Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10](C)[C:9]([CH3:17])([CH3:16])[CH2:8]2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].CCOC(/N=N/C(OCC)=O)=O.Cl>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][C:11]([CH3:13])([CH3:14])[NH:10][C:9]([CH3:17])([CH3:16])[CH2:8]2)=[CH:4][C:3]=1[C:20]([F:23])([F:21])[F:22]
Reactant: CN1C(C)(C)CC(Oc2ccc(Cl)c(C(F)(F)F)c2)CC1(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CC1(C)CC(Oc2ccc(Cl)c(C(F)(F)F)c2)CC(C)(C)N1
Temperature: 110 °C

Procedure:
A mixture of 4-(4-chloro-3-trifluoromethyl-phenoxy)-1,2,2,6,6-pentamethyl-piperidine (1.28 g, 4.26 mmol), toluene (50 ml) and diethylazodicarboxylate (2.0 ml, 12.8 mmol) was heated at 110° C. for 8 h. Hydrochloric acid (20 ml, 2 M) was added at reflux for 2 h. The mixture was cooled on ice. The hydrochloric acid salt precipitated and was isolated by filtration. Yield 1.2 g (87%). Mp 222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.[N-:27]=[N+:28]=[N-:29].[Na+].C(O)(C)C.Cl>[Br-].[Zn+2].[Br-].ClCCl.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[N:24]=3)=[C:8]([C:12]3[CH:17]=[N:16][CH:15]=[N:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(Cc3cccc(C#N)n3)c(-c3cncnc3)[nH]c2c1
Agent: Cl
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: COc1ccc2c(Cc3cccc(-c4nnn[nH]4)n3)c(-c3cncnc3)[nH]c2c1
Yield: 92.4 %

Procedure:
A mixture of 6-(6-methoxy-2-pyrimidin-5-yl-1H-indol-3-ylmethyl)pyridine-2-carbonitrile (100 mg), sodium azide (95.2 mg), zinc bromide (82.5 mg), isopropyl alcohol (1.76 mL) and water (1.17 mL) was heated under reflux for 21 hours while stirring. The reaction mixture was left to be cooled. To the reaction mixture were added 1 mol/L hydrochloric acid and dichloromethane. The insoluble material was collected by filtration, washed with 1 mol/L hydrochloric acid and water successively, and then dried under reduced pressure at 50° C. to obtain the title compound (104 mg). 1H-NMR (DMSO-d6) δ ppm: 3.79 (3H, s), 4.48 (2H, s), 6.69 (1H, dd, J=2.1, 8.7 Hz), 6.91 (1H, d, J=2.1 Hz), 7.25-7.35 (1H, m), 7.43 (1H, d, J=8.7 Hz), 7.90 (1H, t, J=7.8 Hz), 7.98-8.05 (1H, m), 9.00-9.20 (3H, m), 11.49 (1H, s). ESI-MS (m/z): 385 (M+H)+
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=1)=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[CH:20]1[C:14]2[C:13]3[C:21]([C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=4)=[C:11]4[C:6](=[CH:5][C:12]=3[S:16][C:15]=2[CH:17]=[CH:18][CH:19]=1)[CH:7]=[CH:8][CH:9]=[CH:10]4
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A 1.0 M solution of boron tribromide in dichloromethane (130 mL, 130 mmol) was added slowly to a stirrred solution of (2-benzyl-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (14.5 g, 40.45 mmol) in dichloromethane (130 mL) at -78° C. under a dry nitrogen atomosphere. The solution was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was quenched with water and partitioned between water and dichloromethane. Silica gel was added to the dichloromethane phase and the solvent was removed, The adsorbate was flash chromatographed (eluent 4:1 pet. ether:ethyl acetate) to provide a white solid (9.75 g). This solid was recrystalized from acetic acid to provide off-white needles (8.78, 56%): mp: 112-116° C.; NMR (CDCl3); δ 8.33 (s, 1H), 7.94 (dt, J=8 Hz, 1H), 7.77 (dm, J=8 Hz, 1H), 7.64 (dm, J=8 Hz, 1H), 7.52 (ddd, J=8, 7, 1 Hz, 1H), 7.37 (m, 2H), 7.29 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 7.08 (m, 1H), 6.85 (dm, J=8 Hz, 1H), 2.11 (s, 3H, acetic acid CH3); MS (EI): 326 (100%, MI); Anal. Calc. for C22H14OS.C2H4O2: C, 74.59, H, 4.69, N, 0.00. Found: C, 74.40, H, 4.59, N, 0.15.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14](Br)=[C:13]([CH3:18])[N:12]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:11]1=[O:28])([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>C(#N)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:39]2[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]2)=[C:13]([CH3:18])[N:12]([CH2:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[F:27])[C:11]1=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CNCCN1
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Solvent: CC#N
Product: Cc1c(N2CCNC(=O)C2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)c(=O)n1Cc1c(F)cccc1F
Temperature: 140 °C
Reaction time: 3 h
Yield: 57.9 %

Procedure:
{(R)-2-[5-bromo-3-(2,6-difluoro-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (100 mg, 0.182 mmol) and piperazine-2-one (187 mg, 1.82 mmol) were placed into a microwave flask along the wall of which 1 mL of acetonitrile was then added. The solution was stirred at 140° C. for 3 hrs while being irradiated with microwaves. After concentration in a vacuum, the concentrate was purified by column chromatography eluting with a dichloromethane/methanol (35/1) eluent to afford 60 mg of the compound as a yellowish solid (yield 58%). 1H NMR (300 MHz, CDCl3) δ 1.36 (9H, s), 2.43 (3H, s), 2.86 (1H, m), 3.27 (2H, m), 3.50 (1H, m), 3.74 (1H, m), 4.07 (2H, m), 4.27 (1H, m), 5.04 (1H, m), 5.29 (2H, dd), 5.68 (1H, m), 6.30 (1H, m), 6.90 (2H, t), 7.22-7.37 (6H, m)
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](OC=C)(=[O:12])[CH3:11].C(OCCCCCCCC)=C>C1(C)C=CC=CC=1>[C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])(=[O:12])[CH3:11]
Reactant: C=COC(C)=O
Reactant: CCCCCCCCO
Agent: C=COCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(C)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and 4MgCO3-Mg(OH)2-5H2O (0.6 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and vinyl acetate (2 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 2 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl vinyl ether and octyl acetate were produced in yields of 18% and 3%, respectively, with a conversion from 1-octanol of 44%.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([N:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:25]#[N:26])(C)C>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([NH:7][CH:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:11][CH:10]=2)[C:25]#[N:26])=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)C#N
Reactant: CSc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1
Product: CSc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 4-methylthio-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a yellow powder (yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[S:35]>C1COCC1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[S:35])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: Fc1ccccc1N=C=S
Solvent: C1CCOC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
The compound of example 6 (0.150, g, 0.000443 mol) was taken in THF (3 mL) and to this solution was added 2-fluorophenyl isothiocyanate (0.074 g, 0.000448 mol). The reaction mixture was stirred at room temperature for 8-10 h. The reaction mixture was concentrated and directly used for next step without isolation.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[O-2].[O-2].[Zr+4]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: [Zr+4]
Agent: [O-2]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated at 140° C. with 14.1 g of a powdered zirconium dioxide from the Aldrich company. After 2 h reaction time, the phenol conversion was 6.3%, whereby 3.2 g phenyl chloroformate and 7.8 g diphenyl carbonate were formed. The selectivity to carbonate esters was greater than 99%.
Reaction SMILES: [OH-].[K+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([F:36])=[CH:22][CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].I[CH3:38].[OH-].[Na+].Cl>CS(C)=O.C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[C:21]([F:36])=[CH:22][CH:23]=[C:24]4[C:28]=3[N:27]([CH3:38])[CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:13])[CH3:14])#[N:4]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c(F)ccc12
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3c(F)ccc4c(CCC(=O)O)cn(C)c34)no2)cc1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (237 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1H-indol-3-yl]propanoate (D148) (450 mg) and iodomethane (0.76 mL) in DMSO (5 mL) at RT. The reaction mixture was stirred at RT for 4 hours. Then the reaction was quenched with saturated ammonium chloride, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, and dried over anhydrous sodium sulfate. The dried solution was concentrated to afford the crude product as a brown oil. This oil was dissolved in THF (4 mL) and water (4 mL). Sodium hydroxide (100 mg) was then added to the mixture. The reaction mixture was stirred at 90° C. for 1 hour, and then at RT for another 24 hours. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by MDAP to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-6-fluoro-1-methyl-1H-indol-3-yl]propanoic acid (E106) (249 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.31 (6H, d), 2.53 (2H, t), 2.88 (2H, t), 3.33 (3H, s), 4.89-4.95 (1H, m), 7.02 (1H, t), 7.11 (1H, s), 7.50 (1H, d), 7.75 (1H, dd), 8.36 (1H, dd), 8.49 (1H, d), 12.06 (1H, br s); δF (DMSO-d6, 376 MHz): −123.0; MS (ES): C24H21FN4O4 requires 448; found 449.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][OH:18])[CH2:7][CH2:6][CH2:5]2.I.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](SC)=[NH:27]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[OH:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14][CH2:13][CH2:12][N:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:26]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[NH:27])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCO)CCCN1CCCc2cc(N)ccc21
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCO)CCCN1CCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-((3-(6-amino-3,4-dihydroquinolin-1(2H)-yl)propyl)(methyl)amino)ethanol (67 mg, 0.254 mmol) in ethanol (4 ml) under argon was added methyl thiophene-2-carbimidothioate hydroiodide (145 mg, 0.509 mmol). The resulting suspension was stirred overnight at room temperature. The reaction mixture was then diluted with water and aqeuous sodium carbonate (sat.) then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed on silica gel eluting with ethyl acetate, followed by 5-10% (2M NH3 in methanol) in a 1:1 mixture of ethyl acetate and dichloromethane. 1H NMR (DMSO-d6) δ 7.67 (d, J=3.3 Hz, 1H), 7.55 (d, J=5.1 Hz, 7.07 (t, J=4.4 Hz, 1H), 6.55 (m, 2H), 6.48 (s, 1H), 6.23 (brs, 2H), 4.35 (t, J=5.4 Hz, 1H), 3.51-3.44 (m, 2H), 3.24-3.17 (m, 4H), 2.66 (t, J=6.45, 2H), 2.41-2.33 (m, 4H), 2.17 (s, 3H), 1.89-1.81 (m, 2H), 1.63 (quint, J=7 Hz, 2H). ESI-MS (m/z, %) 373 (MH+, 100), 258 (31), 187 (49), 127 (42). ESI-HRMS calculated for C20H29N40S (MH+), calculated: 373.2056, observed: 373.2052.
Reaction SMILES: Cl.[Br-].[Cl:3][C:4]1[CH:5]=[C:6]([NH:11][C:12]2[C:17]3=[C:18]([CH2:21][N+](CC)(CC)CC)[CH:19]=[CH:20][N:16]3[N:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[F:10].Cl.[Cl:30][CH2:31][CH2:32][NH:33][CH2:34][CH2:35][Cl:36].CCN(C(C)C)C(C)C>CC#N>[Cl:30][CH2:31][CH2:32][N:33]([CH2:21][C:18]1[CH:19]=[CH:20][N:16]2[C:17]=1[C:12]([NH:11][C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:4]([Cl:3])[CH:5]=1)=[N:13][CH:14]=[N:15]2)[CH2:34][CH2:35][Cl:36]
Reactant: ClCCNCCCl
Reactant: CC[N+](CC)(CC)Cc1ccn2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: Cl
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1ccc(Nc2ncnn3ccc(CN(CCCl)CCCl)c23)cc1Cl
Temperature: 60 °C

Procedure:
A mixture of Compound 1E (50 mg, 0.1 mmol), bis-(2-chloroethyl)amine hydrochloride (18 mg, 0.1 mmol), DIEA (36 μl, 0.2 mmol) in CH3CN (0.5 ml) was heated to 60° C. for 3 h. The mixture was cooled to rt and concentrated to give Compound 133A which was used directly in next step. 133A had an analytical HPLC retention time=2.986 min. (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=416.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:9]=[C:10]([NH2:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:13]1[CH2:18][CH:17]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH2:15][CH2:14]1>>[O:13]1[CH2:14][CH:15]=[C:16]([C:2]2[C:3]3[N:4]([N:9]=[C:10]([NH2:12])[N:11]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:17][CH2:18]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1cc(Br)c2nc(N)nn2c1
Product: Cc1cc(C2=CCOCC2)c2nc(N)nn2c1

Procedure:
Prepared in analogy to example 160b, starting from 8-bromo-6-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The title compound was obtained a light brown solid (yield: 55%) after column chromatography on silica gel using ethyl acetate as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:43]([O:47][CH2:48][C@H:49]1[NH:54][CH2:53][CH2:52][NH:51][C:50]1=[O:55])([CH3:46])([CH3:45])[CH3:44].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C.N1C=CC=CC=1.C(N(CC)CC)C>[C:43]([O:47][CH2:48][C@@H:49]1[C:50](=[O:55])[NH:51][CH2:52][CH2:53][N:54]1[C:11](=[O:13])[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC[C@H]1NCCNC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC[C@@H]1C(=O)NCCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 5.6 %

Procedure:
10.0 g of (R)-3-t-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butanoic acid (Chemical Formula 2) produced in the above Example 1 was dissolved in 450 mL of toluene in 2 L flask; 13.0 g of bis(2,2′-benzothiazolyl)disulfide and 10.2 g of triphenylphosphine were added; and then the resulting reaction solution was cooled to 0° C. While stirring the reaction solution, a solution prepared by dissolving 0.8 mL of triethylamine to 20 mL of toluene was added, and then stirred for 5 hours at room temperature. The reaction solution was cooled to 0° C., and then a solution prepared by dissolving 5.6 g of (R)-3-(t-butoxymethyl)piperazine-2-one (Chemical Formula 3) produced in the above Example 2 to 40 mL of toluene, and 2.4 mL of pyridine were slowly added. After 30 minutes, the temperature of the reaction solution was increased to room temperature, and then stirred for further 1 hour. pH of the reaction solution was adjusted to 2.5 using saturated citric acid aqueous solution, and then diluted with 400 mL of ethyl acetate. The reaction solution was washed with brine in twice, and an organic layer was dehydration-concentrated with magnesium sulfate. A residue was purified with column chromatography to obtain 838 mg of a title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[SH:18])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:11])[CH3:10]
Reactant: Cc1ccccc1I
Reactant: CC(C)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1ccccc1Sc1ccccc1C(C)C
Yield: 87.9 %

Procedure:
The general procedure in example 39 was followed. 2-Iodotoluene (218 mg, 1.0 mmol), 2-Isopropylbenzenethiol (90% purity, 168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 2-tolyl 2-Isopropylphenyl sulfide (213 mg, 88% yield) as colorless liquid. Column chromatographic solvent (hexane). Rf=0.4 (hexane). 1H NMR (CDCl3, 300 MHz) δ 7.32 (d, 1 H, J=7.5 Hz), 7.18-7.26 (m, 2 H), 7.13 (dd, 1 H, J=1.5 Hz, 7.2 Hz), 7.09-7.11 (m, 1 H), 7.01-7.08 (m, 2 H), 7.00 (dd, 1 H, J=1.5 Hz, 7.2 Hz), 3.49 hept, 1 H, J=6.6 Hz), 2.37 (s, 3 H), 1.25 (s, 3 H), 1.22 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 149.6, 138.6, 135.5, 133.1, 132.2, 131.1, 130.6, 127.9, 127.0, 126.8, 126.7, 126.1, 30.9, 23.9, 20.9. IR (neat, cm−1) 3060, 3012, 2962, 2867. MS (EI) m/z (relative intensity) 242 (100), 225 (80). Anal. Cald. for C16H18S, Cald. C: 79.29, H: 7.49; Found C: 79.33, H: 7.62.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([CH2:13][C@H:14]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:15]([N:17]([CH3:19])[CH3:18])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[Na+]>C1COCC1.CCOCC>[CH:7]1([CH2:13][C@H:14]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15][N:17]([CH3:18])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CN(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN(C)C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.1 %

Procedure:
A 1 M solution of LiAlH4 in THF (35 mL, 35.0 mmol) was added to a solution of (S)-tert-butyl 3-cyclohexyl-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (3.85 g, 12.9 mmol) in THF at −78° C. at a rate to maintain the temperature below −60° C. The reaction was permitted to warm to 25° C. and conversion to product was monitored by LC-MS. After 6 h, the reaction was cooled to 0° C., and H2O (3.0 mL) was added dropwise, followed by 1 N aq NaOH (3.0 mL), maintaining the temperature below 10° C. Ether (100 mL) and Celite (10 g) were added to the heterogenous mixture, stirred for 30 minutes and filtered through a pad of Celite. The solvent was removed and the residue was separated on 12 g of SiO2 with an eluent gradient from hexanes to 30% MeOH in EA. Appropriate fractions were combined and the solvent was removed to afford (S)-tert-butyl 1-cyclohexyl-3-(dimethylamino)propan-2-ylcarbamate (0.26 g, 7%) as a white solid. MS ESI+ve m/z 285 (M+Na)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: COC(=O)c1ccc(Br)s1
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=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 80 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
To a suspension of 2-bromo-5-methoxycarbonylthiophene (1.11 g), 4-fluorophenylboronic acid (0.91 g) and tetrakis(triphenylphosphine)palladium (289 mg) in 1,2-dimethoxyethane (10 ml) was added aqueous solution of sodium carbonate (2M, 6.5 ml) followed by stirring at 80° C. for 6 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 30% dichloromethane in n-hexane to give 2-methoxycarbonyl-5-(4-fluorophenyl)thiophene (1.16 g, 98.3%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH2:14]([CH2:16][NH2:17])[OH:15]>>[Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([NH:17][CH2:16][CH2:14][OH:15])(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)c(F)cc1F
Reactant: NCCO
Product: O=S(=O)(NCCO)c1cc(Br)c(F)cc1F
Yield: 98.6 %

Procedure:
Prepared by general procedure III from 5-bromo-2,4-difluorobenzene sulfonyl chloride (1.0 g, 3.4 mmol) and ethanolamine (231 mg, 3.77 mmol) to give the title compound (1.06 g, 100%) as an off-white solid. MS (ISP) 315.8[(M+H)+].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[OH:13][CH:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:15][NH2:16]>C(O)C.[Pt]=O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:16][CH2:15][CH:14]([OH:13])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)[CH3:11])=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccc(CO)cc1
Reactant: NCC(O)c1ccc(O)c(CO)c1
Agent: O=[Pt]
Solvent: CCO
Product: CC(Cc1ccc(CO)cc1)NCC(O)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-hydroxymethylphenyl)propan-2-one (1.64 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethanamine (1.23 g) in ethanol (80 ml) was refluxed 0.5 hours, cooled to ambient temperature, platinum oxide (0.1 g) added and the mixture hydrogenated at 75 psi and 50°-60° for 8 hours. The solution was filtered, evaporated, the residue taken up in ethyl acetate and filtered again. Removal of the solvent gave the title compound as an oil which was finally obtained as a hard foam, (52:48 mixture of diastereoisomers) from ethyl acetate-benzene.