Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([C:13](=[O:15])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]([CH3:11])[CH3:12])[CH2:25][CH2:24]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N-tert-butoxycarbonyl-L-valine (2.27 g, 10 mmol) and 1-(2-chlorophenyl)piperazine (2.00 g, 10 mmol) in N,N-dimethylformamide (50 ml) under ice-cooling was dropwise added a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.2 g, 11 mmol) and 1-hydroxybenzotriazole (1.5 g, 11 mmol) in dichloromethane (50 ml), and the reaction mixture was stirred at room temperature for 15 hours. The dichloromethane was then distilled off under reduced pressure and ethyl acetate (200 ml) was added to the residue. The ethyl acetate layer was washed successively with 10 w/v % aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, and saturated brine in the order mentioned and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was subjected to silica gel chromatography. Elution with ethyl acetate-n-hexane (1:2, v/v) gave 1,1-dimethylethyl 2-(4-(2-chlorophenyl)-piperazinyl)-2-oxo-(s)-1-(2-propyl)ethylcarbamate. This colorless oil was dissolved in ethyl acetate (50 ml), and 4N HCl/ethyl acetate (50 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction product was filtered and washed with ethyl acetate-n-hexane (1:1, v/v) to give 1-((s)-2-amino-3-methyl-1-oxobutyl)-4-(2-chlorophenyl)piperazine hydrochloride (3.32 g, 95.8%) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[CH3:5][C:6]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]1[NH:11][CH2:12][CH2:13][N:14]=1>C(Cl)(Cl)Cl>[CH3:5][C:6]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:7]=1[O:8][CH2:9][C:10]1[N:14]([C:3](=[S:4])[NH:2][CH3:1])[CH2:13][CH2:12][N:11]=1
Reactant: CN=C=S
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Solvent: ClC(Cl)Cl
Product: CNC(=S)N1CCN=C1COc1cccc(C)c1C
Temperature: 25 °C

Procedure:
A solution of methyl isothiocyanate (1.46 g; 0.20 mole) in chloroform (10 ml) was added dropwise during 10 minutes, to a stirred solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (4.08 g; 0.020 moles) prepared as in Example 1--in chloroform (50 ml) cooling to keep the reaction below 5° C. The reaction mixture was then allowed to warm to room temperature and finally refluxed for 5 hours. Chloroform was then evaporated in vacuo and the residue recrystallised from isopropanol to yield white crystals of 2-(2,3-dimethylphenoxymethyl)-1-N-methylthiocarbamoyl-2-imidazoline, m.p. ca 100° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:18]=1)[O:11][CH2:12][C:13](=[CH2:16])[CH2:14][OH:15].[CH3:31]COCC>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:18]=1)[O:11][CH2:12][C:13]1([CH2:14][OH:15])[CH2:31][CH2:16]1
Reactant: C=C(CO)CO[C@H](CCc1ccccc1Br)c1cccc(COC2CCCCO2)c1
Reactant: CCOCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: OCC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Yield: 59 %

Procedure:
At 0° C., Pd(OAc)2 (500 mg) and ~0.4M CH2N2 in ether (1.84) were added portionwise and simultaneously to a solution of the allylic alcohol of Step 4 (20.45 g, 43.0 mmol) in 80 mL of THF. When the reaction was complete, the mixture was filtered through a small pad of silica and concentrated. The residue was purified by flash chromatography on silica with EtOAc:toluene 15:85 to give 12.40 g (59%) of the title product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Reaction time: 2 h

Procedure:
A solution of p-fluoronitrobenzene (31.8 ml) in dimethylformamide (200 ml) was ice-cooled and to this was added piperidine (60 ml) dropwise, followed by stirring with ice cooling for 2 hours. After the solvent was distilled off, the residual oily product was dissolved in ethyl acetate ester (200 ml), followed by washing in turn with aqueous saturated solution of sodium bicarbonate and water. Then, the solution was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from n-hexane to obtain N-(4-nitrophenyl)piperidine as yellow crystals (52.8 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[C:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])[CH3:25]>>[F:23][C:22]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([C:24](=[O:26])[CH3:25])[CH2:28][CH2:29]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(=O)N1CCNCC1
Reactant: CC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Product: CC(=O)N1CCN(c2ccc3ncc(C(C)c4cc5cccnc5cc4F)n3n2)CC1

Procedure:
The title compound was prepared in analogy to Example 38 using (rac)-6-[1-(6-chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-7-fluoro-quinoline (Intermediate K, 50 mg, 0.153 mmol) and 1-acetylpiperazine (39.2 mg, 0.306 mmol) (tR 3.33 min (conditions 5), MH+=419, 1H-NMR in DMSO-d6: 8.83 (d, 1H); 8.30 (d, 1H); 7.83 (d, 1H); 7.74 (d, 1H); 7.56 (s, 1H); 7.44 (m, 1H); 7.10 (d, 1H); 4.87 (m, 1H); 3.37 (m, 8H); 1.98 (s, 3H); 1.78 (d, 3H)).
Reaction SMILES: [C:1](/[C:3](=[CH:19]\[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)/[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]COC)=[CH:11][CH:10]=1)=[O:5])#[N:2].[ClH:26]>CO.C(O)C>[ClH:26].[C:1](/[C:3](=[CH:19]\[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)/[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])#[N:2]
Reactant: COCOc1ccc(CCNC(=O)/C(C#N)=C/c2cccnc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: N#C/C(=C\c1cccnc1)C(=O)NCCc1ccc(O)cc1
Reaction time: 72 h
Yield: 72 %

Procedure:
(E)-2-cyano-N-(4-methoxymethoxyphenethyl)-3-(3-pyridyl)-2-propenoic acid amide (0.81 g, 2.4 mmol) obtained in Example 1 was dissolved in a mixed solution of methanol (10 ml) and ethanol (10 ml) and concentrated hydrochloric acid (0.3 ml) was added and stirred for 3 days. The precipitated crystal was filtered and washed with ether to yield the titled compound (0.57 g, 72%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:41][CH2:42][CH2:43]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[F:41][CH2:42][CH2:43][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: OCCF
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)cc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(COCCF)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
To a solution of tert-butyl 4-(4-(hydroxymethyl)phenyl)piperazine-1-carboxylate (100 mg, 0.34 mmol) in THF (1 mL) was added triphenylphosphine (135 mg, 0.51 mmol), 2-fluoroethanol (24 μL, 0.41 mmol) and diisopropylazodicarboxylate (99 μL, 0.51 mmol). The reaction mixture stirred at room temperature overnight. The next day the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, and concentrated to obtain a crude oil. Purification of the crude material using silica gel chromatography (gradient of 0% to 100% EtOAc in hexanes) afforded tert-butyl 4-(4-((2-fluoroethoxy)methyl)phenyl)piperazine-1carboxylate as a colorless oil (26 mg, 22% yield). 1H NMR (300 MHz, CDCl3) δ 7.27 (d, 2H, J=9.0 Hz), 6.89 (d, 2H, J=9.0 Hz), 4.65 (m, 1H), 4.52 (s, 2H), 4.49 (m, 1H), 3.74 (m, 1H), 3.64 (m, 1H), 3.58 (dd, 4H, J=6.0, 3.0 Hz), 3.13 (dd, 4H, J=6.0, 3.0 Hz), 1.49 (s, 9H); 19F NMR (282.4 MHz, CDCl3): δ−223.01 (m, 1F); 13C NMR (75.5 MHz, CDCl3); δ 154.7, 150.9, 129.4, 129.2, 116.5, 84.3 (82.0), 79.9, 73.0, 68.8 (68.7), 49.3, 44.0, 28.4; HRMS calcd for C18H27FN2O5: 339.20785 found 339.20790.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([NH2:8])=[CH:3][CH:4]=[CH:5][C:6]=1[NH2:7].[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13].CCCCC>>[CH3:13][C:12]([CH3:14])=[CH:11][CH2:10][C:3]1[CH:4]=[CH:5][C:6]([NH2:7])=[C:1]([CH3:9])[C:2]=1[NH2:8]
Reactant: Cc1c(N)cccc1N
Reactant: C=CC(=C)C
Solvent: CCCCC
Product: CC(C)=CCc1ccc(N)c(C)c1N

Procedure:
A 200 g (1.64 mol) portion of 2,6-toluenediamine, 167 g (2.45 mol) of isoprene, 200 g (2.78 mol) of pentane, and 20 g of powdered H-Y zeolite were reacted at 150° C. in a similar fashion as indicated in Example 1. Isolation of a catalyst free sample was obtained by hot filtration. Selective removal of all residual hydrocarbon by vacuum distillation afforded the following product mixture:
Reaction SMILES: I[C:2]1[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[N:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1.[CH3:26][NH:27][C:28]1[N:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[N:29]=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.O1CCOCC1>[CH3:12][C:9]1[N:8]=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:6]2[C:11](=[C:2]([C:33]3[CH:34]=[C:35]4[C:30](=[CH:31][CH:32]=3)[N:29]=[C:28]([NH:27][CH3:26])[N:37]=[CH:36]4)[C:3]([CH3:25])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: Cc1nc(Nc2cccc(OC(F)(F)F)c2)c2ccc(C)c(I)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(OC(F)(F)F)c5)nc(C)nc34)ccc2n1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
8-Iodo-2,7-dimethyl-N-(3-(trifluoromethoxy)phenyl)quinazolin-4-amine (0.250 g, 0.544 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.186 g, 0.653 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0629 g, 0.0544 mmol) and 2 M aqueous sodium carbonate (0.544 mL, 1.09 mmol) were placed in a microwave vial and dioxane (3 mL) was added. The tube was capped and heated in a microwave reactor at 150° C. for 10 min. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was dried with sodium sulfate and then purified by column chromatography on silica gel using a gradient of 20 to 80% EtOAc in hexanes. The clean fractions were combined and concentrated under vacuum to give a yellow film. The film was triturated with a 1:1 mixture of ether and hexanes. This resulted in the formation of an off-white solid which was collected by filtration and dried in a vacuum oven to give 6-(2,7-dimethyl-4-(3-(trifluoro-methoxy)phenylamino)quinazolin-8-yl)-N-methylquinazolin-2-amine (0.212 g, 79%). MS (M+H)+ 491.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([CH3:30])=[N:25][N:26]([CH3:29])[C:27]=6[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
A small screw cap test tube was charged with 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.244 mmol) and THF (2 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (46.7 mg, 0.244 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude mixture was redissolved into ˜2 mL of EtOAc and then Hexanes were added to causing a precipitate to form. The precipitate was then filtered yielding 45% (0.067 g, 0.109 mmol) of the title compound.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:7][CH:6]([CH:8]=[C:9]([F:11])[F:10])[CH2:5][C:4]1=[O:12].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[CH:26]=[C:20]2[N:19]=1>O1CCOCC1>[Cl:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[C:25]([CH:27]3[CH2:29][CH2:28]3)[C:26]([CH2:2][N:3]3[CH2:7][CH:6]([CH:8]=[C:9]([F:11])[F:10])[CH2:5][C:4]3=[O:12])=[C:20]2[N:19]=1
Reactant: Clc1ccn2nc(C3CC3)cc2n1
Reactant: O=C1CC(C=C(F)F)CN1CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1COCCO1
Product: O=C1CC(C=C(F)F)CN1Cc1c(C2CC2)nn2ccc(Cl)nc12
Yield: 69 %

Procedure:
To a solution of 1-(chloromethyl)-4-(2,2-difluorovinyl)pyrrolidin-2-one x276 (2.55 mmol, 2 eq, 500 mg) in 15 ml of dioxane at 0° C. are added successively AlCl3 (5.1 mmol, 2 eq, 680 mg) and 5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidine x274 (2.55 mmol, 1 eq, 495 mg). The mixture is stirred at reflux for 1 hour, then quenched with an aqueous saturated NH4Cl solution and the resulting mixture extracted with AcOEt. The cumulated organic layers are washed with water, dried over MgSO4, filtered and evaporated under reduced pressure. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 98/2/0.2), followed by a crystallization step in hexane. 1-[(5-chloro-2-cyclopropylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 219 is obtained as a solid (623 mg).
Reaction SMILES: [NH2:1][CH:2]([CH:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1)[CH3:6])[C:3]#[N:4]>C(O)C.N.[Ni]>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH:5]([CH3:6])[CH:2]([NH2:1])[CH2:3][NH2:4])=[CH:8][CH:9]=1
Reactant: CC(c1ccnc2ccccc12)C(N)C#N
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(c1ccnc2ccccc12)C(N)CN
Reaction time: 2 h
Yield: 111.4 %

Procedure:
To 2-Amino-3-quinolin-4-yl-butyronitrile (1.58 g, 6.42 mmol) in 10 ml of ethanol, ammonia gas was bubbled for 15 minutes. 2 g of Raney Ni (washed with 2×50 ml water and 2×50 ml ethanol) was added to the solution and the reaction mixture was hydrogenated at 50 psi for 2 hours, filtered over celite and concentrated to give 1.54 g (96%) of the product which was then used as such for the subsequent step.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49](O)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1.CO>ClCCl>[CH3:31][N:32]([C:42]([NH:44][C@H:45]([C:49]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[O:22][N:21]=[CH:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:50])[CH:46]([CH3:48])[CH3:47])=[O:43])[CH2:33][C:34]1[N:35]=[C:36]([CH:39]([CH3:41])[CH3:40])[O:37][CH:38]=1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccno1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)co1
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2ccno2)C(C)C)co1
Yield: 80 %

Procedure:
Using the procedure of Example 1U but replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)-methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-5-amino-2-(N-((5-isoxazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane and replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with N-((N-methyl-N-((2-isopropyl-4-oxazolyl)methyl)amino)carbonyl)-L-valine provided, after silica gel chromatography using a gradient of 1-4% methanol in dichloromethane, 225 mg (80%) of the desired compound. 1H NMR (DMSO-d6) δ0.74 (d, J=6.9 Hz, 6H), 1.23 (d, J=6.9 Hz, 6H), 1.35-1.54 (m, 2H), 1.80-1.95 (m, 1H), 2.55-2.73 (m, 4H), 2.83 (s, 3H), 2.94-3.09 (m, 1H), 3.53-3.63 (m, 1H), 3.73-3.86 (m, 1H), 3.92 (t, J=8.4 Hz, 1H), 4.08-4.34 (m, 3H), 4.65 (d, J=6 Hz, 1H), 5.04 (s, 2H), 5.91 (d, J=9 Hz, 1H), 6.29 (d, J=2.4 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 7.06-7.27 (m, 10H), 7.69 (d, J=9 Hz, 1H), 7.77 (s, 1H), 8.52 (d, J=2.4 Hz, 1H). Mass spectrum: (M+H)+ =689; (M+NH4)+ =706. Anal. Calcd for C37H48N6O7 : C, 64.52; H, 7.02; N, 12.20. Found: C, 64.52; H, 7.14; N, 12.06.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:20][CH2:21][CH:22]([OH:24])[CH3:23]>>[OH:24][CH:22]([CH3:23])[CH2:21][NH:20][S:16]([C:14]1[S:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(O)CN
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(S(=O)(=O)NCC(C)O)s2)c(C)[nH]c1=O
Yield: 59 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 1-aminopropan-2-ol as described in Step 5, Example 24 to give the title compound as a yellow solid (59% yield). LC/MS: RT 2.33 min; m/e 357 (M+H); 1H NMR (CDCl3, δ, ppm): 11.13 (1H, br), 7.52 (1H, d), 7.23 (1H, s), 6.91 (1H, d), 5.27 (1H, m), 4.00 (1H, m), 3.20 (1H, m), 2.90 (1H, m), 2.53 (2H, q), 2.40 (3H, s), 2.01 (1H, s), 1.20 (6H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.Br[CH:12]([CH2:14][CH3:15])[CH3:13]>>[CH3:13][CH:12]([O:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[CH2:9][OH:10])[CH2:14][CH3:15]
Reactant: CCC(C)Br
Reactant: OCc1ccc(Cl)cc1O
Product: CCC(C)Oc1cc(Cl)ccc1CO

Procedure:
The title compound was prepared from 5-chloro-2-(hydroxymethyl)phenol (PREPARATION 7) and 2-bromobutane according to the procedure for the preparation of Example 111, part A. 1H NMR (400 MHz, CDCl3): δ 0.98 (3H, t, J=7.6 Hz), 1.32 (3H, d, J=6.0 Hz), 1.65-1.79 (2H, m), 2.30 (1H, t, J=6.8 Hz), 4.32-4.40 (1H, m), 4.62 (2H, d, J=6.4 Hz), 6.85 (1H, d, J=1.6 Hz), 6.89 (1H, dd, J=1.6 Hz, 7.6 Hz), 7.19 (1H, d, J=8.4 Hz).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:40]1([C:46]2[N:51]=[CH:50][C:49]([NH2:52])=[CH:48][N:47]=2)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[OH:30])[C:8]([N:10]2[C@H:14]([C:15]([NH:52][C:49]3[CH:48]=[N:47][C:46]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[N:51][CH:50]=3)=[O:17])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1cnc(N2CCOCC2)nc1
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)N1NCC[C@H]1C(=O)Nc1cnc(N2CCOCC2)nc1

Procedure:
(3S)-2-((2R)-3-Cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-[2-(4-morpholinyl)-5-pyrimidinyl]-3-pyrazolidinecarboxamide was prepared according to Example 111, utilizing (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid in place of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid, and 2-(4-morpholinyl)-5-pyrimidinamine in place of 3-pyridazinamine in part A. LCMS: (M+H)+: 476.0.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[Cl-].[C:32]1([N:38]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:39]([N+]2C=CC=CC=2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][C:39](=[O:40])[N:38]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(N(c1ccccc1)c1ccccc1)[n+]1ccccc1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC(=O)N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 110.2 %

Procedure:
A solution of 3.99 g of 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-hydroxymethylimidazole (Example 94) and 10 mL of 1.00N aqueous sodium hydroxide in 60 mL of methanol was added dropwise over 0.25 hour to a solution of 3.73 g of N-(N,N-diphenylcarbamoyl)pyridinium chloride in 30 mL of methanol at 25° C. The resulting mixture was stirred at 25° C. for 0.75 hour and then was diluted with ethyl acetate. This organic solution was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 6.55 g of crude 2-butyl-4-chloro-1-[(2'-(N,N-diphenylcarbamoyloxycarbonyl)biphenyl-4-yl)methyl]-5-hydroxymethylimidazole which was used in the following step without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([NH:23][C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:27][CH:26]=2)[CH:11]=1>N1C=CC=CC=1>[C:1]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([O:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([NH:23][C:24](=[O:42])[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:27][CH:26]=2)[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc(NC(C)=O)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice cooling 1 ml of acetic anhydride was added to a mixture of 200 mg of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride and 5 ml of pyridine followed by stirring at room temperature overnight. The reaction mixture was treated similarly to Example 68 to obtain 150 mg of ethyl 4-acetamido-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.