Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:10]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OB(O)c1cccnc1
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+]
Product: Oc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (139 mg, 0.12 mmol) was added to a flask containing 4-bromophenol (519 mg, 3.0 mmol), 3-pyridyl boronic acid (553 mg, 4.5 mmol) and sodium carbonate (1.27 g, 12.0 mmol). The flask was flushed with nitrogen and ethanol (6 mL) and water (0.6 mL) were added. The mixture was placed in an oil bath at 80° C. for 16 h. Upon cooling to RT the mixture was partitioned between water and chloroform. The aqueous layer was extracted with chloroform (3×) and the combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 40S) eluting with 50% ethyl acetate in hexanes to afford 165 mg (32%) of 4-pyridin-3-yl-phenol as a white solid: mp=194.6° C., MS (Cl) m/z 172.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].C(=O)(O)[O-:14].[Na+]>CS(C)=O.C(OCC)C>[CH2:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[O:14])[CH2:10][C:11]#[CH:12]
Reactant: O=C([O-])O
Reactant: C#CCCOCCCCCCBr
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: C#CCCOCCCCCC=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
6-Bromohexylbut-3-ynyl ether (DE3513885A1) (525 mg) in DMSO (2 ml) was added to a mixture of sodium bicarbonate (1 g) in DMSO (8 ml) at 150° C. with vigorous stirring and nitrogen bubbling through the solution. The mixture was stirred for 20 min at 150° C. and then allowed to cool to room temperature, diluted with diethyl ether and washed with water. The aqueous layer was extracted with diethyl ether and the combined ether layers were washed with dilute hydrochloric acid, brine, dried (MgSO4) and evaporated to dryness to give the title compound (325 mg): IR 1726 cm−1 MS(TSP+ve) m/z 186 (M+MH4)+.
Reaction SMILES: [CH3:1][C:2]1O[C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].O1C=CC=CC1=O.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[CH3:1][C:2]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(C)oc(C)c(C(=O)OCC)c1=O
Reactant: Nc1ccccc1
Agent: O=c1cccco1
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c(C)c(C(=O)OCC)c1=O

Procedure:
2,6-dimethyl-3,5-dicarboethoxy-N-phenyl-4-pyridone was prepared cording to Conrad and Guthzeit (M. Conrad and M. Guthzeit, Chem. Ber., 19, 19-26, (1886)), by reacting 2,6-dimethyl-3,5-dicarboethoxy-4-pyrone (said compound will be called hereinafter "the pyrone") and aniline in acetic acid. (m.p. 170°C).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8].ClC(Cl)(Cl)[C:20]([N:22]=C=O)=[O:21].N>C(#N)C.CO>[NH2:22][C:20]([NH:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:5]([CH3:10])[C:6]=1[C:7]([NH2:9])=[O:8])=[O:21]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: Cc1c(-c2ccc(Cl)cc2)sc(N)c1C(N)=O
Agent: N
Solvent: CO
Solvent: CC#N
Product: Cc1c(-c2ccc(Cl)cc2)sc(NC(N)=O)c1C(N)=O
Reaction time: 0.17 h

Procedure:
2-Amino-4-methyl-5-(4-chlorophenyl)-3-thiophencarboxamide (0.44 g) was suspended in acetonitrile (25 mL) and trichloroacetylisocyanate (0.2 mL) added dropwise with stirring over 10 minutes. Stirring was continued for a further 3 h at room temperature and then a 2M solution of ammonia in methanol (10 mL) was added and stirring continued for a further 2 h. The solvent was evaporated and the residue treated with water. The resultant solid was filtered off and washed with more water. The crude product was chromatographed on silica gel eluting with dichloromethane/methanol mixtures. Trituration with ether gave the title urea (0. 1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:26][C@H:25]([CH2:27][O:28]C(C3C=CC(C)=CC=3)=O)[C@@H:14]([O:15]C(C3C=CC(C)=CC=3)=O)[CH2:13]1)[C:6]([Br:38])=[C:5]2[C:39](=[O:41])[CH3:40].C[O-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C@@H:12]1[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[CH2:13]1)[C:6]([Br:38])=[C:5]2[C:39](=[O:41])[CH3:40]
Reactant: CC(=O)c1c(Br)n([C@H]2C[C@H](OC(=O)c3ccc(C)cc3)[C@@H](COC(=O)c3ccc(C)cc3)O2)c2cc(Cl)c(Cl)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)c1c(Br)n([C@H]2C[C@H](O)[C@@H](CO)O2)c2cc(Cl)c(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
5,6-Dichloro-2-bromo-3-acetyl-1-[3,5-di-O-(p-toluoyl)-2-deoxy-β-D-ribofuranosyl]indole (4.142, 1.24 g, 1.7 mmol) was suspended in absolute MeOH (75 mL) to which was added sodium methoxide (250 mg, 4.6 mmol). The suspension was stirred at room temperature for 2 h, after which time the solution first clarified and then a precipitate formed. Water (100 mL) was added, and the suspension was evaporated until no more MeOH remained. The remaining solids were filtered and recrystallized twice from MeOH/H2O to yield 475 mg (68%) of 4.143 as a white crystalline solid: mp slow dec. >235° C.; Rf 0.5 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.37 (s, 1H), 6.56 (dd, 1H), 5.46 (s, 1H, D2O exch.), 5.31 (s, 1H, D2O exch.), 4.48 (d, 1H), 3.92 (d, 1H), 3.76 (s, 2H), 2.65 (s, 3H), 2.48 (m, 1H), 2.13 (ddd, 1H). 13C-NMR (125 MHz, DMSO-d6): δ 192.59, 133.20, 126.74, 125.89, 125.77, 121.91, 121.80, 115.94, 115.32, 87.59, 87.30, 69.84, 60.66, 39.23 (under DMSO), 30.95. HRMS (EI) m/z calcd. for C15H14BrCl2NO4 420.9483, found 420.9493. Anal calcd for C15H14BrCl2NO4: C, 42.58; H, 3.34; N, 3.31. Found: C, 42.77; H, 3.25; N, 3.22.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[C-:19]#[N:20].[K+]>C(OCC)C>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([OH:8])([C:19]#[N:20])[CH2:4][CH2:3]1
Reactant: [C-]#N
Reactant: CC1CCC(=O)CC1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC1CCC(O)(C#N)CC1

Procedure:
4-Methylcyclohexanone (1.0 g, 8.9 mmol) was added to a stirred solution of water (8.9 mL) containing sodium metabisulfite (0.98 g, 5.2 mmol). The resulting mixture was allowed to stir at ambient temperature for 15-30 minutes before diethyl ether (8.9 mL) was added followed by potassium cyanide (0.91 g, 14 mmol). The biphasic mixture was stirred vigorously for at least 30 minutes before the layers were partitioned and the organic layer was washed with water, followed by brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford 4-methyl-1-hydroxycyclohexanecarbonitrile as a crude residue, which was carried forward without further purification. The crude residue (0.50 g, 3.6 mmol) was combined with pyridine (18.3 mL, 226 mmol), and POCl3 (1.34 mL, 14.4 mmol) in a microwave vial and sealed. The reaction mixture was heated to reflux for 16 hours. The reaction mixture was then cooled to ambient temperature, diluted with diethyl ether, and washed with 2N aqueous HCl saturated with sodium chloride (3×). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo (23° C. water bath) to afford the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[ClH:1].[O:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]2=[C:2]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=2)[CH:7]=1
Reactant: Clc1cc(-c2ccco2)nc2c1CCC2
Reactant: Nc1ccc(CCO)cc1
Product: Cl
Product: OCCc1ccc(Nc2cc(-c3ccco3)nc3c2CCC3)cc1
Yield: 36.7 %

Procedure:
Following general procedure B1, 4-chloro-2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.064 g, 0.29 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.048 g, 0.35 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.038 g, 37%) as a white solid. MW=356.85. 1H NMR (DMSO-d6, 500 MHz) δ 14.14 (s, 1H), 9.57 (s, 1H), 7.95 (s, 1H), 7.52 (s, 1H), 7.35 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 6.77-6.72 (m, 1H), 4.68 (s, 1H), 3.66 (t, J=7.0 Hz, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.78 (t, J=7.0 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); APCI MS m/z 321 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH2:8][Br:10])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)c(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)cc1Br
Yield: 34.4 %

Procedure:
3-Bromo-2-chloro-5-methylpyridine (4 g, 19.37 mmol), N-bromosuccinimide (3.79 g, 21.3 mmol) and benzoic peroxyanhydride (0.239 g, 0.969 mmol) were combined in carbon tetrachloride (40 mL), heated under reflux for 24 hours, cooled, and filtered to remove succinimide. The filtrate was concentrated. The resulting residue was purified by chromatography (silica gel, 0-30% ethyl acetate in heptanes) to afford the title compound (1.9 g, 34%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]3[C:14]([CH:18]=2)=[N:15][O:16][N:17]=3)[CH:5]=[C:6](OC)[CH:7]=1.C[Sn]([C:23]1[N:24]=[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]2[CH:31]=1)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)[CH:53]=[O:54]>>[CH3:53][O:54][C:3]1[CH:2]=[CH:7][C:6]([C:28]2[CH:29]=[CH:30][C:25]3[N:26]([CH:31]=[CH:23][N:24]=3)[CH:27]=2)=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][C:13]2[C:14]([CH:18]=1)=[N:15][O:16][N:17]=2
Reactant: C[Sn](C)(C)c1cn2ccccc2n1
Reactant: CN(C)C=O
Reactant: COc1cc(Br)cc(-c2ccc3nonc3c2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2ccc3nccn3c2)cc1-c1ccc2nonc2c1
Temperature: 125 °C

Procedure:
A stirred mixture of 5-(3-bromo-5-methoxyphenyl)benzofurazan (2.44 g, 8 mmol), 6 (trimethylstannyl)imidazol[1,2-a]pyridine (2.2 g, 7.9 mmol), triphenylphosphine (336 mg, 1.28 mmol), and bis(dibenzylidineacetone)palladium(0) (186 mg, 0.32 mmol) in dimethylformamide (60 mL) is heated at 125° C. under an argon atmosphere for 36 h. The solvent is evaporated off under reduced pressure to yield a crude product which is purified by chromatography (silica gel, 95% ethyl acetate/4.5% ethanol/0.5% aqueous NH3 (25%)) and recrystallised from ethyl acetate-t-butylmethyl ether to give 6-[4-methoxy-3-(5-benzofurazanyl)phenyl]imidazo[1,2-a]pyridine as a pale-yellow crystalline solid, m.p. 190-196° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[CH3:29][C:30]1[S:31][C:32]([CH:36]=O)=[C:33]([CH3:35])[N:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:36][C:32]2[S:31][C:30]([CH3:29])=[N:34][C:33]=2[CH3:35])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Cc1nc(C)c(C=O)s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc(C)c(CNC2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
Sodium triacetoxyborohydride (4.5 g, 21.23 mmol) is added to a stirred solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.63 g, 13.13 mmol), 2,4-dimethyl-thiazole-5-carboxaldehyde (1.95 g, 13.81 mmol, Maybridge), acetic acid (0.80 ml, 13.98 mmol) and 1,2-dichloroethane (125 ml). The reaction is stirred overnight at room temperature under nitrogen. The reaction is poured into 2N NaOH (300 ml) and extracted with ethyl acetate (200 ml×3). The ethyl acetate is dried over sodium sulfate, filtered, and the filtrate concentrated. The crude product is purified by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield (2.93 g, 69%) of 4-{[(2,4-dimethyl-thiazol-5-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=326.2 (M+1); 1H NMR (CDCl3): δ=4.10 (2H, br m), 3.91 (2H, s), 2.88-2.79 (2H, brm), 2.73-2.66 (1H, m), 2.66 (3H, s), 2.34 (3H, s), 1.86 (2H, brd), 1.48 (9H, s), 1.36-1.24 (3H, m).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1)[C@@H:3]([C@H:12]1[CH2:16][C@@H:15]([O:17][CH2:18][CH2:19][CH3:20])[CH2:14][N:13]1C(OC(C)(C)C)=O)[O:4][Si](C(C)(C)C)(C)C.[Si](O[C@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)[C@@H:46]([NH:56][C:57](=[O:67])[C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([C:64](=[O:66])N)[CH:59]=1)[CH2:47][C:48]1C=C(F)C=C(F)C=1)(C(C)(C)C)(C)C.[C:84](OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=CC=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNCCC>ClCCl.C(OCC)(=O)C>[F:35][C:33]1[CH:34]=[C:29]([CH2:28][C@H:2]([NH:1][C:64](=[O:66])[C:60]2[CH:61]=[CH:62][CH:63]=[C:58]([C:57]([N:56]([CH3:84])[CH2:46][CH2:47][CH3:48])=[O:67])[CH:59]=2)[C@H:3]([OH:4])[C@H:12]2[CH2:16][C@@H:15]([O:17][CH2:18][CH2:19][CH3:20])[CH2:14][NH:13]2)[CH:30]=[C:31]([F:36])[CH:32]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)Cc2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(N)=O)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N(C)CCC)c2)C1
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Step 2 (A): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-2-(3-(carbamoyl)benzamido)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid (Step 1 (C), 60 mg, 0.088 mmol) in dichloromethane (2 mL) was added Hunig's base (34 mg, 0.267 mmol) to make a clear solution and HATU (45 mg, 0.12 mmol) was then added. After stirring for 20 min, the reaction mixture was added N-methylpropan-1-amine (13 mg, 0.178 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O, dried and concentrated to give 55 mg of the title compound (85% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.71-0.76 (1H, m), 0.83 (9H, s), 0.87 (3H, m), 0.91-1.00 (2H, m), 1.40-1.53 (12H, m), 1.60-1.67 (1H, m), 2.01-2.05 (1H, m), 2.17-2.20 (1H, m), 2.64 (1H, m), 2.89-3.04 (4H, m), 3.17 (1H, brd s), 3.27-3.36 (3H, m), 3.48 (1H, brd s), 3.74 (1H, m), 3.97 (1H, m), 4.04-4.11 (2H, m), 4.58 (1H, m), 6.58 (1H, m), 6.76 (2H, d, J=5 Hz), 7.41-7.48 (2H, m), 7.86 (2H, s), 8.13 (1H, brd s).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=CC=CC=1.[Mg].[CH:17]([N:30]1[CH2:33][CH2:32][CH:31]1[C:34]#[N:35])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[CH:17]([N:30]1[CH2:33][CH2:32][CH:31]1[C:34](=[NH:35])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#CC1CCN1C(c1ccccc1)c1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Mg]
Solvent: Brc1ccccc1
Solvent: CCOCC
Product: N=C(c1ccccc1)C1CCN1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Suspend phenylmagnesium bromide in ether by adding under gentle reflux a solution of 189.2 g of bromobenzene in 500 ml of ether to a stirred suspension of 24.4 g of magnesium turnings in 1000 ml. of dry ether. Upon completion of the addition, reflux for another 30 minutes, then allow the mixture to cool for 15 minutes at room temperature. Add portionwise, over 3 to 4 minutes, 119.6 g of 1-benzhydryl-2-cyanoazetidine. Stir the mixture for 18 hours at room temperature, cool to 0° C. and quench by the sequential addition of 750 ml. of water, 250 ml. of ether and 400 ml. of methylene chloride. Filter the mixture. Remove the aqueous layer of the filtrate. Wash the organic phase with water and dry over anhydrous sodium sulfate. Remove the solvent in vacuo. Triturate the solid residue with 500 ml of isopropyl ether and filter to obtain the analytically pure title product, m.p. 123.5°-126.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][N:15]([CH2:16][C:5]=3[C:4]=2[CH:3]=1)[CH2:14][CH2:13][CH2:12]4.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH2:24])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH2:24][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=3[C:5]3[CH2:16][N:15]4[CH2:17][CH:11]([C:6]2=3)[CH2:12][CH2:13][CH2:14]4)=[CH:21][CH:20]=1
Reactant: C=Cc1ccc(Cl)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCCC3C1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(Cl)cc2)C2CCCN(C1)C2

Procedure:
The coupling of 10-methyl-1,3,4,5,6,7-hexahydro-2,6-methanoazocino[4,3-b]indole (245.1 mg, 1.083 mmol; Example 201) and 4-chlorostyrene (256.3 mg, 1.709 mmol, Aldrich) was performed as described in Example 202, except that the material was purified by reverse-phase HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.13-1.45 (m, 3H), 1.67-1.79 (m, 1H), 2.31-2.35 (m, 1H), 2.42 (s, 3H), 2.63-2.69 (m, 1H), 2.96-3.11 (m, 5H), 3.82 (d, J=16.3 Hz, 1H), 4.07-4.15 (m, 1H), 4.24 (d, J=16.3 Hz, 1H), 4.34-4.42 (m, 1H), 6.78-6.83 (m, 2H), 6.97-7.00 (m, 1H), 7.12-7.19 (m, 3H), 7.27-7.31 (m, 1H); MS (DCI/NH3) m/z 365 (M+H)+.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[OH:3].C(O)[CH2:13][CH2:14][CH3:15].[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1>C(OCC)(=O)C>[C:1]([O:10][CH2:11][CH2:18][CH2:17][CH3:22])(=[O:9])[CH:2]([CH2:4][C:5]([O:7][CH2:8][CH2:13][CH2:14][CH3:15])=[O:6])[OH:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCO
Reactant: COC(=O)CC(O)C(=O)OC
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CC(O)C(=O)OCCCC
Temperature: 115 °C
Reaction time: 3.7 h

Procedure:
A 100 mL three-neck flask, equipped with a magnetic stir bar, a Claisen adapter with a thermocouple and a nitrogen inlet, and a short path condenser, was charged with 4.45 grams of dimethyl malate, 40 mL 1-butanol, and 0.51 gram of p-toluenesulfonic acid. The reaction was stirred at 115° C. for 3.7 hours with a nitrogen sweep. The reaction mixture was taken up in ethyl acetate, extracted with dilute aqueous sodium bicarbonate, washed three times with water, dried over magnesium sulfate, and filtered. Solvent was removed by rotary evaporation to yield 6.8 grams of a straw-colored liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH2:66]([O:68][C:69](=[O:73])[CH2:70][CH2:71][NH2:72])[CH3:67]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([NH:72][CH2:71][CH2:70][C:69]([O:68][CH2:66][CH3:67])=[O:73])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: COCc1cc(-c2nc(-c3cccc(CC(=O)O)c3)no2)ccc1-c1ccccc1C
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)Cc1cccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.6 %

Procedure:
To a solution (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetic acid (preparation described in Example 24 Step 1, 209 mg, 0.48 mmol) in DMF (2 mL) at 0° C. was added DIEA (252 μL, 1.5 mmol) and HATU (183 mg, 0.48 mmol). After 10 min, a solution of beta-alanine ethyl ester hydrochloride (82 mg, 0.53 mmol) in DMF (1 mL) was added and the reaction mixture stirred at RT overnight. EtOAc was added and the mixture was washed with water. The organic phase was then dried over MgSO4, filtered and concentrated in vacuo affording the title compound (100 mg, 40%). LC/MS (Method B): 514.1 (M+H)+. HPLC (Method A) Rt 4.73 min (Purity: 99.5%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:50])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])C(=O)OC(C)(C)C)=[CH:16][CH:15]=3)[S:13][C:6]=12.Cl.O>CC(O)=O>[F:1][C:2]1[CH:36]=[C:35]([NH:37][C:38]([NH:40][C:41](=[O:50])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([F:49])=[CH:47][CH:48]=2)=[S:39])[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:29][CH2:30][O:31][CH3:32])=[CH:18][N:19]=3)[S:13][C:6]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 14 (45.06 g, 62.6 mmol, 1 eq.,) in AcOH (338 mL) was added 1N HCl (188 mL) over 1 min. The reaction mixture was heated at 40° C. for 2 h. After cooling down to r.t., water (676 mL) was added. The reaction mixture turned into a suspension and was stirred at r.t. for 15 min. The solid was collected by filtration and the product cake was washed with water (2×100 mL) then dried in vacuum for 30 min to afford a crude hydrochloride salt of 15 as a white solid.