Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[Se:8][C:7]=1[C:17]([O:19]CC)=[O:18])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:3][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[Se:8][C:7]=1[C:17]([OH:19])=[O:18])[CH3:1]
Reactant: CCOC(=O)c1[se]c(-c2ccccc2)cc1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)N=Nc1cc(-c2ccccc2)[se]c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.4 %

Procedure:
To a solution of ethyl 3-[(dimethylamino)diazenyl]-5-phenylselenophene-2-carboxylate (200 mg, 0.56 mmol) prepared as described in Example 3 step c) in methanol (5 mL) was added a solution of sodium hydroxide (113 mg, 2.84 mmol) in water (3 mL) and stirred at rt for 16 h. The mixture was diluted with ice cold water and acidified with dil. HCl. The mixture was stirred for 30 min and the precipitated solid was filtered, washed with water and dried. The product was recrystallized from hexane-chloroform to give the product as a brown color solid (100 mg, 54%), mp 212-214° C. IR (neat) νmax 3566, 2924, 1700, 1253, 1180, 1113, 1070, 1011, 838, 766 cm−; 1H NMR (400 MHz, CDCl3): δ 12.27 (1H, s, —COOH), 7.79 (1H, s, H-4), 7.55-7.57 (2H, m, Ar—H), 7.34-7.39 (3H, m, Ar—H), 3.65 (3H, s, —N—CH3), 3.25 (3H, s, —N—CH3); 13C NMR (100 MHz, CDCl3): δ 163.9, 155.2, 154.6, 135.5, 129.2, 129.1, 126.3, 124.9, 116.6, 44.4, 37.1; LC-MS (positive ion mode): m/z 346, 344 (M+Na)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][N:13]1[CH:18]=[C:17]([S:19][CH3:20])[C:16](=[O:21])[C:15]2[S:22][CH:23]=[CH:24][C:14]1=2>ClCCl>[CH3:12][N:13]1[CH:18]=[C:17]([S:19]([CH3:20])=[O:9])[C:16](=[O:21])[C:15]2[S:22][CH:23]=[CH:24][C:14]1=2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(C)c2ccsc2c1=O
Solvent: ClCCl
Product: Cn1cc(S(C)=O)c(=O)c2sccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-chloroperbenzoic acid (85%; 1.63 g) in dichloromethane (60 ml) can be added dropwise during 20 minutes to a stirred solution of 4-methyl-6-methylthiothieno[3,2-b]pyrid-7(4H)-one (2.0 g) in dichloromethane (60 ml) at 0° C.-5° C. After 4 hours, more 3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml) can be added and the mixture stirred overnight at ambient temperature. More 3-chloroperbenzoic acid (0.15 g) in dichloromethane (10 ml) can be added and the mixture can again be stirred overnight at ambient temperature. The resulting solution can be extracted with saturated aqueous sodium bicarbonate solution (5×150 ml) and saturated aqueous sodium chloride solution (1×150 ml) and the organic phase can be discarded. The aqueous extracts are combined and extracted with dichloromethane (5×100 ml). The organic extracts are combined, dried over anhydrous magnesium sulphate and evaporated to give a solid product. This product can be crystallized from industrial methylated spirit to give the compound 4-methyl-6-methylsulphinylthieno[3,2-b]pyrid-7(4H)-one, m.p. 174° C.-176° C.
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][N:7]([CH2:15][CH2:16]Br)[C:6]2=[O:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][NH:31][CH3:32])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].[Cl:33]C1C=CC=CC=1>>[ClH:33].[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][N:7]([CH2:15][CH2:16][N:31]([CH3:32])[CH2:30][CH2:29][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=1)[C:6]2=[O:18]
Reactant: COc1cc2ncn(CCBr)c(=O)c2cc1OC
Reactant: Clc1ccccc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Product: COc1ccc(CCN(C)CCn2cnc3cc(OC)c(OC)cc3c2=O)cc1OC
Product: Cl

Procedure:
1-(6,7-dimethoxy-4(3H)-quinazolinone-3-yl)-2-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-ethane hydrochloride was prepared analogous to Example 1 (b) by reaction of 1-(6,7-dimethoxy-4(3H)-quinazolinone-3-yl)-2-bromoethane with N-(3,4-dimethoxy-phenyl ethyl)-N-methyl amine in chlorobenzene. M.p.: 205 - 208° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=2)[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:20]=3)[CH:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Reactant: Brc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CNc2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Temperature: 80 °C
Yield: 26.9 %

Procedure:
4-Methoxy-benzylamine (3.40 mL, 3.59 g, 26.20 mmol) and anhydrous DMSO (5.20 mL) were added to a high-pressure flask charged with 36 (3.00 g, 9.58 mmol), K3PO4 (4.19 g, 19.73 mmol), CuII (290 mg, 1.52 mmol), and L-(−)-proline (255 mg, 2.21 mmol); the sealed flask was heated to 80° C. for 44 hours. After cooling to room temperature, reaction contents were partitioned between water (100 mL) and EtOAc (200 mL), then were extracted with EtOAc (2×200 mL). The combined organic layers were washed with saturated aqueous NaCl solution (500 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 7:1:1 Hexanes:CH2Cl2:EtOAc) to give 37 as a light orange amorphous solid (952 mg, 27%): 1H NMR (CDCl3, 500 MHz) δ 7.55 (d, J=8.7 Hz, 2H), 7.49 (m, 2H), 7.41 (m, 2H), 7.37-7.32 (m, 3H), 7.15 (dd, J=8.8, 2.6 Hz, 1H), 7.13 (m, 1H), 6.92 (dd, J=8.8, 2.3 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 6.87 (m, 1H), 5.14 (s, 2H), 4.35 (s, 2H), 3.82 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 159.1, 154.6, 137.4, 130.7, 129.3 (2C), 128.8 (2C), 128.1, 128.0, 127.8 (2C), 119.4 (2C), 118.6, 114.3 (2C), 107.9, 70.3, 55.5; IR (film) νmax 3734, 1558, 1456, 1259, 1167, 847, 746, 702, 660 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C25H23NO2, 370.1807. found, 370.1786.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]([CH3:27])([CH3:26])[NH2:25].[ClH:28]>C(#N)C>[ClH:28].[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:23][C:24]([NH:25][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[CH3:1])([CH3:26])[CH3:27]
Reactant: CC(C)(N)Cc1c[nH]c2ccc(Br)cc12
Reactant: Cc1ccccc1OCC1CO1
Agent: Cl
Solvent: CC#N
Product: Cc1ccccc1OCC(O)CNC(C)(C)Cc1c[nH]c2ccc(Br)cc12

Procedure:
(2-Methylphenoxymethyl)oxirane, 4.1 g. (0.025 mole) and 6.65 g. (0.025 mole) of 5-bromo-α,α-dimethyl-1H-indol-3-yl-ethaneamine were mixed and heated at 140° for 1 hr. The mixture was then cooled and dissolved in 40 ml. of acetonitrile while still warm. The product was converted to the hydrochloride salt by treatment of the solution with 5 N ethanolic HCl. The solvent was removed by distillation and the residue dissolved in 30 ml. of acetonitrile. The product crystallized from this solution, yield 11.0 g., m.p. 197°-199°. This material was recrystallized from methanol/isopropanol, yield 8.0 g., m.p. 198.0°-200.0° dec. (corr.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([O:40][C:41](=[O:54])[CH:42]([O:51][CH2:52][CH3:53])[CH2:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)[CH3:39].CCOC(/N=N/C(OCC)=O)=O>>[CH2:38]([O:40][C:41](=[O:54])[CH:42]([O:51][CH2:52][CH3:53])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([O:11][CH2:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([Br:18])=[CH:16][CH:17]=2)[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:46][CH:45]=1)[CH3:39]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCC=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1)OCC
Yield: 56.2 %

Procedure:
Reaction of 3,3-bis-(4-bromophenyl)-prop-2-en-1-ol (0.50 g, 1.36 mmol), triphenylphosphine (0.39 g, 1.50 mmol), 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (0.39 g, 1.63 mmol) and diethy lazodicarboxylate (0.26 g, 1.51 mmol) in an identical manner to example 1 gave the title compound (450 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:34][S:35]([CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:37])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:43]3[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:36])=[O:37])[CH2:45][CH2:44]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Solvent: ClCCl
Product: CCOc1ccccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 7) was reacted with 1-(2-methanesulfonylethyl)-piperazine bishydrochloride in methylene chloride using the procedure as described in example 8 to give [(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone. HR-MS (ES, m/z) calculated for C31H35N4O4SCl2 [(M+H)+] 629.1751, observed 629.1757.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.CC1(C)C(C)(C)OB([C:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:28]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:24]=2)=[CH:3][C:4]=1[O:11][CH:12]([CH3:14])[CH3:13])([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Oc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 64.9 %

Procedure:
A mixture of 3.26 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 4.65 g of 2-methylpropan-2-yl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate, 12.5 ml of a 3M solution of sodium carbonate and 350 mg of bis(triphenylphosphine)dichloropalladium(II) in 41 ml of dioxane is refluxed for 1 h 30. The mixture is diluted with 150 ml of water and 200 ml of ethyl acetate. The aqueous phase is extracted three times with 200 ml of ethyl acetate. The combined organic phases are washed with 100 ml of a saturated sodium chloride solution, dried over magnesium sulfate and concentrated under vacuum. The residue is purified on 600 g of silica, elution being carried out with dichloromethane/ethyl acetate (99/1), so as to give 2.95 g of 2-methylpropan-2-yl 4-[4-nitro-3-(propan-2-yloxy)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3]([C:5]1[C:6]([CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[C:7]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([OH:14])[CH:10]=[CH:9]2)=[O:4].Br[CH2:36][C:37]1[N:42]=[C:41]([N:43]2[C:51](=[O:52])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]2=[O:53])[CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]([CH3:34])([CH3:33])[C:3]([C:5]1[C:6]([CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])=[C:7]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[N:8]2[C:13]=1[CH:12]=[C:11]([O:14][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([N:43]3[C:44](=[O:53])[C:45]4[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=4)[C:51]3=[O:52])[N:42]=1)[CH:10]=[CH:9]2)=[O:4]
Reactant: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(O)ccn2c1C(=O)c1ccc(OC)cc1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cc1c(C(=O)C(C)(C)C)c2cc(OCc3cccc(N4C(=O)c5ccccc5C4=O)n3)ccn2c1C(=O)c1ccc(OC)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A suspension of methyl 3-[1-(2,2-dimethylpropanoyl)-7-hydroxy-3-(4-methoxybenzoyl)indolizin-2-yl]-2,2-dimethylpropanoate (350 mg, 0.75 mmol), 2-(6-bromomethyl-pyridin-2-yl)-isoindole-1,3-dione (286 mg, 0.90 mmol), and potassium carbonate (416 mg, 3.0 mmol) in DMF (4 mL) is stirred for 6 h at 70° C. The mixture is partitioned between CH2Cl2 and brine. The organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, heptane to 50% EtOAc in heptane) gives methyl 3-[1-(2,2-dimethylpropanoyl)-7-{[6-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pyridin-2-yl]methoxy}-3-(4-methoxybenzoyl)indolizin-2-yl]-2,2-dimethylpropanoate that is dissolved in EtOH (5 mL) and treated with a 50% aqueous hydrazine (wt/wt) solution (0.75 mL). The mixture is heated at 70° C. for 2 h then cooled to 23° C. and filtered. The volatile components from the filtrate are removed in vacuo. The residue is purified by flash chromatography (SiO2, heptane to 50% EtOAc in heptane) giving methyl 3-{7-[(6-aminopyridin-2-yl)methoxy]-1-(2,2-dimethylpropanoyl)-3-(4-methoxybenzoyl)indolizin-2-yl}-2,2-dimethylpropanoate (342 mg, 78%) that is dissolved in MeOH (2 mL), THF (2 mL), and aqueous 5M sodium hydroxide (1 mL). The solution is heated at 70° C. for 3 h then cooled and acidified with AcOH. The mixture is partitioned between CH2Cl2 and brine then organics are collected, dried with MgSO4, filtered, and concentrated in vacuo to give 3-{7-[(6-aminopyridin-2-yl)methoxy]-1-(2,2-dimethylpropanoyl)-3-(4-methoxybenzoyl)indolizin-2-yl}-2,2-dimethylpropanoic acid (310 mg, 98%) that is dissolved in DMF (3 mL). This solution is treated with ammonium carbonate (57 mg, 0.73 mmol), Boc-anhydride (136 mg, 0.62 mmol), and pyridine (0.1 mL, 1.5 mmol) and stirred for 30 min. The mixture is directly purified by reverse phase HPLC to give the title compound (115 mg, 40%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CO[C:8](=[O:26])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[C:11]([O:24][CH3:25])[CH:10]=1>>[CH3:23][CH:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:26])=[CH:10][C:11]=1[O:24][CH3:25])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22]
Reactant: CCNCC
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1
Product: CCN(CC)C(=O)c1ccc(OC(C)CCCC(C)C)c(OC)c1

Procedure:
By the procedure described in Example 38, diethylamine is reacted with 4-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-benzoic acid methyl ester to produce 4-[(1,5-dimethyl-hexyl)-oxy]-m-methoxy-N,N-diethyl-benzamide (boiling point = 180°-182°C/0.1 mmHg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[C:11]([CH3:12])=[C:10]([CH2:13][CH:14]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:3]=[C:4]([NH2:27])[C:5]2[C:11]([CH3:12])=[C:10]([CH2:13][CH:14]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH2:15][CH3:16])[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCC(Cc1cnc2nc(N)nc(N)c2c1C)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCC(Cc1cnc2nc(N)nc(N)c2c1C)c1ccc(C(=O)O)cc1
Reaction time: 20 h

Procedure:
A solution of 4 (190 mg, 0.521 mmol) in Me2SO (17 mL) was treated with 1 N NaOH (0.75 mL). After 20 hours at 20°-23° C., the solution was found by TLC (CHCl3 -MeOH, 4:1) examination to contain a small amount of unchanged 4. More 1N NaOH (0.50 mL) was added to the solution, kept at 20°-23° C., and 2 hours later TLC showed completed disappearance of 4. The Me2SO was then removed by distillation in vacuo (less than 1 mm, bath to 45° C). The residue was dissolved in H2O (3 mL), and the resulting clear solution was carefully treated dropwise with 1N HCl to produce pH 5 and cause precipitation of 5 as a pale-beige solid. The mixture was chilled in a refrigerator for several hours before the solid was collected and dried; yield 165 mg (82%). Anal. Calcd. for C19H21N5O2.2H2O: C, 58.90; H, 6.50; N, 18.08. Found: C, 59.40; H, 6.14; N, 17.63. Spectral data: mass, m/z 352, MH+ for C19H21N5O2 ; UV λmax 234 nm (ε 39 300), 322 (7730) at pH 1; 235 nm (ε 37 800), 335 (6050) at pH 7; 236 nm (ε 37 600), 346 (6730) at pH 13.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:35][C@@H:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=[CH2:38].[Cl:47][C:48]1[C:49]2[C:56]([I:57])=[CH:55][NH:54][C:50]=2[N:51]=[CH:52][N:53]=1>O1CCCC1>[Cl:47][C:48]1[C:49]2[C:56]([I:57])=[CH:55][N:54]([CH2:35][C@@H:36]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=[CH2:38])[C:50]=2[N:51]=[CH:52][N:53]=1
Reactant: Clc1ncnc2[nH]cc(I)c12
Reactant: C=C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@@H](Cn1cc(I)c2c(Cl)ncnc21)NC(=O)OC(C)(C)C
Yield: 186.2 %

Procedure:
Diisopropyl azodicarboxylate (2.44 ml) was slowly added to a solution of triphenylphosphine (13.1 g) in tetrahydrofuran (70 ml) under ice-cooling. The reaction mixture was stirred under ice-cooling for 1 hour, and then a solution of (S)-tert-butyl (1-hydroxybut-3-en-2-yl)carbamate (7.0 g) synthesized according to the method disclosed in Non-patent Literature Org. Lett., 2005, vol. 7, No. 5, pp. 847-849 and 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (6.97 g) in tetrahydrofuran (35 ml) was slowly added thereto. After the reaction mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound (20.84 g) as a light-yellow, oily substance.
Reaction SMILES: [CH:1]([CH:4]1[C:9](=[O:10])[NH:8][CH:7]=[CH:6][S:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16].O>O1CCCC1>[CH:1]([CH:4]1[C:9](=[O:10])[N:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[CH:6][S:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)CBr
Reactant: CC(C)C1SC=CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN1C=CSC(C(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of (2RS)-2-isopropyl-3,4-dihydro-2H-1,4-thiazin-3-one (70 mg, Reference compound No. 42-1) in anhydrous tetrahydrofuran (1 ml) is added to a solution of sodium hydride (39 mg) in anhydrous tetrahydrofuran (1 ml) under ice cooling, and the mixture is stirred for 10 minutes. Methyl bromoacetate (74.3 mg) is added to the mixture, the temperature is raised to room temperature, and the whole is stirred for 20 minutes. The reaction mixture is cooled with ice, water is added to the mixture, and the whole is extracted with ethyl acetate. The extract is washed with 1 N hydrochloric acid, water and saturated brine successively and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (90.2 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](=[O:42])[O:34][CH:33]=1>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:31][C:32]1[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[O:42])[O:34][CH:33]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: O=c1occ(CBr)c2ccccc12
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2coc(=O)c3ccccc23)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-Bromomethyl-isochromen-1-one following the procedure of Example 478: MS (ESI) m/z 552; HRMS: calcd for C33H20F3NO4+H+, 552.14172; found (ESI, [M+H]+), 552.1434.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12]Br.[O:14]1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:21]1[CH2:22][CH2:23][C:18]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:19][CH2:20]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: BrCCCc1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2oc(CCCN3CCC4(CC3)OCCO4)cc2c1

Procedure:
A solution of 5 g of 3-(benzofuran-2-yl)-1-bromopropane, 3 g of 1, 4-dioxa-8-azaspiro[4.5]decane and 5.8 g of potassium carbonate in 200 ml of acetone is refluxed for 24 hours, and then evaporated to dryness. The residue is taken up in ethyl acetate, washed with water, dried and evaporated to yield the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](SC)=[NH:15])=[CH:9][C:8]=2[O:18][CH3:19])[CH:6]=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)[C:26](O)=O.[NH2:36][NH2:37]>>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]1[NH:37][N:36]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:5]3[CH:6]=[C:2]([Cl:1])[N:3]=[CH:4]3)=[C:8]([O:18][CH3:19])[CH:9]=2)[N:15]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1
Reactant: COc1cc(NC(=N)SC)ccc1-n1cnc(Cl)c1
Reactant: O=C(O)C(CCCCCl)c1cccc(Cl)c1
Reactant: NN
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3cccc(Cl)c3)n2)ccc1-n1cnc(Cl)c1
Yield: 100 %

Procedure:
Methyl 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylcarbamimidothioate (1.5 g, 5.05 mmol, from preparation A) and 6-chloro-2-(3-chlorophenyl)hexanoic acid (1.320 g, 5.05 mmol, from preparation AP) were coupled and then reacted with hydrazine (0.635 mL, 20.23 mmol) using a procedure analogous to Step A of Example 13. The crude product, 5-(5-chloro-1-(3-chlorophenyl)pentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.78 g, 100% yield), was used in the subsequent step without purification. LC-MS (M+H)+ 507.2.