Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[N:30]=[CH:29][CH:28]=[CH:27][C:21]=2[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:12][CH2:11]1.[Cl:31]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:31][C:28]1[CH:29]=[N:30][C:20]([NH:19][CH2:18][CH2:17][CH2:16][N:13]2[CH2:12][CH2:11][N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH3:2])[CH2:15][CH2:14]2)=[C:21]([CH:27]=1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccccc1N1CCN(CCCNc2ncccc2C(=O)N(C)C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCNc2ncc(Cl)cc2C(=O)N(C)C)CC1
Temperature: 55 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
A mixture of 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide hydrochloride (0.287 g, 0.66 mmol), prepared as in Example 21, in 6 mL of DMF was heated to 50° C. and N-chlorosuccinimide (0.1 g, 0.73 mmol) was added. The mixture was stirred at 55° C. for 4 hours, diluted with water and basified with K2CO3 giving a precipitate. The precipitate was extracted with diethyl ether and the ether layer was washed twice with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with 5% methanol/methylene chloride to give 5-chloro-2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propylamino}-N,N-dimethylnicotinamide (0.188 g, 0.435 mmol) as an oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[N:21]=[C:20]([Br:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:23])=[CH:8][CH:7]=1>N1C=CC=CC=1>[Br:22][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:23])[N:12]([C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:7][CH:8]=2)[N:21]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-n2nc(Br)c3ccccc3c2=O)cc1
Reaction time: 12 h
Yield: 65 %

Procedure:
Acetyl chloride (0.15 g, 1.90 mmol) was added at room temperature to a stirred solution of 2-(4-amino-phenyl)-4-bromo-2H-phthalazin-1-one (0.30 g, 0.95 mmol) in pyridine (3 ml). Stirring was continued for 12 h before the solvent was evaporated in vacuum. The resulting raw product was dissolved in H2O and the title compound was collected by filtration (0.22 g, 65% yield). 1H-NMR: (400 MHz, D6-DMSO) 10.16 (1H, s), 8.37 (1H, d), 8.08 (1H, t), 8.00–8.03 (2H, m), 7.72 (2H, d), 7.52 (2H, d), 2.05 (3H, s); MS (ESI+)=358.15 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH:6]([C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:9])[C:5]([CH3:17])([CH3:16])[CH2:4][O:3]1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:13](=[O:15])[CH2:12][CH2:11][NH:10][C:8]([CH:6]1[C:5]([CH3:17])([CH3:16])[CH2:4][O:3][C:2]([CH3:1])([CH3:18])[O:7]1)=[O:9]
Reactant: Nc1ccccc1O
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)Nc2ccccc2O)O1
Yield: 96.8 %

Procedure:
3-[N-(2,2,5,5-Tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid (0.26 g) and 0.13 g of o-aminophenol were reacted in the same manner as in Reference Example 15 to obtain 0.34 g of the objective compound (yield: 98%).
Reaction SMILES: [CH2:1]([S:11](Cl)(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC.[OH-].[Na+]>[CH2:1]([S:11]([NH:15][C@H:16]([C:24]([OH:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:13])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCCCCCCS(=O)(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of decanesulfonyl chloride (0.8571 g, 3.56 mmol) in ether (7.5 ml) was added to a solution of L-phenylalanine (0.7441 g, 4.40 mmol) in 10 ml of 1.0 N sodium hydroxide and stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate and the aqueous phase was separated and acidified to pH 1 with 6 N hydrochloric acid. The resulting precipitate was extracted into ethyl acetate and the extract was washed with water and dried with magnesium sulfate. Evaporation of the ethyl acetate gave an oil which crystallized (see Table 1). Yield 0.245 g; FABMS m/z 370(M+H)+, 392(M+Na)+, Calculated for C19H32NO4S, 370.20; C19H31NO4SNa, 392.19.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C@H:26]1[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]1)[N:20]=[C:19]2[C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C@H:26]1[C@H:21]([CH2:22][CH2:23][CH2:24][CH2:25]1)[N:20]=[C:19]2[C:32]1[CH:33]=[CH:34][C:35]([N:38]([S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])=[CH:36][CH:37]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.45 g of 4-nitrobenzenesulfonyl chloride in 20 ml of methylene chloride are added dropwise to a solution of 2.0 g of (+/-)-cis-8,9-dimethoxy-6-(4-aminophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine in 50 ml of methylene chloride and 1.0 ml of triethylamine. The solution is stirred overnight at RT, extracted with water, and the organic phase is dried and concentrated. The residue is chromatographed on silica gel using a mixture of petroleum ether/ethyl acetate in the ratio 3:2. After concentration of the corresponding eluate fractions, the title compound of m.p. 234.5° C. is obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:11]1([CH2:17][OH:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>>[CH:11]1([CH2:17][O:18][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OCC1CCCCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(OCC2CCCCC2)nc1

Procedure:
6-(Cyclohexylmethoxy)nicotinic acid was prepared from 6-chloronicotinic acid (0.50 g), cyclohexylmethanol (0.41 ml) and sodium hydride (60%, 0.32 g) according to the method described in Example 54 to give the product as a white solid (0.42 g, 56%): δH (400 MHz, DMSO-d6) 12.97 (1H, br), 8.70 (1H, d, J 2.5 Hz), 8.12 (1H, dd, J 8.5, 2.5 Hz), 6.88 (1H, d, J 8.5 Hz), 4.14 (2H, d, J 6 Hz), 1.81–1.60 (6H, m), 1.20 (3H, sept of triplets, J 12, 2.5 Hz) and 1.03 (2H, dq, J 11, 2.5 Hz); HPLC (XTERRA, 50/80,220 nm) 100% (1.47 min).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2].[NH2:28][CH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:28][CH2:29][C@H:30]2[CH2:34][CH2:33][CH2:32][N:31]2[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:14])=[C:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[N:10]=1)#[N:2]
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)c(NCCc2cccc(F)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)c1ccc(-c2ccccc2C#N)nc1NCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a mixture of 6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinic acid (510 mg, 1.41 mmol), (R)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (424 mg, 2.11 mmol), HOBT (285 mg, 2.11 mmol), and HBTU (800 mg, 2.11 mg) in RB flask was added DMF and the mixture was stirred at r.t. for 1 h. LC/MS indicated the reaction was complete and the mixture was filtered and purified on RP-HPLC using a mixture of acetonitrile and water to give (R)-tert-butyl 2-((6-(2-cyanophenyl)-2-(3-fluorophenethylamino)nicotinamido)methyl)pyrrolidine-1-carboxylate (695.1 mg, 91%). LRMS (M+H+) m/z 544.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[NH2:17][C:18]1[C:19]([I:29])=[C:20]([O:26][CH2:27][CH3:28])[CH:21]=[C:22]([CH:25]=1)[CH:23]=O>>[NH2:17][C:18]1[C:19]([I:29])=[C:20]([O:26][CH2:27][CH3:28])[CH:21]=[C:22]([CH:25]=1)[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: CCOc1cc(C=O)cc(N)c1I
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc(N)c1I
Yield: 8 %

Procedure:
The title compound (4 mg, 8%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 5-amino-3-ethoxy-4-iodo-benzaldehyde. MS: 495.4 (MH+).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][CH2:11][CH:10]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.CCOCC>[Si:1]([O:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][CH2:11][C:10]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(c2cccc(F)c2F)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H](c2cccc(F)c2F)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 mL round-bottomed flask (t=g) was added 2-(tert-butyldimethylsilyloxy)-5-(2,3-difluorophenyl)cycloheptanol (1.73 g, 4.85 mmol) in CH2Cl2 (50 mL) to give a colorless solution. Dess-Martin Periodinane (2.264 g, 5.34 mmol) was added in one portion, and the mixture was stirred at room temperature overnight. 17 h: TLC showed complete conversion. It was diluted with Et2O and treated with 40 ml saturated Na2S2O3 and Na2HCO3 solution (1/1 mixture) until the milky solution became clear (10 min). The layers were separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed with brine, dried with Na2SO4, and concentrated to a colorless oil (with some solids insoluble in hexane). Purification by FCC up to 40% Et2O in hexane afforded two peaks. They were individually pooled and concentrated. The less polar major one (978 mg, 55%) was a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.02-6.90 (m, 3H), 4.34 (d, J=4.6 Hz, 1H), 2.82-2.75 (m, 2H), 2.54-2.46 (m, 1H), 2.45-2.32 (m, 1H), 2.17-1.98 (m, 2H), 1.90-1.68 (m, 3H), 0.94 (s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 213.4, 150.7 (dd, J=247.6 and 13.4 Hz), 147.8 (dd, J=245.7 and 13.4 Hz), 137.5 (d, J=11.5 Hz), 127.7, 122.2, 114.7 (d, J=17.3 Hz), 79.0, 40.0, 39.2, 33.2, 30.7, 29.4, 25.8, 18.2, −5.0. The more polar minor one solidified upon standing to a white solid (698 mg, 39%). It was re-crystallized from hexane and X-ray analysis verified the anti-stereochemistry relation. 1H NMR (500 MHz, CDCl3) δ 7.10-6.97 (m, 2H), 6.97-6.90 (m, 1H), 4.34 (dd, J=3.0 and 9.7 Hz, 1H), 3.04-2.94 (m, 1H), 2.80-2.70 (m, 1H), 2.62-2.50 (m, 1H), 2.18-1.72 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.06 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 211.0, 150.8 (dd, J=248.6 and 13.5 Hz), 148.1 (dd, J=246.7 and 12.5 Hz), 136.4 (d, J=11.5 Hz), 124.2, 122.3, 115.1 (d, J=17.3 Hz), 78.4, 40.3, 39.4, 34.3, 33.0, 30.4, 25.9, 18.5, −4.5, −5.1.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[S:41]([NH2:44])(=[O:43])=[O:42]>>[S:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[C:33]1[S:41]([NH:44][C:23]([NH:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([N:13]2[C:6]3=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]3[N:4]=[C:3]2[CH2:1][CH3:2])=[CH:19][CH:18]=1)=[O:24])(=[O:42])=[O:43]
Reactant: NS(=O)(=O)c1cc2ccccc2s1
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2cc3ccccc3s2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 1-benzothiophene-2-sulfonamide (Chern, J.; Leu, Y.; et al. J. Med. Chem., 1997, 40, 2276.; Graham, S. L.; Shepard, K. L.; et al. J. Med. Chem., 1989, 32, 2548).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:26])[C:4]=1[CH2:27][CH2:28][C:29](O)=[O:30])[CH3:2].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:74]([NH:81][CH2:82][CH2:83][NH2:84])([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75]>CN(C=O)C>[C:77]([O:76][C:74](=[O:75])[NH:81][CH2:82][CH2:83][NH:84][C:29](=[O:30])[CH2:28][CH2:27][C:4]1[C:5]([CH3:26])=[CH:6][C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[CH:15]=3)[O:11][N:10]=2)=[CH:8][C:3]=1[CH2:1][CH3:2])([CH3:78])([CH3:79])[CH3:80]
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(C)C(C)C)c3)n2)cc(C)c1CCC(=O)NCCNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionic acid (41 mg, 0.097 mmol) and DIPEA (38 mg, 0.291 mmol) in DMF (3 mL) is added PyBOP (56 mg, 0.107 mmol) at 0° C. The mixture is stirred for 15 min at 0° C. before N-BOC-ethylenediamine (17 mg, 0.107 mmol) is added and stirring is continued for 1 h at 0° C. The reaction is quenched with 2 mL water, and the mixture is diluted in sat. aq. NaHCO3-solution, and extracted three times with diethyl ether. The combined org. extracts are dried over MgSO4, filtered and dried to give crude {2-[3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionylamino]-ethyl}-carbamic acid tert-butyl ester (44 mg). This material is dissolved in 4 N HCl in dioxane (5 mL) and the mixture is stirred at rt for 18 h. The solvent is evaporated and the crude product is purified on prep. TLC plates with DCM containing 6% of 7 N NH3 in methanol to give N-(2-amino-ethyl)-3-(2-ethyl-4-{5-[2-(isopropyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenyl)-propionamide (23 mg) as a yellow solid; LC-MS: tR=0.72 min; [M+1]+=465.32.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:20][CH2:19][CH2:18][CH2:17][N:8]1[CH:7]([CH2:6][C:5]2[CH:21]=[CH:22][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:32]
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=Nc1ccccc1Cl
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1ccccc1Cl

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 2-chlorophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]([C:9]3[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=3[N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)=[N:8][C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:27]=[CH:26][C:5]3[N:6]([C:22]([CH3:23])([CH3:25])[CH3:24])[C:7]([C:9]4[CH:10]=[C:11]([CH2:20][OH:21])[CH:12]=[CH:13][C:14]=4[N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:8][C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(Br)ccc21
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)n1c(-c2cc(CO)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 110 °C
Yield: 61.9 %

Procedure:
To a sealed vial is added [3-(5-bromo-1-tert-butyl-1H-benzoimidazol-2-yl)-4-[1,2,4]triazol-1-yl-phenyl]methanol (47 mg, 0.11 mmol) in DMF (2 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (29 mg, 0.13 mmol) and tetrakis(triphenylphosphine)palladium(0) (13 mg, 0.011 mmol) and 2M aqueous Na2CO3 (0.25 mL, 0.5 mmol). The reaction mixture is heated under argon at 110° C. for 2 hours. The residue is diluted with EtOAc (10 mL), washed with brine (10 mL), and dried under anhydrous Na2SO4 (500 mg). The mixture is filtered and is concentrated. The residue is purified by silica gel flash chromatography with 0-10% 2M NH3 in MeOH/CH2Cl2 as the eluent. The product fractions are collected and concentrated to afford the title compound (30 mg, 62%). LCMS (ESMS): m/z 441.32 (M++1)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.O.[NH2:12][NH2:13]>C(O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:12][NH2:13])=[O:9]
Reactant: NN
Reactant: COC(=O)c1cnccn1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Methyl 2-pyrazinecarboxylate (I132) (42 g, 304 mmol) was dissolved in ethanol (750 mL) and treated with hydrazine hydrate (22.17 mL, 456 mmol). The solution was stirred at room temperature for 5 minutes whereupon a precipitate started to form. The mixture was cautiously heated to 80° C. for 5 h and cooled to room temperature. Approximately 50% of the solvent was then removed in vacuo, the slurry was heated to reflux and the solution cooled to room temperature overnight. The resulting solid was filtered, washed with a little ethanol, diethyl ether and dried in a vacuum oven to afford product in 39.77 g as beige needles.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([CH:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:9])=[O:15]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)c2ccccc2Cl)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A solution of 4-(dimethylamino)pyridine (33.96 g; 278 mmol) and 2,2-dimethyl-1,3-dioxane-4,6-dione (20.0 g, 139 mmol) in 50 mL of CH2Cl2 was cooled in an ice-salt bath to −10° C. A solution of 2-chlorobenzoyl chloride (29.2 g, 167 mmol) in 20 mL of CH2Cl2 was added dropwise via addition funnel over 1 h. After stirring cold for 1 h, the reaction was allowed to warm to rt and stirred for an additional 3 h. The resulting yellow-orange solution was then extracted with an aq. 10% HCl solution (200 mL) and 200 mL of brine. After drying with MgSO4, the mixture was filtered and the solvent was removed in vacuo. The resulting orange oil was triturated with hexanes (3×50 mL), affording the title compound (20 g) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>ClCCl.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanol (5 g, 25 mmol) in anhydrous dichloromethane (150 mL) was added triethylamine (7.5 g, 75 mmol), DMAP (300 mg, 2.5 mmol) and tert-butyldimethylsilyl chloride (7.5 g, 50 mmol) sequentially. The resulting pale brown solution was stirred at room temperature for overnight. The reaction mixture was extracted with dichloromethane and water three times. The combined organic layers were dried over anhydrous sodiumsulphate, filtered and concentrated in vacuo. The crude product was subjected to column chromatography with PE as eluant to afford the subtitle compound as a brown oil (7.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([C:23]1[O:24][CH:25]=[N:26][N:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[O:24][C:25]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:15])=[N:26][N:27]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(Cc2nnco2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 19, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-benzyl-[1,3,4]oxadiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([O:21]C)=[O:20])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc([C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cccc(C(=O)O)c1
Temperature: -15 °C
Yield: 98.4 %

Procedure:
To a stifling solution of (R)-2-(3-methoxycarbonyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (98.6 g, 319.7 mmol) in MeOH (1000 mL) in a water bath at 15° C. add 10M NaOH aqueous solution (500 mL) portionwise over 5 min (exotherm to 37° C.) and stir the reaction at ambient temp for 20 h. Concentrate the reaction in vacuo at 35° C. to remove MeOH and give a suspension. Dilute the slurry with water (200 mL), cool to −15° C. in a dry ice/iPrOH bath and quench with addition of concentrated HCl (417 mL) over 1 h with vigorous mechanical stirring maintaining internal temp at −5° C., to a final pH of 1. Extract the cold suspension with EtOAc (2×1500 mL), and wash the organics with water (2×1000 mL) and brine (400 mL). Dry the organic layers (Na2SO4), and concentrate at 40° C. to a solid. Suspend this in hexane (750 mL) and filter to give 91.65 g of the product (R)-2-(3-Carboxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a solid.