Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([C@@H:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4C3CCCCO3)[CH3:16])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[C:3]=1[C:35](O)=[O:36].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[F:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([C@@H:15]([NH:17][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:16])[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:4]=2[C:3]=1[C:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:36]
Reactant: C1COCCN1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid (200 mg, 0.39 mmol) and morpholine (42 μL, 0.48 mmol) in DCM (10 mL) was added HATU (197 mg, 0.52 mmol) and the reaction stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc) LCMS (Method C): RT=2.60 min, [M+H]+=571. The product was dissolved HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue loaded onto an SCX 2 cartridge, washed with methanol then eluted with ammonia in methanol (2M). The eluent was concentrated in vacuo and the residue subjected to HPLC purification (C18, 10-90% MeCN in H2O, 0.1% formic acid, 20 min gradient) to give 273 as a white solid (107 mg, 55%) 1H NMR (DMSO-d6+TFA-D, 400 MHz, 80° C.): δ 8.52 (1H, br s), 8.46 (1H, d, J=6.25 Hz), 7.83-7.75 (1H, m), 7.57-7.43 (5H, m), 7.32-7.15 (2H, m), 5.66 (1H, br s), 3.50-3.24 (5H, m), 3.15-3.05 (1H, m), 3.04-2.95 (1H, m), 2.70-2.58 (1H, m), 1.74-1.65 (3H, m). LCMS (Method K): RT=2.63 min, [M+H]+=487, RT=2.66 min, [M+H]+=487
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([OH:17])=[O:16])[CH2:5][O:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:22][CH2:23]O>>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([O:17][CH2:22][CH3:23])=[O:16])[CH2:5][O:4][CH2:3]1
Reactant: CCO
Reactant: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The title compound was prepared according to the procedure described by H. H. Otto, Helvetica Chimica Acta, 2004, 87, 90 using (3R)-5-oxo-4-(phenylmethyl) -3-morpholinecarboxylic acid (D44, 3.13 g, 13.33 mmol) in EtOH (30 mL), cooling in an ice bath before adding Thionyl Chloride (1.46 mL) dropwise, and then stirring at R.T. for 6 hours. Added more thionyl chloride (1 mL) and stirring at R.T. overnight. Added more thionyl chloride (1 mL) and stirred for 4 hours, added further thionyl chloride (0.5 mL) and stirred overnight again. Added thionyl chloride (0.2 mL) and left stirring for 5 hours. Solvent evaporated to afford the title compound as an orange oil in quantative yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:25])(=O)[CH3:2].C(O)COCCO.O.NN.[OH-].[K+]>O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)=[CH:6][C:5]=1[F:25])[CH3:2]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C(C)=O)c(F)c3)CC2)CC1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(CC)c(F)c3)CC2)CC1
Temperature: 25 °C

Procedure:
Successively, anhydrous aluminum chloride (30.8 g, 0.23 mol) was dissolved in nitrobenzene (150 ml), followed by adding to the solution, the total quantity of the above compound 3-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (38.7 g) at room temperature, dissolving the mixture together with stirring, adding acetyl chloride (27.3 g, 0.348 mol) over 15 minutes, reacting the mixture on heating at a reaction temperature of 35°-40° C. for 2 hours, adding the reaction solution after completion of the reaction to a mixture of 6N hydrochloric acid (50 ml) with ice water (500 g) to subject them to decomposition reaction, adding toluene (500 ml) to extract the resulting oily layer, washing the extract solution with an aqueous solution of sodium hydrogen carbonate, further washing it with water until the washing water became neutral, distilling off toluene and nitrobenzene and recrystallizing the residue from ethyl acetate to obtain 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (a compound of the formula (VII) wherein R1 =C3H7 and R"=CH3) (23.8 g). This product exhibited liquid crystal phases and had a crystal-nematic phase transition point (C-N point) of 90.5° C. and a nematic phase-isotropic liquid phase transition point (N-I point) of 204.7° C. (iii) Successively, the compound 2-acetyl-5-[trans-4-(trans-4-propylcyclohexyl) cyclohexyl]fluorobenzene (23.8 g) was added to diethylene glycol (100 ml), followed by agitating the mixture, adding hydrazine hydrate (17.9 g) and potassium hydroxide (20.1 g), gradually raising the temperature with stirring to react the mixture at 180° C. for 3 hours, allowing the resulting material to cool down to room temperature, adding water (500 ml), extracting the deposited crystals with toluene (100 ml), washing the extract solution with water, drying it over anhydrous sodium sulfate, distilling off toluene and recrystallizing from ethyl acetate to obtain 2-ethyl-5-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]fluorobenzene (15.2 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[C:22]3[N:21]=[CH:20][N:19]([CH3:23])[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[NH3:24]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:24])=[O:9])=[C:4]([NH:13][C:14]2[C:22]3[N:21]=[CH:20][N:19]([CH3:23])[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc2c1ncn2C
Product: Cn1cnc2c(Nc3cc(Cl)nnc3C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Ethyl 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxylate (285 mg, 859 μmol) was suspended in ammonia (7M in methanol, 7.87 g, 10.0 mL, 70.0 mmol). The flask was sealed and stirred at room temperature for 18 h. The solvent was evaporated and the residue dried in high vacuum to give 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxamide (260 mg, 100%) as an off-white solid. 1H NMR (DMSO-d6) δ: 11.36 (s, 1H), 8.74 (s, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.41-7.52 (m, 1H), 7.28-7.35 (m, 2H), 7.23 (s, 1H), 3.86 (s, 3H); LC-MS 303.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>ClCCl>[CH2:1]([C:3]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:31](=[O:32])[O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:18][CH:19]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCN)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylamine (step 9 of Example 1, 1.55 g, 5.3 mmol) and triethylamine (0.80 mL, 5.8 mmol) in dichloromethane (26 mL) cooled in an ice bath was added dropwise phenyl chloroformate (0.69 mL, 5.5 mmol), and the mixture was stirred at ambient temperature. After 30 min, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate (30 mL) and dichloromethane (30 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (30 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/hexane to give 1.90 g (87%) of the title compound as pale brown crystals: 1H-NMR (CDCl3) δ 7.43-7.11 (9H, m), 6.91 (1H, s), 5.50 (1H, br.s), 3.57 (2H, pseudo q, J=6.9 Hz), 2.98 (2H, t, J=6.9 Hz), 2.83 (2H, q, J=7.6 Hz), 2.66 (3H, s), 2.52 (3H, s), 1.28 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].[CH3:8][N:9]([CH3:24])[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([N:21]([CH3:23])[CH3:22])[C:19]=1[CH3:20])[C:13](OC)=[O:14]>CS(C)=O>[CH3:23][N:21]([CH3:22])[C:18]1[CH:17]=[C:12]([C:13](=[O:14])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:11]=[C:10]([N:9]([CH3:24])[CH3:8])[C:19]=1[CH3:20]
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1cc(N(C)C)c(C)c(N(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(N(C)C)cc(C(=O)CS(C)(=O)=O)cc1N(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 18.8 g. of dimethylsulfone and 3.6 g. of sodium hydride (50% dispersion in oil) in 80 ml. of dimethylsulfoxide was stirred with the exclusion of moisture for 2 hours at 50° C. Thereupon, 23.6 g. of methyl 3,5-bis(dimethylamino)-4-methylbenzoate were added and the mixture was stirred at room temperature for 1.5 hours. The solution was diluted with 400 ml. of water and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue from methanol, there was obtained 3',5'-bis(dimethylamino)-4'-methyl-2-methylsulfonylacetophenone, having a melting point of 161°-163° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=3)=[O:21])=[N:16][CH:17]=2)=[CH:8][CH:7]=1>ClCCl>[Cl:3][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20](=[O:21])/[CH:19]=[CH:18]/[C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=3)=[CH:17][N:16]=2)=[CH:24][CH:25]=1
Reactant: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 μL (0.680 mmol) thionyl chloride was added to a suspension of 0.190 g (0.520 mmol) (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-N-(4-hydroxymethyl-phenyl)-acrylamide (Z38a) in 20 mL dichloromethane and the mixture was stirred for 2 h at RT . Another 50 μL thionyl chloride were added and the mixture was again stirred for 3 h. The solvent was concentrated by evaporation i. vac., the residue taken up twice in toluene and concentrated by evaporation i. vac. The crude product was obtained as the HCl salt and used in the next reaction step without any further purification.
Reaction SMILES: [NH2:1][CH:2]1[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>>[CH:13]1[C:14]2[CH:2]([NH:1][CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: ClCC1CO1
Reactant: NC1c2ccccc2-c2ccccc21
Product: OC(CCl)CNC1c2ccccc2-c2ccccc21

Procedure:
18.1 g of 9-aminofluorene are reacted with epichlorohydrin, following the procedure described in Example 47, to give 1-(9-fluorenylamino)-2-hydroxy-3-chloropropane, from which, without purification, (9-fluorenylaminomethyl)oxirane is obtained with methanolic sodium hydroxide solution, by the procedure described in Example 48. Reaction of this compound with 17.8 g of 4-trans-propenylguaethol gives 16.1g = 38.7% of theory of 1-(2-ethoxy-5-trans-propenyl-phenoxy)-2-hydroxy-3-(9-fluorenylamino)-propane, which crystallizes out from the reaction solution in the cold in the form of the free base. Colorless crystals which have a melting point of 119°-121° and are identical to the product described in Example 28.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[O:10]/[C:11](=[CH:15]\[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)/[C:12]=2[O:13]C)=[CH:4][CH:3]=1.[Li+].[Br-].OS(O)(=O)=O>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:26])[O:10]/[C:11](=[CH:15]\[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)/[C:12]=2[OH:13])=[CH:4][CH:3]=1
Reactant: COC1=C(c2ccc(Cl)cc2)C(=O)O/C1=C\c1cccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1O/C(=C\c2cccc3ccccc23)C(O)=C1c1ccc(Cl)cc1
Temperature: 150 °C
Yield: 78 %

Procedure:
A stirred mixture of 3-(4-chlorophenyl)-4-methoxy-5-[(Z)-1-naphthylmethyl-idene]furan-2(5H)-one (380 mg, 0.998 mmol) and LiBr (86.6 mg, 0.998 mmol) in DMF is heated at 150° C. for 10 min., cooled to room temperature, poured into 5 mL H2SO4, diluted with water and extracted with EtOAc. The extracts are combined, washed with water, dried over Na2SO4 and concentrated in vacuo. The resultant oil residue is passed through a silica gel pad, using a gradient elution of 100% EtOAc to 9:1 EtOAc:2.5% acetic acid in methanol, to afford the title product as a rust-yellow solid, 270 mg (78% yield), mp 220°-224° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]=1.CN(C)C=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]=2)[CH:8]=1)=[O:6]
Reactant: FC(F)(F)c1cccc(CBr)n1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)n3)c3ccccc3c2=O)cc1F
Yield: 85 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 150 mg (0.505 mmol) of 3-(3-Fluoro-4-methoxy-benzoyl)-1H-quinolin-4-one, 145.3 mg (0.605 mmol) of 2-bromomethyl-6-trifluoromethyl-pyridine, 24.2 mg (0.605 mmol, 60% dispersion in oil), and 1 mL of N,N dimethylformamide. Water was added and the solid was collected by filtration. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane to yield 195.9 mg of 3-(3-Fluoro-4-methoxy-benzoyl)-1-(6-trifluoromethyl-pyridin-2-ylmethyl)-1H-quinolin-4-one. LC-MSD, m/z for C24H16F4N2O3 [M+H]: 457.11 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.5 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]1([C:2]2[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: OCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1cccc(-c2ccccc2)c1
Yield: 129.7 %

Procedure:
This compound was prepared in a manner analogous to that of Example 4, Step B, using 10.0 grams (0.054 mole) of 3-bromophenyl-methanol, 7.2 grams (0.059 mole) of phenylboronic acid, 0.25 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0), and 66 mL (0.135 mole) of aqueous 2M sodium carbonate in 50 mL of toluene. The crude product from this reaction was combined with a previous smaller run conducted on 4.6 grams (0.020 mole) of 3-bromophenylmethanol. The combination was subjected to column chromatography on silica gel. Elution was accomplished using 20:1 methylene chloride and ethyl acetate. The appropriate fractions were combined and concentrated under reduced pressure, yielding 12.9 grams of 3-phenylphenylmethanol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([OH:14])[CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13].N1C=CC=CC=1.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[C:21]1([C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:1][CH2:2][C@H:3]([OH:14])[CH2:4][S:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:12][CH3:13])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccccc1SC[C@@H](O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1ccccc1SC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
19.3 g (0.09 mol) of 1-(3-hydroxy-2-(S)-hydroxy-propylthio)-2-methoxybenzene (XI-1), 150 ml of acetonitrile, 11 ml (0.136 mol) of pyridine and 27.5 g (0.098 mol) of triphenylmethyl chloride are introduced into a round-bottomed flask under an inert atmosphere. The solution is stirred at ambient temperature for 5 hours. The mixture is concentrated under reduced pressure and the residual pyridine is entrained by azeotropic distillation with toluene. The residue is taken up in water and then extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and evaporated, and the residue is purified by flash chromatography on silica gel (eluent: cyclohexane/dichloromethane=30:70). 34.8 g (0.076 mol) of the title compound (XII-1) are recovered in the form of a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>O1CCOCC1.O>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:23]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C@H:10]3[C:14]([OH:16])=[O:15])=[O:39])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (500 mg, 2.171 mmol) in 1,4-dioxane (5 mL) and water (20 mL) was added potassium carbonate (1200 mg, 8.69 mmol) followed by (9H-fluoren-9-yl)methyl carbonochloridate (562 mg, 2.171 mmol) at 0° C. The mixture was stirred at RT for 18 hrs and then treated with water (10 ml). The resulting mixture was extracted with diethyl ether (2×15 ml). The aqueous phase was acidified with aq. HCl (1M) to pH 2-3, and extracted with DCM (3×20 ml). The combined organic layers were dried over MgSO4 and concentrated to give the crude product. The crude product was purified via prep HPLC (10-100% CH3CN:Water with 0.1% TFA buffer) to afford the product (S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (294 mg, 30% yield) as a white solid. 1H NMR (500 MHz, methanol-d4) d 7.83 (t, J=6.6 Hz, 2H), 7.68-7.58 (m, 2H), 7.45-7.38 (m, 2H), 7.38-7.30 (m, 2H), 4.65 (br. s., 1H), 4.58 (d, J=13.7 Hz, 1H), 4.55-4.39 (m, 3H), 4.33-4.18 (m, 1H), 2.91-2.85 (m, 4H), 1.47 (s, 9H). ESI-MS(+) m/z=475 (M+Na).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:7][CH2:6][N:5]1[CH2:29][C:30]([NH:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([CH2:40][NH:41]C(=O)OC(C)(C)C)=[CH:35][C:34]=1[Cl:49])=[O:31])=[O:3].CO.Cl>CC(O)C>[NH2:1][C:2]([CH:4]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:7][CH2:6][N:5]1[CH2:29][C:30]([NH:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([CH2:40][NH2:41])=[CH:35][C:34]=1[Cl:49])=[O:31])=[O:3]
Reactant: CC(C)(C)OC(=O)NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: NCc1cc(Cl)c(NC(=O)CN2CCN(CCCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2C(N)=O)c(Cl)c1
Yield: 44.9 %

Procedure:
A mixture of 8.7 parts of (1,1-dimethylethyl) [[4-[[2-[2-(aminocarbonyl)-4-[5,5bis(4-fluorophenyl)pentyl]-1-piperazinyl]acetyl]amino]-3,5-dichlorophenyl]methyl]carbamate, 120 parts of methanol and 24 parts of 2-propanol, saturated with hydrogen chloride was stirred for 30 minutes at reflux temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was treated with an ammonium hydroxide solution and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (93:7 by volume) as eluent. The desired fraction was collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.34 parts (44.9%) of 2-(aminocarbonyl)-N-[4-(aminomethyl)-2,6-dichlorophenyl]-4-[5,5-bis(4-fluorophenyl)pentyl]-1-piperazineacetamide; mp. 160.8° C. (compound 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH3:9]O>>[CH3:9][N:6]1[C:2]([CH3:8])([CH3:1])[CH2:3][CH2:4][C:5]1=[O:7]
Reactant: CC1(C)CCC(=O)N1
Reactant: CO
Product: CN1C(=O)CCC1(C)C
Yield: 86 %

Procedure:
A solution of 113 g (1 mole) of 5,5-dimethylpyrrolid-2-one and 96 g (3 moles) of methanol was vaporized, and passed over an alumina catalyst at 400° C. Working up the gas mixture in a conventional manner to obtain 1,5,5-trimethylpyrrolid-2one gives this compound in about 86% yield; boiling point: 236°-238° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N+:19]([O-:21])=[O:20])[C:12]([Br:22])=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:22][C:12]1[C:13]([N+:19]([O-:21])=[O:20])=[C:14]([C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:10][CH:11]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)c1c(N)ccc(Br)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Trimethylacetyl chloride (5.09 g) was added to a solution of methyl 6-amino-3-bromo-2-nitro-benzoate (prepared according to Brock et al Tertrahedron, 1963, 19, 1911, 7.74 g) in pyridine (40 mL) and DCM (40 mL) and left to stand at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was dissolved in DCM and 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was triturated with pentane. The solid was filtered to give methyl 3-bromo-6-(2,2-dimethylpropionyl-amino)-2-nitrobenzoate (9.17 g).