Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1C=C[C:12]2[C:15]3[C:5]=1[CH2:6][CH2:7][C:8]=3[CH:9]=[CH:10][CH:11]=2)([O-])=O.C(O[CH2:20][CH3:21])(=O)C>[Pd]>[CH2:15]1[C:12]2=[C:20]3[C:21](=[CH:9][CH:10]=[CH:11]2)[C:4]([NH2:1])=[CH:5][CH:6]=[C:7]3[CH2:8]1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc2cccc3c2c1CC3
Agent: [Pd]
Product: Nc1ccc2c3c(cccc13)CC2

Procedure:
A mixture of 5 and 3-nitroacenaphthene was reduced with Pd/C in ethyl acetate under hydrogen at 40 psi pressure and the resulting amines were separated by recrystallization from cyclohexane/ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[C:37]1(CO)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH2:26][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCc4ccccc4)cc3C)c2cc1OC
Yield: 96.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (100 mg) was added to toluene (10 ml) and triethylamine (1 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (140 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, phenylmethanol (51 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (137 mg, yield 89%).
Reaction SMILES: [Si]([O:8][C:9]1[C:10]([F:20])=[C:11]([CH:14]=[C:15]([O:17][CH2:18][CH3:19])[CH:16]=1)[CH:12]=[O:13])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH2:18]([O:17][C:15]1[CH:16]=[C:9]([OH:8])[C:10]([F:20])=[C:11]([CH:14]=1)[CH:12]=[O:13])[CH3:19]
Reactant: CCOc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(O)c(F)c(C=O)c1
Reaction time: 0.5 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)-5-ethoxy-2-fluorobenzaldehyde (7.25 g, 24.3 mmol), prepared according to WO2003066588 A1, which is incorporated herein by reference, in 50 mL THF at 0° C., was added a 1 M solution of TBAF in THF (24.3 mL, 24.3 mmol). The mixture was stirred for 30 min, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 50% EtOAc/hexanes gradient) to afford Intermediate 7.1, contaminated with tetrabutylammonium salts.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:13]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:32]1[C:37](O)=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:39].CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:33]1([CH3:39])[CH:34]=[CH:35][CH:36]=[C:37]([O:1][CH:2]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([O:10][CH3:13])=[O:9])=[CH:6][CH:5]=2)[CH3:3])[CH:32]=1
Reactant: Cc1cccc(O)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(O)c1ccc(C(=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)Oc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
To the solution of 4-(1-hydroxyethyl)benzoate (300 mg, 1.67 mmol) in tetrahydrofuran (50 mL) was added triphenylphosphine (569 mg, 2.17 mmol) and m-cresol (180 mg, 1.67 mmol), the solution was stirred for 30 minutes at room temperature, then diisopropylazodicarboxylate (438 mg, 2.17 mmol) was added dropwise to the solution at 0° C., the mixture was stirred at room temperature for 12 hours. Then the mixture was concentrated and purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=20:1) to give methyl 4-(1-(m-tolyloxy)ethyl)benzoate (148 mg 33%) as oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1.[CH:20]([C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[C:25]([CH:32]([CH3:34])[CH3:33])[C:24]=1[S:35](Cl)(=[O:37])=[O:36])([CH3:22])[CH3:21].C1N2CCN(CC2)C1.O>C1COCC1.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([O:8][S:35]([C:24]2[C:25]([CH:32]([CH3:33])[CH3:34])=[CH:26][C:27]([CH:29]([CH3:31])[CH3:30])=[CH:28][C:23]=2[CH:20]([CH3:22])[CH3:21])(=[O:37])=[O:36])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]#[N:18])=[CH:12][CH:11]=2)=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: C1CN2CCN1CC2
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: Cc1nc(N)nc(OS(=O)(=O)c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1Cc1ccc(CC#N)cc1
Temperature: 30 °C
Reaction time: 7 h

Procedure:
A suspension of the product from step (ii) (6.0 g, 23.6 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (9.28 g, 30.6 mmol) and DABCO (4.76 g, 42.5 mmol) in THF (48.0 g) was stirred at 30° C. for 7 hours. Water (9.6 g) was added to the mixture and the organic layer was separated and concentrated under reduced pressure to give a solid. The solid was dissolved in acetonitrile (57.0 g) and heated to 60° C. Water (36.0 g) was added to the solution and the mixture was stirred at 60° C. for 1 hour. Water (36.0 g) was added to the mixture and the mixture was cooled to 5° C. and stirred at 5° C. for 1 hour. The resulting precipitate was collected by filtration, washed duplicate with combined solution of water (9.0 g) and acetonitrile (3.6 g), and dried to give the subtitle is compound as a solid, 11.6 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:14][C:15]1([F:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([N:18]2[CH2:19][CH2:20][C:15]([F:21])([F:14])[CH2:16][CH2:17]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)CC2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 83.2 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 3-oxoazetidine-1-carboxylic acid tert-butyl ester (0.51 g, 3 mmol), 4,4-difluoropiperidine hydrochloride (0.71 g, 4.5 mmol) and 4 A molecular sieves (0.8 g) in DCE (8 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (1.27 g, 6 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, EtOAc: cyclohexane, gradient 0:100 to 75:25) to give 3-(4,4-Difluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as a yellow oil (0.69 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 3.94 (dd, J=8.7, 7.1 Hz, 2H); 3.78 (dd, J=8.7, 5.3 Hz, 2H); 3.17-3.10 (m, 1H); 2.45-2.41 (m, 4H); 2.10-1.94 (m, 4H); 1.43 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:8]=1.[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][CH2:2][CH2:3][C:4]2[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][CH3:15])[CH:8]=2)=[O:31])=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCC(CC)(NCCCn1cnc(CCN)c1)c1ccccc1
Product: CCC(CC)(NCCCn1cnc(CCNC(=O)c2ccc(C#N)cc2)c1)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propylamine (0.5 g) was reacted with 4-cyanobenzoyl chloride (0.27 g) in a similar manner to Example 55 to give 4-cyano-N-(2-{1-[3-(1-ethyl-1-phenylpropylamino)propyl]imidazol-4-yl}ethyl)benzamide, m.p. 107°-109° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([O-:15])[O:12][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30].Cl>C(Cl)(Cl)Cl>[CH2:13]([O:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:30][CH2:29][C:28]([O:32][CH3:33])=[O:31])=[O:15])[CH3:14]
Reactant: CCOP([O-])CCCCc1ccccc1
Reactant: C=CC(=O)OC
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCCc1ccccc1)CCC(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-phenylbutyl phosphonous acid, ethyl ester (0.5 g, 0.0022 mole) in chloroform (15 ml) was added triethylamine (0.34 ml, 0.0024 mole), trimethyl silylchloride (0.31 ml, 0.0024 mole) and methyl acrylate (0.22 ml, 0.0024 mole). The reaction mixture was stirred at room temperature for 4 hours and then stirred at reflux for 23 hours; the mixture was poured into crushed ice (15 gm) containing 10 ml 5% HCl acid. It was shaken in a separatory funnel; a chloroform layer was evaporated, and the aqueous layer extracted once with 20 ml chloroform. The combined organic phase was washed with water and 5% NaHCO3, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a clear liquid solid (0.6 g). The crude product was purified through column chromatography (1:1 hexane/acetone eluting solvent system) to yield 0.19 g oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:27][CH:26]=3)[N:18]=2)=[CH:13][C:12]=1[F:44])([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3].[NH:45]1[CH:49]=[CH:48][N:47]=[CH:46]1>>[CH2:1]([O:4][C:5]([NH:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[C:19]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)=[CH:29][CH:30]=3)[N:18]=2)=[CH:13][C:12]=1[F:44])([CH3:10])[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: c1c[nH]cn1
Reactant: C=CCOC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(CCOS(=O)(=O)c4ccc(C)cc4)cc3)ncc2Cl)cc1F
Product: C=CCOC(=O)NC(C)(C)c1ccc(-c2nc(Nc3ccc(CCn4ccnc4)cc3)ncc2Cl)cc1F
Yield: 78.1 %

Procedure:
The title compound was prepared from 4-[4-(1-allyloxycarbonylamino-1-methylethyl)-3-fluorophenyl]-5-chloro-N-[4-(2-p-toluenesulphonyloxyethyl)-phenyl]pyrimidine-2-amine (504 mg, 0.79 mmol) and imidazole (337 mg, 4.95 mmol) following the method described for Example 5. The crude product was purified by column chromatography (silica; 5% methanol in CH2Cl2) to give the title compound as a yellow solid (330 mg) m.p. 88° forms gum. δH (CDCl3) 8.43 (1H, s), 7.69 (1H, dd, J 8.2, 1.8 Hz), 7.61 (1H, dd, J 13.3, 1.8 Hz), 7.54 (2H, d, with fine splitting, J 8.6 Hz), 7.50 (1H, t, J 8.5 Hz), 7.34 (1H, s), 7.18 (1H, s), 7.04 (3H, m), 5.89 (1H, bs), 5.30-5.12 (3H, m), 4.50 (2H, dt, J 5.6, 1.4 Hz), 4.16 (2H, t, J 7.1 Hz), 3.03 (2H, t, J 7.0 Hz), 1.78 (6H, s); MS (ESI) 535 (MH+, 100%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@@H:41]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:42][OH:43]>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:40][C@@H:41]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:42][OH:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 19) and (2S)-2-amino-3-phenyl-1-propanol by the same method as Preparation 20. The title compound was obtained as a yellow foam.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=2)[O:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(=O)OCC)=S)=[N:18][CH:19]=2)=[O:8])=[CH:5][C:4]([CH3:32])=[N:3]1.[Cl-].O[NH3+].C([N:39](CC)C(C)C)(C)C.C(O)C>O.CO>[NH2:23][C:21]1[N:20]=[C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:32])[CH:5]=4)=[O:8])[CH:31]=[CH:30][CH:29]=3)=[CH:19][N:18]2[N:39]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3cc(C)nn3C)c2)cn1
Agent: [Cl-]
Agent: [NH3+]O
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)nn4c3)c2)n(C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A mixture of ethyl ({[5-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenoxy)pyridin-2-yl]amino}carbonothioyl)carbamate (238 mg, 0.524 mmol), hydroxylammonium chloride (364 mg, 5.24 mmol), N,N-diisopropylethylamine (548 μL, 3.14 mmol), ethanol (3 mL) and methanol (3 mL) was stirred at 60° C. for 5 hr and at 80° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/ethyl acetate/methanol=50/50/0→40/100/0→40/90/10) and recrystallized from ethyl acetate-hexane to give the title compound (131 mg, 69%) as a white solid.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:24]=[C:23]([C:25](Cl)=[O:26])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1>C1C=CC=CC=1>[ClH:14].[CH3:13][N:12]([CH:9]1[CH2:10][CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8]1)[C:25]([C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([Cl:14])[CH:24]=1)=[O:26]
Reactant: CNC1CCN(C2CCCCC2)C1
Reactant: O=C(Cl)c1cc(Cl)nc2ccccc12
Solvent: c1ccccc1
Product: CN(C(=O)c1cc(Cl)nc2ccccc12)C1CCN(C2CCCCC2)C1
Product: Cl
Reaction time: 0.5 h

Procedure:
To 12.7 g. (0.07 mole) of 1-cyclohexyl-3-methylaminopyrrolidine in dry benzene was added dropwise with stirring 15 g. (0.07 mole) of 2-chloroquinoline-4-carbonyl chloride in dry benzene. After 0.5 hr. the solution was extracted with dilute hydrochloric acid and the acidic solution made basic with sodium hydroxide solution and extracted with benzene. The benzene extracts were dried over sodium sulfate and concentrated. The residue was chromatographed on an aluminum silicate column eluting with a mixture of acetone benzene progressing from pure benzene to 50% acetone-benzene. The fractions containing the desired product were concentrated and the residue crystallized as the hydrochloride salt from isopropyl ether. The salt was recrystallized from isobutyl methyl ketone. Yield 10 g. (36%); m.p. 230°-233° C.
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.CC(O)=O.[ClH:47]>[Pd].CO>[ClH:47].[C:25]1([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]([NH:16][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](NC(=O)[C@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(e) above from (R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(S)-N-(1-phenylethyl)ornithine amide (2.0 g; 3.5 mmol; from step (b) above), 10% Pd/C (w/w; 150 mg), HOAc (100 mL; instead of MeOH), overnight reaction time. The crude acetate salt was converted to the sub-title hydrochloride and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[CH2:31][S:32][C:33]#[N:34])=[CH:26][CH:25]=1>C(O)CCC>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:22])[CH2:15][C:16]([CH3:20])([CH3:21])[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:32][CH:31]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(CC(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)O
Reactant: N#CSCC(=O)c1ccc(Cl)cc1
Solvent: CCCCO
Product: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc(-c4ccc(Cl)cc4)cs3)cc2)cc1)C(=O)O
Temperature: 90 °C
Yield: 6.9 %

Procedure:
In a 8-mL screw-cap vial, a mixture of 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoic acid (60 mg, 0.20 mmol) and 2-(4-chlorophenyl)-2-oxoethyl thiocyanate (64 mg, 0.30 mmol) in 4 mL n-butanol was heated at 90° C. overnight. The solvent was removed under reduced pressure. The mixture was dissolved in 5 mL 1:4 MeOH/DMF and purified by reverse-phase HPLC to provide 6.8 mg (7%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 11.90 (br s, 1 H), 10.50 (s, 1 H), 7.75-8.00 (m, 10 H), 7.50 (m, 3 H), 3.30 (m, 2 H), 1.05 (s, 6 H); LC-MS m/z 491.2 (MH+), ret. time 3.83 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[N:3][CH:4]=1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(N2CCC(O)CC2)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (LXV) (5.0 g, 31.5 mmol) in DMF (50 mL) was added piperidin-4-ol (LXXXIX) (3.5 g, 34.65 mmol) and K2CO3 (8.7 g, 63.0 mmol). The reaction was headed at 85° C. overnight. The solution was poured into ice water, stirred for 15 min and then filtered. The solid was washed with cold water and dried under vacuum to produce 1-(5-aminopyridin-2-yl)piperidin-4-ol (XC) as a yellow solid (6.62 g, 29.67 mmol, 94.2% yield). 1H NMR (DMSO-d6) δ ppm 1.34-1.42 (m, 2H), 1.77-1.83 (m, 2H), 3.40-3.56 (m, 2H), 3.76-3.83 (m, 1H), 4.12 (brd, 2H), 4.81 (d, J=4 Hz, 1H), 6.94 (d, J=10 Hz, 1H), 8.17 (dd, J=10 Hz, J=3 Hz, 1H), 8.94 (d, J=3 Hz, 1H); ESIMS found for C10H13N3O3 m/z 224.1 (M+H).
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[OH-].[Li+].O1CCCC1.Cl>O.CO>[F:1][C:2]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[CH:16][CH:17]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:6])=[O:7]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(NC(=O)c2ccc(C(=O)O)cn2)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Methyl 6-{N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylate (150 mg, 0.35 mmol, prepared in example 50), lithium hydroxide (52 mg, 1.24 mmol), tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL) were mixed together in a 25 mL 3 neck flask and stirred over night at room temperature. In the morning, the mixture was concentrated under reduced vacuum to yield a white solid. This material was taken into 1N HCl and the desired material was extracted into methylene chloride. The acidic solution was taken to pH 10 with 1N NaOH and the resulting precipitate was again extracted with methylene chloride. Both organic layers were combined and washed once with H2O, dried over MgSO4, filtered, and concentrated under reduced vacuum to yield the title compound (125 mg, 84%) as a tan solid. This material was used without further purification. Ion spray M.S. 403.9 (M*−19 Fluorine).
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C@H:13]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[O:16])[NH2:14])[CH2:8][CH2:7]1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39](O)=[O:40])[CH:37]=2)[CH:32]=[CH:31]1>>[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:39]([NH:14][C@@H:13]([C:15]([N:17]3[CH2:18][CH2:19][N:20]([CH:23]4[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]4)[CH2:21][CH2:22]3)=[O:16])[CH2:12][CH:9]3[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]3)=[O:40])[CH:37]=2)[CH:32]=[CH:31]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CN1CCC(C[C@@H](N)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1
Agent: Cl
Product: CN1CCC(C[C@@H](NC(=O)c2ccc3cc[nH]c3c2)C(=O)N2CCN(C3CCN(C)CC3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-[β-(1-methylpiperidin-4-yl)-D-alanyl]-4-(1-methylpiperidin-4-yl)piperazine tetrahydrochloride and indole-6-carboxylic acid (59%).
Reaction SMILES: Cl.NC1N[C:6]([C:8]2[CH:23]=[CH:22][C:11]3[N:12]([CH:17]4[CH2:21]CC[CH2:18]4)[C:13](=[O:16])[N:14]([CH3:15])[C:10]=3[CH:9]=2)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26](Cl)[CH:25]=2)N=1.Cl.[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:38]([NH2:40])=[NH:39].[CH3:41]N(C=O)C>O>[CH:17]([N:12]1[C:11]2[CH:22]=[CH:23][C:8]([C:6]3[N:39]=[C:38]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][N:32]=4)[NH:40][C:5]=3[C:24]3[CH:25]=[C:26]([CH3:41])[CH:27]=[CH:28][CH:29]=3)=[CH:9][C:10]=2[N:14]([CH3:15])[C:13]1=[O:16])([CH3:18])[CH3:21]
Reactant: Cn1c(=O)n(C2CCCC2)c2ccc(-c3[nH]c(N)nc3-c3cccc(Cl)c3)cc21
Reactant: N=C(N)c1cnccn1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: Cc1cccc(-c2[nH]c(-c3cnccn3)nc2-c2ccc3c(c2)n(C)c(=O)n3C(C)C)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 5-(bromo-m-tolyl-acetyl)-1-isopropyl-3-methyl-1,3-dihydro-benzoimidazol-2-one (prepared as described in example 142, 0.5 gm, 1.25 mmol), pyrazine-2-carboxamidine hydrochloride (0.395 gm, 2,49 mmol) cesium carbonate (1.22 gm, 3.74 mmol) and DMF (4.0 mL) was heated to 60° C. After 1 hour, the reaction was determined to be complete by LCMS. The reaction was cooled to room temperature and diluted with water (40 mL). After stirring for 1 hour, the crude suspension was filtered and the solids were purified by flash chromatography (diethyl ether, followed by ethyl acetate) to afford 40 mg of the title compound as a light tan solid. MS (M+1)=425.1