Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[N:43]1([C:48](N)=[O:49])[CH:47]=[CH:46][N:45]=[CH:44]1>>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:48]([NH:43][CH2:47][CH2:46][N:45]3[CH2:38][CH2:37][CH:30]([CH:31]([CH3:36])[CH3:32])[CH2:29][CH2:44]3)=[O:49])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: NC(=O)n1ccnc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN4CCC(C(C)C)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-[2-4-isopropyl-1-piperidinyl)ethyl]-1H-imidazole-1-carboxamide (Preparation 22) by a similar method to Example 1.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][C:26]=1[F:33])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:8]([N:6]2[CH:5]=[N:4][N:3]=[CH:7]2)[C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:27][C:26]=1[F:33])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Reactant: Fc1cc(CCl)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (600%, 400 mg, 10.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (1.8-52 g, 10.0 mmol) in DMF (50 mL) at room temperature. The mixture was stirred for 1 h at this temperature and 1-benzyloxy-4-chloromethyl-2-fluoro-benzene (CAB03018, 2.51 g, 10.0 mmol) was added. The reaction mixture was stirred overnight and ethyl acetate (200 mL) and water (50 mL) were added. The mixture was transferred into a separation funnel and washed with water (2×50 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was suspended in 2-propanol (40 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 3.12 g (78%). 1H-NMR (400 MHz, d6-DMSO) δ=4.97 (s, 2H), 5.12 (s, 2H), 6.73 (d, J=9.0 Hz, 2H), 7.01 (dd, J=8.2, 1.2 Hz, 1H), 7.16 (dd, J=8.6, 8.6 Hz 1H), 7.21 (dd, J=8.6, 2.4 Hz, 1H), 7.30-7.44 (m, 5H), 7.75 (d, =9.0 Hz, 2H), 8.80 (s, 2H). LRMS (FAB+): 400.1 (100, [M+H]+).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].C1OCCOCCOCCOCCOC1.Br[CH2:57][C:58]#[C:59][C:60]([CH3:70])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:61]>O1CCCC1.O>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:57][C:58]#[C:59][C:60]([CH3:61])([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:70])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 100.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol), 15-crown-5 (10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne (109 mg, 0.375 mmol) in tetrahydrofuran (1 ml) was stirred at 60° C. for 2 hours. The solution was cooled to room temperature and then taken into water and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (82.4 mg, 99%).
Reaction SMILES: [Na].[CH3:2][CH:3]([S-:5])[CH3:4].Br[C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.O>CN(C=O)C>[CH:3]([S:5][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:4])[CH3:2]
Reactant: CC(C)[S-]
Reactant: Nc1cnc(Br)cn1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Sc1cnc(N)cn1
Temperature: 100 °C

Procedure:
Sodium-2-propanethiolate (2.256 g, 20.69 mmol) was added to a stirred solution of 5-bromopyrazin-2-amine (3 g, 17.24 mmol) in DMF (15 mL) and heated at 100° C. under microwave conditions for 4 hours. A further portion of sodium-2-propanethiolate (2.256 g, 20.69 mmol) was added the reaction heated for a further 1 hour at 100° C. under microwave conditions. Water was added and the mixture extracted with EtOAc (×2). The combined organic layers were washed with water (×3), brine (×1), dried, (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a beige oil which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH2:7])[CH3:3].FN[C@@H](CC1C=C(O)C(O)=CC=1)[C:23](O)=[O:24].C([O-])=O.[Na+].C(OC(=O)C)(=O)C>C(O)=O.C(O)C>[CH2:2]([O:4][C:5](=[O:19])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[NH:7][CH:23]=[O:24])[CH3:3]
Reactant: O=C(O)[C@H](Cc1ccc(O)c(O)c1)NF
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)c(OC)c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(OC)c(OC)c1)NC=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a mixture of 3,4-dimethoxy-L-phenylalanine ethyl ester-hydrochloride 1 (Luxen, A., Perlmutter M., Bida, G. T., Van Moffaert, G., Cook, J. S., Satyamurthy, N., Phelps, M. E. and Barrio, J. R. (1990) Remote, semiautomated production of 6- 18F!fluoro-L-dopa for human studies with PET. Appl. Radiat. Isot. 41, 275) (5.3 g, 18.3 mmol) and sodium formate (1.44 g, 21.2 mmol) in formic acid (52 mL) cooled in an ice bath was added acetic anhydride (20 mL) and stirred at room temperature for 3 h. After addition of ethanol (40 mL) the mixture was stirred at room temperature for an additional 3 h and evaporated. The residue was dissolved in ethyl acetate, filtered and the insoluble material was washed with, ethyl acetate. The combined filtrates were washed successively with aqueous 10% HCl, saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic extract was dried over anhydrous MgSO4 and concentrated under reduced pressure to a yellow syrup. Crystallization of the syrup from ethyl acetate-petroleum ether give a white solid 2 (3.1 g, 61%); m.p. 102°-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:33]([NH:35][C:36]2[CH:37]=[C:38]([S:54]([OH:57])(=[O:56])=[O:55])[CH:39]=[C:40]3[C:45]=2[C:44]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:43][C:42]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:41]3)=[O:34])[CH:5]=[C:6]([C:8]([NH:10][C:11]2[CH:12]=[C:13]([S:29]([OH:32])(=[O:31])=[O:30])[CH:14]=[C:15]3[C:20]=2[C:19]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:18][C:17]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:16]3)=[O:9])[CH:7]=1.[F:58][C:59]([F:70])([F:69])[C:60]1[CH:61]=[C:62]([N:66]=[C:67]=[O:68])[CH:63]=[CH:64][CH:65]=1>O>[F:58][C:59]([F:69])([F:70])[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:67](=[O:68])[NH:1][C:2]2[CH:3]=[C:4]([C:33]([NH:35][C:36]3[CH:37]=[C:38]([S:54]([OH:57])(=[O:56])=[O:55])[CH:39]=[C:40]4[C:45]=3[C:44]([S:46]([OH:49])(=[O:47])=[O:48])=[CH:43][C:42]([S:50]([OH:53])(=[O:52])=[O:51])=[CH:41]4)=[O:34])[CH:5]=[C:6]([C:8]([NH:10][C:11]3[CH:12]=[C:13]([S:29]([OH:32])(=[O:30])=[O:31])[CH:14]=[C:15]4[C:20]=3[C:19]([S:21]([OH:24])(=[O:22])=[O:23])=[CH:18][C:17]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:16]4)=[O:9])[CH:7]=2)[CH:61]=1
Reactant: Nc1cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: O
Product: O=C(Nc1cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)cc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c1)Nc1cccc(C(F)(F)F)c1
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 4.0 g of 8,8'-[(5-amino-1,3-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt in 50 ml of water is added 4.0 ml of 3-trifluoromethylphenyl isocyanate. Stirring is continued for 6 hours at room temperature then the resulting mixture is heated to 95° C, is filtered through diatomaceous earth and washed with 50 ml of hot water. The hot filtrate is salted with 55 g of sodium acetate trihydrate and after standing for 40 hours is diluted with 700 ml of anhydrous ethanol. The precipitate is filtered and washed with absolute ethanol and ether. The product is then boiled and triturated with 100 ml of absolute ethanol, cooled to room temperature and is filtered and washed with absolute ethanol followed by ether to give 8,8'-{{5-[3-(α,α,α-trifluoro-m-tolyl)ureido]-1,3-phenylene}bis(carbonylimino)}di-1,3,6-naphthalenetrisulfonic acid, hexasodium salt.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]([CH3:19])[CH2:16][CH2:17][OH:18])[CH:8]=[CH:9][C:2]1=2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[C:26]([O:18][CH2:17][CH2:16][N:15]([CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[CH:6]=1)[CH3:19])(=[O:28])[CH3:27]
Reactant: CN(CCO)CCOCCc1ccc2sccc2c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCCN(C)CCOCCc1ccc2sccc2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In 10 mL of methylene chloride is dissolved 1.00 g of 2-{[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-(methyl)amino}-1-ethanol. The solution thus obtained is cooled to 5° C., to which are added 0.32 mL of pyridine, 0.37 mL of acetic anhydride and 0.04 g of N,N-dimethylaminopyridine. The mixture is stirred at ambient temperature for 30 minutes. Water is added to the mixture, pH is adjusted to 7.5 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform:methanol=100:1 to 50:1) to obtain 1.14 g of 2-{[2-(2-benzo[b]-thiophen-5-ylethoxy)-ethyl](methyl)amino}ethyl acetate as an oily product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH:2]=1.[Li+].[OH-].C1COCC1>C(Cl)Cl.CO.CC(O)=O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCCCc2ccncc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc(OCCCc2ccncc2)cc1
Reaction time: 20 h

Procedure:
A solution of 19-4 (3.2 g, 11.9 mmol), 1N LiOH (25 mL), and THF (50 mL) was stirred overnight at ambient temperature. After 20 h, the solution was washed with EtOAc and then acidified with 10% KHSO4 to give a suspension of white solid. The aqueous portion was extracted with CHCl3 and then the aqueous portion containing the solid was filtered. After drying the solid at 50° C. for 3 h, 19-5 was obtained. Rf 0.47 (silica, 10/1/1 CH2Cl2 /CH3OH/AcOH).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.Cl[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].O>CS(C)=O.C1CCCCC1.CCOC(C)=O>[NH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH3:3])[N:9]([CH2:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])[N:8]=1
Reactant: COc1cccc2[nH]nc(N)c12
Reactant: N#Cc1cccc(CCl)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc2c1c(N)nn2Cc1cccc(C#N)c1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
To a solution of ground potassium hydroxide (6.75 g, 120 mmol) in DMSO (300 mL) at room temperature under nitrogen was added 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (7.85 g, 48.1 mmol), and this gave a deep red solution. After 5 minutes 3-(chloromethyl)benzonitrile (8.84 g, 58.3 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes and then poured into water (500 mL), forming an emulsion. This was extracted using chloroform (3×500 mL). The combined organic solutions were washed with water (400 mL) and passed through a hydrophobic frit. The solvent was removed in vacuo, the residue was applied to a 340 g silica cartridge, and eluted with a gradient of 0-100% ethyl acetate in cyclohexane over 8 CV. This gave an orange solid which was treated with ethyl acetate (10 mL) and cyclohexane (90 mL). The solid was collected by filtration and washed with cyclohexane (50 mL). The solid was dried in vacuo to give the title compound (7.89 g, 59%) as a pale orange solid. LCMS (System A) RT=0.93 min, ES+ve m/z 279 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15](O)=[O:16])[CH2:10]1.Cl.N[C@H]1CC[C@H](C(O)=O)CC1>>[NH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([CH2:15][OH:16])[CH2:10]1
Reactant: N[C@@H]1CCC[C@@H](C(=O)O)C1
Agent: Cl
Agent: N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H]1CCC[C@@H](CO)C1

Procedure:
((1R,3R)-3-Aminocyclohexyl)methanol was synthesized as a white powder (213 mg, 75%) using a procedure analogous to that described in Step 1 of Example 179, substituting (1R,3R)-3-aminocyclohexanecarboxylic acid trifluoroacetate from the previous step for trans-4-aminocyclohexanecarboxylic acid hydrochloride used in Example 179.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([OH:20])[C:18]=1[Br:19])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:20][CH3:21])[C:18]=1[Br:19])[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)c(Br)c(OCc2ccccc2)c1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(Br)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a mixture of methyl 3-(benzyloxy)-4-bromo-5-hydroxybenzoate (3.69 g, 10.94 mmol) and potassium carbonate (3.03 g, 21.98 mmol) in DMF (27 mL) was added methyl iodide (0.753 mL, 12.04 mmol). The mixture was stirred overnight after which time it was diluted with water and extracted with ethyl acetate (4×). The combined extracts were washed with water (8×), brine, dried over magnesium sulfate and concentrated to provide methyl 3-(benzyloxy)-4-bromo-5-methoxybenzoate as a white solid (3.72 g). MS (M+1)=351.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.31-7.59 (m, 7H), 5.24 (s, 2H), 3.99 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[CH:28]1([CH:34]=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH:28]1([CH2:34][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CC4CCCCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and cyclohexane carbaldehyde (0.056 g) dissolved in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (0.13 g) under ice cooling, and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was neutralized with a 1 N aqueous solution of sodium hydroxide, was then concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-cyclohexylmethylpiperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 55) (0.13 g) as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][N:11]([CH3:22])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14]([O:20][CH3:21])[CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:16]([C:15]3[CH:18]=[CH:19][C:12]([N:11]([CH3:22])[CH3:10])=[CH:13][C:14]=3[O:20][CH3:21])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(N(C)C)ccc1C=O
Reactant: Nc1cc(Br)cnc1N
Product: COc1cc(N(C)C)ccc1-c1nc2cc(Br)cnc2[nH]1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and 4-dimethylamino-2-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5](=[CH:8][CH2:9][CH:10]1[CH2:14][CH:13]=[C:12]([CH3:15])[C:11]1([CH3:17])[CH3:16])[CH:6]=[O:7].Cl>C(OCC)C>[CH3:4][CH:5]([CH:8]([CH3:1])[CH2:9][CH:10]1[CH2:14][CH:13]=[C:12]([CH3:15])[C:11]1([CH3:17])[CH3:16])[CH:6]=[O:7]
Reactant: C[Mg]Br
Reactant: CC(C=O)=CCC1CC=C(C)C1(C)C
Agent: Cl
Solvent: CCOCC
Product: CC1=CCC(CC(C)C(C)C=O)C1(C)C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
100 ml (0.30 mol) of methylmagnesium bromide solution in diethyl ether was added to 60.0 g (0.32 mol) of cuprous iodide suspended in 350 ml of the same solvent at -10° C., followed by addition of 52.0 g (0.27 mol) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enal dissolved in 300 ml of anhydrous diethyl ether at 0° C. and stirring at the same temperature was continued for 0.5 hours. The reaction mixture was treated with 200 ml of 1.0 N hydrochloric acid, decanted and the organic layer was washed with 2×300 ml of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: hexane/MTBE 15:1) to give 28.2 g (50% yield) of 2,3-dimethyl-4-(2,2,3-trimethylcyclopent-3-enyl)butanal.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([OH:15])([CH2:13][CH3:14])[CH2:11][CH3:12].[C:16]([O:20][C:21](=[O:29])[NH:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH:25]=O)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:29])[NH:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][NH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([CH2:13][CH3:14])([OH:15])[CH2:11][CH3:12])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCC(O)(CC)c1cccc(OC)c1N
Reactant: CC(C)(CC=O)NC(=O)OC(C)(C)C
Product: CCC(O)(CC)c1cccc(OC)c1NCCC(C)(C)NC(=O)OC(C)(C)C

Procedure:
The product is obtained analogously to intermediate product 1b starting from 3-(2-amino-3-methoxyphenyl)pentan-3-ol and tert-butyl(1,1-dimethyl-3-oxopropyl)carbamate. The crude product is purified by column chromatography (silica gel, cyclohexane/EtOAc, 4:1). Yield: 4.60 g (47%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:26]#[N:27])[C:23]=1[O:24]C)[C:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[CH2:11]1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:26]#[N:27])[C:23]=1[OH:24])[C:8]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:19])(=[O:20])[CH2:11]1)=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(C#N)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1O
Temperature: 120 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
3-(3-t-butyl-5-cyano-4-methoxybenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (364 mg) was dissolved in N,N-dimethylformamide (4 mL), and lithium chloride (401 mg) was added to the solution, and then the mixture was stirred at 120° C. for 16 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was crystallized from n-hexane-ethyl acetate to obtain the title compound (299 mg) as a colorless crystal.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([S+:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-:28].[Na+].[Na+].ClC1C=C(C=CC=1)C(OO)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CC(C)=O>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:21]1([S+:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:28])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3]
Reactant: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CC(C)=O
Product: O=[S+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 157 parts of acetone, 4 parts of triphenylsulphonium hexafluorophosphate, 8.48 parts of sodium carbonate, and 17.2 parts of m-chloroperoxybenzoic acid was stirred at 20° C. for 24 hours. A solution of 40 parts of sodium thiosulphate in 500 parts of water was added. The acetone was removed under reduced pressure and triphenylsulphoxonium hexafluorophosphate was filtered off and dried under vacuum at 50° C. The desired product thus obtained (V1, R7 =H, R6 =C6H4, p=zero, R8 =R9 =C6H5, r=1, Zr- =PF6-), had m.pt. 233°-238° C., NMR (acetone-d6) 7.8-8.3 (m); I.R. (KBr disc) 3100, 3070, 1450, 1225, 1080, 840, 760, 730, 685 cm-1 ; UV (ethanol) λmax 232 nm and 270 nm.