Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:28])=[CH:24][C:25]([OH:27])=[CH:26][C:21]=2[S:20][C:19]=1[CH3:29].[CH3:31][C:32]1[C:37]([CH2:38]O)=[CH:36][CH:35]=[C:34]([C:40]([F:43])([F:42])[F:41])[N:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:28])=[CH:24][C:25]([O:27][CH2:38][C:37]3[C:32]([CH3:31])=[N:33][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:35][CH:36]=3)=[CH:26][C:21]=2[S:20][C:19]=1[CH3:29]
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: COC(=O)Cc1c(C)sc2cc(O)cc(Cl)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)sc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a mixture of tri-n-butylphosphine (0.418 mL), methyl(4-chloro-6-hydroxy-2-methyl-1-benzothiophen-3-yl)acetate (151.2 mg) and (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (112 mg) and THF (5.0 mL) was added ADDP (423 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (165 mg). The solid was crystallized from EtOAc-hexane.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:6]=1[CH3:27])=[O:4].[OH-].[Na+].Cl>O1CCOCC1.O>[CH:21]1([CH2:20][N:7]2[C:8]([C:10]3[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=3[O:18][CH3:19])=[CH:9][C:5]([C:3]([OH:4])=[O:2])=[C:6]2[CH3:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1cc(-c2cc(OC)ccc2OC)n(CC2CCCCC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(OC)c(-c2cc(C(=O)O)c(C)n2CC2CCCCC2)c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
To a solution of 2.3 g of 1-cyclohexylmethyl-5-(2,5-dimethoxy-phenyl)-2-methyl-1H-pyrrole-3-carboxylic acid methyl ester in dioxane (50 ml) and water (50 ml) was added 18.8 ml of a 1N solution of sodium hydroxide. The reaction mixture was heated at reflux for 16 hours. After such time the reaction mixture was allowed to cool down to room temperature before being neutralized with 18.8 ml of a 1N solution of hydrochloride acid. Dioxane was distilled off and the precipitate was then filtered and washed with water to give 2.1 g of the title compound; MS (ISP) 356.3 (M-H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]Br)[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]3)=[CH:4][CH:3]=2)[CH2:17][CH2:16]1
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: BrCC1CCC(CBr)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCc2ccc(OCC3CCC(CBr)CC3)cc2N1
Yield: 30.8 %

Procedure:
A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (196 mg, 1.2 mmol), 1,4-bis(bromomethyl)cyclohexane (972 mg, 3.6 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) was dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column to give 7-((4-(bromomethyl)cyclohexyl)methoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 49) (130 mg, 30%) as a white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[Cl:14][CH:15]1[CH:20]2[CH:18]3[CH:19]2[CH2:21][CH:16]1[CH:17]3[NH2:22].N1C=CC=CC=1>O>[Cl:14][CH:15]1[CH:20]2[CH:18]3[CH:19]2[CH2:21][CH:16]1[CH:17]3[NH:22][C:11]([C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: NC1C2CC3C1C3C2Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1C2CC3C(C2Cl)C31)c1cnc2ccccc2n1
Yield: 37.1 %

Procedure:
Prepared from 2-quinoxaloyl chloride (193 mg, 1.0 mmol), 5-chlorotricyclo[2.2.1.0(2,6)]hept-3-ylamine (129 mg, 0.90 mmol), pyridine (5 mL), and water (50 mL) yielding 100 mg (37%) of (167):
Reaction SMILES: CO/[CH:3]=[CH:4]/[C:5](=[O:7])[CH3:6].[F:8][CH:9]([F:15])[C:10](OCC)=O.CC(C)([O-])C.[K+].C(O)(=O)C.[NH3:26]>O.C(OCC)C>[F:8][CH:9]([F:15])[C:10]1[CH:6]=[C:5]([OH:7])[CH:4]=[CH:3][N:26]=1
Reactant: CO/C=C/C(C)=O
Reactant: CCOC(=O)C(F)F
Reactant: N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: Oc1ccnc(C(F)F)c1
Temperature: 25 °C
Yield: 32 %

Procedure:
A mixture of (E)-4-methoxy-but-3-en-2-one (20 mmol) and ethyl difluoroacetate (24 mmol) is added dropwise to a mixture of potassium tert-butoxide (26 mmol) and diethyl ether (50 ml) under nitrogen atmosphere at −15° C. over 30 min. The mixture is allowed to warm up to room temperature slowly over 3 h. After cooling to 0° C., acetic acid (26 mmol) and H2O (10 ml) are successively added dropwise to the reaction mixture. The organic layer is separated, washed with sat. aq. NaHCO3, dried over MgSO4, and evaporated in vacuo. The residue is dissolved in i-propanol (30 ml). To the solution, conc. HCl (2 ml) is added and the mixture is refluxed for 3 h. After cooling, the reaction mixture is neutralised with sat. aq. NaHCO3 and extracted with CH2Cl2. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is dissolved in i-propanol (20 ml). To the solution, 28% aq. NH3 (50 mmol) is added and the mixture is refluxed for 20 h. After cooling, the reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give 2-difluoromethyl-pyridin-4-ol in 32% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH2:21]Br.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:21][C:20]2[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=2[F:27])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: Fc1cccc(F)c1CBr
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ncc(Cl)cc1OCc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
33 g of 5-chloro-2-nitropyridin-3-ol (Example 12A; 189 mmol, 1 equivalent) and 61.6 g of caesium carbonate (189 mmol, 1 equivalent) were initially charged in 528 ml of DMF, 40.4 g of 2,6-difluorobenzyl bromide (189 mmol, 1 equivalent) were added and the mixture was stirred at RT overnight. The reaction mixture was stirred into water/1N aqueous hydrochloric acid. The solid was filtered off, washed with water and air-dried. This gave 54.9 g (97% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[N:26][CH:25]=[CH:24][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:8]=1O)=[O:5].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:27]=[N:26][CH:25]=[CH:24][C:3]=1[C:4]1[O:5][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:22])([C:18]([F:20])([F:19])[F:21])[C:14]([F:17])([F:16])[F:15])=[CH:12][C:7]=2[N:6]=1
Reactant: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)C(F)(c1ccc2oc(-c3ccncc3Cl)nc2c1)C(F)(F)F
Reaction time: 1.2 h
Yield: 67.4 %

Procedure:
To a mixture of 0.90 g of 3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide, 10 ml of tetrahydrofuran and 0.68 g of triphenylphosphine, 1.13 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature. The reaction mixture was stirred for 1.2 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.58 g of 2-(3-chloropyridin-4-yl)-5-(heptafluoroisopropyl)benzoxazole (hereinafter, referred to as “active compound 68”).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)N)=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH:21]1[CH3:27].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:10][CH2:11][C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[C:23]3[CH2:22][CH:21]([CH3:27])[N:20]([CH3:19])[CH2:25][C:24]=3[C:4]=2[CH:3]=1
Reactant: CC1CC(=O)CCN1C
Reactant: Cc1ccc(CCN(N)c2ccc(Cl)cc2)cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)C(C)C3)cn1
Temperature: 90 °C

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-1-(2-(6-methylpyridin-3-yl)ethyl)hydrazine (1 g, 3.83 mmol) in dioxane (10 mL) was added 1,2-dimethylpiperidin-4-one (0.538 g, 4.59 mmol) and 0.5 mL of conc. sulfuric acid at RT. The reaction was heated at 90° C. for 2 h. After completion of reaction, the mixture was basified by addition of a saturated solution of NaHCO3. The product was extracted with EtOAc, and the organic layer washed with water, dried over sodium sulfate and concentrated. The solid obtained was purified by HPLC. 1HNMR (CD3OD, TFA salt) d (ppm): 8.30 (s, 1H), 8.05 (d, 1H), 7.64 (d, 1H), 7.50 (s, 1H), 7.24 (d, 1H), 7.10 (d, 1H), 4.50 (t, 2H), 4.40 (m, 1H), 4.0 (m, 1H), 3.80 (m, 1H), 3.30 (m, 3H), 3.0 (m, 4H), 2.62 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=O)[CH:24]=3)[CH:19]=[CH:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[OH2:41].[NH4+:42]>O1CCCC1>[C:26]([C:23]1[CH:24]=[C:25]2[C:20]([CH:19]=[CH:18][N:17]2[CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[CH:21][CH:22]=1)(=[O:41])[NH2:42]
Reactant: [NH4+]
Reactant: O
Reactant: O=C(O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC(=O)c1ccc2ccn(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
75.0 g of 1-(1-benzyloxycarbonylpiperidin-4-yl)-1H-indole-6-carboxylic acid was dissolved in 620 ml of tetrahydrofuran. Thereafter, 38.6 g of 1,1′-carbonylbis-1H-imidazole was added thereto. The reaction solution was stirred at room temperature for 1.5 hours, and 134 ml of a 28% ammonium water was then added thereto. After completion of the reaction, the reaction solution was concentrated under a reduced pressure, and then extracted with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution and a saturated ammonium chloride aqueous solution. Tetrahydrofuran was added to the separated organic layer, and a partially solidified subject compound was dissolved therein, followed by drying over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The solidified subject compound was collected by filtration. The thus collected subject compound was suspended in tetrahydrofuran, and the mixture was heated, followed by filtration. The thus collected subject compound was then suspended in a mixed solvent consisting of tetrahydrofuran and methanol, and the obtained mixture was heated, followed by filtration. The generated filtrates were gathered and concentrated, and thus, the subject compound was obtained in the same above manner. The total amount of the subject compounds was 64.8 g.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:30]=[C:29]2[C:20]([NH:21][C:22]3[C:27]([S:28]2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:19]2[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=12.[C:35]([O:39][C:40]([NH:42][CH2:43][C:44](O)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]>C1COCC1.CN(C1C=CN=CC=1)C>[C:35]([O:39][C:40]([NH:42][CH2:43][C:44]([O:16][C:17]1[CH:30]=[C:29]2[C:20]([NH:21][C:22]3[C:27]([S:28]2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:19]2[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=12)=[O:45])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Reaction time: 0.25 h

Procedure:
Dicyclohexylcarbodiimide (21 g) was added to a solution of 5-hydroxy-12H-benzo[a]phenothiazine (4.2 g) and N-tert-butyloxycarbonyl glycine (8.4 g) in THF (150 ml) followed by the addition of DMAP (0.2 g). The reaction mixture was stirred for 15 minutes, filtered and the filtrate evaporated to dryness. The residue was dissolved in EtOAc, washed with a solution of NaHCO3, dried and evaporated to dryness. The resulting oily residue was chromatographed on silica gel (5% EtOAc/CH2Cl2) to afford 5-tert-butyloxycarbonylamino acetoxy-12H-benzo[a]phenothiazine. m.p. 175° as an intermediate.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:50]=[CH:49][C:10]([CH2:11][N:12]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([CH:40]=2)=[CH:38][CH:37]=[C:36]([O:41]CC2C=CC=CC=2)[CH:35]=3)[C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:15]=2)=[CH:9][CH:8]=1>C1(OC)C=CC=CC=1.CO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]([C:31]2[CH:32]=[N:33][C:34]3[C:39]([CH:40]=2)=[CH:38][CH:37]=[C:36]([OH:41])[CH:35]=3)[C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:15]=2)=[CH:49][CH:50]=1
Reactant: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2cnc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: COc1ccccc1
Product: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2cnc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of AlCl3 (44 mg, 0.33 mmol) in anhydrous anisole (150 μl) was added to 32 (43 mg, 0.07 mmol) in anhydrous anisole (150 μl) and the resulting solution was stirred at room temperature for 18 hours. The reaction was diluted with MeOH (150 μl) and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 80:20:1 EtOAc:Hexanes:MeOH) to give 33 as a yellow amorphous solid in quantitative yield: 1H NMR (CDCl3, 500 MHz) δ 8.35 (s, 1H), 7.74 (s, 1H), 7.58 (d, J=8.9 Hz, 1H), 7.52 (bs, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 7.25-7.11 (m, 5H), 6.84-6.77 (m, 3H), 6.74 (d, J=8.6 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.64 (s, 1H), 5.16 (s, 2H), 3.76 (s, 3H), 3.70 (s, 3H), 3.68 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.3, 159.4, 159.3, 158.0, 138.8, 135.5, 132.3, 130.4, 130.3, 130.1 (2C), 129.6, 129.1 (2C), 127.1, 123.0, 122.0, 114.9, 114.3 (2C), 113.3, 110.7, 55.8, 55.4, 53.9; IR (film) νmax 2926, 1601, 1506, 1248, 1177, 1030, 818 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C32H28N2O5, 521.2076. found, 521.2030.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19](C(O)(C)C)=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2.Br[CH2:28][CH2:29][CH2:30][OH:31].C(=O)([O-])[O-:33].[K+].[K+]>C(#N)C>[F:1][C:2]1[C:10]([O:11][C:12]2[C:17]3=[C:18]([CH3:25])[C:19]([O:33][CH2:28][CH2:29][CH2:30][OH:31])=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:26])[NH:6]2
Reactant: Cc1cc2c(F)c(Oc3ncnn4cc(C(C)(C)O)c(C)c34)ccc2[nH]1
Reactant: O=C([O-])[O-]
Reactant: OCCCBr
Agent: [K+]
Solvent: CC#N
Product: Cc1cc2c(F)c(Oc3ncnn4cc(OCCCO)c(C)c34)ccc2[nH]1
Yield: 43.9 %

Procedure:
A mixture of Example 1 (50 mg, 0.16 mmol), 3-bromo-1-propanol (100 μL, 1.1 mmol) and potassium carbonate (100 mg, 0.72 mmol) in acetonitrile (1.5 mL) was stirred overnight at 35° C. The mixture was filtered, concentrated and purified by chromatography on silica gel eluting with 30% ethyl acetate in dichloromethane to provide the title compound (26 mg, 39% yield) as a light beige solid. MS: (M+H)+=371
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([CH2:27][C:28]2([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:21]3=[O:26])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].C1COCC1>C(O)C>[C:13]([C:11]1[CH:10]=[C:9]([C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][CH:20]([CH2:27][C:28]2([CH3:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:21]3[OH:26])[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=1)([CH3:14])([CH3:15])[CH3:16]
Reactant: CC1(CC2Cc3c(cccc3-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)C2=O)CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(CC2Cc3c(-c4cc(C(C)(C)C)cc(C(C)(C)C)c4)cccc3C2O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Sodium borohydride (1.32 g, 34.83 mmol, 1.5 equiv) was added in portions at 0° C. to a solution of compound 13 (10.0 g, 23.22 mmol, 1.0 equiv), THF (100 mL) and ethanol (100 mL). The reaction mixture was stirred at room temperature overnight, when LCMS indicated that the reaction was complete. The mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (300 mL) and water (50 mL). 1M HCl was added dropwise to quench the reaction. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated brine (500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 14 (10.0 g, >99% yield) as a pale-yellow oil. This material was used subsequently.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:43][S:44](Cl)(=[O:46])=[O:45].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([NH:11][C@H:12]([C@@H:20]([O:42][S:44]([CH3:43])(=[O:46])=[O:45])[C@H:21]([O:41][S:44]([CH3:43])(=[O:46])=[O:45])[C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]([C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 90 %

Procedure:
A slurry of 1.50 g (2.64 mmol) of (2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane in 50 ml of anhydrous dichloromethane was cooled to 0° C. and treated sequentially with 0.43 ml of methanesulfonyl chloride, 64 mg of 4-dimethylaminopyridine and 1.1 ml of triethylamine. The resulting mixture was stirred for 15 h with the temperature being allowed to slowly climb to ambient temperature. After treatment with aqueous NH4Cl, the separated organic layer was washed with aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo to provide 1.70 g (90%) of the desired compound, m.p. 153°-155° C. 1H NMR (CDCl3) δ 2.73 (m, 2 H), 2.92 (m, 2 H), 3.09 (s, 6 H), 4.61 (m, 2 H), 4.83-5.06 (m, 8 H), 7.12-7.37 (m, 20 H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:20](=[O:37])[N:19]([CH2:38][C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[O:40])[N:18]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:21]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:3][C:4](=[O:7])[O:5][N:36]=3)=[CH:27][CH:28]=2)[C:20](=[O:37])[N:19]([CH2:38][C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[O:40])[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nn(CC(=O)c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(CC(=O)c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.07 g), sodium hydrogen carbonate (1.61 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({3-butyl-1-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-carbonitrile (0.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.2 g, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[CH:15][N:14]=3)[N:12]=2)=[C:4](F)[CH:3]=1.C1(=O)O[CH2:25][CH2:24][O:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[N:9]([CH:10]=[C:11]([C:13]4[N:17]([CH:18]([CH3:20])[CH3:19])[N:16]=[CH:15][N:14]=4)[N:12]=3)[CH2:25][CH2:24][O:23][C:4]=2[CH:3]=1
Reactant: O=C1OCCO1
Reactant: CC(C)n1ncnc1-c1c[nH]c(-c2ccc(Br)cc2F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
A solution of 5-[2-(4-bromo-2-fluoro-phenyl)-1H-imidazol-4-yl]-1-isopropyl-1H-[1,2,4]triazole (10.0 g, 28.6 mmol) in DMF (100 mL) was treated with ethylene carbonate (5.3 g, 60.1 mmol) and cesium carbonate (13.9 g, 42.5 mmol) and then heated at 100° C. for 72 h. Further cesium carbonate (9.0 g, 27.5 mmol) and water (0.5 mL) were added and heating continued for 24 h before concentrating the reaction mixture in vacuo. The resultant residue was partitioned between DCM and water, the organic layer was isolated, washed with water then brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, 1% MeOH in DCM) to give 194 as an off-white solid (5.78 g, 58%). 1H NMR δ (ppm) (CDCl3): 8.04 (1 H, s), 7.83 (1 H, s), 7.50-7.38 (3 H, m), 5.93-5.84 (1 H, m), 4.07-4.02 (2 H, m), 3.93-3.88 (2 H, m), 1.53-1.46 (6 H, m)