Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:40])[CH2:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:25]1[C:26]2[C:21](=[CH:20][C:19]([NH:18][C:10]3[N:9]=[C:8]([CH2:7][CH2:6][C:5]4[CH:36]=[CH:37][CH:38]=[CH:39][C:4]=4[CH2:3][C:2]([NH2:1])=[O:40])[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][N:11]=3)=[CH:28][CH:27]=2)[CH2:22][CH2:23][NH:24]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc3c(c2)CCNC3)ncc1C(F)(F)F
Yield: 73.1 %

Procedure:
tert-Butyl 6-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (I82) (136 mg, 0.245 mmol), DCM (10 mL) and TFA (1 mL) were stirred together at room temperature. After three hours the solution was concentrated and the residue treated with 1M sodium hydroxide (25 mL). The resulting suspension was extracted with ethyl acetate (3×50 mL) and the combined organic extracts washed with brine (100 mL), dried and evaporated to give the title compound (21) (81.6 mg, 74% yield) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.06 (s, 1H), 8.65 (s, 1H), 7.51 (s, 1H), 7.48 (dd, J=8.3, 2.1 Hz, 1H), 7.42 (s, 1H), 7.26-7.21 (m, 1H), 7.19-7.13 (m, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.90 (s, 1H), 3.81 (s, 2H), 3.49 (s, 2H), 3.17 (d, J=3.1 Hz, 1H), 3.14-3.06 (m, 2H), 3.05-2.97 (m, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.67 (t, J=5.6 Hz, 2H). LCMS Method C: rt: 4.76 min; m/z 456.1 [M+H]+; m/z 454.1 [M−H]−.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12](=O)[CH2:13][C:14](OCC)=[O:15])=[C:7]([F:20])[CH:6]=1.O>C(O)COCCO>[Cl:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:3][N:2]([CH3:1])[C:14](=[O:15])[CH:13]=2)=[C:7]([F:20])[CH:6]=1
Reactant: CCOC(=O)CC(=O)c1cc(C)c(Cl)cc1F
Reactant: CNN
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc(-c2cc(=O)n(C)[nH]2)c(F)cc1Cl
Reaction time: 6 h

Procedure:
34.7 g (0.75 mol) of methylhydrazine were added to a solution of 177 g (0.68 mol) of ethyl 3-(4-chloro-2-fluoro-5-methylphenyl)-3-oxopropionate in 500 ml of diethylene glycol. After 6 hours at 100° C., the mixture was poured into 4 l of water. The solids were subsequently separated off and dried. Yield: 133 g; m.p.: 155-156° C.
Reaction SMILES: [CH3:1][C:2]([CH3:40])([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)=[CH:8][CH:7]=1)[CH:3]=[O:4].[CH3:41][Mg]Br.C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1>[OH:4][CH:3]([CH3:41])[C:2]([CH3:1])([CH3:40])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:17](=[O:18])[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)=[C:15]([CH2:34][CH2:35][CH3:36])[N:14]3[N:37]=[CH:38][N:39]=[C:13]23)=[CH:8][CH:7]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C=O)cc2)c2ncnn12
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC(C)(C)C(C)O)cc2)c2ncnn12
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 4′-({4-[4-(1,1-dimethyl-2-oxoethoxy)phenyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.97 g) in tetrahydrofuran (10 mL) was added dropwise methylmagnesium bromide (1 M tetrahydrofuran solution, 0.91 mL) at 0° C., and the mixture was stirred for 3 hr. Ethyl acetate and then saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.72 g, 72%).
Reaction SMILES: [ClH:1].C[C:3]1C=C2[C:6]([NH:7]C=C2CCN)=[C:5](Br)[CH:4]=1.Cl.[CH3:17][C:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[ClH:1].[CH3:17][C:18]([C:21]1[CH:26]=[C:25]2[C:24]([NH:27][CH:3]=[C:4]2[CH2:5][CH2:6][NH2:7])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(NN)cc1
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Agent: Cl
Product: CC(C)(C)c1ccc2[nH]cc(CCN)c2c1

Procedure:
5-(1,1-dimethylethyl)-tryptamine hydrochloride was prepared (2.95 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 7, except using 4-(1,1-dimethylethyl) phenylhydrazine hydrochloride (6.00 g) as starting material. ##STR54##
Reaction SMILES: [Si:1]([O:18][C@H:19]1[CH2:24][C@@H:23]([C:25]([O:27]C(C)(C)C)=[O:26])[C@H:22]([C:32](=[O:41])[N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Si:1]([O:18][C@H:19]1[CH2:24][C@@H:23]([C:25]([OH:27])=[O:26])[C@H:22]([C:32](=[O:41])[N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])[CH3:34])[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
To a solution of compound 39 (1.07 mmol) in anhydrous DCM (70 mL) was added TFA (42.6 mmol) slowly. The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated and purified by silica gel chromatography (DCM/MeOH) to yield compound 40 as a yellow oil in 48% yield. MS (ESI, EI+): m/z=522 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][CH:36]1[CH2:38][CH2:37]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:34][CH2:35][CH:36]3[CH2:38][CH2:37]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: NCC1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NCC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hours. Aminomethylcyclopropane hydrochloride (3.01 g, 0.028 mole) and triethylamine (2.83 g, 0.028 mole) were added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with water. The solid was collected by filtration, washed with water, and dried under high vacuum overnight. The solid was recrystallized from isopropyl alcohol with cooling. The crystalline precipitate was collected by filtration, washed with cold isopropyl alcohol and water, and dried under high vacuum at 60° C. overnight to give 3.92 g (82%) of crystals, mp 228°-229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:26][C:27]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:30]2[CH2:31][CH2:32][C:27]([OH:26])([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:28][CH2:29]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: OC1(c2ccccc2)CCNCC1
Product: COc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 57.9 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.59 g) was coupled to 4-hydroxy-4-phenylpiperidine (0.27 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.26 g); mp 154°-180° C. (d); MS: m/z=539(M+1); NMR(CD3SOCD3): 1.73-1.77 (m,2), 2.0 (m,1), 3.79 (two peaks,3), 5.46 (d,1, J=9.5), 6.98 (d,1, J=8), 7.03 (m,2), 7.17-7.58 (m,7), 7.82 (d,1, J=8). Analysis for C30H32Cl2N2O3.2.0 HCl: Calculated: C, 58.83; H, 5.59, N, 4.57; Found: C, 58.39; H, 5.60; N, 4.66.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[CH:23][N:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:25]=3)[C:8]([CH2:12][CH2:13][NH:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[N:9][C:10]=2[CH:11]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[CH:23][N:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:25]=3)[C:8]([CH2:12][CH2:13][N:14]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[C:39]([NH:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:40])=[N:9][C:10]=2[CH:11]=1
Reactant: N#Cc1ccc(NCCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(N(CCc2nc3cc(Cl)ccc3c3nn(-c4ccccc4)cc23)C(=O)Nc2ccccc2)cc1
Yield: 67.5 %

Procedure:
A solution of 100 mg (0.24 mmol) of the compound of Example 1, 150 mg (1.26 mmol) of phenylisocyanate, and 8 ml of methylene chloride is stirred at ambient temperature for four days. The resulting precipitate is collected and triturated with ether to afford 88 mg (68%) of title compound: IR (KBr) 3440, 2240, 1670, 1605, 1520, 1510, and 1440 cm-1 ; NMR (DMSO-d6) δ 9.56 (s, 1H), 8.72 (s, 1H, exchangeable), 8.48-6.96 (complex m, 17H), 4.46 (t, 2H), and 3.5 (t, 2H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:39]3[CH:40]=[C:41]4[C:45](=[CH:46][CH:47]=3)[CH2:44][CH2:43][CH2:42]4)[CH:32]=2)[O:11][C@@H:10]1[CH2:48][O:49]CC1C=CC=CC=1)C1C=CC=CC=1.CO>C1COCC1.[Pd]>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:12]2[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:48][OH:49])[O:11]2)=[CH:32][C:33]=1[CH2:38][C:39]1[CH:40]=[C:41]2[C:45](=[CH:46][CH:47]=1)[CH2:44][CH2:43][CH2:42]2
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCC2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc4c(c3)CCC4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(4-chloro-3-((2,3-dihydro-1H-inden-5-yl)methyl)phenyl)- tetrahydro-2H-pyran (122) (425 mg, 0.56 mmol) in THF:MeOH (v/v=1:1)(8 mL) at room temperature was added Pd/C. The mixture was stirred under H2 for 2 h, Pd/C was removed by filtration and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC to furnish the title compound (42 mg, 0.10 mmol, 18%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1

Procedure:
A solution containing N-benzyl piperidone 1 (5 g, 26.4 mmol) and pyrrolidine 2 (2.82 g, 39.6 mmol) in toluene (60 mL) was heated to reflux with azeotropic removal of water. The reaction mixture was then cooled and concentrated under reduced pressure. The resulting oil was dissolved in ether, dried over magnesium sulfate, and concentrated under reduced pressure. The crude enamine 3 was used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[C:26](Cl)(=[O:30])[C:27](Cl)=[O:28].[N:32]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:26](=[O:30])[C:27]([NH2:32])=[O:28])=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: c1ccncc1
Reactant: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1cccc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 17 %

Procedure:
To a suspension of 140 mg (0.407 mmol) of [[6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 5 mL of chloroform was added 0.053 mL of oxalyl chloride followed by 0.10 mL of pyridine. The reaction was stirred for 30 hours at ambient temperature then an additional 0.10 mL of oxalyl chloride was added. This mixture was stirred and additional 2 days then quenched into 4.0 mL of dilute ammonium hydroxide. The product was extracted into 4.0 mL of methylene chloride. The organic phase was washed with saturated sodium chloride, dried with sodium sulfate and concentrated to 300 mg of crude oil. The residue was purified by flash chromatography (30 g of silica, hexanes-ethyl acetate gradient 100:0 to 25:75) to provide 28 mg (17%) of [[5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (300 MHz, CDCl3) δ1.20 (t, 3H), 2.88 (q, 2H), 3.70 (s, 3H), 4.98 (s, 2H), 5.44 (s, 2H), 6.00 (s, 1H), 6.60 (s, 1H), 6.84 (m, 2H), 6.90 (dt, 1H), 7.20 (dt, 1H), 8.39 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[I:11]I.O>O1CCCC1.C([Li])CCC.CCCCCC>[I:11][C:9]1[N:4]2[N:3]=[C:2]([CH3:1])[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1nc2ccccn2n1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cccc(I)n2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 2-methyl[1,2,4]triazolo[1,5-a]pyridine (63.2 g, 475 mmol) in tetrahydrofuran (1.37 L) was added dropwise 2.5 M n-butyllithium/hexane solution (5.62 mL, 8.99 mmol) at −78° C. and the mixture was stirred at −78° C. for 30 min. A solution of iodine (181 g, 712 mmol) in tetrahydrofuran (1.00 L) was added, and the mixture was stirred at −78° C. for 30 min, and at room temperature for 1 hr. Water (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (45.0 g, yield 37%).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH2:38][C@H:39]([C:46]([O:48][CH3:49])=[O:47])[CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43].Cl.Cl.C(N(CC)CC)C>O1CCCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:38][C@H:39]([C:46]([O:48][CH3:49])=[O:47])[CH2:40][O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](N)COC(C)(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](COC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
27.0 g (90 mmols) of Z-Phe-OH are dissolved in 250 ml of absolute tetrahydrofurane together with 12.5 ml (90 mmols) of triethylamine, and cooled. 14.7 ml (112 mmols) of chlorocarbonic acid isobutyl ester are added dropwise at -18°C and the mixture is stirred for one-half an hour at <-10°C. 18.1 g of H-Ser(tBu)-OCH3 hydrochloride (85.5 mmols) in a finely powdered form are now added to the white suspension (triethylamine hydrochloride), the mixture is diluted with 350 ml of tetrahydrofurane, and 15.0 m (108 mmols) of triethylamine in 100 ml of tetrahydrofurane are then added dropwise. The mixture is stirred for a further 3 hours at about -10°C and then overnight at room temperature. The suspension is then concentrated to about 250 ml in vacuo, taken up in a large amount of ethyl acetate and extracted by shaking with dilute citric acid solution (3 × 200 ml), dilute sodium carbonate solution (3 × 200 ml) and saturated sodium chloride solution (5 × 200 ml), dried over sodium sulphate and evaporated. The crude product is dissolved in 200 ml of ethyl acetate-hexane (1 : 1). White husks crystallise out of the solution on cooling and these are isolated and dried. The product melts at 92.5°- 94°C. [α]D20 = 3° ± 0.5° (c = 2.2 % in methanol).
Reaction SMILES: [Al].Br[CH:3]([CH3:6])[C:4]#[CH:5].[CH:7](=[O:13])[C:8]1[O:12][CH:11]=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[O:12]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:7]([OH:13])[CH:4]([CH3:5])[C:3]#[CH:6]
Reactant: C#CC(C)Br
Reactant: O=Cc1ccco1
Agent: [Al]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(C)C(O)c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Aluminum (5.0 g, 0.18 mole), mercuric chloride (100 mg) and tetrahydrofuran (THF) (70 ml) were added to a reactor, and a solution of 3-bromo-1-butyne (20 g, 0.15 mole) in THF (20 ml) was added dropwise at 40° to 50° C. to prepare a Grignard reagent. Thereafter, to this THF solution of the Grignard reagent was added dropwise a solution of furfural (11.5 g, 0.12 mole) in THF (20 ml) at 20° to 30° C. over about 1 hour, followed by stirring at room temperature for further 2 hours. After completion of the reaction, the reaction solution was poured into an aqueous ammonium chloride solution (about 100 ml) and extracted with ether. The extract was washed with water, dried and concentrated. The residue obtained was distilled under reduced pressure to obtain 10.4 g (yield, 58%) of pure 1-(2-furyl)-2-methyl-3-butyn-1-ol having a boiling point of 75°-85° C./3 mmHg.
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:26][C:27]1([CH3:30])[O:29][CH2:28]1>>[CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]([OH:29])([CH3:30])[CH3:28])[CH2:22][CH2:21]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=3)[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1(C)CO1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)cc1
Product: CC(C)(O)CN1CCC(N(C(=O)c2cc(-c3ccc(C#N)cc3)on2)C2CC2)CC1

Procedure:
The title compound is prepared from 5-(4-cyano-phenyl)-isoxazole-3-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 1,1-dimethyloxirane following a procedure analogous to that described for Intermediate 2. LC (method 4): tR=1.17 min; Mass spectrum (ESI+): m/z=409 [M+H]+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1[CH:11]=[CH:12][C:13]2N(O)N=N[C:14]=2[CH:15]=1.C(Cl)CCl.[C:24]([O:28][C:29]([N:31]([CH3:71])[C@H:32]([C:36]([NH:38][C@H:39]([C:43]([N:45]([C@@H:47]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:48]([O:65][CH3:66])[CH2:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[C@H:57]([O:63][CH3:64])[C@H:58]([C:60](O)=[O:61])[CH3:59])=[O:51])[CH3:46])=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH:33]([CH3:35])[CH3:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].Cl.[CH2:73]([O:80][CH2:81][C@@H:82]([NH2:90])[CH2:83][C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)C1C=CC=CC=1>CN(C=O)C>[C:24]([O:28][C:29]([N:31]([CH3:71])[C@H:32]([C:36]([NH:38][C@H:39]([C:43]([N:45]([C@@H:47]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:48]([O:65][CH3:66])[CH2:49][C:50]([N:52]1[CH2:56][CH2:55][CH2:54][C@H:53]1[C@H:57]([O:63][CH3:64])[C@@H:58]([CH3:59])[C:60]([NH:90][C@@H:82]([CH2:83][C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)[CH2:81][O:80][CH2:73][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:15]=1)=[O:61])=[O:51])[CH3:46])=[O:44])[CH:40]([CH3:42])[CH3:41])=[O:37])[CH:33]([CH3:34])[CH3:35])=[O:30])([CH3:25])([CH3:27])[CH3:26]
Reactant: N[C@H](COCc1ccccc1)Cc1ccccc1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: On1nnc2ccccc21
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
15.3 μl (88 μmol) of N,N-diisopropylethylamine, 6.7 mg (44 μmol) of HOBt, and 6.7 mg (35 μmol) of EDC were added to a solution of 20 mg (29 μmol) of N-(tert.-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (intermediate 15) in 1 ml DMF and the composition was then stirred for 30 minutes. Then, 7.8 mg (32 μmol) of (2S)-1-(benzyloxy)-3-phenylpropane-2-amine-hydrochloride (intermediate 31) were added. After having stirred the reaction composition overnight, the components thereof where directly separated by means of preparative HPLC. The yield was 26 mg (98% o. th.) of the title compound.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:8][C:7]=1[CH3:22].[NH:35]1[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([N:35]2[CH2:40][CH2:39][CH2:38][C@@H:37]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:36]2)=[O:29])=[CH:31][CH:32]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][N:17]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: Cc1cc(-c2ncc(C(F)(F)F)cn2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-c4ncc(C(F)(F)F)cn4)cc3C)cc2)C1

Procedure:
A solution of 4-((4,4,4-trifluoro-1-(2-methyl-4-(5-(trifluoromethyl)pyrimidin-2-yl)phenyl)butyl)amino)benzoic acid, ethyl (3R)-piperidine-3-carboxylate (2.29 mL), 1-hydroxybenzotriazole (2.01 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.85 g) and diisopropylethylamine (2.60 mL) in dimethylformamide (30 mL) was stirred at room temperature overnight. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and 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 (hexane/ethyl acetate) to give the title compound (4.96 g).