Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[F:21])[CH:5]=1)=[O:3].[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH3:1][S:2]([C:4]1[S:12][C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[S:33])=[CH:16][C:15]=2[F:21])[CH:5]=1)=[O:3]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CS(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Solvent: C1CCOC1
Product: CS(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 3 h
Yield: 52.8 %

Procedure:
To a suspension of 234 (280 mg, 0.868 mmol) in THF (8 mL) was added 2-phenyl acetyl isothiocyanate (185 mg, 1.04 mmol). The reaction mixture was stirred for 3 hours, concentrated; the solid residue washed with Et2O and dried, to afford title compound 235 (229 mg, 53% yield) as a white-rose solid. 1HNMR: (DMSO-d6) δ (ppm):12.41(s,1H), 11.75(s,1H), 8.54(d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.96(d, J=13.5 Hz, 1H), 7.48(d, J=5.0 Hz, 2H), 7.30-7.26(m, 2H), 7.26-7.18(m, 3H), 6.69(d, J=5.5 Hz, 1H), 3.25(s, 2H), 2.98(s, 3H). MS (m/z): 500.1 (M+1).
Reaction SMILES: [C:1]([N:8]1[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([N:8]1[C@H:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:13][CH:14]=2)[CH2:9]1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)[C@@H]1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2CN1C(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H]1Cc2ccc(-c3ccccc3)cc2CN1C(=O)OC(C)(C)C

Procedure:
The triflate from Step 2 was coupled with phenyl boronic acid following the procedure of Example 11 to give the title compound as an oil.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1>C(O)(=O)C.O>[CH3:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: Cn1ccc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
Sodium cyanoborohydride (63 mg, 1. 004 mmol) was added to an ice-cold solution of the N-methyl indole (110 mg, 0.335 mmol) in glacial acetic acid (6 mL). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, cooled in an ice bath, and diluted with H2O (10 mL). Ice-cold concentrated aq. ammonium hydroxide (30 mL) was added until the solution reached pH 12. After extraction (2×) with CH2Cl2, the organic layer was dried over MgSO4/Na2SO4, filtered, and concentrated in vacuo. Purification by column chromatography (SiO2, 10 g, 10% EtOAc/hexanes) gave the desired N-methyl indoline product (15 mg, 15%) as brown oil. The material is air-sensitive and requires storage under nitrogen: 1H NMR (500 MHz, CDCl3) δ7.28-7.25 (m, 1H), 7.01 (dd, J=10.4, 2.0 Hz, 1H), 6.95 (dd, J=8.2, 1.9 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 6.28 (d, J=8.1 Hz, 1H), 4.11 (t, J=5.9 Hz, 1H), 3.50 (dd, J=13, 2.0 Hz, 2H), 3.36-3.32 (m, 2H), 2.88 (dd, J=11.3, 5.2 Hz, 1H), 2.82 (t, J=8.2 Hz, 2H), 2.73 (s, 3H), 2.56 (dd, J=11.4, 7.0 Hz, 1H), 2.41 (s, 3H); IR (KBr) 3052, 2925, 2850, 2786, 1609, 1422, 1265, 739 cm−1; ESI MS m/z=331 [C19H20ClFN2+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:62])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:62])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)Oc1ccon1
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)Oc1ccon1

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-(3-isoxazolyloxy)propane IIIj1 is allowed to react and worked up by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH3:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][C:42](Cl)=[O:43]>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:42](=[O:43])[CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH3:33])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: COCCOCCOCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COCCOCCOCC(=O)Nc1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (14 mg, 31 μmol) was dissolved in abs. pyridine (0.7 ml). At room temperature, 2-[2-(2-methoxyethoxy)ethoxy]acetyl chloride (12 mg, 61 μmol, 2 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (12.4 mg, 70% of theory).
Reaction SMILES: CS([O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])[CH2:7]1)(=O)=O.[F:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[C:32]([F:35])([F:34])[F:33]>>[F:24][C:25]1[CH:30]=[CH:29][C:28]([O:5][CH:6]2[CH2:9][N:8]([C:10]3[N:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=3[C:12]([OH:14])=[O:13])[CH2:7]2)=[CH:27][C:26]=1[C:32]([F:33])([F:34])[F:35]
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(OS(C)(=O)=O)C1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Product: O=C(O)c1cc(C(F)(F)F)cnc1N1CC(Oc2ccc(F)c(C(F)(F)F)c2)C1
Yield: 98.7 %

Procedure:
The title compound (D125) (108 mg) was prepared according to the experimental procedure described in Description 103A starting from methyl 2-(3-((methylsulfonyl)oxy)azetidin-1-yl)-5-(trifluoromethyl)nicotinate (D68) (100 mg, 0.258 mmol) and 4-Fluoro-3-(trifluoromethyl)phenol (60.98 mg, 0.338 mmol).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[O:5]=[CH:6][CH:7]([CH3:12])[CH2:8][C:9]#[C:10][CH3:11].[Cl-].[NH4+]>O1CCCC1>[OH:5][CH:6]([CH:7]([CH3:12])[CH2:8][C:9]#[C:10][CH3:11])[C:1]#[CH:2]
Reactant: CC[Mg]Br
Reactant: CC#CCC(C)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)C(C)CC#CC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 50 ml of 2M ethylmagnesium bromide in tetrahydrofuran at 0° C. was added a solution of 1-oxo-2-methylhex-4-yne in 20 ml of tetrahydrofuran. The mixture was stirred for 11/2 hour at 0° C., poured into saturated ammonium chloride solution, and extracted three times with diethyl ether. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane, to give 6.0 g of 3-hydroxy-4-methyloct-1,6-diyne, the compound of formula (LXV).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([N:21]3[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([N:21]3[CH2:22][CH2:23][CH:24]([OH:27])[CH2:25][CH2:26]3)=[O:20])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:28]([F:31])([F:29])[F:30]
Reactant: O=C1CCN(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(4-oxo-piperidine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (20 mg), sodium borohydride (10 mg) in 1 mL of methanol was stirred at room temperature overnight. To the mixture was added water and the resulting mixture was extracted with ethyl acetate three times. The organic layer was washed with brine and dried. After the removal of solvents the residue was further purified by flash column (50% ethyl acetate in hexane) to afford the title compound as a white solid: 1H NMR: (CDCl3, ppm) δ 8.12 (d, 1H), 8.09 (d, 1H), 7.95 (dd, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 4.05 (m, 1H), 3.88 (m, 1H), 3.47 (m, 1H), 3.36 (m, 1H), 3.02 (m, 1H), 1.94 (m, 1H), 1.73 (m, 1H), 1.58 (m, 1H), 1.48 (m, 2H); MS: (M+H)/z=498.0.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Cl:1][C:2]1[C:3]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(Cl)c(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5 g, 16.75 mmol) in dioxane (200 ml) was added (4-fluorophenyl)boronic acid (4.7 g, 33.59 mmol), water (20 ml), K3PO4 (7 g, 32.98 mmol), Pd(PPh3)4 (924 mg, 0.80 mmol) with an inert atmosphere of nitrogen. The resulting solution was stirred for 8 h at 95° C. and then concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 5% to 20% ethyl acetate in petroleum ether to produce 5-chloro-4-(4-fluorophenyl)-2-nitroaniline as a yellow solid (4.1 g, 91%). Next, a solution of 5-chloro-4-(4-fluorophenyl)-2-nitroaniline (4.1 g, 15.38 mmol) in ethanol (100 ml) was added to hydrogen chloride (4 ml, 48 mmol, conc) and Zn (6 g, 460 mmol) at room temperature. The resulting solution was stirred for 3 h at 85° C. The resulting mixture was concentrated under vacuum and dissolved in water (200 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with dichloromethane (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 5% to 10% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine as a brown oil (2.5 g, 70%). Finally, a solution of 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine (100 mg, 0.42 mmol) in hydrogen chloride (1 ml) and trifluoroacetic acid (5 ml) was stirred overnight at 80° C. The reaction was quenched by the addition of water (50 ml) and the pH value of the solution adjusted to 7 with aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (50.7 mg, 38%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[S:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[C:1]([C:5]1[S:9][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][C:22]4[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[S:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)s2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)C=C(c2ccc(C(C)(C)C)s2)c2cc(CCc3ccc(C(=O)O)cc3)ccc2S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of ethyl 4-[[4-(5-tert-butylthiophen-2-yl)-2,2-dimethyl(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 232, 88.0 mg, 0.181 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (160.0 mg, 4.0 mmol, 4.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 68.0 mg (82%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.03 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.3 Hz), 7.62 (1H, s), 7.44 (2H, d, J=1.2 Hz), 6.87 (2H, s), 6.11 (1H, s), 1.45 (6H, s), 1.39 (9H, s).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[C:14](=O)([O-])[O-].[K+].[K+].IC.Cl>CN(C=O)C>[CH3:14][O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
A slurry of 1-(2-hydroxy-3-nitrophenyl)ethanone (1.00 g, 5.52 mmol) and potassium carbonate (3.05 g, 22.08 mmol) in DMF (20 mL) was stirred at room temperature for 30 minutes, then iodomethane (1.338 mL, 16.56 mmol) was added dropwise and the resulting mixture was allowed to stir at room temperature overnight. LCMS indicated some un-reacted starting material remained, therefore additional iodomethane (1.338 mL, 16.56 mmol) was added and the mixture was warmed to 50° C. over 2 days. Reaction was quenched by the addition of water to give a solution followed by adjusting the pH with 1N HCl to ˜7. The resulting solution was extracted with ethyl acetate (80 mL×3) and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the product, 1-(2-methoxy-3-nitrophenyl)ethanone (1.05 g, 5.38 mmol, 97% yield) as a tan oil. HPLC (Method N) RT=1.86 minutes.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:42][N:43]=[C:44]=[O:45]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:14][C@@H:15]([OH:37])[C@@H:16]([NH:25][C:26](=[O:36])[O:27][C@@H:28]3[C@H:35]4[C@H:31]([O:32][CH2:33][CH2:34]4)[O:30][CH2:29]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:44]([NH:43][CH3:42])=[O:45])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)Oc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S, 2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-hydroxybenzyl)propylcarbamate (80 mg), methyl isocyanate (0.5 mL), dichloromethane (3 mL) and disopropylamine (0.05 mL) was stirred at ambient temperature for 1 h. Solvent was evaporated and the residue was purified by chromatography (silica gel, hexanes/ethyl acetate, 3:1) to provide the title compound as a solid foam (57 mg). 1H NMR (DMSO-d6): δ 0.78 (3H, d), 0.82 (3H, d), 1.17 (1H, dd), 1.30-1.45 (1H, m), 1.9-2.0 (1H, m), 2.42 (1H, t), 2.6 (3H, d), 2.62-2.80 (3H, m), 2.99 (2H, dd), 3.15-3.20 (1H, m), 3.50-3.63 (4H, m), 3.7 (1H, t), 3.8 (1H, dd), 4.8 (1H, dd), 5.04 (1H, d), 5.5 (1H, d), 6.18 (2H, s), 6.95 (2H, d), 7.05 (1H, d), 7.15 (2H, d), 7.2 (1H, s), 7.25 (1H, d), 7.5 (1H, quartet), 8.08 (1H, d); MS: 650 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:9]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C:10]=2[NH:11][N:12]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[NH2:7][C:8]1[C:9]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C:10]=2[N:11]([C:1]([O:2][CH2:3][CH3:4])=[O:5])[N:12]=1
Reactant: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Reactant: CCOC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(N)c2c1CN(C(=O)OC(C)(C)C)C2
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of ethyl chlorocarbonate (8.9 ml, 93 mmol) in tetrahydrofuran (THF, 250 ml) was slowly added to a mixture of tert-butyl 3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate (20 g, 89 mmol) and diisopropylethylamine (DIEA, 92 ml, 528 mmol) in THF (500 ml) at 0-5° C. The reaction was kept at the same temperature for two hours then allowed to reach room temperature and stirred overnight. The obtained mixture was evaporated to dryness under vacuum, and the resulting residue extracted with ethyl acetate (AcOEt) and water. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The mixture was purified by flash-chromatography (eluent: ethyl acetate/cyclohexane 4/6 to 7/3) to give 19 g of the title compound as a white solid. [M+H]+ 297
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][NH:12]3)[O:10][C:5]2=[CH:4][C:3]=1[Cl:16].Cl.[CH2:18]=O>C(O)=O.CCOCC>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C@H:11]3[CH2:15][CH2:14][CH2:13][N:12]3[CH3:18])[O:10][C:5]2=[CH:4][C:3]=1[Cl:16]
Reactant: C=O
Reactant: Clc1cc2oc([C@H]3CCCN3)cc2nc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: O=CO
Product: CN1CCC[C@@H]1c1cc2nc(Cl)c(Cl)cc2o1
Temperature: 60 °C
Yield: 46 %

Procedure:
5,6-Dichloro-2-(2-(R)-pyrrolidinyl)furo[3,2-b]pyridine from Example 39b (56 mg, 0.22 mmol) was dissolved in an aqueous solution of 37% formaldehyde (excess) and 88% formic acid (excess). The aqueous mixture was heated to 60° C. for 1 hour and then allowed to cool to ambient temperature. The reaction mixture was washed with Et2O, basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The organic phases were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a solid. The solid was dissolved in Et2O (10 mL) and a saturated solution of HCl in Et2O was added dropwise. The solvent was removed and the product recrystallized from MeOH/Et2O to afford a white solid (31 mg, 46%): mp 244-246° C.; 1H NMR (D2O, 300 MHz) δ 2.27-2.37 (m, 2H), 2.47-2.71 (m, 2H), 2.93 (s, 3H), 3.38 (m, 1H), 3.78 (m, 1H), 4.81 (m, partially buried under H2O peak, 1H), 7.27 (s, 1H), 8.26 (s, 1H); MS (CI/NH3) m/z: 271 (M+H)+ ; Anal. Calcd for C12H12Cl2N2O.HCl: C, 46.85; H, 4.26; N, 9.11. Found: C, 46.53; H, 4.21; N, 8.82.
Reaction SMILES: [C:1]1([S:7][C@@H:8]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C@H:9]2[O:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1.CSC>C(Cl)Cl>[C:11]([O:10][C@@H:9]1[C@@H:17]([O:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:21])[CH3:22])[C@H:25]([O:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:30])[CH3:31])[C@@H:33]([CH2:35][O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[O:34][C@H:8]1[S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:51])(=[O:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Sc2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CSC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](S(=O)c2ccccc2)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: -15 °C
Yield: 89.4 %

Procedure:
To a solution of 44 (1.24 g, 2.04 mmol) in 25 mL of CH2Cl2 at -78° C. is added a solution of 64% m-CPBA (550 mg, 2.04 mmol) in 10 mL of CH2Cl2. The reaction mixture is allowed to warm to -15° C., quenched with methyl sulfide (2.07 mL, 1.75 g, 6.8 mmol) and warmed to room temperature. The reaction mixture is then diluted with 25 mL CH2Cl2, washed with saturated NaHCO3 (50 mL), H2O (50 mL), saturated NaCl (50 mL), dried over Na2SO4, filtered, concentrated and purified by flash chromatography (30% EtOAc/hexane) to afford 1.14 g (89%) of the title compound 45 as a mixture of diastereomers: Rf 0.14 and 0.28 (10% EtOAc/hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C@H:6]([OH:10])[CH2:7][C:8]#[N:9])[CH3:2].[CH3:12]C(=O)OCC>IC.[Ag]=O>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6]([O:10][CH3:12])[CH2:7][C:8]#[N:9])[CH3:2]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CCOC(C)=O
Agent: O=[Ag]
Solvent: CI
Product: CCOC(=O)CC(CC#N)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
(R)4-cyano-3-hydroxy butyric acid ethyl ester (1.5 g, 9.54 mmol) was dissolved in iodomethane (20 ml). Silver oxide solid (3.3 g, 14.32 mmol) was added, and the reaction mixture was agitated at room temperature overnight. TLC (PE/EA=2/1) was employed to monitor the reaction. After the reaction completed, the silver oxide solid was removed by filtration, and the solvent was evaporated. Column chromatography (PE/EA=10/1) afforded colorless transparent liquid 1.0 g, yield 63.1%.
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:6]([CH2:40][CH2:41][CH3:42])[C:5]=1[OH:43]>CO.O1CCOCC1.[OH-].[Na+]>[Cl:10][C:8]1[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:19]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:6]([CH2:40][CH2:41][CH3:42])[C:5]([OH:43])=[C:4]([CH:9]=1)[C:3]([OH:44])=[O:2]
Reactant: CCCc1c(O)c(C(=O)OC)cc(Cl)c1OCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCc1c(O)c(C(=O)O)cc(Cl)c1OCCCCCCc1cccc(OCc2ccccc2)c1OCc1ccccc1
Yield: 71.6 %

Procedure:
A solution of 0.30 g of 5-chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid methyl ester in 10 mL of methanol, 5 mL of dioxane and 2.5 mL of 1N sodium hydroxide was left at room temperature for 3 days. The solvent was removed under reduced pressure and the residue was acidified and extracted with ethyl acetate. The dried extract was concentrated and chromatographed on 30 g of silica gel using acetic acid:ethyl acetate:toluene (1:25:75) to give 0.21 g of 5-chloro-2-hydroxy-4-[6-[2,3-bis(phenylmethoxy)phenyl]hexyloxy]-3-propylbenzoic acid as an oil.