Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:24](=O)[O:25]C3C=CC=CC=3)=[CH:17][CH:16]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40]([NH2:43])(=[O:42])=[O:41]>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:40]([NH:43][C:24]([NH:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([N:4]2[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[N:7]=[C:3]2[CH2:1][CH3:2])=[CH:20][CH:19]=1)=[O:25])(=[O:42])=[O:41]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Product: CCc1nc(-c2ccc(F)cc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-{4-[2-ethyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]phenyl}ethylcarbamate and 2-chlorobenzenesulfonamide. MS (ESI) m/z 527 [M+H]+, 525 [M−H]−, 1H-NMR (CDCl3)δ1.25 (3H, t, J=7.5 Hz), 2.71 (2H, q, J=7.5 Hz), 2.85 (2H, t, J=7.0 Hz), 3.47-3.54 (2H, m), 6.57 (1H, br), 7.07 (2H, t, J=8.8 Hz), 7.19 (1H, s), 7.26 (2H, s), 7.40-7.46 (1H, m), 7.57-7.61 (2H, m), 7.73-7.78 (2H, m), 8.00 (2H, d, J=7.5 Hz).
Reaction SMILES: [C-:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][C:12](=O)[CH2:11][CH2:10]2.Cl>[I-].[Zn+2].[I-].C(#N)C>[C:1]([C:12]1[CH2:11][CH2:10][C:9]2[C:14](=[C:5]([O:4][CH3:3])[CH:6]=[CH:7][CH:8]=2)[CH:13]=1)#[N:2]
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: [C-]#N
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: CC#N
Product: COc1cccc2c1C=C(C#N)CC2
Temperature: 120 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
Trimethylsylyl cyanide (6.9 g, 9.3 ml, 0.07 mol) is added dropwise in 10 minutes to a mixture of 8-methoxy-3,4-di-hydronaphthalen-2(1H)-one (10.9 g, 0.06 mol) prepared as described in the literature (J. Chem. Soc., 1958, 409), anhydrous acetonitrile (60 ml) and a catalytic amount of zinc iodide under nitrogen atmosphere and the obtained mixture is heated to 80° C. ext. for 3 hours. The reaction mixture is cooled, 1N HCl (20 ml) is slowly added thereto and stirring is continued for 2 hours at room temperature. The solvent is then evaporated off under vacuum, the residue is taken up in ethyl acetate, and the organic solution is washed with water, dried over sodium sulfate, filtered and evaporated to dryness. The obtained product is triturated with petroleum ether, filtered and dissolved in pyridine (100 ml). POCl3 (20 ml) is added dropwise in 10 minutes and the obtained mixture is heated to 120° C. ext. for 3 hours. The reaction mixture is then poured into ice, made acidic by the addition of concentrated hydrochloric acid and extracted with ethyl ether. The organic phase is washed with water, dried and evaporated to dryness and the obtained residue is crystallised from isopropyl ether yielding 2-cyano-8-methoxy-3,4-dihydronaphthalene (7.2 g); m.p. 66°-68° C.
Reaction SMILES: [C:1]([N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)(=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22].C(C(O)=O)(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:24]1([C:1](=[O:23])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH2:9][CH:10]=[CH:11][CH2:12][CH:13]=[CH:14][CH2:15][CH:16]=[CH:17][CH2:18][CH:19]=[CH:20][CH2:21][CH3:22])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC=CCC=CCC=CCC=CCC=CCC=CCCC(=O)N1CCNCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a mixture of tert-butyl 4-docosa-4,7,10,13,16,19-hexaenoylpiperazine-1-carboxylate (1.5 g, 3 mmol) in CH2Cl2 (20 mL) at 0° C. was added CF3CO2H (7 mL, 91 mmol). The mixture solution was stirred (0° C., 2 h) and then 10% Na2CO3 was added to adjust pH=10. The mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica chromatography (CH2Cl2: CH3OH, 20:1) to afford 1-(piperazin-1-yl)docosa-4,7,10,13,16,19-hexaen-1-one (1.17 g, 97.5%) as a colorless oil. Mass calculated for C26H40N2O=396.61. found: [M+H]+=396.7, 398.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C@@H:9]2[C@@:4]3([C:11]4[N:12]([C:15](=[O:18])[CH2:16][CH:17]=4)[CH2:13][CH2:14][N:3]13)[CH2:5][CH2:6][CH2:7][CH2:8]2>O1CCCC1>[O:1]=[C:2]1[CH2:10][C@@H:9]2[C@@:4]3([C@H:11]4[CH2:17][CH2:16][C:15](=[O:18])[N:12]4[CH2:13][CH2:14][N:3]13)[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: O=C1CC=C2N1CCN1C(=O)C[C@H]3CCCC[C@]231
Solvent: C1CCOC1
Product: O=C1CC[C@H]2N1CCN1C(=O)C[C@H]3CCCC[C@@]321

Procedure:
985 mg (4 mmol) of (9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,10,11,12,13,13a-decahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]indole, dissolved in 40 ml of tetrahydrofuran, are hydrogenated with hydrogen in the presence of 98 mg of PtO2 at room temperature under normal pressure until the absorption of hydrogen ceases. The catalyst is filtered off and the filtrated is concentrated by evaporation in vacuo. The resulting oily crude product is crystallised from ethyl acetate. In this manner (9aR*,9bR*,13aR*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pyrrolo[2',1':3,4]pyrazino[2,1-i]-indole is obtained which melts at 135° to 136°. The mother liquor is concentrated by evaporation in vacuo and chromatographed on silica gel (0.040-0.063 mm) with trichloromethane and trichloromethane/methanol (99:1) as eluants. There is thus obtained (9aR*,9bS*,13aS*)-2,7-dioxo-1,4,5,7,8,9,9a,10,11,12,13,13a-dodecahydro-2H-pryrrolo[2',1':3,4]pyrazino[2,1-i]indole, which is stereoisomeric as regards the relative configuration of the 9a C-atom, in the form of an oil which is crystallised from ethyl acetate and then melts at 177°-179°.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=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.[NH2:43][C:44]1[CH:45]=[C:46]([CH:61]=[CH:62][CH:63]=1)[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]2[CH:54]=[C:55]([C:57]([O:59][CH3:60])=[O:58])[S:56][C:49]=12.Cl>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:43][C:44]1[CH:45]=[C:46]([CH:61]=[CH:62][CH:63]=1)[O:47][C:48]1[CH:53]=[CH:52][N:51]=[C:50]2[CH:54]=[C:55]([C:57]([O:59][CH3:60])=[O:58])[S:56][C:49]=12)=[O:9]
Reactant: COC(=O)c1cc2nccc(Oc3cccc(N)c3)c2s1
Reactant: Cc1ccoc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2nccc(Oc3cccc(NC(=O)c4occc4C)c3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-methyl-2-furoic acid (166 mg, 1.32 mmol) in anhydrous DMF (10 ml) were added HATU (552 mg, 1.45 mmol) and DIPEA (341 mg, 2.64 mmol). The mixture was stirred at room temperature for 10 minutes, and 330 mg of crude methyl 7-(3-aminophenoxy)thieno[3,2-b]pyridine-2-carboxylate from step 1 was added. The mixture was then heated at 65° C. for 2 hours, cooled to room temperature, and poured into 100 ml of water. 2M HCl was added until pH=4. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel chromatography eluting with 2˜3% of MeOH in chloroform to afford methyl 7-{3-[(3-methyl-2-furoyl)amino]phenoxy}thieno[3,2-b]pyridine-2-carboxylate as off-white solid. Yield: 230 mg, 26% for 2 steps.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:21])[CH2:4][C:5]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].CCCCCC>C(OCC)(=O)C>[C:22]([O:1]/[N:2]=[C:3](\[NH2:21])/[CH2:4][C:5]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:6][CH2:7][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:13][CH2:14]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(CC1(c2ccccc2)CCC2(CC1)OCCO2)NO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)O/N=C(\N)CC1(c2ccccc2)CCC2(CC1)OCCO2
Yield: 85.17 %

Procedure:
A mixture of N-hydroxy-2-(8-phenyl-1,4-dioxa-spiro[4.5]dec-8-yl)-acetamidine (266) (600 mg, 2.01 mmol) and acetic anhydride (2 mL) was stirred at room temperature for 16 h (TLC, ethyl acetate:hexane=7:3/UV/SiO2, Rf=0.4). The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (2×25 mL), brine (25 mL), dried and concentrated in vacuo to get crude mass which was purified by CombiFlash using a gradient eluent mixture of ethyl acetate and hexane to get pure (Z)-(1-amino-2-{8-phenyl-1,4-dioxaspiro[4.5]decan-8-yl}ethylidene)amino acetate (267) (585 mg, 85.17%) as a white sticky solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][CH:6]([CH2:10][CH3:11])[C:7](Cl)=[O:8].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([C:7](=[O:8])[CH:6]([CH3:5])[CH2:10][CH3:11])=[CH:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2ccccc2)cc1
Reactant: CCC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(C)C(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 0.15 mole(15.0 g) of (S)-(+)-2-methylbutyric acid and 0.3 mole(35.5 g) of thionyl chloride in 100 ml of chloroform was refluxed for three hours. After chloroform and the excessive thionyl chloride had been distilled out at reduced pressure, the reaction solution was concentrated at reduced pressure to obtain 12.8 g of 2-methylbutyryl chloride. A suspension of 0.1 mole(13.3 g) of aluminium chloride in 100 ml of dry methylene chloride was cooled to 0° C., then 12.8 g of 2-methylbutyryl chloride was added dropwise thereto, and stirred for 30 min. Maintaining the mixed solution at 0° C., a solution of 0.08 mole(14.7 g) of 4-methoxybiphenyl in 80 ml of dry methylene chloride was added dropwise, and stirred for 10 hours at room temperature. The reaction mixture was decomposed by adding into ice and dil. hydrochloric acid, and the organic layer was washed with dil. hydrochloric acid and an aquious sodium hydrogen carbonate solution, and then dried with magnesium sulfate. The concentrated product was purified by column chromatography to obtain 10.3 g of 4'-methoxy-4-(2-methylbutyryl)biphenyl. (yield: 48%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O.C(=O)(O)[O-].[Na+]>C(#N)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Brc1ccc2nccn2c1
Yield: 83.4 %

Procedure:
Reflux a solution of 2-amino-5-bromo-pyridine (Maybridge; 1.0 g, 5.78 mmol), 50% aqueous chloroacetaldehyde (2 mL, 12.7 mmol) in acetonitrile (100 mL) for 14 h. Dilute the reaction with saturated aqueous sodium bicarbonate and extract into ethyl acetate. Flash chromatography using appropriate ethyl acetate/hexane mixtures gives 0.95 g (83%) of the subtitled compound as a tan solid. MS (electrospray, m/z) 196.7, 198.7 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.9 (d, J=1.5 Hz, 1H), 7.90 (s, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.29 (dd, J=9.2, 2 Hz, 1H).
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([NH:10][C:11]1[C:12]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25](OC)=[O:26])=[CH:21][N:20]=2)=[O:18])=[CH:13][S:14][CH:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O1CCOCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:3]([O:7][C:8]([NH:10][C:11]1[C:12]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][N:20]=2)=[O:18])=[CH:13][S:14][CH:15]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C(=O)Nc2cscc2NC(=O)OC(C)(C)C)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cscc1NC(=O)c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
Under ice cooling, lithium tetrahydroborate (1.5 g, 70 mmol) was added to a mixed solution of N-(4-t-butoxycarbonylaminothiophen-3-yl)-5-methoxycarbonylpyridine-2-carboxylic acid amide (Reference Compound No. 2-1, 24 g, 64 mmol) in THF (1.3 L)-1,4-dioxane (1.3 L), and then the reaction mixture was stirred at same temperature overnight. Lithium tetrahydroborate (0.30 g, 14 mmol) was added thereto and the mixture was stirred at room temperature for 2 hours. Under ice cooling, water (0.40 L) and 10% aqueous citric acid solution (25 mL) were added thereto. The precipitates were filtered off and the filtrate was evaporated under reduced pressure. Water (0.30 L) was added thereto and the precipitates were filtered and dried under reduced pressure to give 21 g of the title reference compound as a pale yellow solid. (Yield 95%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][N:12](CC(OC(C)(C)C)=O)[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:33](NN)([CH3:36])([CH3:35])[CH3:34]>>[CH3:34][C:33]([N:11]1[C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:14][CH:13]=[N:12]1)([CH3:36])[CH3:35]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Product: CC(C)(C)n1nccc1-c1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the major isomer (80%). ESMS (M-C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO) δ 8.32 (d, 2H), 7.7 (d, 2H), 7.48 (d, 1H), 6.25 (d, 1H), 1.42 (s, 9H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[N:19]=[C:20]([O:24][CH3:25])[NH:21][C:22](=O)[C:17]=3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:28])=O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([O:24][CH3:25])=[N:21][C:22]([Cl:28])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1nc2c(cnn2C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Solvent: CN(C)C=O
Product: COc1nc(Cl)c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 80 °C

Procedure:
A mixture of 4-(6-methoxy-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1 mmol), phosphorus oxychloride (2 mmol) and dimethylformamide (5 drops) is heated at 80° C. for 6 h. The mixture is allowed to cool, the solvent is evaporated and the residue is poured into ice-water. The mixture is extracted three times with ethyl acetate. The combined ethyl acetate extracts are washed with brine, dried (magnesium sulfate), filtered, and evaporated to give crude 4-(4-chloro-6-methoxy-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:14]=[N:15][C:16]([Cl:20])=[C:17](Cl)[N:18]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:12][C:13]1[N:14]=[N:15][C:16]([Cl:20])=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:18]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: Clc1nnc(Cl)c(Cl)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2nc(Cl)nnc2Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-amino-dimethylphenylphosphine oxide (1.6 mmol) and 3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in CH2Cl2, is added triethylamine (2 mmol). The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])[CH2:30][CH2:31][C:32]([OH:34])=[O:33]>CC(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])[CH2:30][CH2:31][C:32]([O-:34])=[O:33]
Reactant: O=C(O)CCC(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: O
Solvent: CC(C)O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of succinic acid (0.59 g) in 2-propanol (35 ml) and water (5 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 167.5° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18](=[O:31])[NH:19][CH:20]1[CH:27]2[CH2:28][CH:23]3[CH2:24][C:25]([OH:30])([CH2:29][CH:21]1[CH2:22]3)[CH2:26]2)=O)C1C=CC=CC=1>C(O)C.[Pd]>[OH:30][C:25]12[CH2:29][CH:21]3[CH2:22][CH:23]([CH2:28][CH:27]([CH:20]3[NH:19][C:18]([C@@H:12]3[CH2:13][C:14]([F:17])([F:16])[CH2:15][NH:11]3)=[O:31])[CH2:26]1)[CH2:24]2
Reactant: O=C(NC1C2CC3CC1CC(O)(C3)C2)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(NC1C2CC3CC1CC(O)(C3)C2)[C@@H]1CC(F)(F)CN1
Reaction time: 10 h
Yield: 96.4 %

Procedure:
Pd—C (10%, 0.5 g) was added to a solution of (S)-4,4-difluoro-2-(5-hydroxy-adamantan-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (1.2 g) in ethanol (50 mL) and the reaction mixture was hydrogenated (1 atm pressure) under stirring condition for 10 h. Reaction was monitored by TLC. After completion, reaction mixture was filtrated through Celite®. The filtrate was concentrated under reduced pressure using a rotary evaporator to give 0.8 g (93%) of the desired (S)-4,4-difluoro-pyrrolidine-2-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide.
Reaction SMILES: [C:1]1(=[O:14])[C:6]2=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:5]2[CH:4]=[CH:3][NH:2]1.[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[C:17]=1[CH:18]=[O:19].C([O-])(=O)C.[K+].COC1C2C(=C3C(=CC=2)C(OC)=CC=N3)N=CC=1>>[Br:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([N:2]2[CH:3]=[CH:4][N:5]3[C:13]4[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=4[CH:7]=[C:6]3[C:1]2=[O:14])[C:17]=1[CH:18]=[O:19]
Reactant: O=c1[nH]ccn2c3c(cc12)CCCC3
Reactant: O=Cc1c(Br)cc(F)cc1Br
Agent: CC(=O)[O-]
Agent: COc1ccnc2c1ccc1c(OC)ccnc12
Agent: [K+]
Product: O=Cc1c(Br)cc(F)cc1-n1ccn2c3c(cc2c1=O)CCCC3
Temperature: 100 °C
Yield: 49.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 121e (500 mg, 2.66 mmol), 2,6-dibromo-4-fluorobenzaldehyde (1.50 g, 5.32 mmol), and potassium acetate (521 mg, 5.32 mmol). After bubbling argon through the suspension for 30 minutes, 4,7-dimethoxy-1,10-phenanthroline (638.4 mg, 2.66 mmol) and cuprous iodide (506 mg, 2.66 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and then heated at 100° C. for 16 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×100 ml). The combined filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (10:1 to 3:1) to afford 121f (510 mg, 49%) as a yellow solid. MS: [M+H]+ 389.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][CH2:10][CH2:11][OH:12].[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][NH:31]1)=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1>C(#N)C>[CH3:13][CH:14]([CH3:40])[CH:15]([NH:27][C:28]([CH:30]1[CH2:34][CH:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][N:31]1[CH2:9][CH2:10][CH2:11][OH:12])=[O:29])[CH:16]1[CH:21]([OH:22])[CH:20]([OH:23])[CH:19]([OH:24])[CH:18]([S:25][CH3:26])[O:17]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: OCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(CCCO)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Triethylamine (0.2 mL, 1.38 mmol, 3 equiv), followed by 3-bromo-1-propanol (60 μL, 0.69 mmol, 1.5 equiv), were added to a stirred solution of crude 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (192.5 mg, 0.46 mmol, 1 equiv), prepared as in Example 10, in anhydrous acetonitrile (2 mL), under nitrogen. The resulting mixture was stirred at rt for 18 h and evaporated to dryness. The residue obtained was purified by chromatography over silica gel with an eluent of 5% methanolic ammonia in dichloromethane. The desired fractions were pooled together, evaporated to dryness, and lyophilized to furnish the title compound as a white fluffy powder (13.5 mg, 6%).
Reaction SMILES: [CH:1]([C@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=1)[CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.O>ClCCCl>[CH:1]([C@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH3:30])[CH:18]=1)[CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6])([CH3:2])[CH3:3]
Reactant: COCCCOc1cc(C(=O)[C@@H](C/C=C/C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: O
Solvent: ClCCCl
Solvent: CCOCC
Product: COCCCOc1cc(C[C@@H](C/C=C/C[C@H](C(=O)O)C(C)C)C(C)C)ccc1OC
Temperature: 33 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To a solution of (2S,7S)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)-benzoyl]-8-methylnon-4-enoic acid (1.4 g; 3.2 mmol) in 1,2-dichloroethane were added triethylsilane (3.7 g; 32 mmol) and boron trifluoride diethyl etherate (2.7 g; 19.2 mmol), and the solution was stirred at 33° C. for 3 days. The reaction mixture was added to water and the aqueous layer was extracted 3× with tert-butyl methyl ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The remaining residue was purified by flash chromatography (silica gel; hexane/acetone 4:1) to obtain (2S,7R)-trans-2-isopropyl-7-[4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnon-4-enoic acid (0.97 g, 2.3 mmol, 72% yield). The NMR data are identical to the data described in US2003/0149303 A1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:18])([CH3:17])[O:12][CH2:11][C:10](=[S:19])[NH:9]2)[CH:7]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]3([CH3:20])[C:14]([F:16])([F:15])[C:13]([CH3:17])([CH3:18])[O:12][CH2:11][C:10](=[S:19])[NH:9]3)[CH:7]=2)=[O:30])=[N:27][CH:28]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OCC(=S)N[C@](C)(c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)C1(F)F

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17B) (150 mg, 0.47 mmol) and commercially available 5-chloro-pyridine-2-carboxylic acid [CAS No. 86873-60-1] (111 mg, 0.71 mmol). The compound was obtained as a yellow foam (330 mg, 99%, 65% purity). MS (ISP): m/z=460.4 [(M+H)+] and 462.1 [(M+2+H)+].