Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[ClH:1].[ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: OB(O)c1cccnc1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Cc1csc(Nc2ncc(-c3cccnc3)cc2OCc2ccccc2)n1

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1; 0.125 g, 0.332 mmol), pyridin-3-ylboronic acid (0.0490 g, 0.399 mmol), bis(triphenylphosphine)palladium(II) chloride (0.00700 g, 0.00997 mmol), and sodium carbonate (0.106 g, 0.997 mmol) were combined in DME (10 mL), and water (5 mL) and heated overnight at 80° C. The reaction mixture was cooled and partitioned between dichloromethane and water. The layers were separated, and the organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography to afford the title compound as the free base. The free base was dissolved in dichloromethane and 2M HCl in ether was added. The mixture was concentrated to afford 3-(benzyloxy)-N-(4-methylthiazol-2-yl)-5-(pyridin-3-yl)pyridin-2-amine dihydrochloride (0.109 g, 87.6% yield). 1H NMR (DMSO-d6) δ 9.27 (m, 1H), 8.81 (d, 1H), 8.75 (d, 1H), 8.48 (d, 1H), 8.08 (m, 1H), 7.97 (m, 1H), 7.66 (d, 2H), 7.43 (m, 2H), 7.37 (m, 1H), 6.82 (s, 1H), 5.45 (s, 2H), 2.31 (s, 3H). Mass spectrum (apci) m/z=375.1 (M+H-2HCl).
Reaction SMILES: [CH:1]([NH:4][C:5](=[O:19])[C@@H:6]([CH3:18])[NH:7]C(OCC1C=CC=CC=1)=O)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([NH:4][C:5](=[O:19])[C@@H:6]([CH3:18])[NH2:7])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)NC(=O)[C@@H](C)N

Procedure:
N-Benzyloxycarbonyl-D-alanine isopropyl amide (1.322 g, 5 mmol) is hydrogenated in 20 mL MeOH over 100 mg 10% Pd/C in a Parr Apparatus at 40 psi and room temperature until no more hydrogen is consumed. The methanolic suspension is filtered through a Celite pad to remove the catalyst and the filtrate is evaporated to dryness. The desired product is purified by conversion into a crystalline amino acid amide salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:24](O)=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:24]([Cl:30])=[O:25])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C(=O)O)c2ccc(C3CCCCC3)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CC(C(=O)Cl)c2ccc(C3CCCCC3)cc2)cc1
Yield: 98.3 %

Procedure:
A solution of 4-[2-carboxy-2-(4-cyclohexylphenyl)ethyl]-benzoic acid methyl ester (5.58 g, 15.2 mmol) in toluene was stirred and thionyl chloride (2.79 mL, 38.20 mmol) was added. The mixture was stirred and refluxed for 15 minutes and the toluene removed under reduced pressure. The residue was stripped twice with toluene to afford 5.75 g (98%) of 4-[2-chlorocarbonyl-2-(4-cyclohexylphenyl)ethyl]benzoic acid methyl ester.
Reaction SMILES: C1(C)C(S([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15](=[O:36])[C:16]2[CH:21]=[C:20]([NH:22]C(=O)C(F)(F)F)[CH:19]=[C:18]([NH:29]C(=O)C(F)(F)F)[CH:17]=2)(=O)=O)=CC=CC=1.[OH-].[K+]>CCO>[NH2:29][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([NH2:22])[CH:19]=1)[C:15]([C:11]1[NH:10][CH:14]=[CH:13][CH:12]=1)=[O:36]
Reactant: Cc1ccccc1S(=O)(=O)n1cccc1C(=O)c1cc(NC(=O)C(F)(F)F)cc(NC(=O)C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(N)cc(C(=O)c2ccc[nH]2)c1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirred EtOH (10 mL) solution of N-toluenesulfonyl-2-(3,5-di(trifluoroacetylamino)benzoyl)pyrrole (1.00 g, 1.83 mmol), was added 40% KOH solution (2 mL) and the mixture was heated at reflux until TLC analysis showed complete conversion. The resulting solution was cooled to room temperature and worked up as in Example 7. The crude product was purified by column chromatography (SiO2, CH2Cl2:MeOH) to afford the purified product 2-(3,5-diaminobenzoyepyrrole (237 mg, 65% yield). 1H NMR (500 MHz, CD3OD, 25° C.) δ 2.43 (s, 3H), 6.45 (m, 1H), 6.90 (m, 1H), 7.41 (d, 2H), 7.88 (m, 3H), 7.93 (d, 2H), 8.39 (t, 1H); 13C NMR (100 MHz, CD3OD, 25° C.) δ 104.8, 105.7, 109.4, 119.5, 125.2, 130.5, 139.8, 147.8, 186.0; HRMS (EI): m/z 201.0896 (100) {M}+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[NH2:20][CH2:21][C:22]([N:24]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>C(N(CC)CC)C>[C:25]1([N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:22]([CH2:21][NH:20][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: NCC(=O)N(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(NCC(=O)N(c1ccccc1)c1ccccc1)c1ccc2ccccc2c1
Yield: 59.5 %

Procedure:
Working in a manner similar to that described in Example 9, but starting with 2-naphthalenecarboxylic acid (0.95 g), oxalyl dichloride (0.7 g), 2-amino-N,N-diphenylacetamide (1.2 g) and triethylamine (0.8 g), and after recrystallization in acetonitrile, N-(diphenylcarbamoylmethyl)-2-naphthalenecarboxamide (1.2 g), m.p. 205° C., is obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[O:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[O:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=2)=[CH:23]1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([NH:13][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:34](=[O:35])[CH2:33][C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:24]4[CH:25]=[CH:26][O:22][CH:23]=4)[CH:28]=3)[CH2:17]2)=[O:15])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)C1CCCNC1
Reactant: O=C(O)Cc1cccc(-c2ccoc2)c1
Agent: Cl
Product: COC(=O)c1cc(Cl)ccc1NC(=O)C1CCCN(C(=O)Cc2cccc(-c3ccoc3)c2)C1

Procedure:
Using the same method as in Example 9-(ii), the target methyl 5-chloro-2-{[(1-{[3-(furan-3-yl)phenyl]carbonyl}piperidin-3-yl)carbonyl]amino}benzoate was quantitatively obtained using the methyl 5-chloro-2-[(piperidin-3-ylcarbonyl)amino]benzoate hydrochloride obtained in Example 11-(ii) and [3-(furan-3-yl)phenyl]acetic acid.
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl>[O:1]([CH2:8][CH2:9][Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCOc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: ClCCOc1ccccc1
Temperature: 0 °C
Yield: 101.7 %

Procedure:
Into a three-necked flask fitted with a stirrer, dropping funnel, thermometer and reflux condenser, was added 34.7 g 2-phenoxy-ethanol, 75 g dichloromethane and 1.25 g benzyl-trimethyl-ammonium chloride. The mixture was cooled to about 0° C. and 34 g thionyl chloride was added dropwise over a period of 45 minutes. After this addition, the mixture was warmed to room temperature, stirred for an hour and then heated to reflux (50° C.) for an additional three hours. At the end of the reaction (determined by GLC) the mixture was washed with water, an aqueous 10% sodium hydroxide solution and then again with water. The solvent was distilled off to afford 40 g of 2-phenoxy-ethyl chloride in a concentration of 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)=[CH:16][C:10]=3[N:9]=2)=[CH:4][C:3]=1[N+:26]([O-])=O>[Pd].C(OCC)(=O)C.CO>[NH2:26][C:3]1[CH:4]=[C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([N:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]4)=[CH:16][C:10]=3[N:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(-c2nc3cc(N4CCN(CCO)CC4)ccc3[nH]2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2nc3cc(N4CCN(CCO)CC4)ccc3[nH]2)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-{4-[2-(4-amino-3-nitro-phenyl)-1H-benzoimidazol-5-yl]-piperazin-1-yl}-ethanol (1.0 g, 2.6 mmol) in 4:1 ethyl acetate/methanol (100 ml) under nitrogen, was added 5% palladium on carbon (200 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 2-{4-[2-(3,4-diamino-phenyl)-1H-benzoimidazol-5-yl]-piperazin-1-yl}-ethanol as a reddish solid that was used in the next step without any purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([N:8]([CH2:19][CH:20](OC)OC)S(C1C=CC(C)=CC=1)(=O)=O)[CH3:7].O1CCOCC1.Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:25]([CH:20]=[CH:19][N:8]=[C:6]2[CH3:7])=[CH:26][CH:27]=1
Reactant: COc1cccc(C(C)N(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2ccnc(C)c2c1

Procedure:
A mixture of 39.3 g. (0.1 mole) of 3-methoxy-α-methyl-N-(2,2-dimethoxyethyl)-N-tosyl-benzylamine, one liter of dioxane and 80 ml. of 6 N hydrochloric acid is refluxed for six hours and allowed to stand for sixteen hours. The mixture is poured into two liters of water and extracted with ether. The aqueous phase is made alkaline with concentrated ammonium hydroxide and extracted with chloroform. The chloroform extract is washed, dried and evaporated to yield 7-methoxy-1-methylisoquinoline.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC>>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:4]2[CH:3]=[C:2]([CH:20]=[CH2:21])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=2)=[CH:14][CH:15]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Oc1ccc(-c2cc(Br)c3cc(O)ccc3n2)cc1
Product: C=Cc1cc(-c2ccc(O)cc2)nc2ccc(O)cc12
Yield: 69 %

Procedure:
This compound was prepared from 6a and tributyl(vinyl)tin according to method J. Yellow solid; Yield: 69%; mp>200° C. (dec.); 1H-NMR (400 MHz, DMSO-d6) δ 5.69 (d, J=11.7 Hz, 1H), 6.23 (dd, J=18.3, 1.0 Hz, 1H), 6.90 (d, J=8.5 Hz, 2H), 7.31 (dd, J=9.0, 2.7 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H), 7.40 (dd, J=17.3, 11.0 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 8.11 (d, J=8.8 Hz, 2H), 9.73 (s, 1H), 9.98 (s, 1H); MS (ESI) m/z 262 ([M−H]−), 264 ([M+H]+); Anal. Calcd for C17H13NO2: C, 77.55; H, 4.98; N, 5.32. Found: C, 74.26; H, 5.38; N, 4.82.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13]Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:16]([NH2:19])([CH3:18])[CH3:17]>>[CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH2:13][NH:19][CH:16]([CH3:18])[CH3:17])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(S(=O)(=O)CCCl)cc1
Reactant: CC(C)N
Product: CC(C)NCCS(=O)(=O)c1ccc(N(C)C)cc1

Procedure:
2-Chloroethyl 4-dimethylaminophenyl sulfone is reacted as in Preparation 19 with isopropylamine to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=1.[H-].[Na+].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:20]([C:30]([F:33])([F:32])[F:31])[CH:19]=1.[NH4+].[Cl-]>CN(C=O)C>[CH:24]1([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][S:13][C:10]3[CH:11]=[CH:12][C:7]([CH:2]4[O:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:8][CH:9]=3)=[CH:19][C:20]=2[C:30]([F:31])([F:32])[F:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Sc1ccc(C2OCCCO2)cc1
Reactant: FC(F)(F)c1cc(CBr)ccc1C1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(CSc2ccc(C3OCCCO3)cc2)ccc1C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Crude 4-[1,3]dioxan-2-yl-benzenethiol (0.9 mmol) is dissolved in DMF (15 mL, anhydrous). The solution is cooled to 0° C. followed by addition of NaH (76 mg, 1.8 mmol). After stirring for 30 min, the 4-bromomethyl-1-cyclohexyl-2-trifluoromethyl-benzene prepared above (0.8 mmol) dissolved in DMF (2 mL) is added dropwise via syringe. The mixture is stirred for 1 h, then poured into a mixture of ice and saturated aqueous NH4Cl. The aqueous phase is extracted with diethyl ether (3×30 mL). The combined organic layers are washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. The residue obtained is purified by silica gel chromatography (10% ethyl acetate in hexanes) to give 2-[4-(4-cyclohexyl-3-trifluoromethyl-benzylsulfanyl)-phenyl]-[1,3]dioxane as white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[F:13][C:12]([F:14])([F:15])[CH:11]([CH3:16])[O:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CC(Oc1ccc(N)cc1)C(F)(F)F
Reaction time: 12 h
Yield: 98.6 %

Procedure:
Nitro-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzene (6.74 g) was dissolved in MeOH (70 mL). Pd on carbon (10% Pd, 500 mg) was added and the mixture was hydrogenated at RT for 12 hours. The suspension was filtered and the filtrate was concentrated in vacuo to provide the title compound as a brown liquid (5.8 g). Rf: 0.38 (silica gel, ether/heptane 1:1). MS (m/e): 206.1 (MH+).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.C(=O)([O-])O.[Na+]>CN(C)C(=O)C.C(OCC)(=O)C>[NH2:32][C:28]1[CH:27]=[C:26]([NH:33][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Nc1cccc(N)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1cccc(N)c1
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a solution of N-Boc-β-alanine (1.00 g) in N,N-dimethylactamide (5 mL), carbonyldiimidazole (888 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour and 20 minutes. To the reaction mixture, a solution of 1,3-phenylenediamine (1.15 g) in N,N-dimethylactamide (5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 18 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain tert-butyl (3-((3-aminophenyl)amino)-3-oxopropyl)carbamate (B6, 978 mg).
Reaction SMILES: [C:1]1([C@H:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16](C(OCC3C=CC=CC=3)=O)[CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1>CO.[C].[Pd]>[C:1]1([C@H:11]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Product: C[C@@H](N[C@@H]1CCCNC1)c1cccc2ccccc12
Reaction time: 40 h
Yield: 96.6 %

Procedure:
To a solution containing 54.6 g of benzyl (R)-3-[chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 700 ml of tetrahydrofuran was added 350 ml of water, and the mixture was stirred under reflux for 15 hours. After tetrahydrofuran was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added thereto, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:140:1) to obtain 24.3 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APC I (m/z): 389 [M+H]+ (6) To a solution containing 24.2 g of benzyl (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate dissolved in 250 ml of methanol was added 2.5 g of palladium carbon (10% wet), and the mixture was shaked under hydrogen atmosphere at 3 atm at room temperature for 40 hours. Palladium carbon was removed, and the solvent was evaporated, the residue was washed with ethyl acetate-chloroform (10:1), and collected by filtration to obtain 15.3 g of (R)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine (the following Reference example Table, Reference example 3.001(a)). MS•APCI (m/z): 255 [M+H]+ (7) By using 14.5 g of benzyl (S)-3-chlorocarbonyl-(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate, the same treatment was carried out as in the above-mentioned (5) to obtain 4.74 g of benzyl (S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]piperidine-1-carboxylate. MS•APCI (m/z): 389 [M+H]+
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:25][CH2:26][CH2:27][OH:28])[S:23][CH:24]=2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([N:25]3[CH2:26][CH2:27][O:28][C:1]3=[O:2])[S:23][CH:24]=2)=[CH:18][CH:19]=1
Reactant: OCCNc1nc(-c2ccc(Cl)cc2)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1OCCN1c1nc(-c2ccc(Cl)cc2)cs1
Reaction time: 72 h
Yield: 6 %

Procedure:
1,1′-Carbonyldiimidazole (0.16 g, 1 mmol) was added to a solution of 2-{[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}ethanol (0.15 g, 0.58 mmol), prepared in the previous step, in dry tetrahydrofuran (5 mL) at room temperature under nitrogen. After 72 h, the mixture was evaporated and the residue purified by silica gel column chromatography (ethyl acetate:hexanes, 1:3 as eluant) to afford the title compound (9.8 mg, 5%) as a white solid, MS (ES) m/z 281 [M+H]+. ANLC 96.4%@210 nm, 96.2%@230 nm; RT=8.0 min, the Xterra® MS C18m instrument, 3.5μ, 4.6×50 mm column, 0.8 mL/min, Grad: 5/95-95/5 (A) the PIC™ B6 reagent (5 mM Hex. Sulfonic Acid); (B) AcCN.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:20])[NH:12][C:13]([NH:16][N+]([O-])=O)=[N:14][CH:15]=2)[CH:5]=[N:6][C:7]=1[CH3:8].[Br:21][C:22]1[C:23]([CH2:28][S:29][CH2:30][CH2:31]N)=[N:24][CH:25]=[CH:26][CH:27]=1>C(O)C>[Br:21][C:22]1[C:23]([CH2:28][S:29][CH2:30][CH2:31][NH:16][C:13]2[NH:12][C:11](=[O:20])[C:10]([CH2:9][C:4]3[CH:5]=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=3)=[CH:15][N:14]=2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCCSCc1ncccc1Br
Reactant: Cc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cnc1C
Solvent: CCO
Product: Cc1cc(Cc2cnc(NCCSCc3ncccc3Br)[nH]c2=O)cnc1C

Procedure:
A mixture of 5-(5,6-dimethyl-3-pyridylmethyl)-2-nitroamino-4-pyrimidone and 1.2 molar equivalents of 2-(3-bromo-2-pyridylmethylthio)ethylamine was heated under reflux in ethanol for 48 hours, evaporated to dryness and the product isolated as 2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-5-(5,6-dimethyl-3-pyridylmethyl)-4-pyrimidone, m.p. 105°-7°.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=[C:6]([F:16])[C:3]=1[CH2:4][OH:5].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30](Cl)=[O:31])[C@H:26]([CH2:33][CH3:34])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=[C:6]([F:16])[C:3]=1[CH2:4][O:5][C:30]([N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:23])[CH2:25][C@H:26]1[CH2:33][CH3:34])=[O:31]
Reactant: COCCCOc1cc(F)c(CO)c(Cl)c1
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cc(OCCCOC)cc1Cl
Yield: 77 %

Procedure:
This compound was prepared from 2-chloro-6-fluoro-4-(3-methoxy-propoxy)-benzylalcohol and (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester according to the procedure described in Example 179 to give the product as a colorless oil (576 mg; 77%); MS (ISP): 506.4 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:32])[CH2:17][CH:18]([CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.Cl>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:32])[CH2:17][CH:18]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Yield: 95.2 %

Procedure:
To a solution of ethyl 4-(4′-nitro-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (5.35 g, 12.4 mmol) in 85% ethanol (160 mL) was added iron powder (6.94 g) followed by a 2 N aqueous solution of hydrochloric acid (6.2 mL). The resulting mixture was refluxed for 2.5 h, filtered through a pad of Celite®, and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford ethyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (4.74 g, 95%). LC-MS ret. time 3.22 min, m/z 402.0 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.18 (t, 3H), 1.83–2.10 (m, 2H), 2.65 (t, 2H), 3.03–3.12 (m, 2H), 3.41–3.48 (m, 1H), 4.12 (q, 2H), 6.70 (d, 2H), 7.19 (d, 4H), 7.25 (m, 1H), 7.38 (d, 2H), 7.53 (d, 2H), 7.89 (d, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>CN(C=O)C.C(Cl)Cl>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:20])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-phenoxybenzoic acid (500 mg, 2.33 mmol) and DMF (1 drop) in CH2Cl2 (10 mL) under argon was added oxalyl chloride (1.3 mL, 2.0M in CH2Cl2, 2.6 mmol) dropwise. Bubbling of escaping gasses continued for 5 min after addition. The reaction was stirred at room temperature for 1 h, then concentrated in vacuo to give the title compound as a crude pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH:24]=[CH2:25].C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:25][CH2:24][CH:23]=[CH2:22])[C:10]=1[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)c1c(O)cccc1OCc1ccccc1
Reactant: C=CCCBr
Agent: BrCc1ccccc1
Product: C=CCCOc1cccc(OCc2ccccc2)c1C(=O)N(C)C

Procedure:
The title compound is prepared analogously to Example 1, step B, from 2-benzyloxy-6-hydroxy-N,N-dimethylbenzamide (Example 13, step C) except using 4-bromo-but-1-ene to replace benzyl bromide.