Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1>>[C:34]([O:33][C:31]([N:28]1[CH2:29][CH2:30][CH:25]([NH:24][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[C:13]([CH3:17])=[CH:12][C:11]=3[O:18][CH3:19])=[CH:6][N:5]=2)[CH2:26][CH2:27]1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: CCS(=O)c1ncc(C(=O)c2cc(F)c(C)cc2OC)c(N)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc(C)c(F)cc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone (Example 341) and 4-amino-1-Boc-piperidine (Astatech) to give 4-[4-amino-5-(5-fluoro-2-methoxy-4-methyl-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. MS (M+H)+, 460.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][O:5][C:6]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([CH3:25])=[C:9]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[CH:10]=[N:11]2.C[Si](C)(C)[O-].[K+]>O1CCCC1>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][C:9]2[CH:10]=[N:11][C:12]3[C:7]([C:8]=2[CH3:25])=[C:6]([O:5][CH2:4][C:3]([OH:26])=[O:2])[CH:15]=[C:14]([CH3:16])[CH:13]=3)=[CH:23][CH:22]=1
Reactant: COC(=O)COc1cc(C)cc2ncc(Cc3ccc(Cl)cc3)c(C)c12
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)O)c2c(C)c(Cc3ccc(Cl)cc3)cnc2c1
Temperature: 100 °C

Procedure:
A mixture of [3-(4-chlorobenzyl)-4,7-dimethylquinolin-5-yloxy]acetic acid methyl ester (1.8 g), tetrahydrofuran and potassium trimethylsilanolate (0.19 g) was heated at 100° C. in a microwave reactor for 5 minutes. The mixture was concentrated under reduced pressure, diluted with water and acidified by the addition of concentrated hydrochloric acid. The resulting precipitate was collected by filtration and purified by preparative reverse-phase HPLC, using a gradient over 30 minutes of acetonitrile in water (35% to 95% organic modifier) to afford title compound, 0.015 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[C:8]([CH2:11][N:12]([CH3:14])[CH3:13])[S:9][CH:10]=1.[O:15]([C:22](OC1C=CC=CC=1)=[CH:23][N+:24]([O-:26])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:13][N:12]([CH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][S:4][CH2:3][CH2:2][NH:1][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][N+:24]([O-:26])=[O:25])[N:7]=1)[CH3:14]
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Reactant: CN(C)Cc1nc(CSCCN)cs1
Solvent: ClCCl
Product: CN(C)Cc1nc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
According to the general procedure of Example 2, a solution of 1.65 (6.8 mmol) of 95% pure 4-[[(2-aminoethyl)thio]methyl]-N,N-dimethyl-2-thiazolemethanamine and 1.8 g (7.0 mmol) of 1,1-diphenoxy-2-nitroethene dissolved in 25 ml of methylene chloride was stirred at room temperature for about two hours to provide N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-2-nitro-1-phenoxy-1-etheneamine in situ. This compound was reacted with gaseous monomethylamine to provide 0.8 g of nizatidine. Yield 35.5%.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.Cl.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:34][C:35]([F:39])([F:38])[CH2:36][NH:37][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:32])([F:1])[F:31])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 2,2,2-trifluoroethylamine hydrochloride (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated, the residue was suspended in water, and the solid was collected by vacuum filtration to afford 72 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][CH2:9][CH2:10]I.Cl>C1COCC1.CCOCC.[Zn]>[ClH:7].[Cl:7][CH2:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: ClCCCI
Agent: Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: ClCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
Step 1. To a solution of morpholine (1.0 g, 11.47 mmol) and 1-chloro-3-iodopropane (2.35 g, 11.5 mmol) in dry THF (30 ml) was added activated zinc powder (0.75 g, 11.47 mmol). After the mixture was stirred at rt overnight, it was filtered, washed with EtOAc (20 ml), and concentrated. The residue was dissolved in EtOAc (50 ml), washed with 10% aq. NaHCO3 (10 ml), water (2×10 ml), dried over MgSO4, and concentrated. The residue was dissolved in ether (20 ml) before a 1 M ethereal HCl solution (11.5 ml, 11.5 mmol) was added dropwise at 0° C. The resulting precipitate was filtered, washed with ether (2×10 ml), and dried to afford 4-(3-chloropropyl)morpholine hydrochloride (0.70 g, 31%) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 2.17-2.28 (m, 2H), 3.01-3.09 (m, 2H), 3.15-3.19 (m, 2H), 3.39-3.42 (m, 2H), 3.76 (t, J=6.4 Hz, 2H), 3.81-3.86 (m, 2H), 3.92-3.96 (m, 2H), 11.46 (brs, 1H). Step 2. To a solution of OZ288 (0.50 g, 1.40 mmol) in dry acetonitrile (50 ml) were added powdered NaOH (0.225 g, 5.61 mmol) and tetrabutylammonium hydrogensulfate (0.1 g, 0.28 mmol). After the reaction mixture was stirred at rt for 30 min, 4-(3-chloropropyl)morpholine hydrochloride (0.25 g, 1.26 mmol) was added. The mixture was stirred at 60° C. overnight before the inorganic solid was filtered off and washed with EtOAc (2×25 ml). After removal of the solvents in vacuo, the residue was dissolved in EtOAc (50 ml). The organic layer was washed with water, brine, dried over MgSO4, and concentrated. After the residue was dissolved in EtOAc (20 ml), a solution of methanesulfonic acid (0.14 g, 1.40 mmol) in ether (10 ml) was added dropwise at 0° C. The resulting precipitate was filtered, washed with ether (25 ml), and dried in vacuo at 40° C. to afford trioxolane OZ461 (0.475 g, 58%) as a colorless solid. mp 158-160° C.; 1H NMR (500 MHz, CDCl3) δ 1.61-2.07 (m, 22H), 2.32-2.40 (m, 2H), 2.44-2.55 (m, 1H), 2.79 (s, 3H), 2.88-2.98 (m, 2H), 3.22-3.31 (m, 2H), 3.57 (d, J=12.2 Hz, 2H), 3.97-4.18 (m, 6H), 6.79 (d, J=8.8 Hz, 2H), 7.11 (d, J=8.8 Hz, 2H), 11.39 (brs, 1H); 13C NMR (125.7 MHz, CDCl3) δ 23.63, 26.41, 26.80, 31.54, 34.63, 34.73, 36.34, 36.72, 39.37, 41.93, 52.23, 55.81, 63.69, 64.51, 108.29, 111.32, 114.20, 127.71, 139.10, 156.40. Anal. Calcd for C30H45NO8S: C, 62.15; H, 7.82; N, 2.42. Found: C, 62.05; H, 7.63; N, 2.51.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N+:11]([O-:23])=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc2c(ccc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-tert-butylquinoline (400 mg, 2.16 mmol, Journal of the Indian Chemical Society, 1998, 823) and mCPBA (639 mg, 2.59 mmol) in chloroform (10 ml) was stirred for 2 hours at room temperature. The mixture was concentrated and the crude residue was applied to a silica gel (NH silica) column chromatography and eluted with dichloromethane/methanol (20:1) to furnish the title compound (433 mg, quant.) as pale orange oil. 1H NMR (300 MHz, CDCl3) δ 1.43 (9H, s) 7.26-7.30 (1H, m), 7.73 (1H, d, J=8.1 Hz), 7.78 (1H, s), 7.85 (1H, dd, J=1.5, 8.8 Hz), 8.49 (1H, d, J=5.9 Hz), 8.67 (1H, d, J=8.8 Hz). MS (ESI): m/z 202 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[C@:16]1([CH3:27])[C:21]([F:23])([F:22])[CH2:20][C@:19]([F:25])([CH3:24])[C:18](=[S:26])[NH:17]1.C(O)(C(F)(F)F)=O>ClCCl.C1(C)C=CC=CC=1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@@:16]2([CH3:27])[NH:17][C:18](=[S:26])[C@@:19]([F:25])([CH3:24])[CH2:20][C:21]2([F:23])[F:22])[CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c([C@@]2(C)NC(=S)[C@](C)(F)CC2(F)F)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(F)CC(F)(F)[C@@](C)(c2cc(N)ccc2F)NC1=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.3 %

Procedure:
tert-butyl (4-fluoro-3-((2R,5R)-3,3,5-trifluoro-2,5-dimethyl-6-thioxopiperidin-2-yl)phenyl)carbamate (816 mg, 2.01 mmol) was dissolved in dichloromethane (9.2 mL). The solution was cooled to 0° C. and TFA (4.6 mL, 59.5 mmol) was added. The solution was stirred at 0° C. for 1 h 20 min. The reaction was diluted with toluene (15 mL) and concentrated to approx. 10 mL under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous NaHCO3 (25 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure to afford (3R,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione (587 mg, (50% purity), 47.7% yield). The material was used in the next reaction step without further purification.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[Cl:12][C:13]([F:18])([F:17])[C:14](O)=[O:15].[Cl-].[NH4+]>C(OCC)C>[Cl:12][C:13]([F:18])([F:17])[C:14]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[O:15]
Reactant: O=C(O)C(F)(F)Cl
Reactant: Cc1ccccc1Br
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: Cc1ccccc1C(=O)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Magnesium (flake, 6.2 g) was suspended in diethyl ether (10 mL), and iodine (small amount) was added and a solution of 2-bromotoluene (43.26 g) in diethyl ether (100 mL) were slowly added dropwise. After stirring at room temperature for 1 hr, the reaction mixture was added dropwise to a solution of chlorodifluoroacetic acid (10.0 g) in diethyl ether (100 mL) at −10° C., and the mixture was stirred at 0° C. for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was distilled under reduced pressure (boiling point: 81-82° C./12-13 mmHg) to give the title compound as a pale-yellow oil (yield 4.9 g, 31%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]CC)=O)=[O:4].[CH2:19]=[N:20][C:21]([CH3:31])([C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=1)[CH3:22]>C1(C)C(C)=CC=CC=1>[F:18][C:2]([F:1])([F:17])[C:3]1[O:4][CH2:19][N:20]([C:21]([CH3:31])([C:23]2[CH:24]=[C:25]([Cl:30])[CH:26]=[C:27]([Cl:29])[CH:28]=2)[CH3:22])[C:6](=[O:8])[C:5]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C(=O)C(F)(F)F)c1ccccc1
Reactant: C=NC(C)(C)c1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1C
Product: CC(C)(c1cc(Cl)cc(Cl)c1)N1COC(C(F)(F)F)=C(c2ccccc2)C1=O
Yield: 83.7 %

Procedure:
Ethyl 2-trifluoroacetyl-2-phenylacetate (1.30 g) and N-methylene-1-methyl-1-(3,5-dichlorophenyl)ethylamine (1.19 g) were mixed, and xylene (10 ml) was added thereto. The mixture was allowed to react by refluxing for 30 minutes. The solvent was removed by evaporation, and the crude product was recrystallized from a mixture of hexane and ethyl acetate to afford the captioned compound (1.80 g, yield 84%).
Reaction SMILES: [C:1]([NH:9][CH:10]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:11](=[O:32])[CH2:12][NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]([O:25]CC)=[O:24])[CH:18]2[CH2:28][CH:29]=[CH:30][CH:31]=[C:17]2[S:16][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[C:1]([NH:9][CH:10]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:11](=[O:32])[CH2:12][NH:13][CH:14]1[C:20](=[O:21])[N:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]2[CH2:28][CH:29]=[CH:30][CH:31]=[C:17]2[S:16][CH2:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1C(=O)C(NCC(=O)C(Cc2ccccc2)NC(=O)c2ccccc2)CSC2=CC=CCC21
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C(=O)C(NCC(=O)C(Cc2ccccc2)NC(=O)c2ccccc2)CSC2=CC=CCC21

Procedure:
The ester product from part (f) is treated with 1N sodium hydroxide according to the procedure of Example 29(h) to yield (±)-dihydro-3-[[3-(benzoylamino)-2-oxo-4-phenylbutyl]amino]-4-oxo-1,5-benzothiazepine-5(2H)-acetic acid.
Reaction SMILES: FC(F)(F)C(O)=O.B1([O-])OO1.[OH2:12].[OH2:13].O.O.[Na+].[NH2:17][C:18]1[C:27]([F:28])=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([F:29])[C:19]=1[CH3:30]>C(O)(=O)C>[F:29][C:20]1[C:19]([CH3:30])=[C:18]([N+:17]([O-:13])=[O:12])[C:27]([F:28])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: O
Reactant: COC(=O)c1cc(F)c(N)c(C)c1F
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)c([N+](=O)[O-])c(C)c1F
Temperature: 60 °C
Reaction time: 24 h
Yield: 70.8 %

Procedure:
Trifluoroacetic acid (50 ml), acetic acid (50 ml) and sodium perborate tetrahydrate (26.6 g) were added to methyl 4-amino-2,5-difluoro-3-methylbenzoate (7.5 g), and the mixture was stirred at 60° C. for 24 hours. Impurities in the reaction mixture was removed by filtration, chloroform was added to the resultant filtrate, and the resultant mixture was washed with water. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain the title compound (6.1 g) as a reddish brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[N:30]1(OC(N(C)C)=[N+](C)C)[C:34]2[CH:35]=CC=C[C:33]=2N=N1.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH:34]([CH3:35])[CH3:33])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)O)cn1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (98.5 mg, 0.3 mmol) in DMF (1.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (106 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (257 μL, 1.5 mmol) and isopropylamine (28.3 μL, 0.33 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 0:100) afforded the title compound 57 mg, 51%) as an off white solid. MS: m/e=370.1 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1>>[NH2:21][CH2:20][CH2:19][C@H:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:2][CH3:1])=[CH:5][CH:6]=2)[CH2:13][CH2:14]1)[CH3:22]
Reactant: CCOc1ccc(N)cc1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Product: CCOc1ccc(NC2CCN([C@H](C)CCN)CC2)cc1
Yield: 71.8 %

Procedure:
Using general procedure A with p-phenetidine (137 mg, 1.20 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (166 mg, 1.20 mmol) followed by general procedure J gave [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-(4-ethoxy-phenyl)-amine (251 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]Cl>>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: COCCOCCOCCCl
Reactant: Cc1nc2ccccc2[nH]1
Product: COCCOCCOCCn1c(C)nc2ccccc21
Yield: 82 %

Procedure:
1-[2-[2-(2-Methoxyethoxy)ethoxy]ethyl]-2-methyl-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-methylbenzimidazole was used instead of benzimidazole and an equimolar amount of 2-chloroethyl 2-(2-methoxyethoxy)ethyl ether was used instead of 2-chloroethyl methyl ether. Yield 82%.
Reaction SMILES: C(N1C(=O)C(=C2N(C)C3C(O[CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=CC=CC=3S2)SC1=NC1C=C(C=CC=1NCC)C#N)C1C=CC=CC=1.[CH2:45]([N:52]1[C:56](=[O:57])[C:55](=[C:58]2[N:62]([CH3:63])[C:61]3[CH:64]=[CH:65][C:66]([O:68]CCO)=[CH:67][C:60]=3[S:59]2)[S:54][C:53]1=[N:72][C:73]1[CH:74]=[C:75]([CH:78]=[CH:79][C:80]=1[NH:81][CH2:82][CH3:83])[C:76]#[N:77])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([N:52]1[C:56](=[O:57])[C:55](=[C:58]2[N:62]([CH3:63])[C:61]3[CH:64]=[CH:65][C:66]([O:68][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:67][C:60]=3[S:59]2)[S:54][C:53]1=[N:72][C:73]1[CH:74]=[C:75]([CH:78]=[CH:79][C:80]=1[NH:81][CH2:82][CH3:83])[C:76]#[N:77])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(OCCO)ccc3N2C)C(=O)N1Cc1ccccc1
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cccc(OCCN4CCOCC4)c3N2C)C(=O)N1Cc1ccccc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3cc(OCCN4CCOCC4)ccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 60 by replacing the product of Example 60 with the product of Example 261. MS(ESI): 627 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:6][C:5]=1[OH:21])([O-])=O>O1CCCC1.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:11]=2)=[CH:6][C:5]=1[OH:21]
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3cccnc3)no2)cc1O
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc(-c2nc(-c3cccnc3)no2)cc1O

Procedure:
A solution of the product of Example 25 (284 mg, 1 mmol) in tetrahydrofuran (10 mL) was stirred with Raney®-nickel (Aldrich, 100 mg) under hydrogen at ambient temperature for 2 hours. The catalyst was then removed by filtration and the organic solution concentrated to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 5.67 (s, 2H), 6.74 (d, J=8.1 Hz, 1H), 7.41-7.50 (m, 2H), 7.62 (dd, J=8.3, 4.6 Hz, 1H), 8.39 (dt, J=8.2, 1.9, 1.7 Hz, 1H), 8.78 (dd, J=4.7, 1.7 Hz, 1H), 9.20 (d, J=1.7 Hz, 1H), 9.74 (s (broad), 1H) ppm; MS (DCl/NH3) m/z 255 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([CH:24]=1)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:9]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH3:25])=[C:6]([NH:7][C:8]3[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[N:11]=[C:10]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:9]=3)[CH:24]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: Cc1ccc(N)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: Cc1ccc(NC(=O)c2ccc(Cl)cc2)cc1Nc1cc(C(F)(F)F)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from a mixture of 4-(5-amino-2-methylanilino)-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (10 mg, 0.029 mmol) and 4-chlorobenzoyl chloride (6 mg, 0.035 mmol) similar to Example 139 and isolated as a white solid (7 mg, 50%). 1H NMR (CDCl3): 8.77 (d, J=6.0 Hz, 2H), 8.29 (d, J=6.0 Hz, 2H), 8.00 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.81 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.35 (s, 2H), 7.01 (s, 1H), 6.75 (s, 1H), 2.30 (2, 3H).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].CC(OC)(C)C.C1COCC1.[NH2:24][C:25]1[C:26]([C:33](OC(C)=CC(=O)NC(C)(CC)C)=[O:34])=[N:27][C:28]([Br:32])=[C:29]([NH2:31])[N:30]=1>O>[NH2:24][C:25]1[C:26]([C:33]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:34])=[N:27][C:28]([Br:32])=[C:29]([NH2:31])[N:30]=1
Reactant: CSC(=N)N
Reactant: CCC(C)(C)NC(=O)C=C(C)OC(=O)c1nc(Br)c(N)nc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CSC(=N)NC(=O)c1nc(Br)c(N)nc1N

Procedure:
To NaOH (1 mol/l in water; 30 mL; 30 mmol) is added S-methylisothiourea sulfate (5.42 g; 19.5 mmol. The mixture is stirred until complete solution is achieved. TBME/THF (1:1; 100 mL) and then 1-(2-methyl-2-butyl-carbamoyl)prop-1-en-2-yl 3,5-diamino-6-bromopyrazine-2-carboxylate (Intermediate B.62; 7.52 g; 19.5 mmol) are added and the mixture is stirred at r.t. over night, then water (100 mL) is added. The precipitate formed is filtered off with suction, washed with THF/water (1:2) and then dried at 50° C. to yield the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([O:39]C(C)(C)C)=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([OH:39])=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)O)cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.40 g) and chloroform (10 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (20 ml) under ice-cooling, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and to the residue were added ethyl acetate and water. The aqueous layer was separated, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and diethyl ether was added to the residue for solidification, followed by washing with diethyl ether and a 50% aqueous methanol solution. Further, it was purified by silica gel column chromatography (0→2% MeOH/chloroform), and the obtained solid was washed with a 50% aqueous methanol solution to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylic acid (0.25 g).