Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[C:9][CH2:10][N:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:3]1=[O:16])(=[O:19])[CH3:18]
Reactant: O=C1[C@@H](O)CCN1CC#CCN1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)O[C@H]1CCN(CC#CCN2CCCC2)C1=O

Procedure:
A solution of 0.4 g of (S)-3-hydroxy-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone and 1.0 ml of acetic anhydride in 20 ml of dichloromethane was stirred overnight. The solvent was removed in vacuo. The residue was basified with potassium bicarbonate solution and extracted with dichloromethane. The dichloromethane solution was washed with water, dried, concentrated in vacuo and the residue was purified by chromatography (alumina), giving the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][SH:14]>>[F:11][C:12]([F:16])([F:15])[CH2:13][S:14][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: FC(F)(F)CS
Product: CC(=O)c1ccc(SCC(F)(F)F)nc1
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (0.39 g, an orange solid) from 1-(6-chloropyridin-3-yl)ethanone (0.40 g, 2.54 mmol) and 2,2,2-trifluoroethanethiol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:32]([CH3:34])[CH3:33])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:45][C:43]=2C=1.CCN(CC)CC.CN>ClCCl>[CH:32]([N:8]([C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23](=[O:24])[NH:45][CH3:43])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:34])[CH3:33]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(-c2cc(-c3ccccc3)c3nc(C(=O)O)cn3c2)s1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1cn2cc(-c3cnc(N(C(=O)OC(C)(C)C)C(C)C)s3)cc(-c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
A solution of 6-(2-(tert-butoxycarbonyl(isopropyl)-amino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.21 mmol) in dichloromethane was treated with EDC (48 mg, 0.25 mmol), HOBT (34 mg, 0.25 mmol), Et3N (25 mg. 0.25 mmol), methylamine (2 M in THF: 3 ml, 6 mmol) and stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator and the residue purified by chromatography on silica gel using ethyl acetate/hexanes (50%) as eluent to give 30 mg (30% yield) of tert-butyl isopropyl(5-(2-(methylcarbamoyl)-8-phenylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl)carbamate as a white solid. LCMS (Conditions C): 4.26 min (RT); (M+H)+=492.43 (100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.Cl.[CH2:30]([O:32][C:33](=[O:38])[C@H:34]([CH2:36][OH:37])[NH2:35])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([O:32][C:33](=[O:38])[C@@H:34]([NH:35][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])[CH2:36][OH:37])[CH3:31]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CCOC(=O)[C@@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CO)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 83.1 %

Procedure:
(S)-3-Hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionic acid ethyl ester (213 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (200 mg), L-serine ethyl ester hydrochloride (91 mg), HBTU (223 mg), and DIEA (128 uL).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[CH2:32]([O:35][CH2:36][CH2:37][NH2:38])[CH2:33][CH3:34]>>[CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:38][CH2:37][CH2:36][O:35][CH2:32][CH2:33][CH3:34])=[O:25])[C:6]1=[O:29]
Reactant: CCCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: CCCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and [2-(propyloxy)ethyl]amine employing methods similar to those described in Example 245 and was purified by reverse phase preparative BPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.63 (1H, br), 8.21 (1H, br s), 7.30 (1H, br s), 7.28 (2H, dd, J˜9, 5.6 Hz), 7.11 (2H, t, J˜9 Hz), 4.95 (2H, s), 4.01 (2H, s), 3.43-3.30 (6H, m), 3.08 (3H, s), 2.79 (3H, s), 1.50 (2H, m, J=7 Hz), 0.85 (3H, t, J=7 Hz); HRMS calcd for C25H29FN4O5+H+: 485.2200. Found: 485.2190.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].I[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>CCOCC>[CH2:10]([O:3][CH:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCI
Reactant: CCOC(=O)[C@H](C)O
Solvent: CCOCC
Product: CCCCCOC(C)C(=O)OCC
Yield: 43.5 %

Procedure:
98 g of ethyl L-lactate, 313 g of 1-iodopentane and 245 g of freshly prepared Ag2O were stirred at 60°-65° C. for 16 hours, and diluted with ether, followed by removal of insoluble matter by filtration. After distilling off the ether, the reaction liquid was distilled in vacuo to obtain 68 g of ethyl 2-pentyloxypropionate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18](O)=[O:19])=[CH:14]2.Cl.C[N:34](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH2:34])=[O:19])=[CH:14]2
Reactant: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=O)[nH]c12
Temperature: 25 °C
Reaction time: 14 h
Yield: 68.2 %

Procedure:
A mixture of 7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylic acid (940 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (817 mg), 1-hydroxybenzotriazole ammonium salt (648 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was washed with a mixed solvent of ethyl acetate-diethyl ether to give the title compound (640 mg, yield 68%) as a pale-yellow solid. MS 441 (MH+).
Reaction SMILES: [Cl:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]([F:12])([F:13])[C:3]1[N:8]=[CH:7][C:6]([CH:9]([OH:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(C(F)(F)Cl)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccc(C(F)(F)Cl)nc1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a solution of 1-{6-[chloro(difluoro)methyl]pyridin-3-yl}ethanone (B) (0.85 g, 4.14 mmol) in MeOH (10 mL) at 0° C. was added NaBH4 (0.16 g, 4.14 mmol). The mixture was stirred for 30 min and 2 M HCl aqueous solution was added until pH reached 7. Solvent was removed under reduced pressure and the remaining mixture was extracted with CH2Cl2 (2×50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and dried in vacuo to give 0.798 g of analytically pure 1-{6-[chloro(difluoro)methyl]-pyridin-3-yl}ethanol (C) on GC-MS as a light yellow oil in 93% yield. GC-MS: mass calcd for C8H6ClF2NO [M]+207. Found 207.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[CH2:4][CH:3]1[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].C([SiH](CC)CC)C>ClCCCl.O>[CH3:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])[CH2:2]2
Reactant: CCOC(=O)NC1Cc2ccc(C)cc2C1O
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)NC1Cc2ccc(C)cc2C1
Temperature: 25 °C
Yield: 90.6 %

Procedure:
With stirring at room temperature, the compound (3.30 g, 13.9 mmol) obtained in step C, triethylsilane (4.4 ml, (27.8 mmol) and boron trifluoride-diethyl ether complex (3.4 ml, 27.8 mmol) dissolved in 1,2-dichloroethane (20 ml) were added to 1,2-dichloroethane (90 ml), and the mixture was stirred at 83° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with water, and extracted with dichloromethane. The organic layer was washed with diluted aqueous sodium hydroxide solution, diluted hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give the title compound (2.76 g, yield 91%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[CH:19]([CH3:21])[CH3:20])=[CH:6][N:5]=[C:4]([S:22][CH3:23])[N:3]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=2[CH:19]([CH3:21])[CH3:20])=[CH:6][N:5]=[C:4]([S:22][CH3:23])[N:3]=1)[CH3:25]
Reactant: CCN
Reactant: COc1cc(Cc2cnc(SC)nc2Cl)c(C(C)C)cc1OC
Product: CCNc1nc(SC)ncc1Cc1cc(OC)c(OC)cc1C(C)C
Temperature: 50 °C
Yield: 63 %

Procedure:
To a glass pressure vessel containing 4-chloro-5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methylsulfanyl-pyrimidine (0.212 g, 0.6 mmol) was added 5.0 mL ethyl amine via a cold finger condenser. The vessel was capped and warmed to 50° C. After 16 hours the solution was cooled to room temperature, evaporated and taken up in H2O. The mixture was extracted with ethyl acetate, washed with H2O and then washed with brine. The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo. Purification via flash chromatography (4:1 hexane/ethyl acetate) afforded ethyl-[5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methylsulfanyl-pyrimidin-4-yl]-amine (0.136 g, 63%) as a white solid.
Reaction SMILES: C([O:4][CH:5]([CH2:21][CH2:22][S:23]([CH3:25])=[O:24])[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:7])(=O)C.[OH-].[Na+]>CO.ClCCl>[CH2:9]([NH:8][C:6](=[O:7])[CH:5]([OH:4])[CH2:21][CH2:22][S:23]([CH3:25])=[O:24])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCNC(=O)C(CCS(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCCCCCNC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of 1-(dodecylamino)-4-(methylsulfinyl)-1-oxobutan-2-yl acetate (25 g, 62.6 mmol) in methanol (350 mL) was added 2.5 N NaOH (40 mL, 100 mmol) and the resulting solution was stirred at room temperature for 5 hrs. The reaction was quenched with concentrated HCL (12.5 mL) and then evaporated to a small volume. The resulting mixture was treated with EtOAc (200 mL) and then washed with 1N HCl (150 mL), saturated sodium bicarbonate (50 mL), dried over magnesium sulfate, filtered and evaporated to give a solid. The solid was dissolved in dichloromethane and purified by silica gel chromatography with 0-10% methanol/dichloromethane. The desired fractions were collected and evaporated to give a white solid (16.7 g, 80%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.83 Hz, 3 H) 1.15-1.33 (m, 18 H) 1.33-1.46 (m, 2 H) 1.72-1.87 (m, 1 H) 1.92-2.09 (m, 1 H) 2.51 (d, J=1.27 Hz, 3 H) 2.56-2.87 (m, 2 H) 3.00-3.12 (m, 2 H) 3.90-4.00 (m, 1 H) 5.69 (d, J=5.40 Hz, 1 H) 7.71-7.82 (m, 1 H). m/z 334 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]([OH:10])[CH3:9])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[OH-].[K+].[SH2:21].C(O)(=O)C>CO.O>[NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]([OH:10])[CH3:9])[CH:5]=[N:4][C:3]=1[C:17](=[S:21])[NH2:18]
Reactant: S
Reactant: CCCCCCC(C(C)O)n1cnc(C#N)c1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCC(C(C)O)n1cnc(C(N)=S)c1N

Procedure:
A solution of erythro 5-amino-1-(2-hydroxynon-3-yl)-1H-imidazole-4-carbonitrile (1.02 g; 0.004 m) and potassium hydroxide (0.91 g; 0.163 m) in dry methanol (80 ml) was cooled to 0°, saturated with hydrogen sulphide, and heated to 100° for 5 hours. After cooling to 0°, nitrogen was passed through the solution to remove excess hydrogen sulphide and the residue was evaporated in vacuo to give a yellow solid. This solid was suspended in water and acetic acid added dropwise to pH5. The resulting precipitate was collected by filtration and washed with water. The residue was dissolved in dichloromethane/ethyl acetate, dried (Na2SO4) and evaporated in vacuo to give a white solid (1.22 g). Recrystallisation from ethyl acetate/charcoal gave a pale yellow solid, which was triturated in ether to give the product as white crystals (0.74 g) mp 170°-171°.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][N:11]1[C:15]2=[N:16][CH:17]=[C:18]([OH:20])[CH:19]=[C:14]2[CH:13]=[CH:12]1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:37](Br)[CH:38]=[CH2:39].C(OCC)(=O)C>CN(C)C=O>[CH2:39]([O:20][C:18]1[CH:19]=[C:14]2[CH:13]=[CH:12][N:11]([CH2:10][C:9]3[S:8][C:7]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=4)=[N:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])[C:15]2=[N:16][CH:17]=1)[CH:38]=[CH2:37]
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2cc(O)cnc21
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cnc2c(ccn2Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2CCCC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
730 mg 1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridin-5-ol were dissolved in 20 ml dimethylformamide and 1.1 mg cesium carbonate and 410 mg allylbromide were added. The reaction mixture was stirred at room temperature for one hour then 100 ml ethyl acetate were added and the mixture was washed five times with portions of 20 ml of water The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. This gives 800 mg 5-Allyloxy-1-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3-b]pyridine as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([C:28]([O:30][CH3:31])=[O:29])[NH:19]1>CO.C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:19]2[CH:20]([C:28]([O:30][CH3:31])=[O:29])[CH2:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C1Cc2ccccc2CN1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1Cc2ccccc2CN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Aldrich), the title compound was prepared as a solid (mp=37-40° C.). The reaction was monitored by tlc (Rf=0.64 in 10% MeOH/DCM).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([NH:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]2[C:51]=1[N:50]([CH2:52][C:53]([OH:55])=O)[CH:49]=[CH:48]2)=[O:40])([CH3:37])([CH3:36])[CH3:35].[N:56]1[CH:61]=[CH:60][C:59]([N:62]2[CH2:67][CH2:66][C:65]3([CH2:72][CH2:71][NH:70][CH2:69][CH2:68]3)[CH2:64][CH2:63]2)=[CH:58][CH:57]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[O:55]=[C:53]([N:70]1[CH2:69][CH2:68][C:65]2([CH2:66][CH2:67][N:62]([C:59]3[CH:60]=[CH:61][N:56]=[CH:57][CH:58]=3)[CH2:63][CH2:64]2)[CH2:72][CH2:71]1)[CH2:52][N:50]1[C:51]2[C:47](=[CH:46][CH:45]=[CH:44][C:43]=2[CH2:42][NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:37])[CH3:35])[CH:48]=[CH:49]1
Reactant: c1cc(N2CCC3(CCNCC3)CC2)ccn1
Reactant: CC(C)(C)OC(=O)NCc1cccc2ccn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc2ccn(CC(=O)N3CCC4(CC3)CCN(c3ccncc3)CC4)c12
Reaction time: 0.25 h
Yield: 95 %

Procedure:
HATU (464 mg, 1.22 mmol, 1.0 equiv.) and DIPEA (0.8 ml, 4.88 mmol, 4.0 equiv.) were added at 0° C. to a suspension of 2-(7-((tert-butoxycarbonylamino)methyl)-1H-indol-1-yl)acetic acid (372 mg, 1.22 mmol, 1.0 equiv.) in THF (8 ml), and the mixture was stirred for 15 min. A solution of 3-pyridin-4-yl-3,9-diazaspiro[5.5]undecane (F-14) (283 mg, 1.22 mmol, 1.0 equiv.), dissolved in a mixture of THF (4 ml) and DMF (0.5 ml), was added, and stirring was carried out for 14 h at RT. The reaction mixture was diluted with ethyl acetate (30 ml) and extracted with sodium bicarbonate solution (2×20 ml), NH4Cl solution (2×20 ml), water (20 ml) and sat. NaCl solution (20 ml) and dried over Na2SO4. The solvent was removed under vacuum and the crude product was purified by column chromatography (Alox neutral; 0.5% MeOH/DCM), and the desired product was thus obtained in the form of a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]>C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][N:23]=[C:24]4[CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCCc1nccc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCC(=O)O)nccc34)no2)cc1Cl
Temperature: 70 °C
Yield: 15.9 %

Procedure:
Sodium hydroxide (16 mg) was added to a suspension of ethyl 4-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]butanoate (D41; 0.1 g) in isopropanol (10 ml) and water (10 ml). The reaction mixture was heated to 70° C. for 2 hours. After cooling, isopropanol was evaporated in vacuo and the remaining aqueous solution was acidified with aq. HCl (0.5 N) to pH=1. The aqueous solution was extracted with DCM (2×20 ml). The organic fractions were combined and dried over anhydrous sodium sulphate. The dried solution was filtered and the filtrate was concentrated. The residue was washed with THF (3×10 ml) to afford the title compound (15 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.04 (2H, m), 2.40 (2H, m), 3.34 (2H, m), 4.89 (1H, m), 7.47 (1H, d), 7.88 (1H, dd), 8.17 (1H, dd), 8.24 (1H, d), 8.57 (4H, m), 12.11 (1H, s).
Reaction SMILES: Cl.[NH:2]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:3]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:25]([NH:27][CH2:28][C:29]([NH:31]N)=[O:30])=[O:26])[CH2:23][OH:24])=[O:20])[CH3:18])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.N[C@H:44]([CH2:49][OH:50])[CH2:45][C:46](=[O:48])[NH2:47].C(N(CC)CC)C>O1CCOCC1.N(OC(C)(C)C)=O.CN(C=O)C.C(OCC)(=O)C>[NH:2]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:3]([C:14]([NH:16][C@H:17]([C:19]([NH:21][C@H:22]([C:25]([NH:27][CH2:28][C:29]([NH:31][C@H:44]([CH2:49][OH:50])[CH2:45][C:46](=[O:48])[NH2:47])=[O:30])=[O:26])[CH2:23][OH:24])=[O:20])[CH3:18])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1
Reactant: NC(=O)C[C@H](N)CO
Reactant: C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)NCC(=O)NN
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@H](CO)CC(N)=O
Reaction time: 0.25 h

Procedure:
2.9 ml of 5.6 N HCl in dioxan and 0.67 ml of tert. butyl nitrite are added at -20° to a solution of 3.2 g of Z-Trp-Ala-Ser-Gly-NHNH2 in 50 ml of DMF. After standing 15 minutes at -20° 1.89 of L-Asparaginol hydrochloric and 2.5 ml of triethylamine are added. After standing for 15 hours at room temperature the reaction mixture is considerably reduced in volume, diluted with ethyl acetate and washed with dilute aqueous hydrochloride acid and with water. The title compound precipitates from the concentrated solution.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[CH:3]=1.[B:13]1(B2OC(C)(C)C(C)(C)O2)[O:17]C(C)(C)C(C)(C)[O:14]1.C([O-])(=O)C.[K+]>O1CCOCC1.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][C:4]1[CH:3]=[C:2]([B:13]([OH:17])[OH:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(B(O)O)cc1C
Temperature: 95 °C
Reaction time: 2 h
Yield: 45.4 %

Procedure:
To a solution of methyl 4-bromo-2-methylbenzoate (6.9 g) in 1,4-dioxane (150 ml) was added bis(pinacolato)diboron (8.03 g), dichlorobis(triphenylphosphine)palladium(II) (1.69 g) and potassium acetate (8.87 g), and the mixture was stirred at 95° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated. To a suspension of the crude product (11 g) in acetone (200 ml) and water (200 ml) was added ammonium acetate (5.1 g) and sodium periodate (14.1 g), and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, and the mixture was diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The resultant solid was triturated with diisopropyl ether to give [3-methyl-4-(methoxycarbonyl)phenyl]boronic acid (2.65 g).