Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B>C1COCC1>[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:10]([CH2:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]1)([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)Nc2ccccc2)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2ccccc2)C1
Yield: 91.5 %

Procedure:
(R)-1-Boc-piperidine-3-carboxylic acid phenyl amide 26 (5.26 g, 17.28 mmol) in 20 mL of dry THF was added slowly to 34.5 mL of 1.0 M borane in THF while stirring in an ice bath. The mixture was refluxed for 2 hours, then cooled in an ice bath, and quenched with 20 mL of aqueous HCl (10%), then treated with NaOH (10%) to pH ˜10. The mixture was extracted with ethyl acetate (3×100 mL). The extracts were combined and washed with brine (2×50 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to afford (R)—N-(1-Boc-piperidin-3-ylmethyl)-aniline 28 as a colorless oil (4.59 g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH3:13]>CCOC(C)=O.[Pt](=O)=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC=Cc1ccncc1Br
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCCCCCc1ccncc1Br
Reaction time: 1 h

Procedure:
A mixture of 3-bromo-4-(hex-1-en-1-yl)pyridine (Intermediate 12; 360 mg; 1.50 mmol) and platinum dioxide (34 mg; 0.15 mmol) in EtOAc (35 mL) was hydrogenated at 7 atm for 1 hour in a PARR apparatus. The reaction mixture was filtered, evaporated and purified by flash column chromatography, eluting with cyclohexane containing increasing amounts of EtOAc, affording the title compound as a colorless liquid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2cccnc2)ccn1
Yield: 96 %

Procedure:
Using the method of Example 3, Step A, pyridin-3-ol (0.450 g, 4.73 mmol), 60% sodium hydride in mineral oil (189 mg, 4.73 mmol), and 2-chloro-4-nitropyridine (0.750 g, 4.73 mmol) were reacted to provide 2-chloro-4-(pyridin-3-yloxy)pyridine (0.938 g, 96% yield) as a clear oil. 1H NMR (CDCl3) δ 8.57 (d, 1H), 8.49 (d, 1H), 8.28 (d, 1H), 7.39-7.48 (m, 2H), 6.86 (s, 1H), 6.82 (d, 1H).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+:2]=[N-:3]>CC(C)=O>[N:1]([C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:6]2([CH3:7])[C@@H:5]1[OH:24])[C:18]1[CH:17]=[CH:16][C:15]([O:22][CH3:23])=[CH:14][C:13]=1[CH2:12][CH2:11]3)=[N+:2]=[N-:3]
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@H](N=[N+]=[N-])C[C@@H]12
Solvent: CC(C)=O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@H](O)[C@H](N=[N+]=[N-])C[C@@H]12

Procedure:
Using 150 ml acetone, finally also 0.4 g 16α-azido-3-methoxy-estra-1,3,5(10)-triene-17β-ol (13%) is eluted.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[CH3:19][C:20]1([CH3:29])[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22](=O)[CH2:21]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21]2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Product: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(C#N)cc2)cc1
Yield: 50.2 %

Procedure:
The general McMurry protocol, described for 14 was used. The reaction was conducted between 4-{[4-(methyloxy)phenyl]carbonyl}benzonitrile (1.00 g, 4.21 mmol) and 3,3,5,5-tetramethylcyclohexanone (1.95 g, 12.64 mmol) to afford 0.760 g (50%) of the title compound 209 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.01 (s, 2H), 1.95 (s, 2H), 1.32 (s, 2H), 0.96 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C@H:14]2[C@H:19]3[CH2:20][CH2:21][C@H:16]([CH2:17][N:18]3[S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH2:15]2)=[O:13])=[N:9][CH:10]=1)([CH3:3])[CH3:2].CCCCCC>C(O)C>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([CH:14]2[CH:19]3[CH2:20][CH2:21][CH:16]([CH2:17][N:18]3[S:22]([C:25]3[N:26]=[CH:27][N:28]([CH3:30])[CH:29]=3)(=[O:24])=[O:23])[CH2:15]2)=[O:13])=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(NC(=O)[C@@H]2C[C@@H]3CC[C@H]2N(S(=O)(=O)c2cn(C)cn2)C3)nc1
Solvent: CCO
Solvent: CCCCCC
Product: CC(C)Oc1ccc(NC(=O)C2CC3CCC2N(S(=O)(=O)c2cn(C)cn2)C3)nc1
Yield: 20.6 %

Procedure:
The compound (561 mg, 1.29 mmol)synthesized in Example 48 was optically resolved using normal-phase chiral HPLC(CHIRALPAK OD 2 cm ø×25 cmL (Daicel Chemical Industries, Ltd.); mobile phase: hexane:ethanol=70:30; flow rate: 10 ml/min; isogradient), and (1R**,4S**,6R**)-N-(5-isopropoxypyridin-2-yl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide (retention time: 22 min; 109 mg), and (1S**,4R**,6S**)-N-(5-isopropoxypyridin-2-yl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide (retention time: 48.5 min; 115 mg) were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27]([NH2:29])=[S:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O>[F:31][C:15]1[CH:16]=[C:17]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27]([NH2:29])=[S:28])[O:22][C:21]2=[O:30])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@H](CNC(N)=S)OC3=O)cc2F)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=S)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Reaction time: 96 h

Procedure:
A solution of 649 mg 4-[2-fluoro-4-{(5S)-2-oxo-5-thio-ureidomethyl-oxazolidin-3-yl}-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (1.43 mmol) in a mixture of 6 ml of a 1.25 M solution of hydrochloric acid in methanol and 1 drop water was stirred for 4 days. The solvent was evaporated, and the residue was neutralized at pH 7 with a saturated solution of sodium bicarbonate. The water was evaporated and the residue was digested in a 95/5 dichloromethane/methanol mixture and the solid filtered. The filtrate was purified by chromatography using a 95/5 dichloromethane/methanol mixture with 1% acetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([CH2:17][C:18]([OH:20])=O)[CH:15]=[N:14][CH:13]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:21])#[N:2].[Li].[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:12]2[N:16]([CH2:17][C:18]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=3)=[O:20])[CH:15]=[N:14][CH:13]=2)([OH:11])[CH3:10])=[CH:5][C:4]=1[F:21])#[N:2]
Reactant: NCCc1ccccc1-c1cccc(O)c1
Reactant: CC(O)(c1ccc(C#N)c(F)c1)c1cncn1CC(=O)O
Agent: On1nnc2ccccc21
Agent: [Li]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCCl
Product: CC(O)(c1ccc(C#N)c(F)c1)c1cncn1CC(=O)NCCc1ccccc1-c1cccc(O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {5-[1-(4-cyano-3-fluorophenyl)-1-hydroxyethyl]imidazol-1-yl}acetic acid, lithium salt from Step H (40 mg, 0.145 mmol), 1-amino-2-(3′-hydroxybiphenyl-2-yl)ethane from Example 6, Step C (33 mg, 0.155 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.17 mmol), EDC (33 mg, 0.17 mmol), and N,N-diisopropylethylamine (40 mg, 0.31 mmol) in dry, degassed DMF (1 mL) was stirred at ambient temperature for 18 hrs. The solvent was removed under reduced pressure and the residue was partitioned between sat. aq. NaHCO3 (1 mL) and CHCl3 (3 mL). The aqueous layer was extracted further with CHCl3 (2×2 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography, eluting with 6% MeOH/0.6% NH4OH in CH2Cl2 to give the titled product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.C(S([C:28]1[N:33]=[C:32]([N:34]2[C:42]3[C:37](=[C:38]([O:43][CH2:44][CH2:45][CH2:46][S:47]([NH2:50])(=[O:49])=[O:48])[CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)[CH:31]=[CH:30][N:29]=1)=O)CCC.O>CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:28]2[N:33]=[C:32]([N:34]3[C:42]4[C:37](=[C:38]([O:43][CH2:44][CH2:45][CH2:46][S:47](=[O:48])(=[O:49])[NH2:50])[CH:39]=[CH:40][CH:41]=4)[CH:36]=[CH:35]3)[CH:31]=[CH:30][N:29]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(N)CC1
Reactant: CCCCS(=O)c1nccc(-n2ccc3c(OCCCS(N)(=O)=O)cccc32)n1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCC(Nc2nccc(-n3ccc4c(OCCCS(N)(=O)=O)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Aminocyclohexane carboxylic acid ethyl ester (588.4 mg, 3.44 mmol) was dissolved in NMP (5 mL) and treated with DIEA (0.993 mL, 5.7 mmol) and the reaction mixture allowed to stir at RT for 5 min. 3-[1-(2-Butylsulfinyl-pyrimidin-4-yl)-1H-indol-4-yloxy]-propane-1-sulfonic acid amide (500 mg, 1.14 mmol) was then added, and the reaction mixture heated to 120° C. for 1 h. The reaction was then allowed to cool to RT, water was added, the mixture was sonicated, filtered, and the solid dried in vacuo to yield 4-{4-[4-(3-sulfamoyl-propoxy)-indol-1-yl]-pyrimidin-2-ylamino}-cyclohexanecarboxylic acid ethyl ester (Compound 318).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[N:6]=[CH:5][CH2:4][CH2:3]1.[CH2:8]([Mg]Br)[CH:9]=[CH2:10].C(OCC)C>C1COCC1>[CH2:10]([CH:5]1[NH:6][C:2]([CH3:7])([CH3:1])[CH2:3][CH2:4]1)[CH:9]=[CH2:8]
Reactant: C=CC[Mg]Br
Reactant: CC1(C)CCC=N1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1CCC(C)(C)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 5,5-dimethyl-1-pyrroline (2.3 g, 23.7 mmol) in anhydrous THF (50 ml) 1.0 M solution of allylmagnesium bromide in diethyl ether (43.3 ml, 47.3 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 1 hour and brought to room temperature and stirred for 3 hours. Analysis of the reaction mixture by LC-MS indicated the completion of the reaction. The reaction mixture was cooled to 0° C. and quenched with 5 ml of 1N aqueous HCl and partitioned with 50 ml of EtOAc. Organic layer was separated and the aqueous layer was worked up with 2×50 ml of EtOAc. Combined organic layers were dried over MgSO4 and concentrated under vacuum gave the product as light yellow oil in 44% yield (1.5 g). The crude product was taken to the next step without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16]C([O-])(C)C.[Na+].CCCCCC.CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-3-methyl-piperidin-4-one (7.0 g, 34 mmol) and Mel (2.4 mL) in THF (100 mL) was added NaOt-Bu (4.2 g, 44 mmol) at 0° C. The reaction was slowly allowed to warm to room temperature and stirred overnight. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. Flash column chromatography (Hexane/EtOAc, gradient) of the residue gave 1-benzyl-3,3-dimethyl-piperidin-4-one, which was converted into 1-benzyl-3,3-dimethyl-piperidin-4-ylamine (2) using the same procedure as in Scheme 1-1. LCMS m/z: 220 (M+H)+. This material was used without further purification.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][N:12]=[C:13]([C:20]2[N:24]([CH3:25])[N:23]=[N:22][N:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][CH:5]=1.[H-].[Na+].I[CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C.[Cl-].[Na+].O>[CH:29]1([O:1][N:2]=[CH:3][C:4]2[N:9]=[C:8]([CH2:10][O:11][N:12]=[C:13]([C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Cn1nnnc1C(=NOCc1cccc(C=NO)n1)c1ccccc1
Reactant: IC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nnnc1C(=NOCc1cccc(C=NOC2CCCCC2)n1)c1ccccc1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a stirred solution of N-({6-[(hydroxyimino)methyl]pyridin-2-yl}methoxy)-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.2 g, 0.593 mmol, 1 eq.) in 2.5 ml of dry DMF, was added NaH (0.024 g, 0.623 mmol, 1.05 eq.) in one portion. After 10 mins, 1-iodocyclohexane (0.130 g, 0.623 mmol, 1.05 eq.) was added rapid dropwise. Stirring was continued for 20 hrs and warmed at 45° C. for 4 hrs. “brine” was added and the reaction was extracted with EtOAc (2×75 ml). The combined organic layers were washed with water (2×), dried over MgSO4 and evaporated. The residue was purified by chromatography on silica gel to give N-[(6-{[(cyclohexyloxy)imino]methyl}pyridin-2-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.107 g, 41% yield) as a colourless viscous oil.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:8][CH:7]=1)=[O:5].C([BH3-])#N.[Na+].CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C.Cl>CO>[Br:2][CH2:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:10][CH:11]=1)[OH:5]
Reactant: O=C(CBr)c1ccc(-n2ccnc2)cc1
Agent: Br
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Solvent: CO
Product: OC(CBr)c1ccc(-n2ccnc2)cc1

Procedure:
Stir a mixture of 2-bromo-1-[4-(1H-imidazol-1-yl)-phenyl]ethanone hydrobromide (15.45 g, 44.6 mmol) and sodium cyanoborohydride (5.61 g, 89.3 mmol) in methanol (250 mL). Add a crystal of methyl orange and adjust the pH to 3.0 with 1.35M hydrochloric acid in methanol. Maintain the pH at 3.0 for about 2 hr. Treat the resulting solution with decolorizing carbon and filter through celite. Concentrate the filtrate and add water (200 mL) and methylene chloride (100 mL) to the residue. Adjust the pH to 7.5 with 2N NaOH solution. Separate the layers and extract the aqueous layer with methylene chloride (100 mL) and combine, dry over Na2SO4, filter and concentrate in vacuo. Add ethyl acetate to the residue to afford crystals of the title compound.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][N:28]2[CH2:33][CH2:34][NH2:35])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][N:28]2[CH2:33][CH2:34][NH:35][C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: NCCN1CCCCC1CN1CCOCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCCC2CN2CCOCC2)c2ccccc21
Yield: 30 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(morpholin-4-yl)methyl]-piperidin-l-yl]ethanamine in a yield of 30% of theory. Colourless crystals, m.p. 167° C. (acetonitrile using fuller's earth).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:29]=[CH:28][C:27](C4C=CC=CC=4)=[CH:26][CH:25]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:41](N[C@H](CC1C=CC(OC)=CC=1)C(N1CCC[C@H]1C(O)=O)=O)(=[O:43])C>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH:13][C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21](=[O:40])[C@H:22]([NH:36][C:37](=[O:39])[CH3:38])[CH2:23][C:24]3[CH:25]=[CH:26][C:27]([O:43][CH3:41])=[CH:28][CH:29]=3)=[O:15])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Reactant: COc1ccc(C[C@@H](NC(C)=O)C(=O)N2CCC[C@H]2C(=O)O)cc1
Product: COc1ccc(C[C@@H](NC(C)=O)C(=O)N2CCC[C@H]2C(=O)NCc2ccc3c(N)nccc3c2)cc1
Yield: 80 %

Procedure:
Using the procedure described for example 97f 0.140 g of 1-(2-(R)-acetylamino-3-(4-methoxyphenyl)-propionyl)-pyrrolidine-2-(S)-carboxylic acid was converted into 0.160 g (80%) of the title compound. (+)-APCI-MS: 490 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.Cl[CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22]>>[CH3:22][C:21]1[O:20][C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:18][C:17]=1[CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)c1cc2cc(O)ccc2o1
Product: COC(=O)c1cc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2o1
Yield: 87 %

Procedure:
In the same manner as in Reference Example 4, methyl 5-hydroxybenzofuran-2-carboxylate was reacted with 4-chloromethyl-5-methyl-2-phenyloxazole to yield methyl 5-(5-methyl-2-phenyl-4-oxazolylmethoxy)bezofuran-2-carboxylate (yield 87%), which was then recrystallized from acetone-ethyl acetate to yield colorless prisms having a melting point of 177° to 178° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH3:8])([OH:7])[CH2:5][CH2:4][NH:3]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[CH:11]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[OH:7][C@@:6]1([CH3:8])[CH2:5][CH2:4][N:3]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[CH:11]=2)[C@H:2]1[CH3:1]
Reactant: C[C@@H]1NCC[C@]1(C)O
Reactant: COc1cc(F)ccc1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: COc1cc(N2CC[C@](C)(O)[C@@H]2C)ccc1C#N

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (228 mg), 4-fluoro-2-methoxybenzonitrile (317 mg) and lithium carbonate (206 mg), the title compound was obtained as a colorless solid (yield: 170 mg, yield: 49%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14](OCC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]([NH2:32])([CH3:31])([CH3:30])[CH3:29]>CN(C=O)C>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:25]([NH:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: CC(C)(C)N
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 153.7 %

Procedure:
A solution of N-(tert-butyloxycarbonyl)-O-benzyl-L-tyrosine (Bachem, 2.00 g, 5.38 mmol) in 20 mL of DMF was cooled to 0° C. and treated with iPr NEt (1.5 mL) followed by O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)-uronium hexafluoro phosphate (2.04 g, 5.38 mmol, Novabiochem, La Jolla, Calif.). The resulting suspension was stirred for 30 minutes at 0° C. and then treated with tert-butylamine (0.48 g, 6.56 mmol). The reaction mixture was stirred for 1 hour at 0° C. and warmed to room temperature. The reaction mixture was poured into Et O and washed sequentially with saturated aqueous NaHCO3 solution, and saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated. The crude residue was purified by chromatography (silica gel, 3:1 heptane/ethyl acetate) to give (S)-[2-[(1,1-dimethylethyl)amino]-2-oxo-1-(phenylmethyl)ethyl]-carbamic acid 1,1-dimethylethyl ester (2.65 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:13]([C@@:16]1([CH3:42])[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C@@H:19]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[N:18]([C@@H:36]([CH2:39][CH3:40])[CH:37]=[O:38])[C:17]1=[O:41])[CH:14]=[CH2:15]>C1COCC1.C(OCC)(=O)C>[CH2:13]([C@@:16]1([CH3:42])[CH2:21][C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[C@@H:19]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:18]([C@H:36]([CH:37]([OH:38])[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:39][CH3:40])[C:17]1=[O:41])[CH:14]=[CH2:15]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)CCCO[Si](C)(C)C(C)(C)C)C1=O
Reaction time: 2 h

Procedure:
The Grignard reagent derived from of (3-bromopropoxy)(tert-butyl)dimethylsilane was prepared on 1.8 mmol scale according to Minguez, et al. Biorg. Med. Chem. 11, 3335, 2003 as a gray solution in THF (˜3 mL). About 1.5 mL of the Grignard regent was added slowly to a solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (100 mg, 0.22 mmol; Example 91, Step C) in THF (1 mL) at ambient temperature. After 2 h, the reaction was diluted in ethyl acetate and washed with saturated ammonium chloride solution followed by sat. aq. NaCl solution. The organic layer was dried over sodium sulfate and concentrated. Purification by silica chromatography eluting with ethyl acetate/hexane provided the title compound as a mixture of diastereomers.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:38]=[CH:37][C:9]2[N:10]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([C:23](=[O:30])[NH:24][CH:25]([C:27](=[O:29])[NH2:28])[CH3:26])[CH:17]=[CH:16]4)=[N:12][C:8]=2[CH:7]=1)=[O:5])C.N[C@H](C(N)=O)C[C:42]1[N:46]=[CH:45][NH:44][CH:43]=1.C(C(NC(C1C=CC2C(=CC=C(C3N(C4CCCCC4)C4C=CC(C(O)=O)=CC=4N=3)C=2)N=1)=O)C)(=O)N>>[C:27]([CH:25]([NH:24][C:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[N:10]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[C:9]4[CH:37]=[CH:38][C:6]([C:4]([OH:3])=[O:5])=[CH:7][C:8]=4[N:12]=3)[CH:14]=2)[N:19]=1)=[O:30])[CH2:26][C:45]1[NH:44][CH:43]=[CH:42][N:46]=1)(=[O:29])[NH2:28]
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc3nc(C(=O)NC(C)C(N)=O)ccc3c1)n2C1CCCCC1
Reactant: NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CC(NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1)C(N)=O
Product: NC(=O)C(Cc1ncc[nH]1)NC(=O)c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1

Procedure:
The title compound (8 mg yield) was prepared as described for Compound 497a using L-histidinamide in place of L-alaninamide and hydrolyzed as described for Compound 497.