Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:47]([O:54][C:55](=[O:59])[CH2:56][CH2:57][NH2:58])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[CH2:47]([O:54][C:55](=[O:59])[CH2:56][CH2:57][NH:58][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:10]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1

Procedure:
For the preparation of the ester starting material, m-(1-t-butoxyformamido)benzoic acid in THF is activated (2 hours, 0° C.) with 2-chloro-4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine and reacted with β-alanine benzyl ester p-toluenesulphonate and N-methylmorpholine to give N-[m-(1-t-butoxyformamido)benzoyl]-β-alanine benzyl ester, m.p. 130°-131° C. Cleavage with trifluoroacetic acid gives N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate. Nα -Z-Nω -Nitro-L-arginine is activated (4 minutes, -10° C.) with isobutyl chloroformate and triethylamine in THF and coupled with N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate and triethylamine to give the desired benzyl ester, m.p. 157°-160° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]([OH:29])([CH3:28])[CH3:27])[N:18]=[C:17]2[CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:46]=[N+:47]=[N-:48])(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[OH:29][C:26]([C:19]1[N:18]=[C:17]([CH2:30][CH2:31][CH3:32])[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:48][N:47]=[N:46][N:2]=3)=[CH:10][CH:11]=2)[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:27])[CH3:28]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.00 g of ethyl 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in Example 71(b)] and 100 g of tributyltin azide in 7.5 ml of toluene was stirred at 100° C. for 5 days. 2.5 g of sodium hydrogencarbonate and 20 ml of water were then added to the mixture, and the resulting mixture was stirred at room temperature for 8 hours. At the end of this time, the mixture was diluted with ethyl acetate and acidified with 3N aqueous hydrochloric acid to a pH value of 3. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate as a syrup. 0.80 g of trityl chloride was added to a solution of the whole of this syrup in 15 ml of pyridine, and the mixture was stirred at 60° C. for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent; it was then crystallized in diisopropyl ether, to give 1.15 g of the title compound as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH3:2].[CH3:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([NH:19][CH3:18])=[O:33])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOc1cc(CN2CCN(c3ccc(C(=O)NC)cc3)CC2)cc2c1OC(C)C(=O)N2

Procedure:
Using 398B and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (t, J=7.07 Hz, 3H) 1.37-1.44 (m, 3H) 2.41-2.49 (m, 4H) 2.74 (d, J=4.55 Hz, 3H) 3.24 (d, J=5.05 Hz, 4H) 3.40 (s, 2H) 3.98-4.12 (m, 2H) 4.55-4.65 (m, 1H) 6.51 (d, J=1.77 Hz, 1 H) 6.63 (d, J=1.77 Hz, 1H) 6.94 (d, J=8.84 Hz, 2H) 7.70 (d, J=8.84 Hz, 2H) 8.14 (q, J=4.72 Hz, 1H) 10.57 (s, 1H). ESI-MS: m/z 439.4 (M+H)+. mp 228.2-233.0° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:36]([NH:39][CH:19]1[CH2:20][N:15]([C:13]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:14])[CH:16]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:17][CH2:18]1)([CH3:38])[CH3:37]
Reactant: CC(C)N
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(=O)CCC2CNC(=O)c2cccc3cccnc23)s1
Product: Cc1nc(-c2ccccc2)c(C(=O)N2CC(NC(C)C)CCC2CNC(=O)c2cccc3cccnc23)s1

Procedure:
N-((5-(Isopropylamino)-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and isopropyl amine. (ESI) 528 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][NH:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH:10]=[CH:11][CH:12]=1.Cl[CH2:26][C:27]([NH2:29])=[O:28].C(N(CC)CC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][N:15]([CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[CH2:26][C:27]([NH2:29])=[O:28])[CH:10]=[CH:11][CH:12]=1
Reactant: Fc1cccc(COc2cccc(CCNCc3ccco3)c2)c1
Reactant: NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)CN(CCc1cccc(OCc2cccc(F)c2)c1)Cc1ccco1
Yield: 99.3 %

Procedure:
A solution of 1.8 g (5.53 mmol) of [2-[3-(3-fluoro-benzyloxy)-phenyl]-ethyl]-(furan-2-ylmethyl)amine, 0.57 g (6.08 mmol) of 2-chloro-acetamide and 0.92 ml (6.62 mmol) of triethylamine in 5 ml of dry dimethylformamide was heated at 120° C. for 2 hours with microwaves. Solvent was removed under vacuum, water was added and the product was extracted with ethyl acetate. The crude reaction mixture was purified by flash chromatography (dichloromethane/methanol 95:5 v:v). 2.1 g (99% yield) of a yellow oil were isolated.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.F[C:15]1[CH:39]=[CH:38][C:18]([C:19]([NH:21][C:22]2[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:20])=[C:17]([O:40][CH:41]2[CH2:46][CH2:45][N:44]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][CH2:42]2)[CH:16]=1.[OH:54][CH:55]1[CH2:59][CH2:58][NH:57][CH2:56]1>>[C:50]([O:49][C:47]([N:44]1[CH2:45][CH2:46][CH:41]([O:40][C:17]2[CH:16]=[C:15]([N:57]3[CH2:58][CH2:59][CH:55]([OH:54])[CH2:56]3)[CH:39]=[CH:38][C:18]=2[C:19]([NH:21][C:22]2[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=2[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:25])=[O:20])[CH2:42][CH2:43]1)=[O:48])([CH3:52])([CH3:51])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: OC1CCNC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCC(O)C3)ccc2C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
Using methods substantially equivalent to those described in example 4-F except that the workup used saturated aqueous citric acid instead of water, 2-[2-(1-tert-butoxy-carbonylpiperidin-4-yloxy)-4-(3-hydroxypyrrolidin-1-yl)benzoylamino]-N-(5-chhloro-pyridin-2-yl)benzamide (160 mg, 0.25 mmol, 47%) was prepared from 2-[4-fluoro-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoylamino]-N-(5-chloropyridin-2-yl)-benzamide and 3-hydroxypyrrolidine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=[O:17])[CH:10]([CH2:11][Se:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl(O)(=O)(=O)=[O:19]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH:14]2[C:16]([OH:19])([OH:17])[CH:10]([CH2:11][Se:12][CH2:13]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: O=C1C2C[Se]CC1CN(Cc1ccccc1)C2
Solvent: c1ccccc1
Product: OC1(O)C2C[Se]CC1CN(Cc1ccccc1)C2
Yield: 90.2 %

Procedure:
7-Benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9-one (0.65 g, 2.2 mmol) was dissolved in dry benzene (250 mL). Perchloric acid (60%, 1.0 g, 6.0 mmol) was added dropwise very slowly with cooling and swirling. This pecipitated an orange solid which adhered to the side of the flask. The benzene was decanted and the solid was recrystallized (95% ethanol) to give 7-benzyl-3-selena-7-azabicyclo[3.3.1]nonan-9,9-diol hydroperchlorate (0.62 g, 68.3%) as white needles: mp 214.0°-216.0° C. (dec); IR (KBr) cm-1 3430, 1080; 1H NMR (DMSO-d6) δ2.43 [br s, 2H, H(2,4)ax ], 2.72 [br d, 2H, H(2,4)eq ], 3.22-3.50 [m, 6H, H(6,8)ax, H(1,5), OH], 3.50-3.64 [m, 2H, H(6,8)eq ], 4.35 [d, 2H, H(10-NCH2)], 7.40-7.70 [m, 5H, ArH], 9.20 [br s, 1H, H(7)]; 13C NMR (DMSO-d6) ppm 21.1 [C(2,4)], 34.7 [C(1,5)], 54.9 [C(6,8)], 60.1 [C(10)-NCH2)], 92.5 [C(9)], 129.2, 129.7, 130.0, 130.5 [ArC]; 15N NMR (DMSO-d6) ppm 51.88 [N(7)]; 77Se NMR (DMSO-d6) ppm 62.39 [Se(3)]. Analysis calculated for C14H20NClSeO6 : N, 3.39; Se, 19.13. Found: N, 3.20; Se, 19.51. ##STR29##
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: Cc1cccc(C(=O)O)c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,3-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.85-0.91 (m, 3 H) 1.25-1.34 (m, 2 H) 1.65-1.75 (m, 2 H) 2.23 (s, 3 H) 2.27 (s, 3 H) 2.48 (s, 3 H) 4.12 (t, 2 H) 6.09-6.13 (m, 1 H) 7.07-7.14 (m, 1 H) 7.16-7.23 (m, 2 H); MS (ESI) m/z 303 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24].[Cl:25]/[CH:26]=[CH:27]\[CH2:28]I.[Cl-].[NH4+]>O1CCCC1.[Cu]Br>[Cl:25][CH:26]=[CH:27][CH2:28][C:7]1[C:20]([F:21])=[C:19]([F:22])[C:10]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[C:9]([F:23])[C:8]=1[F:24]
Reactant: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1Br
Reactant: Cl/C=C\CI
Agent: [Cu]Br
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1c(F)c(COC2CCCCO2)c(F)c(F)c1CC=CCl
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (2.5M in hexane, 3 cm3) was added portionwise to a solution of 2-[4-bromo-2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran (1.7 g) in dry tetrahydrofuran (10 cm3) under an atmosphere of dry nitrogen, whilst the reaction temperature was maintained at -70° C. After 30 minutes, copper (I) bromide--dimethyl sulphide complex (1.54 g) was added in one portion and the reaction temperature allowed to warm to 0° C., for a period of 15 minutes. After cooling to -70° C., a solution of Z-1-chloro-3-iodoprop-1-ene (2.03 g) in dry tetrahydrofuran (3 cm3) was added portionwise, and the reaction mixture stirred for a further hour at -70° C. After warming to the ambient temperature, (ca. 25° C.), aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure to give an orange oil. The residue was then subjected to medium pressure column chromaatography on a silica gel column using a Gilson apparatus, eluting with petroleum ether (boiling range 40°-60° C.) containing diethyl ether (5% by volume) to give 2-[4-(3-chloroprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyloxy]-tetrahydropyran, as a mixture consisting predominantly of the Z isomer.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:26][CH:27]=1
Reactant: CCSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
152 mg (2.33 mmol) of potassium cyanide were added to 510 mg (1.16 mmol) of the compound from Example 53A in 7 ml of DMF. The mixture was stirred at 80° C. for 2 h and, after cooling, water was added, the mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 222 mg (52% of theory) of the target compound were obtained.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[OH:14][C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[O:66]([CH2:73][CH:74]1[O:78][C:77](=[O:79])[N:76]([CH2:80][CH2:81][CH2:82]O)[CH2:75]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1C=CC=CC=1>[O:66]([CH2:73][CH:74]1[O:78][C:77](=[O:79])[N:76]([CH2:80][CH2:81][CH2:82][O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:19][CH:20]3[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:21]3=[O:45])=[CH:46][CH:47]=2)[CH2:75]1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1OC(COc2ccccc2)CN1CCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: O=C1OC(COc2ccccc2)CN1CCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Yield: 55.2 %

Procedure:
A procedure similar to that described in Preparation 6 was repeated, except that 1.29 g of tributylphosphine, 30 ml of anhydrous benzene, 2.98 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione, 1.61 g of azodicarbonyldipiperidine and 1.33 g of 3-(5-phenoxymethyl-2-oxooxazolidin-3-yl)propanol (prepared as described in Preparation 114) were used, to give 2.04 g of the title compound, melting at 70° C. to 73° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[C:4]([NH:20][CH2:17][CH2:18][CH3:19])[N:3]=1
Reactant: CCCN
Reactant: Clc1nc(Cl)c2ncn(C3CCOC3)c2n1
Solvent: CCCCO
Product: CCCNc1nc(Cl)nc2c1ncn2C1CCOC1

Procedure:
The operation is carried out as in Stage 2 of Example 2 starting from 181 mg of the product obtained in Stage 1 of Example 2 and 3 ml of butanol and using 0.062 ml of 1-propanamine in place of the benzylamine. In this way 136 mg of expected product is obtained in the form of beige crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>O1CCCC1>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:28])[CH:7]=1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (2.71 g) was dissolved in tetrahydrofuran (60 ml) under a nitrogen atmosphere, and then triethylamine (2.27 ml) and phenyl chloroformate (2.05 ml) were added dropwise thereto while cooling in an ice water bath, followed by stirring at room temperature for 25 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to provide a crude product of 4-(2-fluoro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (5.00 g). The crude product was dissolved in tetrahydrofuran (50 ml), and then pyrrolidine (3.64 ml) was added at room temperature, followed by stirring for 1 hr. To the reaction mixture was added a saturated aqueous solution of ammonium chloride, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and an brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2 to 1:4, then ethyl acetate) to provide the titled compound (2.927 g, 78%) as pale brown crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[CH2:23][N:24]=[C:25]=[O:26]>>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:12][N:13]([C:25](=[O:26])[NH:24][CH2:23][C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[Cl:15])[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC12CNC2
Product: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCc1ccc(Cl)cc1Cl)C2

Procedure:
In analogy to the experimental procedure of example 8) 1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of 1-benzyl-1,6-diaza-spiro[3.3]heptane was converted using 2,4-dichloro-1-isocyanatomethyl-benzene instead of (3-isocyanato-propyl)-benzene into the title compound which was used directly in the next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:11])=[CH:7][CH:6]=[C:5]([Cl:20])[CH:4]=1.Cl[O-].[Na+]>O.CO>[Cl:20][C:5]1[CH:4]=[CH:3][C:8]2[NH:9][C:10](=[O:11])[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:7]=2[CH:6]=1
Reactant: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2n1-c1ccc(Cl)cc1
Reaction time: 5 h

Procedure:
A solution of sodium hydroxide (4 grams (g)) in water (15 milliliters (ml)) was added to a solution of 4,4'-dichlorocarbanilide (14.1 g, 0.05 mole) in methanol (300 ml). Sodium hypochlorite solution (100 ml, 1 N in 0.1 molar sodium hydroxide) was then added dropwise over 30 minutes to the vigorously stirred reaction mixture, maintaining the temperature below 35° C. by means of an ice bath. Stirring was continued at room temperature for 5 hours after which the small amount of solid present was removed by filtration. The filtrate was evaporated to a volume of about 50 ml, diluted with water (500 ml), and subsequently acidified to a pH of 3 with hydrochloric acid. The product was then filtered, washed with water, dried at 80° C. and identified as 6-chloro-1-(4-chlorophenyl)-2-benzimidazolinone by infrared spectra. The product recovery was 66 percent of theoretical and the product melted at 239° C. (recrystallized from toluene).
Reaction SMILES: [CH:1]1(C2CCC3C(=C(Cl)C(Cl)=C(OC)C=3)C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([CH3:34])[C:32]=1[CH3:33])[C:29](=[O:35])[CH2:28][CH2:27][CH2:26]2.CI.C1(Br)CCCC1>>[CH:1]1([CH:28]2[CH2:27][CH2:26][C:25]3[C:30](=[C:31]([CH3:34])[C:32]([CH3:33])=[C:23]([O:22][CH3:21])[CH:24]=3)[C:29]2=[O:35])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Reactant: COc1cc2c(c(C)c1C)C(=O)CCC2
Agent: BrC1CCCC1
Solvent: CI
Product: COc1cc2c(c(C)c1C)C(=O)C(C1CCCC1)CC2

Procedure:
By the procedure of Example III, Step 1, but substituting for the 2-cyclopentyl-6-methoxy-7,8-dichloro- 1-tetralone used therein an euivalent amount of 6-methoxy- 7,8-dimethyl-1-tetralone, and for the methyl iodide there used an equivalent amount of cyclopentyl bromide, then 2-cyclopentyl-6-methoxy-7,8-dimethyl-1-tetralone is obtained.
Reaction SMILES: N#N.[CH2:3]([C:5]1[O:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:10](O)=[O:11])[N:9]=1)[CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>C1(C)C=CC=CC=1>[CH2:3]([C:5]1[O:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:8]([C:10]([Cl:27])=[O:11])[N:9]=1)[CH3:4]
Reactant: CCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc(C(=O)Cl)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-ethyl-5-phenyl-oxazole-4-carboxylic acid (54 mg, 0.25 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.08 mL, 0.86 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-ethyl-5-phenyl-oxazole-4-carbonyl chloride.