F:40])[F:41])=[CH:39][CH:38]=2)[C@@H:4]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[CH2:3]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CCN2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CCN2Cc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.6 %

Procedure:
To a solution of methyl 4-((S)-1-((R)-4,4-difluoropiperidine-2-carboxamido)ethyl)benzoate (D97) (66 mg, 0.20 mmol) in dry MeCN (4 ml), Cs2CO3 (198 mg, 0.60 mmol) and the 4-(Trifluoromethyl)benzylbromide (0.037 ml, 0.24 mmol) were added in sequence and the resulting mixture was stirred at RT for 18 hrs. The solid was filtered off, the acetonitrile was evaporated and the crude was purified by flash chromatography SNAP HP_SiO2 (10 g) eluting with a gradient DCM/EtOAc from 100/0 to 90/10. Collected fractions after solvent evaporation were purified onto reverse phase column GOLD-C18 (15 g) eluting with a gradient of H2O/MeCN (containing 0.1% Acetic acid) from 10/90 to 80/20. Collected fractions after solvent evaporation afforded the title compound (D135) (20 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[C:8](=O)([O:11]C)[O:9][CH3:10].C[O-].[Na+]>CS(C)=O>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH2:4][C:8]([O:9][CH3:10])=[O:11]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)CC(=O)C(C)(C)C
Temperature: 45 °C
Yield: 69 %

Procedure:
3,3-Dimethyl-2-butanone (10 g; 0.10 mol) was dissolved in DMSO (50 mL) and dimethyl carbonate (27 g; 0.30 mol; 3.0 equiv) was added. Sodium methoxide (10.8 g; 0.20 mol; 2.0 equiv) was added, resulting in a temperature rise to 30° C. The reaction mixture was heated to 40-50° C. for 4 h and then cooled to room temperature overnight. The reaction was quenched into a mixture of water (25 mL) and concentrated HCl (25 mL). Toluene (25 mL) was added and an additional 25 mL of water was added to dissolve salts. The layers were allowed to settle and the lower aqueous layer was removed and discarded. The organic layer was washed with water (25 mL), dried (Na2SO4), and filtered to afford 60 g of a toluene solution of 11. Analysis of this solution indicated 18.2 wt % of 11 to indicate a 69% yield.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH2:15]O>C(Cl)Cl>[Br:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=1[CH2:15][Br:2]
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)c(Br)cc1F
Solvent: ClCCl
Product: COc1cc(CBr)c(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
Phosphorus tribromide (11.56 mL, 122.5 mmol) was added to a solution of (2-bromo-4-fluoro-5-methoxy-phenyl)-methanol (Preparation 33, 14.4 g, 61.26 mmol) in DCM (235 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred at that temperature for 18 hours. The reaction mixture was cooled to 0° C. and quenched by slow addition of saturated sodium hydrogen carbonate aqueous solution until effervescence had ceased. The layers were separated and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (17.48 g) in a 96% yield.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:46]=[CH:45][C:15]([O:16][CH2:17][C:18]#[C:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[S:23][CH2:22][C:21]2([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)[CH3:34])=[CH:14][CH:13]=1)(C(C)(C)C)(C)C>C(O)C.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][CH2:10][O:11][C:12]1[CH:46]=[CH:45][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH2:31][O:32][CH3:33])=[CH:27][CH:28]=3)[S:23][CH2:22][C:21]2([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][O:43][CH3:44])=[CH:37][CH:36]=2)[CH3:34])=[CH:14][CH:13]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2C#CCOc2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2CCCOc2ccc(OCCO)cc2)cc1
Reaction time: 17 h
Yield: 70.8 %

Procedure:
4-{3-[4-(2-t-Butyldimethylsilyloxyethoxy)phenoxy]-1-propynyl}-7-methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methylthiochroman (6) prepared in Step 4 (408 mg) was dissolved in a solvent mixture of ethanol (6 ml) and tetrahydrofuran (2 ml), 20% palladium hydroxide/carbon (130 mg) washed with ethanol was added, and the resulting mixture was stirred under hydrogen for 17 hours. The reaction solution was filtered through cellite, concentrated, and subjected to silica gel column chromatography to give 4-(3-[4-(2-hydroxyethoxy)phenoxy]propyl}-7-methoxymethoxy-3-[4-(methoxymethoxy)phenyl]-3-methylthiochroman (7) (241 mg, yield 71%) as a yellow oily substance.
Reaction SMILES: [OH:1][C:2]([C:17]([F:20])([F:19])[F:18])([CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])([CH3:8])[CH3:7])[CH:3]=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH2:31]>C1(C)C=CC=CC=1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[F:20][C:17]([F:18])([F:19])[C:2]([CH:3]=[N:31][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=1)([OH:1])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])([CH3:7])[CH3:8]
Reactant: Nc1ccc2ccccc2c1
Reactant: COc1ccccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccccc1C(C)(C)CC(O)(C=Nc1ccc2ccccc2c1)C(F)(F)F
Yield: 89.8 %

Procedure:
150 mg (0.517 mmol) of 2-hydroxy-4-(2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-pentanal is converted into imine with 74 mg (0.517 mmol) of 2-naphthylamine in toluene with the aid of titanium tetraisopropylate. After working-up and chromatography, 192.8 mg (89.8%) of the desired imine is isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20](F)=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C:20]2[CH:19]=[CH:18][C:17]([Br:16])=[CH:22][C:21]=2[N+:23]([O-:25])=[O:24])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])C[C@H]1CO
Temperature: 25 °C
Yield: 72.1 %

Procedure:
Heat a mixture of (2S,4S)-4-amino-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.14 mol, 31 g), 5-bromo-2-fluoronitrobenzene (0.29 mol, 64.0 g) and triethylamine (0.58 mol, 59 g) in ethyl acetate (320 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (42 g, crude) as a thick, dark, orange oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][C:13]([CH3:41])([CH3:40])[C:14](=[O:39])[C:15](=[N:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[CH:30][CH:29]=1)[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:17].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH2:5]([O:4][C:2]([N:18]([C:16](=[O:17])[C:15](=[N:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[CH:32][CH:33]=1)[C:14](=[O:39])[C:13]([CH3:40])([CH3:41])[CH3:12])[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[Cl:26])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)c1ccc(N=C(C(=O)Nc2ccc(Cl)cc2Cl)C(=O)C(C)(C)C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ccc(N=C(C(=O)N(C(=O)OCc2ccccc2)c2ccc(Cl)cc2Cl)C(=O)C(C)(C)C)cc1
Yield: 39 %

Procedure:
Benzyl chloroformate (0.16 mL, 1.12 mmol) was added to a solution of N-[4,4-dimethyl-2-[4-diethylaminophenyl]imino-3-oxopentanoyl]-2,4-dichloroaniline, prepared as in Example 5 above (478 mg, 1.07 mmol), triethylamine (0.15 mL, 1.08 mmol) and DMAP (135 mg, 1.1 mmol) in dry dichloromethane (5 mL) and the resultant solution was stirred for 3 hours under nitrogen. Additional benzyl chloroformate (0.2 mL, 1.4 mmol) was then added, followed one hour later by more benzyl chloroformate (0.2 mL, 1.4 mmol) and additional triethylamine (0.15 mL, 1.08 mmol). The resultant solution was stirred under nitrogen for 7 days, after which the solvent was removed. The crude product was purified by flash chromatography on silica gel with 3% ethyl acetate/hexanes as eluant to give slightly impure Dye C. Further purification was effected by a second chromatographic separation on silica gel in the same manner as above. Dye C (240 mg, 39% yield) was obtained as an orange foam which had a principal absorption in the visible region of the electromagnetic spectrum at 438 nm, ε=15,900. The structure of this compound was confirmed by mass spectroscopy and by 1H and 13C NMR spectroscopy.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18]>C(#N)C>[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])=[CH:21][CH:20]=1)#[N:18]
Reactant: NC(=O)c1cccc(O)c1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(COc2cccc(C(N)=O)c2)cc1

Procedure:
3-hydroxybenzamide (0.137 g; 1 mmol) was dissolved in anhydrous acetonitrile (20 ml) under a nitrogen atmosphere. To this was added potassium carbonate (0.138 g; 1 mmol) and 4-cyanobenzyl bromide (0.138 g; 1 mmol). This was left to reflux for 5 hours.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=2)[C:14]([CH3:26])([CH3:25])[C:13](=[O:27])[C:12]=1[C:28](OCC)=[O:29].Cl.[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1>[F:22][C:21]([F:24])([F:23])[C:17]1[CH:16]=[C:15]2[C:20]([C:11]([OH:10])=[C:12]([C:28]([NH:41][CH2:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])=[O:29])[C:13](=[O:27])[C:14]2([CH3:26])[CH3:25])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C(F)(F)F)cc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 15 h
Yield: 21.4 %

Procedure:
DIPEA (1870 μL, 10738 μmol, 2.5 eq) was added to a mixture of ethyl 4-hydroxy-1,1-dimethyl-2-oxo-7-(trifluoromethyl)-naphthalene-3-carboxylate (1.41 g, 4295 μmol) and glycine tert-butyl ester hydrochloride (864 mg, 5154 μmol) in dioxane (50 mL). The reaction mixture was stirred at 75° C. for 15 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The crude solid was purified by silica flash chromatography (0-40% DCM/hexane) to give the desired ester as a white solid (380 mg). MS (m/e)=358.1 (M+H-tBu)+.
Reaction SMILES: [Cl-].[Li+].[Cl-].[Al+3].[Cl-].[Cl-].[C:7]1([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20](Cl)(=[O:22])[CH3:21]>ClC(Cl)C>[CH3:21][C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1)=[O:22]
Reactant: CC(=O)Cl
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(Cl)Cl
Product: CC(=O)c1ccc(Oc2ccccc2)cc1
Yield: 90.3 %

Procedure:
To an agitated mixture of lithium chloride (3.18 g., 0.075 mole) and aluminium chloride (20 g., 0.15 mol) in dichloroethane (20 ml) was slowly added diphenyl ether (8.51 g., 0.05 mole) and acetyl chloride (3.93 g., 0.05 mol) in dichloroethane (7 ml) following the procedure of example 12. The 4-phenoxyacetophenone obtained (9.57 g., 90.3% yield, m.p. 43.5°-51° C. had 1H NMR purity of 90%.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][N:9]1[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=[CH:10]1.CN(C)CCN(C)C.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[O:30])=[CH:27][CH:26]=1.N>O1CCCC1>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)([C:10]2[N:9]([CH2:8][O:7][CH3:6])[C:13]([CH3:14])=[C:12]([CH3:15])[N:11]=2)[OH:30])=[CH:27][CH:26]=1
Reactant: COCn1cnc(C)c1C
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1c(C(O)(c2ccc(Cl)cc2)c2ccc(Cl)cc2)nc(C)c1C
Reaction time: 8 h

Procedure:
At a temperature of -60° C. and under a nitrogen atmosphere, 114 ml. (0.24 mol) of butyllithium solution (20% in hexane) were added drop-wise with stirring to a solution of 28 g. (0.20 mol) of 1-(methoxymethyl)-4,5-dimethylimidazole and 28 g. (0.24 mol) of N,N,N',N'-tetramethylethylenediamine in 200 ml. of anhydrous tetrahydrofuran. After 2 hours stirring, 50 g. (0.20 mol) of 4,4'-dichlorobenzophenone in 250 ml of anhydrous tetrahydrofuran were added drop-wise at -60° C. After being kept standing overnight, the reaction mixture was extracted with water and the organic phase was concentrated by distilling off the solvents. The residue was treated with 2 N hydrochloric acid and diethyl ether, which resulted in the formation of an organic and aqueous layer with an oily intermediate layer. The aqueous and oily layers were made alkaline with ammonia and extracted with diethyl ether. The extract was dried over sodium sulphate and the solvent was distilled off. The oily residue was thrice recrystallised from isopropyl alcohol. α,α-Bis(p-chlorophenyl)-1-(methoxymethyl)-4,5-dimethylimidazole-2-methanol was obtained. Melting point 151° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3](O)([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.C(N(S(F)(F)[F:40])CC)C.O>ClCCl>[F:1][C:2]([F:33])([F:32])[C:3]([F:40])([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: OC(CCCc1cccc(Oc2ccccc2)c1)(c1ccc(OC(F)(F)F)cc1)C(F)(F)F
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(C(F)(CCCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 1,1,1-trifluoro-2-hydroxy-2-(4-trifluoromethoxyphenyl)-5-(3-phenoxyphenyl)pentane (0.18 g) in dichloromethane (6 cm3) was cooled to -78° C. and diethylaminosulphur trifluoride (0.1 g) was added. The mixture was allowed to warm to room temperature, stirred for a further 20 minutes and poured into water. The products were extracted into dichloromethane. The combined organic extracts were dried and the solvent evaporated under reduced pressure to leave an oil. The oil was purified by chromatography to give 1,1,1,2-tetrafluoro-2-(4-trifluoromethoxyphenyl)-5-(3-phenoxyphenyl)pentane.