Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[CH2:11][C@H:10]2[CH:12]=O)[CH:6]=[CH:7][CH:8]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO[N:22](C)[C:23]([C@@H:25]1[CH2:27][C@H:26]1C1C=CC=C(OC)C=1)=[O:24].S([O-])(O)(=O)=O.[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:9]2[CH2:11][C@H:10]2[CH2:12][NH:22][C:23](=[O:24])[CH2:25][CH2:26][CH3:27])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@@H]2C[C@H]2C=O)c1
Reactant: COc1cccc([C@@H]2C[C@H]2C(=O)N(C)OC)c1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(OC)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
(trans)-2-(3-Methoxyphenyl)cyclopropanecarboxaldehyde: To a rapidly stirred suspension of LiAlH4 (7.74 g, 204 mmol) in THF (800 mL) at -45° C. was added a solution of the (trans)-N-methoxy-N-methyl-2-(3-methoxyphenyl)cyclopropanecarboxamide (40 g, 171 mmol) in THF (100 mL) maintaining the temperature below -40° C. by dropwise addition. After addition the cooling bath was removed and the reaction was allowed to warm to 5° C., then immediately recooled to -45° C. Potassium hydrogen sulfate (40 g, 300 mmol) in H2O(120 mL) was cautiously added dropwise, the temperature maintained below -30° C. throughout. After addition the cooling bath was removed and the suspension was stirred at room temperature for 30 min. The mixture was filtered through celite and the filter cake was washed with ether. The combined filtrates were then washed with cold 1N HCl, 5% K2CO3, brine, and dried over MgSO4. Concentration by rotary evaporation yielded the title compound as a clear oil (29.9 g, 99%): 1H NMR (300 MHz, CDCl3) δ 1.49-1.58 (m, 1H), 1.65-1.73 (m, 1H), 2.10-2.19(m, 1H), 2.58-2.67 (m, 1H), 3.80 (s, 3H), 6.66-6.78 (m, 3H), 7.21 (t, J=6.6 Hz, 1H), 9.32 (d, J=2.0 Hz, 1H).
Reaction SMILES: C(OC1C=CC(CO)=CC=1)CC1C=CC=CC=1.[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.[CH3:30][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:18][O:19][C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:31]([CH3:30])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CNc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: OCc1ccc(OCCc2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(CN(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following the procedure in J.Org. Chem. 1996, 61 (11), 3849-3862, methyl-4-formylbenzoate (0.821 g, 5.00 mmol) was dissolved in 1,2-dichloroethane (75 ml) at room temperature. N-methylaniline (0.542 ml, 5.00 mmol) was added followed by sodium triacetoxyborohydride (1.484 g, 7.00 mmol). The mixture was allowed to stir at room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution and extracted with diethyl ether. The organic extracts were dried over anhydrous sodium sulfate and concentrated en vacuo. The residue was purified by-flash chromatography on silica eluted with 4:1 hexane/acetone to give 1.097 g (85.9%) of a slightly yellow oil of 4-[(methyl-phenyl-amino)-methyl]-benzoic acid methyl ester. Reduction to {4-[(methyl-phenyl-amino)-methyl]-phenyl}-methanol, condensation with(R)-2-isocyanato-3-phenyl-propionate of formula 5 and hydrolysis as described for example in Example 1 Steps 2-4, yielded about 1.5 g of 2-{4-[(methyl-phenyl-amino)-methyl]-benzyloxycarbonylamino}-3-phenyl-propionic 169, mp. 69.6-70.1° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH2:9]1
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C4CCN(C(=O)OC(C)(C)C)C4)c3n2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4CCNC4)c3n2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
7-Iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine 0.057 gm, 0.1 mM was placed in an oven dried flask and 1 ml anhydrous THF was added. The flask was chilled in an Acetone-dry ice slurry and evacuated and refilled 3 times with nitrogen. Via syringe 0.061 ml of 2.13M Buli in hexane solution (0.13 mM, 1.3 eq) was added and the now yellow mixture was stirred for 30 seconds then 3-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, 0.052 gm, 0.2 mM, 2 eq.) in a minimal amount of THF was added by syringe. The mixture was stirred for 30 minutes, removed from the dry ice-acetone bath and immediately quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted two times with ethyl acetate and the organic extracts dried over magnesium sulfate. After filtering and concentrating, the oil was redissolved in THF and 0.2 ml of 1M Tetrabutylammonium Fluoride in THF added. After 5 minutes the mixture was concentrated and purified on a preparative thin-layer chromatography plate (Ethylacetate/hexane) to give 3-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester. The 3-[2-(3,4,5-Trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in 3 ml of dichloromethane and 0.4 ml trifluoroacetic acid was added and stirred overnight. The solution was concentrated and the solid dried overnight at 2 torr in a 60° C. vacuum oven to give 0.012 gm of Pyrrolidin-3-yl-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone trifluoroacetate salt. (M+H)+=383.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:26]=[CH:25][C:8]([C:9]([NH:11][CH2:12][C:13]2([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])=[CH:7][CH:6]=1)([O-])=O.[OH-].[Na+].O.NN>O.C(O)C.[Ni]>[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][CH2:12][C:13]2([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:10])=[CH:25][CH:26]=1
Reactant: O=C(NCC1(N2CCCCC2)CCCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)NCC2(N3CCCCC3)CCCCC2)cc1
Reaction time: 2 h
Yield: 57.5 %

Procedure:
A solution of 1-[1-(p-nitrobenzamidomethyl) cyclohexyl]piperidine hydrochloride (2 g.) in water (20 ml) was made alkaline with 5N NaOH and the suspension extracted with chloroform (3 × 30 ml.). The combined chloroform extracts were dried (anhyd. Na2SO4) and evaporated to give a yellow solid (1.7 g.). To a stirred solution of this in ethanol (100 ml) containing Raney Nickel in suspension was added dropwise a solution of hydrazine hydrate (5 ml) in ethanol (5 ml) over 30 mins. The suspension was stirred for a further 31/2 hrs., the suspension was heated to boiling for 30 mins. and filtered through Hyflo. The filtrate was evaporated to dryness and the white solid which formed was crystallised from benzene to give 1-[1-(p-aminobenzamidomethyl) cyclohexyl]piperidine (0.95 g. 50%), m.p. 160°-163°.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([NH:12][C:13]([C:15]2[CH:45]=[CH:44][C:18]3[N:19]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[C:20]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:26]=[N:25]5)=[N:21][C:17]=3[CH:16]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1(C(OCC2C3C(=CC=CC=3)C3C2=CC=CC=3)=O)CC2C(=CC=CC=2)C[C@H:47]1C(O)=O>>[CH:38]1([N:19]2[C:18]3[CH:44]=[CH:45][C:15]([C:13]([N:12]4[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][C:1]5[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=5)[CH2:47]4)=[O:14])=[CH:16][C:17]=3[N:21]=[C:20]2[C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[C:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:26]=[N:25]3)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(NC(CC1CCCCC1)C(=O)O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Product: O=C(O)C1Cc2ccccc2CN1C(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)cnc3c1)n2C1CCCCC1
Yield: 41 %

Procedure:
The general procedure described for Compound 242 was used with Fmoc-Tic Wang resin (143 mg, 0.7 mmol/g), producing 25 mg of the title compound (41% yield). MS: 606.22 (M−H+) HPLC Procedure A, retention time=17.18 min.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:32])[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]2[CH:22]=[C:21]([CH:29]([OH:31])[CH3:30])[CH:20]=[CH:19][C:18]1=2.[C:33]([O:44][CH2:45][CH:46]=[CH2:47])(=[O:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38]([O-])=[O:39])=[CH:36][CH:35]=1.ClCCl.CCCCCC>CN(C)C1C=CN=CC=1.C1COCC1.ClCCl>[CH3:32][C:17]1([CH3:16])[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[C:23]2[CH:22]=[C:21]([CH:29]([O:31][C:38]([C:37]3[CH:41]=[CH:42][C:34]([C:33]([O:44][CH2:45][CH:46]=[CH2:47])=[O:43])=[CH:35][CH:36]=3)=[O:39])[CH3:30])[CH:20]=[CH:19][C:18]1=2
Reactant: C=CCOC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(C(=O)OC(C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.54 g (7.44 mmol) of dicyclohexylcarbodiimide and 0.91 g of 4-dimethylaminopyridine are added to a solution of 1.73 g (7.44 mmol) of (+)-1-(5,6,7,8-tetrahydro -5,5,8,8-tetramethyl-2-naphthyl) ethyl alcohol and 1.54 g (7.44 mmol) of allyl monoterephthalate in 50 ml of THF. The reaction medium is left stirring at room temperature for 3 h. After treatment and chromatography on silica in dichloromethane, 2.42 g (77%) of the expected derivative are isolated in the form of a colorless oil (Rf=0.46; dichloromethane/hexane, 50:50).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[O:6].C(N(C(C)C)CC)(C)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl.CCOCC>[C:25]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[O:6])(=[O:27])[CH3:26]
Reactant: CCCCCOc1ccc(C=O)cc1O
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCOc1ccc(C=O)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
3-Hydroxy-4-pentyloxy-benzaldehyde (0.750 g., 3.6 mmol, 1 equiv. ) is dissolved in 10 mL of methylene chloride. Diisopropyl ethyl amine (0.840 g., 6.5 mmol, 1.8 equiv. ) is then added, and the mixture is cooled to 0° C. Acetyl chloride (0.340 g., 4.32 mmol, 1.2 equiv. ) dissolved in 2 mL of methylene chloride is added slowly, and the reaction is stirred at 0° C. for 20 min., followed by stirring 30 min. at room temperature. The mixture is diluted with ether, and washed twice with water, dilute HCl, then brine. The organic phase is dried (MgSO4), and evaporated. Trituration with ether affords 3-acetoxy-4-pentyloxy-benzaldehyde (0.750 g., 3.0 mmol, 83%) as a white solid: UVmax (EtOH) 232 nm (ε=17514), 276 nm (ε=12951), 208 nm (ε=10508), 314 nm (ε=10472 ); 1H NMR (300 MHz, CDCl3) δ 9.85 (s, 1H, CHO), 7.45-7.40 (m, 2H, ArH), 6.95 (d, J=8 Hz, 1H, ArH), 4.15 (t, J=7 Hz, 2H, OCH2R), 2.03 (s, 3H, CH3CO), 1.90-1.85 (m, 2H, OCH2CH2R), 1.57-1.40 (m, 4H, pentyl), 0.95 (t, J=7 Hz, 3H, RCH3); 13C NMR (75 MHz, CDCl3) δ 191.07 (C=O), 151.31, 146.17, 130.39, 124.56, 113.99, 110.85, 69.27, 28.67, 28.04, 22.38, 13.96; IR (KBr) 2950, 1750, 1680, 1600, 1580, 1510, 1230, 1250 cm-1 ; MS (DCI) m/e 251 (MH+). Anal. Calcd for C14H18O4 : C, 67.20; H, 7.20. Found: C, 66.92; H, 7.62.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26](S(C)(=O)=O)[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:33][CH:34]([CH3:43])[C:35](N1CCNCC1)=[O:36]>>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:35](=[O:36])[CH:34]([CH3:43])[CH3:33])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: CC(C)C(=O)N1CCNCC1
Product: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Yield: 91 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate b) and 1-(2-methylpropanoyl)-piperazine to afford the desired product as light-brown foam (91%). MS (ISP): 454.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([C:28](=[O:41])[C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH2:23]1.Cl.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[O:12][CH2:11][CH2:10][C:9]([C:13]([N:27]3[CH2:26][CH2:25][N:24]([C:28](=[O:41])[C:29]4[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=4)[CH2:23][CH:22]3[CH2:21][O:20][CH3:19])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: COc1cc2c(cc1OC)OCCC(C(=O)Cl)=C2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2OCC1
Reaction time: 0.5 h

Procedure:
A solution of 7,8-dimethoxy-2,3-dihydro-1-benzoxepine-4-carbonyl chloride (300 mg) in dichloromethane (10 ml) is added dropwise, taking 30 minutes under ice-cooling while stirring, to a mixture of 3-methoxymethyl-1-(3,4,5-trimethoxybenzoyl)piperazine×hydrochloride (400 mg) obtained in Reference Example 6, triethylamine (1 ml) and dichloromethane (30 ml). The reaction mixture is washed with an aqueous solution of citric acid and an aqueous solution of sodium hydrogencarbonate, then dried over magnesium sulfate, followed by concentration. The concentrate is subjected to a silica gel column chromatography (eluent: ethyl acetate-methanol =95:5) to afford 1-(7,8-dimethoxy2,3-dihydro-1-benzoxepin-4-ylcarbonyl) -2-methoxymethyl4-(3,4,5-trimethoxybenzoyl)piperazine (520 mg) as colorless crystals, m.p. 142° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][C:4]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:5]=1[C:6]#[N:7].Br[C:23]1[S:24][C:25]([Br:28])=[CH:26][N:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:28][C:25]1[S:24][C:23]([C:9]2[CH:10]=[CH:11][C:4]([CH2:3][CH:2]([CH3:1])[CH3:21])=[C:5]([CH:8]=2)[C:6]#[N:7])=[N:27][CH:26]=1
Reactant: CC(C)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C#N
Reactant: Brc1cnc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)Cc1ccc(-c2ncc(Br)s2)cc1C#N
Temperature: 25 °C
Yield: 59.2 %

Procedure:
To a suspension of 2-(2-methylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (D59) (600 mg), 2,5-dibromo-1,3-thiazole (767 mg), and Cs2CO3 (1028 mg) in 1,2-dimethoxyethane (DME) (10 mL)/water (2 mL) stirred under nitrogen at room temperature was added PdCl2(dppf)-CH2Cl2 adduct (344 mg). The reaction mixture was sealed and heated under microwave at 120° C. for 4 h. After cooling the reaction, the mixture was diluted with ethyl acetate and filtered through silical gel. The filtrate was washed with aqueous saturated ammonium chloride and saturated brine. The organic phase was collected and dried over anhydrous sodium sulphate. The solvent was removed in vacuo to give the crude product, which was purified by column chromatography to afford 5-(5-bromo-1,3-thiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D91) (400 mg). MS (ES): C14H13BrN2S requires 320. found 321.0 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Cl:24][C:25]1[C:26]([CH3:38])=[N:27][C:28]([S:36][CH3:37])=[N:29][C:30]=1[CH2:31]S(C)(=O)=O.[NH4+].[Cl-]>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:31][C:30]3[C:25]([Cl:24])=[C:26]([CH3:38])[N:27]=[C:28]([S:36][CH3:37])[N:29]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CSc1nc(C)c(Cl)c(CS(C)(=O)=O)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1nc(C)c(Cl)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (614 mg, 1.961 mmol) in THF (20 mL) was cooled to 0° C. NaH (58.8 mg, 2.451 mmol) was added. The mixture was stirred at 0° C. for 30 min. The title compound from Step E (462 mg, 1.63 mmol) in THF (30 mL) was added. The mixture was stirred at 0° C. and then room temperature for 4 h. Saturated NH4Cl (10 mL) was added. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with brine (saturated, 10 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40S, eluting with EtOAc/hexane (30/70) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz) δ 7.94 (s, 1H), 7.82 (s, 2H), 5.85 (d, J=8.5 Hz, 1H), 5.00 (d, J=17.5 Hz, 1H), 4.46 (m, 1H), 4.31 (d, J=18.0 Hz, 1H), 2.60 (s, 6H), 0.83 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)C[CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([N:52]([CH3:61])[C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][CH2:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].FC(F)(F)C(O)=O.[CH:79](S)(S)[CH3:80]>CSC>[NH:1]1[CH2:80][CH2:79][CH2:63][CH2:62][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([N:52]([CH3:61])[C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][CH2:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CC(S)S
Solvent: O=C(O)C(F)(F)F
Solvent: CSC
Product: CCCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1

Procedure:
Condensation of BocPro-DTrp-PheOH (part B of Example 17, 0.700 g.) and HDTrp-Leu-MeNleNH2 (0.520 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DTrp-Leu-MeNleNH2 in 64% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-Leu-MeNleNH2 (0.750 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-Leu-MeNleNH2, which was isolated as the amorphous white solid phosphate (1:1) salt tetrahydrate in 30% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33]>CN(C=O)C.[NH4+].[Cl-].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:28])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[N:17]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:18]([C:21]2[CH:22]=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)n1COCC[Si](C)(C)C)C(C)C
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (2.6 g, 5.8 mmol) in DMF (60 mL) was treated with NaH (60% dispersion in mineral oil, 256 mg, 6.4 mmol) in one portion. After 5 min, the mixture was treated with SEMCl (1.08 mL, 6.1 mmol) in 0.1 mL portions over 10 min. The reaction was stirred for 2 hours and diluted with saturated NH4Cl solution (50 mL) and EtOAc (100 mL). The organic layer was washed with H2O (3 50 mL) and brine (50 mL). The solution was dried over MgSO4 and subjected to a 120 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford (1-{2-[5-(4-bromo-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl)-2-methyl-propyl)-carbamic acid methyl ester (2.4 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:15][CH2:16][N:17]([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:6]=1
Reactant: CN(C)CCCl
Reactant: Brc1cn[nH]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (5 g, 34 mmol) in DMF were added K2CO3 (11.75 g, 85.03 mmol, 2.5 eq.) and 2-chloro-N,N-dimethylethanamine HCl (7.35 g, 51 mmol, 1.5 eq) and the mixture was stirred at RT for 12 h. The mixture was quenched with water and extracted with DCM (3×150 ml). The combined organic layer was washed with water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by column chromatography (60-120 silica gel, 1% methanol in DCM) to give the product in 86% yield (6.4 g). 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.25 (s, 1H), 4.18 (t, 2H), 2.61 (t, 2H), 2.15 (s, 6H); LC-MS (ESI): Calculated mass: 218.09; Observed mass: 219.8[M+H]+ (RT: 0.439 min).