Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[OH:40]>CN1CCCC1=O>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[O:40][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1C(=O)OC(C)(C)C
Temperature: 140 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
Compound 1a (3.60 g) was dissolved in N-methylpyrrolidin-2-one (14 mL), and diisopropylethylamine (6.55 mL) and 2-fluoro-4-nitrophenol (2.89 g) were added to the solution. The mixture was heated to 140° C. and stirred for 4 hours. To the reaction mixture, distilled water was added on an ice bath, and the precipitate was filtrated, to thereby yield compound 1b (4.71 g, yield: 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=[C:4]2[C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.CC1(C)C(C)(C)OB([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:3]2[C:4]3[N:5]([C:8](=[O:14])[N:9]([CH2:11][O:12][CH3:13])[N:10]=3)[CH:6]=[CH:7][C:2]=2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:16][CH:17]=1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Reactant: COCn1nc2c(-c3ccc(Cl)cc3)c(Br)ccn2c1=O
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCn1nc2c(-c3ccc(Cl)cc3)c(-c3ccncc3)ccn2c1=O
Temperature: 20 °C
Yield: 80.2 %

Procedure:
To a degassed mixture of 7-bromo-8-(4-chlorophenyl)-2-(methoxymethyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (300 mg, 0.81 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (332 mg, 1.62 mmol) and K2CO3 (280 mg, 2.0 mmol) in 1,4-dioxane (10 mL) and H2O (3.0 mL) under argon at 20° C. was added Pd(PPh3)4 (47 mg, 0.043 mmol). The reaction mixture was refluxed for 15 h under argon and then cooled to 20° C. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extract was washed with saturated aqueous NaHCO3 solution (20 mL), then brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 0-60% gradient of EtOAc in hexanes to obtain the title compound as a yellow solid (241 mg, 0.65 mmol). MS: [M+H]+=367.2. 1H NMR (400 MHz, CDCl3) δ 3.45 (s, 3H), 5.32 (s, 2H), 6.59 (d, J=7.03 Hz, 1H), 7.04 (d, J=6.15 Hz, 2H), 7.18-7.23 (m, 2H), 7.26-7.30 (m, 2H), 7.85 (d, J=7.47 Hz, 1H), 8.53 (d, J=6.15 Hz, 2H).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH2:10][C:11]([OH:13])=O)=O)(C)(C)C.[Cl:25][C:26]1[C:45]([Cl:46])=[CH:44][C:29]2[N:30]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:31]([C@@H:33]3[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]3)=[N:32][C:28]=2[CH:27]=1>>[NH2:8][C@H:9]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH2:10][C:11]([N:35]1[CH2:36][CH2:37][CH2:38][C@@H:33]([C:31]2[N:30]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[C:29]3[CH:44]=[C:45]([Cl:46])[C:26]([Cl:25])=[CH:27][C:28]=3[N:32]=2)[CH2:34]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc2ccccc2c1
Reactant: COCCCn1c([C@@H]2CCCNC2)nc2cc(Cl)c(Cl)cc21
Product: COCCCn1c([C@@H]2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2cc(Cl)c(Cl)cc21

Procedure:
The title compound was prepared according to the procedure outlined in Example DI, Steps A-F, using reagents (R)-3-(tert-butoxycarbonylamino)-4-(naphthalen-2-yl)butanoic acid and (R)-5,6-dichloro-1-(3-methoxypropyl)-2-(piperidin-3-yl)-1H-benzo[d]imidazole in Step E. ESI-MS: m/z 553.4 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35-1.52 (m, 1H) 1.65-1.89 (m, 3H) 1.91-2.10 (m, 2H) 2.60-2.82 (m, 2H) 2.89-3.18 (m, 7H) 3.18-3.44 (m, 3H) 3.69-3.99 (m, 2H) 4.07-4.21 (m, 1H) 4.23-4.53 (m, 2H) 7.40-7.57 (m, 3H) 7.75-8.00 (m, 6H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15](Cl)=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](P(CCCC)CCCC)[CH2:19][CH2:20]C.C([Mg]Cl)CC>O1CCCC1>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][CH:11]([C:15](=[O:16])[CH2:18][CH2:19][CH3:20])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCCN(C(=O)c2ccccc2)C1
Reactant: CCCCP(CCCC)CCCC
Agent: CCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCC(=O)C1CCCN(C(=O)c2ccccc2)C1
Temperature: -20 °C
Yield: 38.5 %

Procedure:
1-benzoyl-3-piperidinecarbonyl chloride (1.01 g; 4.02 mmol) was dissolved in dry tetrahydrofuran (30 ml) under a nitrogen atmosphere, and cooled to −20° C. Tributylphosphine (1.1 ml; 4.4 mmol) was then added and after 20 minutes of stirring at −20° C., propylmagnesium chloride (2 ml; 4.0 mmol; 2 M in ether) was added. After stirring for 5 minutes, the reaction was quenched by addition of 1 N HCl (5 ml), and the mixture was allowed to warm to ambient temperature. It was then diluted with 1 N HCl and extracted with diethyl ether. The ether was washed with saturated sodium bicarbonate solution, and then brine. It was then dried with anhydrous magnesium sulfate and evaporated at ambient temperature under reduced pressure. The crude product was purified by chromatography on silica eluting with 50% ethyl acetate in hexane, giving 1-benzoyl-3-butyrylpiperidine (401.7 mg) as a colorless oil. MS m/z (positive ion) 260 (MH+; 100).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[CH2:13]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:13]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])=[O:24])=[CH:26][CH:27]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CCCCCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCOc1ccc(C(=O)NCC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.9 %

Procedure:
To a solution of 2-amino-4′-bromoacetophenone hydrochloride (8.2 g), 4-pentyloxybenzoic acid (6.8 g) and 1-hydroxybenzotriazole (4.42 g) in dichloromethane (80 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSCD) (6.0 ml), and stirred for 3 hours at ambient temperature. The reaction mixture was diluted with dichloromethane (800 ml), and washed with 1N hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in ethyl acetate, and collected by filtration to give 2-(4-pentyloxybenzamido)-4′-bromoacetophenone (2.49 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH:8]([OH:11])CO)[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][CH:8]=[O:11])[CH3:2]
Reactant: CCOC(=O)CN(CC(O)CO)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)CN(CC=O)C(=O)OCc1ccccc1
Reaction time: 4.5 h
Yield: 92.7 %

Procedure:
To a solution of [benzyloxycarbonyl-(2,3-dihydroxy-propyl)-amino]-acetic acid ethyl ester (1.98 g, 6.37 mmol) in DCM (30 mL) is added NaIO4-impregnated silica (13.04 g). The slurry is stirred rapidly for 4.5 h, and then filtered through a coarse porosity sintered glass funnel. The filtrate is concentrated to afford [benzyloxycarbonyl-(2-oxo-ethyl)-amino]-acetic acid ethyl ester (1.65 g, 92%). MS: 280 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.60-9.68 (m, 1H), 7.26-7.40 (m, 5H), 510-5.19 (m, 2H), 4.00-4.22 (m, 6H), 1.18-1.30 (m, 3H). (see Y.-L. Zhong, T. K. M. Shing J. Org. Chem. 1997, 62 (8), 2622-2624).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]1=[O:22].[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:34][C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH2:15]([N:4]1[C@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH2:8][C@H:2]([NH:1][C:37](=[O:38])[C@H:35]([CH3:36])[NH:34][C:32](=[O:33])[CH2:31][C:26]2[CH:27]=[C:28]([F:30])[CH:29]=[C:24]([F:23])[CH:25]=2)[C:3]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H]1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CC=C[C@@H](c2ccccc2)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
To a solution of (3S,7S)-3-amino-1-benzyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (5d) (40 mg) in DCM (2 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (33 mg), HOBt-hydrate (46 mg), EDAC.HCl (39 mg) and N-methyl morpholine (22 mg). The reaction mixture was stirred 1 h at 0° C. and 3 h at RT, then diluted with 30% hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1%-2% MeOH/DCM) to afford a white solid (50 mg, 71%). Sample contains approx. 20% 5A.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([OH:23])[CH2:21]Cl)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]2[CH2:21][O:23]2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c([C@@H](O)CCl)ccc(OCc3ccccc3)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1ccc2c([C@@H]3CO3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A suspension of (R)-8-benzyloxy-5-(2-chloro-1-hydroxyethyl)carbostyril (130 mg, 0.4 mMol) in acetone (10 ml) containing potassium carbonate (276 mg, 2 mMol) was stirred at 60° C. under an argon atmosphere for 18 hours. After cooling, the suspension was filtered and the filter pad was washed with acetone. The filtrates were combined and evaporated. Purification of the residue by chromatography on silica gel eluting with ethyl acetate gave the title compound as a pale yellow solid; m.p. 146°-150° C.; [α]D25 -30° (c=0.91, chloroform).
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:28](O)=[O:29])[N:18]([CH3:27])[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[CH2:1]([NH:7][C:28]([C:17]1[N:18]([CH3:27])[C:19]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([CH3:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Product: CCCCCCNC(=O)c1nc(-c2ccc(C)cc2)c(-c2ccc(C)cc2)n1C

Procedure:
Using essentially the same procedure as Example 9, Step B, but using hexylamine (0.020 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound. HPLC/MS: 390 (M+1); Rt=4.45 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[N:12][CH:13]=1)([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[CH3:47][P:48](Cl)([CH3:50])=[O:49]>ClCCl>[CH3:47][P:48]([CH3:50])(=[O:49])[O:1][CH2:2][CH2:3][O:4][C:5]([C:8]1[CH:13]=[N:12][C:11]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[CH:10][N:9]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(OCCO)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reactant: CP(C)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(OCCOP(C)(C)=O)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reaction time: 2 h
Yield: 8.4 %

Procedure:
To a solution of 1-(((5S,7S)-3-(5-(2-(2-hydroxyethoxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (60 mg, 0.119 mmol) in dichloromethane (DCM) (1127 μl) was added DIEA (62.3 μl, 0.357 mmol) and dimethylphosphinic chloride (40.1 mg, 0.357 mmol) at RT. The mixture was stirred for 2 hours, concentrated and reconstituted in DMSO/MeOH and filtered. The solution was purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile: Water TFA 30-70%, 50 mL/min, 15 min.). The product was free based with PL-HCO3 resin SPE to yield 2-((2-(5-((5S,7S)-7-((6-cyano-1H-benzo[d]imidazol-1-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-3-yl)pyrazin-2-yl)propan-2-yl)oxy)ethyl dimethylphosphinate as a white solid (5.8 mg, 8%). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J=1.51 Hz, 1H), 8.60 (d, J=1.26 Hz, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 7.83 (d, J=8.53 Hz, 1H), 4.12-4.21 (m, 2H), 3.94-4.03 (m, 2H), 3.88 (dd, J=23.09, 10.04 Hz, 2H), 3.42 (t, J=4.77 Hz, 2H), 2.00 (d, J=13.30 Hz, 1H), 1.88 (d, J=14.05 Hz, 1H), 1.59-1.78 (m, 3H), 1.30-1.56 (m, 15H), 1.07 (s, 3H). MS (m/z) 581.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:29][CH:28]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Trifluoromethyl benzene boronic acid. MS (M+H) 421.1
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19](Br)=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH3:29])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC[C@H](OCC(Br)=Cc2ccccc2)CC1)OCc1ccccc1
Reactant: Cc1ccccc1B(O)O
Product: Cc1ccccc1C(=Cc1ccccc1)CO[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1

Procedure:
From trans-[4-(2-bromo-3-phenyl-allyloxy)-cyclohexyl]-carbamic acid benzyl ester, and 2-methylphenylboronic acid using the procedure described above for Example 11, Step 4, gave the product as a white crystalline solid: MS (m+1)=456.5; 1H NMR (400 MHz, CDCl3) 7.3 (m, 2H), 7.2 (m, 7H), 7.05 (m, 3H), 6.85 (m, 2H), 6.66 (s 1H), 5.05 (s, 2H), 4.55 (s, 1H), 4.28 (s, 2H), 3.5 (m, 1H), 3.42 (s, 3H), 3.3 (m, 1H), 2.0 (m, 4H), 1.4 (dd, 2H), 1.15 (dd, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.BrN1C(=[O:33])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH2:18][OH:33])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2CO)o1
Temperature: 70 °C
Reaction time: 4 h
Yield: 2.8 %

Procedure:
To a solution of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (1.95 g, 5.56 mmol) in carbon tetrachloride (20 mL) was added N-bromo succinimide (990 mg, 5.56 mmol) and 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) and the reaction mixture was stirred for 4 h at 70° C. Further 2,2′-azobis(2-methylpropionitrile) (46 mg, 0.28 mmol) was added and stirring was continued for another 14 h at 70° C. N-Bromo succinimide (378 mg, 2.12 mmol) was added and the mixture stirred for another 4 h at 90° C. After the reaction mixture was cooled to 0° C. the suspension was filtered off and was washed with dichloromethane (30 mL 1) and aqueous sodium hydrogencarbonate (1 N). It was extracted with dichloroemthane and dried over sodium sulfate resulting in crude material (1.66 g). A part of this light brown solid (200 mg) was suspended in water (0.5 mL) and DMSO (2.0 mL) and the reaction mixture was stirred for 18 h at 60° C. the resulting solution was diluted with ethyl acetate (10 mL) and washed with water (10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate. Drying over sodium sulfate and urification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 20:60:20) afforded the title compound (57 mg, 33%) as a white solid. MS: m/e=368.1 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:4][C:5]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[N:12]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:23]([CH2:25][C:26](O)=[O:27])[CH:24]=2)=[CH:16][C:15]=1[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:23]([CH2:25][C:26]([N:9]3[CH2:10][CH2:11][C:5]4[S:4][C:3]([CH3:2])=[N:12][C:6]=4[CH2:7][CH2:8]3)=[O:27])[CH:24]=2)=[CH:16][C:15]=1[CH3:35]
Reactant: Cc1nc2c(s1)CCNCC2
Reactant: Cc1cc(-c2cn(CC(=O)O)c(-c3ccccc3)n2)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1nc2c(s1)CCN(C(=O)Cn1cc(-c3ccc(F)c(C)c3)nc1-c1ccccc1)CC2
Temperature: 25 °C
Yield: 22.5 %

Procedure:
45 mg 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrochloride was added to 60 mg (4-(4-fluoro-3-methyl-phenyl)-2-phenyl-imidazol-1-yl)-acetic acid, 70 mg TBTU, 0.06 mL TEA in 1 mL DMF. The reaction was stirred over night at RT. The mixture was purified by HPLC (ZORBAX StableBond C18; 5 μm; 30×100 mm; gradient: water (+0.3% formic acid)/acetonitril=90/10-10/90 in 9 min; flow: 50 ml/min.) to give 20 mg desired product. Rt: 0.94 (method A), (M+H)+: 461
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH:11]([C:13](OC)=[O:14])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[C:1]1([CH:7]2[NH:12][CH:11]([CH2:13][OH:14])[CH2:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCCC(c2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CCCC(c2ccccc2)N1
Yield: 29.9 %

Procedure:
A solution of methyl 6-phenylpipecolinate (0.23 g) in THF (15 mL) was treated with 1M lithium aluminum hydride in ether (10 mL) at room temperature for 2 h. The reaction mixture was quenched with EtOAc, then MgSO4 was added and the mixture was filtered. The filtrate was concentrated to give a residue, which was purified by chromatography on silica gel plates (2, 1000 μm) using EtOAc:hexane 1:1 as the eluent, to give (6-phenyl-piperidin-2-yl)-methanol as a white solid (0.06 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:44][O:45][CH2:46][CH:47](O)[CH3:48]>C1COCC1.O>[CH3:44][O:45][CH2:46][CH:47]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:48]
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: COCC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COCC(C)Oc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.8 %

Procedure:
To 2-methylquinolin-8-ol (1.0 g, 6.28 mmol) in THF (5 mL) was added PPh3 (6.92 g, 26.4 mmol), DEAD (1.58 ml, 10.1 mmol) and 1-methoxypropan-2-ol (0.736 g, 8.17 mmol). The reaction was stirred for 24 hours at ambient temperature and then water was added. The aqueous phase was extracted with DCM and the combined organic phases dried over MgSO4, filtered and purified by reverse chromatography (SP4, 40M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-(1-methoxypropan-2-yloxy)-2-methylquinoline (1.0 g, 68.8% yield) as a clear liquid
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([CH3:26])[CH:20]=[CH:19][C:18]([S:21]([O:24][NH2:25])(=[O:23])=[O:22])=[CH:17][CH:16]=1.CCOCC>ClCCl>[C:15]1([CH3:26])[CH:16]=[CH:17][C:18]([S:21]([O-:24])(=[O:22])=[O:23])=[CH:19][CH:20]=1.[NH2:25][N+:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccn1
Reactant: Cc1ccc(S(=O)(=O)ON)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: N[n+]1ccccc1C(=O)c1ccccc1
Reaction time: 2 h

Procedure:
The starting substance is prepared as follows: To a solution of 1 g (5.5 millimoles) of 2-benzoyl-pyridine in 10 ml of dichloromethane a solution of 1.04 g (5.5 millimoles) of O-(p-toluenesulfonyl)-hydroxylamine in 20 ml of dichloromethane is added. The reaction mixture is allowed to stand for 2 hours, then ether is added. 1.5 g (74%), of 1-amino-2-benzoyl-pyridinium-p-toluene sulfonate are obtained.