Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:34])=[N:29]2.C(O)(=O)C.O>C1(C)C=CC=CC=1.CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@@:11]([C:14]([F:16])([F:15])[F:17])([OH:18])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:34])=[N:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Reactant: Cc1ncc2c(N)cccc2n1
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(F)c1OC
Temperature: 100 °C
Yield: 81.2 %

Procedure:
300 mg (0.92 mmol) of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal and 146 mg (0.92 mmol) of 5-amino-2-methylquinazoline are dissolved in 20 ml of toluene, and the solution is admixed with 0.29 ml (0.92 mmol) of titanium tert-butoxide and 0.1 ml of acetic acid. The reaction mixture is heated at 100° C. for 2 hours, cooled, poured into water and stirred vigorously. The suspension is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo to give 349 mg of (2R,4R)-4-(3,4-difluoro-2-methoxyphenyl)-1-[(2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol as a crude product. The crude imine is dissolved in 35 ml of CH2Cl2 and the solution is cooled to −30° C. 6 ml (6 mmol) of a 1 M BBr3 solution in dichloromethane are added slowly dropwise over 5 minutes and the reaction solution is allowed to warm to room temperature over 16 hours. It is poured onto a mixture of saturated NaHCO3 solution and ice. Extraction is carried out repeatedly with ethyl acetate and the extracts are washed with saturated NaCl solution and dried over Na2SO4. Purification by column chromatography on silica gel (hexane/isopropanol 0-10%) and subsequent HPLC separation on a chiral stationary phase afford 70 mg of product (analytical HPLC: Rt=8.36 min (Chiralcel OD 5μ, 250×4.6 mm, hexane/ethanol 5%, 1 ml/min flow rate) as the (−)-enantiomer.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([Cl:9])[S:8][C:4]=2[CH:3]=1.[CH:12](=O)[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O>[Cl:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][CH2:12][CH3:13])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: CC=O
Reactant: Nc1ccc2nc(Cl)sc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CCNc1ccc2nc(Cl)sc2c1
Reaction time: 2 h

Procedure:
To a solution of (29) (0.2 mmol, 36.8 mg) in 2 ml dichloroethane was added 0.2 mmol acetaldehyde, followed by 63.6 mg sodium triacetoxyborohydride, and 12 μl acetic acid. After 2 h, the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and the solvent removed by rotary evaporation.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1)[CH2:2][CH3:3].C1(N(CCC(OCC)=O)C(=O)C2C=CC(NCC)=C(N)C=2)C=CC=CC=1.[Cl:49][CH2:50][C:51](O)=[O:52]>O1CCCC1>[CH2:1]([N:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH:14][C:51](=[O:52])[CH2:50][Cl:49])[CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc(NC)c(N)c1
Reactant: O=C(O)CCl
Agent: CCNc1ccc(C(=O)N(CCC(=O)OCC)c2ccccc2)cc1N
Solvent: C1CCOC1
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc(NC)c(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.8 g (5.9 mmol) of 3-amino-4-methylaminobenzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide [prepared analogously to 3-amino-4-ethylaminobenzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide], 1.1 g (6.8 mmol) of N,N′-carbonyldiimidazole, and 0.65 g (6.9 mmol) of chloroacetic acid in 75 mL tetrahydrofuran was stirred for 1 hour at room temperature. Then the solvent was distilled off in vacuo, and the crude product was purified by flash chromatography (silica gel; methylene chloride/ethanol=49:1). Yield: 1.7 g (77% of theory) yellow oil; Rf value: 0.58 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]([C:20]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][N:24]4C3CCCCO3)=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:5][CH:4]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]([C:20]3[N:28]=[C:27]([CH3:29])[N:26]=[C:25]4[C:21]=3[N:22]=[CH:23][NH:24]4)=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2nc3ccccc3cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2nc3ccccc3cc2-c2nc(C)nc3[nH]cnc23)cn1

Procedure:
A solution of N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)quinolin-2-amine (21 mg, 0.045 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 30 min. The solvents were removed under vacuum and the residue was dissolved in DCM, washed with saturated aqueous sodium bicarbonate (2×), water, and brine. The organic layer was dried over Na2SO4. The crude material was adsorbed onto a plug of silica gel and purified by silica gel chromatography (1 to 4% MeOH/CH2Cl2). The title compound was obtained as a yellow solid. m/z (ESI, +ve ion) 384 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 13.71 (s, 1H); 12.73 (s, 1H); 10.24 (s, 1H); 8.86 (s, 1H); 8.71 (s, 1H); 8.40 (d, J=7.0 Hz, 1H); 7.92 (d, J=7.8 Hz, 1H); 7.71 (br. s., 2H); 7.37 (br. s., 1H); 6.92 (d, J=8.6 Hz, 1H); 3.88 (s, 3H); 2.91 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:14][C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH:24]1([NH:28][C:29](=[O:40])[NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:24]1([NH:28][C:29](=[O:40])[NH:30][C:31]2[CH:32]=[CH:33][C:34]([C:35]([N:11]3[CH2:12][CH2:13][N:8]([CH2:14][C:15]4[O:16][CH:17]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=4)[CH2:9][CH2:10]3)=[O:36])=[CH:38][CH:39]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)c1coc(CN2CCNCC2)n1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)NC1CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1coc(CN2CCN(C(=O)c3ccc(NC(=O)NC4CCC4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 15 %

Procedure:
To a N,N-dimethylformamide (3 mL) solution of methyl 2-(piperazin-1-yl-methyl)oxazole-4-carboxylate 2,2,2-trifluoroacetate (174 mg, 513 μmol) and 4-(3-cyclobutylureido)benzoic acid (120 mg, 513 μmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (357 μL, 2.05 mmol), followed by O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl uronium hexafluorophosphate (293 mg, 770 μmol; HATU). The mixture was stirred at room temperature for 22 hours and was then concentrated under vacuum. The residue was taken up in ethyl acetate and washed with saturated aqueous ammonium chloride and brine. The organic phase was dried on magnesium sulfate, filtered and concentrated under vacuum. The crude residue was applied to a silica gel column and eluted with 25% ethyl acetate in n-hexanes to give the title compound (34 mg). MS (ESI) m/z 442.1 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]([CH2:20][C:21]([O:23]C)=[O:22])[CH2:11][CH2:10]1)=[O:8].[CH3:25][CH:26]([N:28]=[C:29]=[O:30])[CH3:27].[OH-].[Na+]>C(OCC)(=O)C>[CH3:25][CH:26]([NH:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([N:9]1[CH2:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]([CH2:20][C:21]([OH:23])=[O:22])[CH2:11][CH2:10]1)=[O:8])=[O:30])[CH3:27]
Reactant: COC(=O)CC1CCN(C(=O)NCCCCN)Cc2ccccc21
Reactant: CC(C)N=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)NCCCCNC(=O)N1CCC(CC(=O)O)c2ccccc2C1
Temperature: 60 °C

Procedure:
A solution of methyl 2-(2-(N-(4-aminobut-1-yl) carbamoyl)-1H,3H,4H-5H-benzo[e]azapin-5-yl)acetate and 2-propyl isocyanate (1 eq) in ethyl acetate (2 mL) was heated at 60° C. for 48 hrs. The solvent was removed in vacuo and the residue was dissolved in methanol (0.1M) and 1N sodium hydroxide (3 eq). The mixture was heated at 60° C. for 24 hrs. The product was purified by preparative HPLC as a white solid (TFA salt, 55.5 mg, 59%): EI-MS m/z 405 (M+H); 1H-NMR (400 MHz, MeOH-d4): 7.29-7.14 (m, 4H), 4.54 (q, J=15.0 Hz, 2H), 3.79 (m,1H), 3.66 (m, 1H), 3.54 (m, 2H), 3.15-3.06 (m, 4H), 2.84-2.79 (m, 1H), 2.74-2.68 (m, 1H), 2.05-2.00 (m, 1H), 1.62-1.58 (m, 1H), 1.40-1.38 (m, 4H), 1.1 (d, J=6.8 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[CH:9]=[CH:10]/[N:11](C)C)=[CH:4][CH:3]=1.Cl.[NH:16]([C:18]1[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=1)N>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C:18]3[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][N:19]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: N#Cc1ccnc(-n2nccc2-c2ccc(Br)cc2)c1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of (2E)-1-(4-bromophenyl)-3-(dimethylamino)prop-2-en-1-one (100 mg, 0.39 mmol) and 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (90 mg, 0.43 mmol, PREPARATION 3) in MeOH (10 mL) was heated under reflux conditions for 30 min and then cooled to rt. The solution was concentrated, and the residue was purified by flash column chromatography (hexanes:EtOAc=1:1) to give the title compound (108 mg, 85%) as an orange-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([O:14][C:15]([C:17]1([NH2:26])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13].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>CN(C=O)C.O>[CH2:12]([O:14][C:15]([C:17]1([NH:26][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[CH3:1])[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C1(NC(=O)c2ccc(C)cc2C)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 2,4-dimethyl-benzoic acid (219 mg, 1.46 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (300 mg, 1.46 mmol), HATU (666 mg, 1.75 mmol) in anhydrous DMF (1.8 mL) is added DIPEA (381 μL, 2.19 mmol). The resulting solution is stirred at RT overnight. Water (10 mL) is poured into the reaction mixture, and then extracted with EtOAc (3×5 mL). The combined organic layers and concentrated in vacuo. The residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0-30% EtOAc in heptane) to give product (274) as white solid (414 mg, 84%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:18][O:17][C:16]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:26]1[CH2:31][CH:30]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:28][CH2:27]1.C(OCC)(=O)C>CS(C)=O>[O:14]1[C:15]2[C:22]3[CH2:23][CH2:24][O:25][C:21]=3[CH:20]=[CH:19][C:16]=2[O:17][CH2:18][CH:13]1[CH2:12][N:26]1[CH2:27][CH:28]=[C:29]([C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][CH:33]=2)[CH2:30][CH2:31]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CCO4)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2COc3ccc4c(c3O2)CCO4)C1
Temperature: 25 °C

Procedure:
A solution of 0.65 g (1.8 mmole) of (2R)-2,3,8,9-tetrahydrofuro[3,2-f]-[1,4]benzodioxin-2-ylmethyl 4-methylbenzenesulfonate and 1.0 g (5.0 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 10 mL of DMSO was heated under nitrogen at 80° C. for 4 hours. After the reaction had cooled to room temperature, 400 mL of ethyl acetate was added and the solution was washed with 250 mL portions of saturated aqueous sodium bicarbonate, water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform to give 0.32 g of the (S)-enantiomer of the title compound as a gold solid, m.p. 207-209° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(N(CC)CC)C.[CH3:15][C:16]1[C:20]([I:21])=[C:19]([CH3:22])[NH:18][N:17]=1>C(Cl)Cl>[I:21][C:20]1[C:16]([CH3:15])=[N:17][N:18]([C:5](=[O:7])[CH3:6])[C:19]=1[CH3:22]
Reactant: Cc1n[nH]c(C)c1I
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1nc(C)c(I)c1C
Yield: 84.2 %

Procedure:
Acetic anhydride (0.51 mL, 5.4 mmol) and triethylamine (0.75 mL, 5.4 mmol) were added to a solution of 3,5-dimethyl-4-iodopyrazole (1 g, 4.5 mmol) in CH2Cl2. After 1 h the reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with 1N HCl, saturated NaHCO3, brine, dried over Na2SO4, and concentrated to give the title compound as a white solid (1 g, 85%). 1H NMR (CDCl3): δ 2.27 (s, 3H), 2.60 (s, 3H), 2.66 (s, 3H).
Reaction SMILES: [S:1]([C:8]1[CH:28]=[CH:27][C:11]([N:12](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:10][CH:9]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2]>C(O)=O.CO.[Pd]>[S:1]([C:8]1[CH:28]=[CH:27][C:11]([NH2:12])=[CH:10][CH:9]=1)([C:4]([F:5])([F:6])[F:7])(=[O:3])=[O:2]
Reactant: O=S(=O)(c1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1)C(F)(F)F
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1

Procedure:
To a stirred solution of 0.1 g of palladium black in 4.4% formic acid-methanol is added 37.3 g (0.1 mole) of 4-triflyl-N,N-dibenzylaniline in 4.4% formic acid-methanol. The reaction is stirred under an argon atmosphere until complete as indicated by thin layer chromatographic analysis. The catalyst is removed by filtration and washed with additional portions of methanol followed by water. The combined methanol and water washes are evaporated, and compound B is purified by distillation.
Reaction SMILES: [CH:1]1([C:6]([CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Na]>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:10][CH2:9][CH:8]([C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:7])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:28][CH2:27]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=CCC(C(=O)C1CCCC1)c1ccccc1
Agent: [Na]
Product: COc1ccccc1N1CCN(CCC(C(=O)C2CCCC2)c2ccccc2)CC1
Yield: 66.9 %

Procedure:
Following the procedures described in the Example 1, Step C, the reaction of 3-cyclopentanecarbonyl-3-phenylpropionaldehyde (1.36 mmol) and 1-(2-methoxyphenyl)piperazine (1.49 mmol) with sodium triacetoxyboranehydride (1.77 mmol) gave pure product 1-(2-methoxyphenyl)-4-[3-(cyclopentanecarbonyl)-3-(phenyl)propyl]piperazine (370 mg) in 67% yield. The di-hydrochloric acid salt was prepared as described above.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O-]S([O-])(=O)=O.[Mg+2].[CH2:14]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.OC(C)(C)[C:29]#[N:30]>CN(C)C(=O)C>[CH2:14]([N:21]1[CH2:26][CH2:25][N:24]([C:1]2([C:29]#[N:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(O)C#N
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Product: N#CC1(N2CCN(Cc3ccccc3)CC2)CCCCC1
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
5.7 g of cyclohexanone, 20 g of dry MgSO4, 10 g of N,N-dimethylacetamide, 10 g of 1-benzylpiperazine and 9.5 ml of 2-hydroxyisobutyronitrile are mixed together and heated at 45° C. for 48 hours with vigorous stirring. The reaction mixture is poured onto ice and left stirring for 30 minutes. The mixture is extracted with ether, the organic phase is washed several times with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. 15 g of the expected product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[N:13]=[CH:12]3)=[CH:7][C:6]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH3:33]B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[N:13]=[CH:12]3)=[CH:7][C:6]([CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:5]([CH3:33])[CH:4]=1
Reactant: CB(O)O
Reactant: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC)cc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(OC)cc1C
Temperature: 120 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A solution of Intermediate 4 (23 mg) in DMF (1.0 ml) was added with methyl boronic acid (18 mg, Ald), sodium carbonate (30 mg), and PdCl2dppf·CH2Cl2 (8.0 mg, Ald), and stirred at 120° C. for 8 hours. The reaction mixture was added with water (30 ml), and ethyl acetate (30 ml×2) for extraction, and then successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (yield: 15 mg).
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]([O:15][CH3:16])=[O:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.[C:17]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:17]([NH:27][C@H:28]([C:36]([CH:4]1[C:3]2([NH2:2])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]1([C:13]([O:15][CH3:16])=[O:14])[CH2:6]3)[CH2:10]2)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C2
Reaction time: 24 h

Procedure:
To 30 ml of a 1 N sodium hydroxide solution is added 4.95 g of L-phenylalanine. The solution is cooled and stirred in an ice bath and 5.4 ml of a 6.1 M solution of carbobenzoxychloride is added dropwise along with additional 1 N sodium hydroxide solution so that the pH remains at 11.0-11.5. The reaction mixture is washed with ether. The aqueous layer is acidified to pH 1.0 with 12 N hydrochloric acid, then the solution is extracted with ethyl acetate. The ethyl acetate extract is separated and is washed three times with water then dried over magnesium sulfate. The solvent is removed under vacuum. The residue crystallizes on rubbing with water to give N-carbobenzoxy-L-phenylalanine. 3.99 Grams of methyl 3-amino-1-adamantanecarboxylate hydrochloride and 4.78 g of carbobenzoxy-L-phenylalanine are dissolved in 40 ml methylene chloride. To this solution is added 1.8 ml of N-methylmorpholine followed immediately by 2.19 g of dicyclohexylcarbodiimide. The reaction mixture is allowed to stand for 24 hours at room temperature, then the treatment with carbobenzoxy-L-phenylalanine and dicyclohexylcarbodiimide is repeated. The reaction mixture is again allowed to stand for 24 hours at room temperature. The dicyclohexylurea is removed by filtration and washed with methylene chloride. The combined filtrates are washed twice with 0.5 M potassium bisulfate, water and 1 M solution of potassium bicarbonate and dried over magnesium sulfate. The dicloromethane is removed under vacuum and the residue is purified by low pressure chromatography on silica gel using mixtures of hexane and chloroform as eluting solvent to give methyl carbobenzoxy-L-phenylalanyl-3-amino-1-adamantanecarboxylate which has the following structural formula ##STR13## wherein Cbz represents carbobenzoxy.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(Br)oc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(OC)cc2)oc1C
Yield: 88.9 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.6 g), 4-methoxy-phenylboronic acid (2.3 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (15 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 15% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.6 g, 88%) as a white solid.
Reaction SMILES: [OH-].[Na+].[N:3]1([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>O1CCCC1.CO.C(OCC)(=O)C>[N:3]1([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(N2CCC(N3CCCC3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCC(N3CCCC3)CC2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
A 5 M sodium hydroxide solution (15 mL, 75.0 mmol) was added to a solution of methyl 4-(4-(pyrrolidin-1-yl)piperidin-1-yl)benzoate described in Production Example 8-1 (2.06 g, 7.14 mmol) in tetrahydrofuran (10 mL) and methanol (10 mL). The reaction liquid was stirred at 50° C. for 4 hours. The reaction liquid was cooled to 0° C. and then 5 M hydrochloric acid was dripped until pH reached 1. The liquid mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum to obtain the title compound (1.61 g, 82%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.[Ru](=O)=O>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2CCNCC2)cc1
Agent: O=[Ru]=O
Solvent: C1COCCO1
Product: CC(C)(C)C1CCC(N2CCNCC2)CC1

Procedure:
90 g (0.41 mole) of N-(4-tert-butylphenyl)-piperazine in 1.6 l of dioxane are hydrogenated over 5 g of ruthenium(IV) oxide at 130° C. and under 150 bar for 74 hours. Working up in the usual manner gives a white solid.