Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[NH:6][C@@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[NH:6][C@@H:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)C[C@@H](Nc1ccccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](Nc1ccccc1N)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (3R)-3-(2-nitroanilino)-3-phenylpropanoate (100 mg, 292 μmol) in a mixture of ethanol and water (4 mL, 3:1), was added palladium on carbon (20 mg, 10% w/w Pd) and ammonium formate (191 mg, 3.03 mmol). The suspension was heated to reflux for 10 minutes, and was then cooled to room temperature, filtered through a pad of Celite®, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (98:2) to afford the title compound, 1H NMR: (CD3OD) 7.41 (d, J=7.3, 1H), 7.33-7.31 (m, 2H), 7.25-7.21 (m, 1H), 6.75-6.73 (m, 1H), 6.72-6.52 (m, 2H), 6.47-6.45 (m, 1H), 4.82 (obs., 1H), 2.87 (dd, J=14.6, 7.7, 1H), 2.74 (dd, J=14.6, 6.2, 1H), 1.41 (s, 9H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.ClC(Cl)(O[C:38](=[O:44])OC(Cl)(Cl)Cl)Cl.[NH:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:48][CH2:47]1>ClCCl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH:5]3[CH2:6][CH2:7][CH:2]([NH:1][C:38]([N:46]4[C:54]5[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=5)[CH2:48][CH2:47]4)=[O:44])[CH2:3][CH2:4]3)[CH2:15][CH2:14]2)=[O:17])=[CH:19][CH:20]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)cc3)CC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1)C1CCN(CCC2CCC(NC(=O)N3CCc4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans {1-[2-(4-amino-cyclohexyl)-ethyl]-piperidin-4-yl}-(4-fluoro-phenyl)-methanone (example 1, intermediate F) (80 mg, 0.24 mmol) was dissolved in 1.5 ml dichloromethane and N-ethyldiisopropylamine (0.33 ml, 1.93 mmol) was added. Triphosgene (79 mg, 0.27 mmol) was added carefully and the solution stirred for 30 minutes at room temperature. Indoline (32 mg, 0.27 mmol) was added and stirred for 30 minutes at room temperature. The reaction mixture was extracted with sat. NaHCO3-solution and dichloromethane. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The desired compound was obtained as a white solid (51 mg, 44%), MS: m/e=478.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CN(C1C=CC=CN=1)C.Cl>C(Cl)Cl.O.C(N(CC)CC)C>[CH2:12]([C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Yield: 42.5 %

Procedure:
A solution of 4-hydroxybenzoic acid (3 g), decanoic acid chloride (4.3 g), triethylamine (2.4 g) and dimethylaminopyridine (0.2 g) in methylene chloride (50 ml) was stirred at room temperature for 24 hours, and then poured in water. The solution was neutralized with dilute aqueous hydrochloric acid solution and extracted with dimethyl ether. The extracted product was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was washed enough with hexane to obtain the titled compound (2.7 g).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH:18][CH2:19][CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N([CH2:27][CH3:28])CC)C>ClCCl>[C:1]1([S:7]([N:18]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:19][CH2:20][O:21][S:7]([C:28]2[CH:27]=[CH:3][CH:2]=[CH:1][CH:6]=2)(=[O:9])=[O:8])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: OCCNCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: O=S(=O)(OCCN(Cc1ccccc1)S(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 198.6 %

Procedure:
Benzenesulfonyl chloride (2.2 ml, 0.0175 mol) was added dropwise at 0° C. to a well-stirred solution of N-benzyl ethanolamine (1 g, 0.7 mmol) and triethylamine (2.4 ml. 0.0175 mol) in dry dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 1 h and quenched with water. The compound was extracted with dichloromethane, organic layer was washed with water, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded 0.6 g of the desired product as a solid. This was directly taken for next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:9]1([C:5]2[CH:4]=[C:3]([CH2:2][N:25]3[CH2:24][CH:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:27][CH2:26]3)[CH:8]=[CH:7][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: ClCc1cccc(-c2ccccc2)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C1=C(c2ccccc2)CCN(Cc2cccc(-c3ccccc3)c2)C1
Temperature: 25 °C

Procedure:
To a solution of 45 mg of 3-chloromethylbiphenyl in 5 mL of chloroform was added 50 mg of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 0.5 mL triethylamine. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature, washed successively with 50 mL aliquots of dilute sodim hydroxide and brine. The chloroform was removed by evaporation under reduced pressure to yield 3-phenyl[(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]benzene which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded a solid which was treated with ethereal-HCl to give 15 mg of 3-[(4-1,2,3,6-tetrahydropyridin-1-yl)methyl]biphenyl hydrochloride (Compound 3), mp 236-238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]5[CH2:29][O:28]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:41][CH2:40]O[CH2:38][CH2:37]1.[CH3:42][N:43](C)C=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:20]4[CH:21]=[C:22]([O:25][CH2:26][CH:27]([OH:28])[CH2:29][N:36]5[CH2:41][CH2:40][N:43]([CH3:42])[CH2:38][CH2:37]5)[CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCC4CO4)cc32)nc1-c1cccc(Cl)c1
Reactant: CN(C)C=O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCN(CC(O)COc2ccc3ncn(-c4nc(-c5cccc(Cl)c5)c(C(N)=O)s4)c3c2)CC1

Procedure:
A mixture of 0.021 g (0.05 mmole) of 4-(3-chloro-phenyl)-2-(6-oxiranylmethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.39a), 0.5 mL of dimethylformamide, 0.035 g (0.25 mmole) of potassium carbonate and 0.009 mL (0.1 mmole) of morpholine was heated at 100 degrees for 3 hours. The mixture was cooled, the solid was removed by filtration and the filtrate purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient 20:80-100:0) to give 0.012 g of 4-(3-chloro-phenyl)-2-{6-[2-hydroxy-3-(4-methyl-piperazin-1-yl)-propoxy]-benzoimidazol-1-yl}-thiazole-5-carboxylic acid amide (I.40) as a white powder. MH+/Z=514
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:14]=[C:13]([C:15](=[O:23])[NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:12]=[C:11]([O:24][CH3:25])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH2:27]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH:33]=O)[CH3:28].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([O:8][C:9]1[CH:10]=[C:11]([O:24][CH3:25])[CH:12]=[C:13]([C:15](=[O:23])[NH:16][CH:17]2[CH2:18][CH2:19][N:20]([CH2:33][C:32]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:30]([O:29][CH2:27][CH3:28])[CH:31]=3)[CH2:21][CH2:22]2)[CH:14]=1)([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(OC)cc(C(=O)NC2CCN(Cc3ccc(OC)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 2-[3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 66b) was reacted with 3-ethoxy-4-methoxybenzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white amorphous solid. MS: 529.3 (MH+).
Reaction SMILES: [N:1]([C@H:4]([C:19](=[O:31])[NH:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[N+]=[N-].[OH-].[Na+].P(C)(C)C>C1COCC1>[NH2:1][C@H:4]([C:19](=[O:31])[NH:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(C[C@H](N=[N+]=[N-])C(=O)Nc2cnc3ccccc3c2)CC1
Agent: CP(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C[C@H](N)C(=O)Nc2cnc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-[(2S)-2-azido-2-[(quinolin-3-yl)carbamoyl]ethyl]piperidine-1-carboxylate LXXVIII (262 mg, 0.62 mmol) in THF (20 mL) and 0.1 M NaOH (2.0 mL) was added Me3P (1 M in THF, 0.65 mL). The reaction was stirred at r.t. overnight. The solvent was removed under reduced pressure to give crude tert-butyl 4-[(2S)-2-amino-2-[(quinolin-3-yl)carbamoyl]ethyl]piperidine-1-carboxylate LXXIX (275 mg), which was directly used in step 8. ESIMS found for C22H30N4O3 m/z 399 (M+H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[C:24]([C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:22][C:23]1[C:24]([C:29]2[CH:37]=[CH:36][C:32]([C:33]3[NH:10][C:5]4[CH:4]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:8]=[CH:7][C:6]=4[N:9]=3)=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc2nc(-c3ccc(-c4ncccc4Cl)cc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
0.44 g (2.5 mmol) 4-trifluoromethylbenzene-1,2-diamine, 1.0 mL (5.0 mmol) diisopropylethylamine and 1.1 g (6 mmol) O-(7-azabenzotriazol-yl)-N,N,N′,N′-tetramethyleuronium hexafluorophosphate were added to a solution of 0.59 g (2.5 mmol) 4-(3-chloropyridin-2-yl)benzoic acid in 25 mL dimethylformamide, which was then stirred at room temperature for 16 hours and vacuum concentrated. The concentrate thus obtained was dissolved in ethyl acetate, washed with saturated NaHCO3 and saturated NaCl, dried over magnesium sulfate, and concentrated in a vacuum. The residue was dissolved in acetic acid/toluene (15 mL/1.5 mL) and stirred at 75° C. for 3 hours, followed by vacuum concentration. Again, the concentrate was dissolved in ethyl acetate, washed with saturated NaHCO3 and saturated NaCl, dried over magnesium sulfate, and vacuum concentrated. The residue was separated using column chromatography (developing solvent: chloroform/methanol=30/1) to produce 0.77 g of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-trifluoromethyl-1H-benzoimidazole (yield 82%).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[NH:14]1[CH2:17][CH2:16][CH:15]1C(O)=O>C1(C)C=CC=CC=1>[N:14]12[CH2:17][CH2:16][CH:15]1[CH2:3][CH:2]1[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: O=C(O)C1CCN1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CC2CC3CCN3C2C1

Procedure:
17.1 g (0.1 mol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated under reflux overnight in a water separator with 10 g (0.1 mol) of azetidine-2-carboxylic acid in 200 ml of toluene. Unreacted amino acid is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5]P(=O)(OC)OC.[C:18]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][C:31](=[O:33])[CH3:32])[CH:25]=O)(=[O:20])[CH3:19]>O.C(COC)OC.CS(C)=O>[C:18]([O:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:5][C:4](=[O:3])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:27]=[CH:28][C:29]=1[O:30][C:31](=[O:33])[CH3:32])(=[O:20])[CH3:19]
Reactant: CCCCCCC(=O)CP(=O)(OC)OC
Reactant: CC(=O)Oc1ccc(C=O)cc1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: COCCOC
Product: CCCCCCC(=O)C=Cc1ccc(OC(C)=O)c(OC(C)=O)c1
Yield: 80.4 %

Procedure:
To a mixture of 400 mg of oily sodium hydride (60%) and 50 ml of 1,2-dimethoxyethane was added dropwise a mixture of 3.06 g of dimethyl 2-oxooctylphosphonate and 10 ml of dimethoxyethane with stirring under ice-cooling. After adding thereto 5 ml of dimethyl sulfoxide and stirring the mixture for one hour at room temperature, a mixture of 2.22 g of 3,4-diacetoxybenzaldehyde and 10 ml of dimethoxyethane was added dropwise to the mixture. After stirring the resultant mixture for 4 hours at room temperature, 400 ml of water was added to the reaction mixture and the product was extracted twice each time with 50 ml of ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was applied to silica gel (120 g) column chromatography and eluted with a mixture of toluene and ethyl acetate (20:1) to provide 2.67 g of 1-(3,4-diacetoxyphenyl)-1-nonen-3-one.
Reaction SMILES: C(N(CC)CC)C.Cl[CH2:9][C:10]1[O:14][N:13]=[C:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)=[O:16])[N:11]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC.CC(C)=O>[C:24]1([S:30][CH2:9][C:10]2[O:14][N:13]=[C:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:16])[N:11]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(C(=O)c2noc(CCl)n2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)c2noc(CSc3ccccc3)n2)cc1
Reaction time: 1 h

Procedure:
A solution of 13.4 ml of triethylamine in 35 ml Et2O was added dropwise to a solution of 11.4 g of 5-chloromethyl-3-(4-toluoyl)-1,2,4-oxadiazole and 4.9 ml of thiophenol in 25 ml acetone and 100 ml Et2O at room temperature. The resulting mixture was stirred for one hour. The reaction mixture was diluted with Et2O, washed with 5% HCl (2×), water (2×), and brine, and dried over MgSO4. Concentration gave 13.2 g of an oil. Purification by high pressure liquid chromatography with 70% CH2Cl2 /hexane as an eluent yielded 11.0 g (79%) of an oil.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13](C3C=CC(C#N)=C(F)C=3)[N:14]([C:17](OC(C)(C)C)=O)[CH2:15][CH2:16][C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.[CH2:33]([C:35]1([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([OH:50])[CH:45]=2)[CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[C:36]1=[O:43])[CH3:34].[F-].[K+].C1O[CH2:69][CH2:68]OCCOCCOCCOCCOC1>CC#N>[CH2:33]([C:35]1([C:44]2[CH:45]=[C:46]([CH:47]=[CH:48][CH:49]=2)[O:50][C:69]2[CH:68]=[C:17]([N:14]3[C:13]4[NH:10][CH:9]=[N:8][C:12]=4[CH2:11][CH2:16][CH2:15]3)[CH:15]=[CH:16][C:11]=2[C:12]#[N:8])[CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[C:36]1=[O:43])[CH3:34]
Reactant: CCC1(c2cccc(O)c2)CCCCN(C)C1=O
Reactant: CC(C)(C)OC(=O)N1CCc2ncn(C(=O)OC(C)(C)C)c2C1c1ccc(C#N)c(F)c1
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCC1(c2cccc(Oc3cc(N4CCCc5nc[nH]c54)ccc3C#N)c2)CCCCN(C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(4-Cyano-3-fluoro-phenyl)-6,7-dihydro-4H-imidazo[4,5-c]pyridine-3,5-dicarboxylic acid di-tert-butyl ester (as described above in Step B) (0.120 g, 0.270 mmol), 3-ethyl-3-(3-hydroxy-phenyl)-1-methyl-azepan-2-one (0.067 g, 0.270 mmol), KF.Al2O3 (0.080 g) and 18-Crown-6 (0.007 g) were refluxed in CH3CN (5 mL) under Ar for 24 h. The solution was filtered and concentrated in vacuo. The residue was dissolved in CH2Cl2 (10 mL) and TFA (5 mL) and stirred at RT for ½ h. The solution was concentrated in vacuo, purified using reverse phase chromatography (95/5 to 5/95 H2O/CH3CN w/0.1% TFA, flow=65 mL/min), lyophilized, and then further separated into two diastereomers using a Chiralpak AS column.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[N:15])=[CH:4][CH:3]=1.C[Si]([N:20]=[N+:21]=[N-:22])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[NH:22][N:21]=[N:20][N:15]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To 4-methyl-2'-cyanobiphenyl (53 mg, 0.274 mmol) dissolved in toluene (0.5 mL) was added trimethylsilyl azide (100 μL, 0.73 mmol) and dibutyltin oxide (74 mg, 0.300 mmol). The reaction mixture was heated at ~105° C. for 91 hours, cooled to ambient temperature, concentrated under reduced pressure and flash chromatographed on silica gel eluting with methanol in methylene chloride to give the title compound (61.2 mg). The 300 MHz 1H NMR spectrum was found to be consistent with the desired product.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[H-].[Na+].[Cl:6][C:7]1[C:8]([NH:17][C:18]2[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[C:20](Cl)[C:19]=2[N+:32]([O-:34])=O)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.CS(C)=O.[OH2:39]>>[Cl:6][C:7]1[C:8]([NH:17][C:18]2[C:19]([N+:32]([O-:34])=[O:39])=[CH:20][C:21]([C:27]([F:30])([F:28])[F:29])=[C:22]([O:3][CH2:1][CH3:2])[C:23]=2[N+:24]([O-:26])=[O:25])=[N:9][CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Nc1ncc(C(F)(F)F)cc1Cl
Reactant: O
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOc1c(C(F)(F)F)cc([N+](=O)[O-])c(Nc2ncc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]

Procedure:
In 30 ml. of ethanol, 1.5 g. of sodium hydride was added with stirring and a solution of 7.0 g. of N-(3-chloro-5-trifluoromethyl-2-pyridyl)-2,6-dinitro-3-chloro-4-trifluoromethylaniline (obtained in Preparation 4) in 50 ml. of dimethylsulfoxide was added dropwise to react them at room temperature for 3 hours. The reaction mixture was poured into water and the product was extracted with methylene chloride. The extracted layer was washed with water and dehydrated and the solvent was distilled, the product was separated by a silica gel column with an eluent of a mixture of n-hexane and ethyl acetate (4:1) and the solvent was distilled off to obtain 4.0 g. of the object compound having the melting point of 106° to 108° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.CN([C:14]([O:18][N:19]1N=NC2C=CC=N[C:20]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C.O>[CH3:14][O:18][N:19]([CH3:20])[C:8]([C@H:5]1[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]1)=[O:10]
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@H]1CC[C@H](C)CC1
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-methylcyclohexanecarboxylic acid (100 g, 0.70 mol) in DMF (1.2 L) were added HATU (294 g, 0.77 mol) and DIPEA (273 g, 2.1 mol) at room temperature. After stirring for 0.5 h, TLC showed no starting material left (petroleum ether/ethyl acetate=5:1). Then N,O-dimethylhydroxylamine hydrochloride (75.5 g, 0.77 mol) was added slowly. The mixture was stirred at room temperature for 3 h. TLC (petroleum ether/ethyl acetate=5:1) showed the reaction was complete. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water twice, washed with brine, dried over Na2SO4 and concentrated to give crude trans-N-methoxy-N,4-dimethylcyclohexanecarboxamide, which was used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:20][CH2:21][O:22][CH3:23])[C@@H:12]([CH3:16])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN(C(=O)OCc1ccccc1)[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11.9 %

Procedure:
In a 100 mL round-bottomed flask, (S)-2-(benzyloxycarbonylamino) propanoic acid (1 g, 4.48 mmol, Eq: 1.00) was combined with DMF (9 mL) to give a colorless solution. Sodium hydride (394 mg, 9.86 mmol, Eq: 2.2) was added. After 30 min, 1-bromo-2-methoxyethane (747 mg, 505 μL, 5.38 mmol, Eq: 1.2) was added and the reaction was stirred at rt overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine then dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 0% to 10% MeOH in DCM) to give (S)-2-[benzyloxycarbonyl-(2-methoxy-ethyl)-amino]-propionic acid (0.15 g).
Reaction SMILES: [CH:1]1([C@H:4]([O:26][CH2:27][C:28](OCC)=[O:29])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:33]([NH2:35])[CH3:34]>CO>[CH:1]1([C@H:4]([O:26][CH2:27][C:28]([NH:35][CH2:33][CH3:34])=[O:29])[C:5]([N:7]2[CH2:11][C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])=[CH:9][C@H:8]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CO[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)CO[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Reaction time: 20 h

Procedure:
A solution of ethyl ({(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}oxy)acetate (40-1, 16 mg, 0.036 mmol) and ethylamine (10 equiv) in methanol (1 mL) was heated in a sealable tube at 75 deg C. for 20 h. The reaction mixture was concentrated, then purified by reverse-phase liquid chromatography (acetonitrile/H2O with 0.1% TFA present) to provide 2-({(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}oxy)-N-ethylacetamide (40-2) as a light yellow oil. LRMS m/z (M+H) 441.5 found, 441.5 required.