Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(O/[CH:12]=[CH:13]/[C:14]1[C:19]([CH3:20])=[CH:18][N:17]=[C:16]([Cl:21])[N:15]=1)CCC.[I-].[NH2:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)Cl>CN(C=O)C.CCOC(C)=O>[Cl:21][C:16]1[N:15]=[C:14]([C:13]2[CH:12]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)[C:19]([CH3:20])=[CH:18][N:17]=1
Reactant: CCCCO/C=C/c1nc(Cl)ncc1C
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1-c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.6 %

Procedure:
K2CO3 (10.60 g, 76.68 mmol) was added to a mixture of 4-[(E)-2-butoxyethenyl]-2-chloro-5-methylpyrimidine (Intermediate 6, 6.95 g, 30.67 mmol) and 1-aminopyridinium iodide (9.19 g, 41.40 mmol) in DMF (40 mL) at r.t. The resulting dark blue suspension was stirred at r.t. for 3 days (became deep red color) and was then heated at 110° C. for 3 h. The mixture was then cooled, diluted with EtOAc (100 mL) plus a little CH2Cl2. This solution was washed with water (100 mL) and the aqueous wash solution was extracted with EtOAc (100 mL). The combined organic solutions were washed with water (4×100 mL) and sat. brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in THF (100 mL) and filtered through a 30 g silica pad. The eluted solution was concentrated in vacuo and the residue was washed with −70° C. CH3OH to give the title compound (2.223 g, 30%) as a beige crystalline solid; 1H NMR: 2.53 (3H, s), 7.22 (1H, m), 7.64 (1H, m), 8.53-8.59 (2H, m), 8.70 (1H, s), 8.90 (1H, d); m/z: ES+ MH+ 245.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[C:16]([OH:18])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1[N:17]=[C:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1CCCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 20B (950 mg, 2.4 mmol) in CH2Cl2 (30 mL) was added para-toluenesulfonyl chloride (1.09 g, 5.7 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol) and triethylamine (1.1 mL. 7.9 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 (100 mL), washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with EtOAc:hexanes (25:75) to provide the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[I:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([C:16](O)=[O:17])[C:7]=1[O:19][CH3:20].[NH4+:21].[OH-]>C1(C)C=CC=CC=1.CN(C=O)C>[I:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[C:8]([C:16]([NH2:21])=[O:17])[C:7]=1[O:19][CH3:20]
Reactant: [NH4+]
Reactant: COc1c(C(=O)O)cc2c(c1I)CCCC2
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1c(C(N)=O)cc2c(c1I)CCCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (1.59 mL, 21.80 mmol) was added dropwise over 5 min to a stirred suspension of 4-iodo-3-methoxy-5,6,7,8-tetrahydro-2-naphthalenecarboxylic acid (2.9 g, 8.73 mmol) in toluene (10 mL) and DMF (0.25 mL) at room temperature. After heating at reflux for 3.5 h, the reaction was cooled to 0° C. and added to cooled (0° C.) 28% NH4OH (25 mL). The mixture was stirred at 0° C. for 10 min and at room temperature overnight. The mixture was filtered and the collected solid was thoroughly washed with H2O. The light brown solid (2.07 g, 72%) was dried under high vacuum at 50° C. 1H NMR (CDCl3) δ 7.79 (s, 1H), 7.61 (s, 1H), 5.90 (s, 1H), 3.84 (s, 3H), 2.76 (m, 4H), 1.79 (m, 4H). MS m/z 332 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O.C(N(CC)CC)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]([C:22]2[CH:23]=[CH:24][C:19]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:20][CH:21]=2)=[O:26])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (150 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (6 mL) were added biphenyl-4-carboxylic acid (100 mg), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (116 mg), 1-hydroxybenzotriazole (82 mg) and triethylamine (84 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized (methanol/ethyl acetate) to give the title compound (131 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH:20]([CH3:22])[CH3:21]>C(OCC)(=O)C.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:20]([CH3:22])[CH3:21])[CH:5]=[O:6]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C=O)cc1Br
Temperature: 25 °C
Yield: 58.7 %

Procedure:
To a mixture of 3-bromo-4-hydroxybenzaldehyde (2.5 g, 12.4 mmol), potassium carbonate (2.57 g, 18.6 mmol), potassium iodide (0.21 g, 1.24 mmol) and N,N-dimethylformamide (30 mL) was added 2-bromopropane (1.46 mL, 15.5 mmol) under stirring at room temperature, and the mixture was stirred at 70° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-3/1) to give the title compound (1.77 g, yield 59%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=2[N+:24]([O-])=O)[CH:3]=1.CO.[H][H]>[Pt].C(OCC)(=O)C>[NH2:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)Cc1ccc(Nc2cc(Cl)ccc2C(=O)OC)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Nc2cc(Cl)ccc2C(=O)OC)c(N)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of Example 695B (0.73 g, 1.93 mmol), 5% Pt/C, methanol (15 mL) and ethyl acetate (15 mL) was equipped with a balloon of hydrogen gas and stirred at room temperature. After uptake of the hydrogen was complete, the solution was filtered through diatomaceous earth (Celite®). The filtrate was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 0.64 g (95%) of the desired product. MS (DCI) m/e 349 (M+H)+, 366 (M+NH4)+; 1H NMR (500 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.69-6.72 (m, 2H), 6.50 (dd, J=7.8, 1.8 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 5.00 (s, 2H), 3.86 (s, 3H), 3.63 (s, 3H), 3.55 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Br:38][CH2:39][CH2:40][CH2:41]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([O:36][CH2:41][CH2:40][CH2:39][Br:38])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCCCBr)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 71 %

Procedure:
A mixture of 4.0 g (7.67 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 7.8 ml (76.7 mmol) of 1,3-dibromopropane and 5.3 g (38.3 mmol) of potassium carbonate in 75 ml of acetone and 15 ml of DMF was stirred at reflux under argon for 41 hours. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to a solidwhich was purified by HPLC using 5% ethyl acetate-toluene to give 3.5 g (72% yield, mp 67°-69°) of N-[3-(3-bromopropoxy)-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl) glycine methyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: CI.[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]1=[S:10].[CH3:11]CO>CC(C)=O>[CH3:11][S:10][C:4]1[NH:3][CH2:9][CH2:8][CH2:7][CH2:6][N:5]=1
Reactant: S=C1NCCCCN1
Reactant: CCO
Solvent: CC(C)=O
Solvent: CI
Product: CSC1=NCCCCN1
Temperature: 25 °C
Yield: 86 %

Procedure:
Methyl iodide (0.55 ml, 1.15 mmol) was added to a solution of 1,3-diazepane-2-thione (1.00 g, 7.68 mmol) in acetone (8 ml). The reaction mixture was refluxed for 15 min. EtOH was added to the hot solution to dissolve the solids. After cooling to r.t. hex. was added and the precipitate was collected by filtration, washed with hex. and dried to give 1.79 g (86%) crude title compound which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:15][C:16]1[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:13][CH3:14])[C:10]([NH:15][C:16]2[S:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: CCC(C(=O)O)c1ccc(OC)cc1
Reactant: CCOC(=O)c1cnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(NC(=O)C(CC)c2ccc(OC)cc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.7 %

Procedure:
To a solution of 2-(4-methoxyphenyl)butanoic acid (135 mg, 0.70 mmol) and ethyl 2-aminothiazole-5-carboxylate (100 mg, 0.58 mmol) in DMF were added DIEA (112 mg, 0.87 mmol) and HATU (264 mg, 0.70 mmol). The reaction was stirred at room temperature for 4 hrs and partitioned between ethyl acetate and water. The organic layer was dried and concentrated. The residue was purified by biotage column chromatography to afford ethyl 2-(2-(4-methoxyphenyl)butanamido)thiazole-5-carboxylate (163 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20]C(CN)=C[CH:17]=1.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])C.[C:31]([C:35]1[CH:40]=CC(OB=O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:31]([C:35]1[CH:36]=[CH:37][C:27]([N:26]([C:29]2[CH:30]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[CH3:24])=[CH:28][CH:40]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1cc2nccc(Oc3ccc(CN)cc3)c2cc1OC
Reactant: CC(C)(C)c1ccc(OB=O)cc1
Reactant: CCN(CC)CC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(N(C)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 15 %

Procedure:
[4-(6,7-Dimethoxy-4-quinolyloxy)phenyl]methylamine (100 mg) was dissolved in chloroform (10 ml) to prepare a solution. Triethylamine (0.3 ml), 4-tert-butylphenylboranic acid (100 mg), and copper(II) acetate (50 mg) were then added to the solution, and the mixture was stirred at room temperature for 3 days. The insolubles were removed by filtration, and the solvent was then removed by evaporation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel using chloroform/acetone for development to give the title compound (21 mg, yield 15%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:19])[CH:8]=2)[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3]1.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:19])[CH2:18][CH2:17]1)(=[O:34])=[O:33]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(S(C)(=O)=O)CC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyllmethyl]acetamide (EXAMPLE 20, 125 mg) and pyridine (60 μL) in dry methylene chloride (1.9 mL) at 0° C. is treated with methanesulfonyl chloride (32 μL), and the resulting mixture was stirred at 0° C. for one hour and at ambient temperature for 16 hours. The reaction mixture is then diluted with methylene chloride (30 mL), washed with water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is recrystallized from methylene chloride/diethyl ether to give the title compound, mp 240-242° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C)[C@@H:9](C)C(N[C@@H](C1C=CC=CC=1)C(N1C2C(=CC=CC=2)C[C@H]1C(O)=O)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC1C=CC(C)=C(CN)C=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1C(=O)O)c1ccccc1)N(C)C(=O)OC(C)(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cc1ccc(F)cc1CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 359.2 %

Procedure:
To a solution of (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-2-phenyl-acetyl}-2,3-dihydro-1H-indole-2-carboxylic acid (50 mg, 104 μmol, Eq: 1) and (5-fluoro-2-methylphenyl)methanamine (28.9 mg, 208 μmol, Eq: 2) in DCM (3 mL) cooled to 0° C. was added 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (50% weight solution in EtOAc, volume added: 150 μL, Eq: 2) and diisopropylethylamine (54 μL, Eq: 3). The reaction mixture was stirred at 0° C. for 20 min and then at 23° C. for 1 h. The reaction was quenched with saturated aqueous NaHCO3 to pH=8. The two phases were separated and aqueous phase was re-extracted with DCM. The organic layers were combined and concentrated in vacuo. The mixture was purified by flash chromatography (silica gel, 0% to 70% EtOAc in hexanes) to give ((S)-1-{(S)-2-[(S)-2-(5-fluoro-2-methyl-benzylcarbamoyl)-2,3-dihydro-indol-1-yl]-2-oxo-1-phenyl-ethylcarbamoyl})-ethyl)-methyl-carbamic acid tert-butyl ester as a white powder (49 mg), m/z=603 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([C:36]([F:39])([F:38])[F:37])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([C:36]([F:39])([F:37])[F:38])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C(F)(F)F)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 107D]) to give 2-methyl-2-{2-methyl-4-[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as off-white powder of mp. 149–151° C., dec.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]2[CH:10]3[CH:6]2[CH2:7][CH2:8][CH:9]3[OH:11])[CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:1]1([CH2:4][CH:5]2[CH:10]3[CH:6]2[CH2:7][CH2:8][C:9]3=[O:11])[CH2:2][CH2:3]1
Reactant: OC1CCC2C(CC3CC3)C12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C1CCC2C(CC3CC3)C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-cyclopropylmethyl-bicyclo[3.1.0]hexan-2-ol (220 mg, 1.45 mmol) in 10 mL DCM was added sequentially 4 A Molecular sieves (200 mg), NMO (N-Methyl morpholine N-oxide) (339 mg, 2.90 mmol), TPAP label (25.448 mg, 0.0725 mmol). The mixture was stirred overnight at room temperature and plugged through silica gel (3:1 DCM:Et2O) to give 6-cyclopropylmethyl-bicyclo[3.1.0]hexan-2-one as a clear oil; 1H NMR (400 MHz, CDCl3): δ 2.32-2.21 (m, 2H), 2.16 (dd, 1H, J1=13.4 Hz, J2=5.4 Hz), 1.97-1.86 (m, 3H), 1.61-1.53 (m, 1H), 1.38-1.28 (m, 2H), 0.82-0.73 (m, 1H), 0.49-0.44 (m, 2H), 0.09-0.05 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:17][C:18]2[N:19]=[CH:20][N:21]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:22]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:75][N:76]([CH3:87])[C:77](=[O:86])[O:78][C:79]1[CH:84]=[CH:83][CH:82]=[C:81]([NH2:85])[CH:80]=1>C(OC(C)C)(=O)C.CCOC(C)=O>[CH3:75][N:76]([CH3:87])[C:77]([O:78][C:79]1[CH:80]=[C:81]([NH:85][C:14]([C:11]2([CH2:17][C:18]3[N:19]=[CH:20][N:21]([C:23]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=3)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2)=[O:15])[CH:82]=[CH:83][CH:84]=1)=[O:86]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)(C(=O)O)CC1
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-((1-trityl-1H-imidazol-4-yl)methyl)piperidine-4-carboxylic acid from step B (270 mg, 0.6 mmol) in isopropyl acetate (5 mL) were added HATU (273 mg, 0.73 mmol) and N,N-diisopropylethylamine (205 μL, 1.2 mmol). The mixture was stirred for 5 min, and 3-aminophenyl dimethylcarbamate (108 mg, 0.6 mmol) was added. The resulting mixture was heated at 90° C. for 2 hours. The reaction mixture was diluted with EtOAc (10 mL), washed with aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (10-70% EtOAc:Hexanes) to afford the title compound (185 mg, 43%). MS (ES+) [M+H]+=714.2.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]=1[CH2:9][CH2:10][CH3:11].[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]=1[CH2:9][CH2:10][CH3:11])[C:16](=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: CCCc1c(CNC)oc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(C)Cc1oc2ccccc2c1CCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
A solution of methyl-(3-propyl-benzofuran-2-ylmethyl)amine (1.10 g, 5.41 mmol) in CH2Cl2 (40 mL) was treated with acryloyl chloride (0.45 mL, 5.68 mmol) and triethylamine (1.5 mL, 10.8 mmol). The mixture was stirred at room temperature for 2 h. The solution was washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (1.46 g, 99%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 7.59 (d, J=5.4 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.28-7.15 (m, 2H), 6.89-6.70 (m, 1H), 6.20 (t, J=2.4 Hz, 1H), 5.75 (t, J=4.5 Hz, 1H), 4.83-4.71 (m, 2H), 3.33-3.07 (m, 2H), 2.87-2.67 (m, 3H), 1.65-1.58 (m, 2H), 0.95-0.88 (m, 3H); ESI MS m/z 258 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28]C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([N:39]1[CH:43]=[CH:42]N=C1)(N1C=CN=C1)=[O:33].[CH2:44](N)CC>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][C:32]([NH:39][CH2:43][CH2:42][CH3:44])=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCCC(=O)O)c(C)c1OCc1ccccc1
Solvent: C1CCOC1
Product: CCCNC(=O)CCCc1c(C)c(OCc2ccccc2)c(C)c(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 32.8 %

Procedure:
A solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanoic acid (325 mg) in 3 mL THF was treated with carbonyldiimidazole (177 mg, 1.06 mmol). The cloudy yellow solution was stirred at room temperature for 1.5 h. One portion of ˜0.45 mmol was added to a solution of n-propylamine (155 μL, 111 mg) in 2 mL THF and let stir overnight. The reaction mixture was concentrated to a pink-tan solid, dissolved into 5 mL CH2Cl2 and washed with 1×3 mL 2.5 M HCl, 1×3 mL saturated aqueous NaHCO3, 2×2 mL saturated aqueous NaCl, dried over Na2SO4 and concentrated to yield 117 mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)-N-propylbutanamide as a white powder. MS M++H at 460 m/z; 1H NMR (400 MHz, CDCl3) δ=7.50 (m, 4 H), 7.44-7.35 (m, 6 H), 5.47 (br m, 1 H), 4.74 (s, 2 H), 4.73 (s, 2 H), 3.03 (q, 2 H), 2.70 (t, 2 H), 2.27 (s, 3 H), 2.25 (s, 3 H), 2.23 (s, 3 H), 2.14 (t, 2 H), 1.84 (pent, 2 H), 1.39 (m, 2 H), 0.84 (t, 3 H) ppm.