Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:29]=[CH:28][C:14]([C:15](OC3C=C(F)C(C#N)=C(F)C=3)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH3:2].C(OC[C@H]1CC[C@H](C2C=CC(C(O)=O)=CC=2)CC1)C.S(Cl)([Cl:51])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:29]=[CH:28][C:14]([C:15]([Cl:51])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC[C@H]1CC[C@H](c2ccc(C(=O)Oc3cc(F)c(C#N)c(F)c3)cc2)CC1
Agent: CCOC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1

Procedure:
Preparation of 3,5-difluoro-4-cyanophenyl 4-(trans-4-(ethoxymethyl)cyclohexyl)benzoate (in the formula (1), R=C2H5, l=1, m and n=both, 1, o=0, A1 =trans-1,4-cyclohexylene group, A2 =1,4-phenylene group, Z1 =covalent bond, Z2 =--COO--, X=CN, and Y1 and Y2 =both, F) (Compound No. 187) 4-(Trans-4-(ethoxymethyl)cyclohexyl)benzoic acid (1.9 g, 7.1 mmol) was mixed with thionyl chloride (1.3 g, 10.6 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(trans-4-(ethoxymethyl)cyclohexyl)benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH3:18])=[C:8]2CO)=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[K].[OH2:33].CN([CH:37]=[O:38])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH3:18])=[CH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:16][CH2:17][C:37]([OH:38])=[O:33]
Reactant: O
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)c(C)c(CO)n2Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: Cc1ccccc1
Product: COCC(=O)O
Product: COc1ccc2c(c1)c(C)cn2Cc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
The product from Step 2 above (1.0 g) was dissolved in dry DMF (10 ml) at -20° C. Potassium hexamethyl disilazane base in toluene (0.69M) was added (1.1 molar equivalents) and the reaction stirred for 1 hr. Ethyl 2-bromo acetate (580 mg)=1.2 equivalents was added and the reaction stirred for 16 h at 21° C. Water was added (3 ml). The product was isolated after extraction from the aqueous DMF with ether. Following purification on column chromatography, the title ethyl ester was hydrolysed in 3N NaOH according to the procedure in Example 2.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: C1COCCN1
Reactant: Clc1nccnc1Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccnc1N1CCOCC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A mixture of 2,3-dichloropyrazine (894 mg, 6 mmol), morpholine (523 mg, 6 mmol) and DIEA (1.55 g, 12 mmol) in DMSO (8 mL) was stirred at 70° C. for 2 h. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 2N aq HCl (30 mL), water (2×30 mL) and brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(3-chloropyrazin-2-yl)morpholine as a light yellow solid (1.01 g, 92.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=2.4 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 3.86 (t, J=9.3 Hz, 4H), 3.45 (t, J=9.6 Hz, 4H). LCMS (ESI) m/z 200 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[C:31](=O)[C:32]([O:34]CC)=O.CC(O)=O>COCCO>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[C:25]=1[C:31]1[C:32](=[O:34])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)c1c(Cl)cccc1Cl
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Solvent: CC(=O)O
Solvent: COCCO
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)nc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Yield: 37.2 %

Procedure:
A mixture of 0.60 g (2 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 0.74 g (3 mmol) ethyl 2-(2,6-dichlorophenyl)-2-oxoacetate (T. H. Kress and M. R. Leanna, Synthesis, 1988:803–805), and 0.3 mL HOAc in 25 mL of 2-methoxyethanol is heated under reflux for 16 hours before the solvent is removed under vacuum. The residue is extracted into EtOAc and, after being washed with water, the solution is dried over Na2SO4. Removal of the solvent and chromatography on silica, eluting with hexane/EtOAc 3:2 gives 0.36 g (37%) of the title compound (Compound 2 in Tables 1 and 2): mp (EtOH) 292–293° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:16](OC=C)(=[O:18])[CH3:17].C(CC([O-])=O)=C>C1(C)C=CC=CC=1>[C:16]([O:15][C@@H:13]([C:10]1[N:11]=[N:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)[CH3:14])(=[O:18])[CH3:17]
Reactant: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: C=COC(C)=O
Agent: C=CCC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(=O)O[C@H](C)c1nnn(-c2cccc(Cl)c2)n1
Temperature: 30 °C
Yield: 400.4 %

Procedure:
2.22 g (9.93 mmol) racemic 1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]ethanol and 0.40 g Novozyme 435® are taken up under Ar in toluene (120 mL). After addition of 109 μL (1.18 mmol) vinyl acetate the reaction was run at r.t. o.n., followed by addition of 0.12 g Novozyme 435® and 218 μL (2.36 mmol) vinylacetate and increasing the temperature to 30° C. o.n. Further addition of 2 g Novozyme 435® and 150 μL (1.63 mmol) vinylacetate gave after 7 h ca 41% conversion of starting material. To enhance yield, the reaction was filtered over celite washed with DCM, evaporated to dryness, then taken up in toluene (250 mL). After addition of 0.3 g Novozyme 435® and 200 μL (2.17 mmol) vinylacetate under Ar, 48% conversion after 4 h at r.t. were achieved. Filtration over celite and washing with DCM gave crude which was purified over silica using DCM neat, followed by EA/Hep=1/2, yielding 1.26 g (48%) of the title compound. 1H NMR: 8.15 (m, 1H), 8.03 (m, 1H), 7.48 (m, 2H), 6.27 (q, 1H), 2.14 (s, 3H), 1.77 (d, 3H).
Reaction SMILES: O.[SH-:2].[Na+].C([O-])([O-])=O.[K+].[K+].Br[CH2:11][C:12](=[O:15])[CH2:13][CH3:14].Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH:23]=O>O.CN(C=O)C>[S:2]1[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:23]=[C:11]1[C:12](=[O:15])[CH2:13][CH3:14]
Reactant: O=Cc1cnccc1Br
Reactant: [SH-]
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)c1cc2cnccc2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
To a solution of sodium hydrosulfide hydrate (1.31 g, 17.7 mmol) in 5 mL water was added DMF (30 mL) and K2CO3 (3.27 g, 23.7 mmol). The mixture was cooled to 0° C. in an ice bath before adding 1-bromo-2-butanone (2.68 g, 17.7 mmol). After 15 minutes, a solution of 4-bromopyridine-3-carbaldehyde (2.20 g, 11.8 mmol) in DMF (20 mL) was added. The reaction mixture was stirred at 45° C. for 2.5 days. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, and evaporated to give the crude product (1.80 g, 80%) which was used in the next step without further purification. MS m/z 192 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([NH:7][CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:6])[C:4]#[N:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>COC(C)(C)C>[NH2:5][CH2:4][C:3]([NH:7][CH:8]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:9][OH:10])([CH3:6])[C:2]([F:17])([F:18])[F:1]
Reactant: CC(C#N)(NC(CO)c1ccccc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Product: CC(CN)(NC(CO)c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
31 g (120.0 mmol) of 3,3,3-trifluoro-2-[(2-hydroxy-1-phenylethyl)amino]-2-methylpropionitrile Example 242A were initially charged in tert-butyl methyl ether (3.1 l), the mixture was cooled to 0° C., 18.25 g (480.2 mmol) of lithium aluminium hydride were added and the reaction mixture was stirred at RT for 16 h. The mixture was then cooled to 0° C. and initially quenched with 24 ml of water, and 24 ml of 15% strength aqueous potassium hydroxide solution and 48 ml of water were then added. The mixture formed was filtered through silica gel and washed with tert-butyl methyl ether. The organic phase was separated off, dried over sodium sulphate, filtered and concentrated. This gave 29.2 g (83% of theory, purity 89%) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1(C)C=CC=C(C)C=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:35])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=3[F:25])[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1NC(=O)C2(CC(c3cccc(F)c3F)Oc3ccc(Br)cc32)N1
Solvent: Cc1cccc(C)c1
Product: O=C1NC(=S)NC12CC(c1cccc(F)c1F)Oc1ccc(Br)cc12
Temperature: 150 °C
Yield: 73.7 %

Procedure:
A suspension of 6-bromo-2-(2,3-difluorophenyl)spiro[chroman-4,4′-imidazolidine]-2′,5′-dione (212 mg, 0.52 mmol) and Lawesson's Reagent (201 mg, 0.52 mmol) in dry m-xylene (4.5 mL) was heated at 150° C. in a 10 mL CEM microwave test tube for 25 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-bromo-2-(2,3-difluorophenyl)-2′-thioxospiro[chroman-4,4′-imidazolidine]-5′-one (163 mg, 74%). 1H-NMR (CDCl3): 2.33 (t, 3H), 2.54 (d, 1H), 5.36 (s, 1H), 6.17 (d, 1H), 6.91 (d, 1H), 7.17 (m, 3H), 7.30 (m, 2H), 7.46 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)[CH3:13].[CH2:25]([O:27][C:28](=[O:34])[CH:29]=[C:30]([CH2:32][CH3:33])[NH2:31])[CH3:26]>C(O)C>[CH2:25]([O:27][C:28]([C:29]1[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:24])=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:31][C:30]=1[CH2:32][CH3:33])=[O:34])[CH3:26]
Reactant: CCOC(=O)C=C(N)CC
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C(CC)N1
Yield: 68 %

Procedure:
7.5 g of 3-nitrobenzaldehyde 9.5 g of oxalacetic acid diethyl ester and 7.2 g of β-ethyl-β-aminoacrylic acid ethyl ester in 40 ccs of ethanol are heated to the boil for several hours, and after cooling, filtration and washing (ether/petroleum ether) yellow crystals of melting point 153°C are obtained in 68% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=1)[CH3:25].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>ClCCl>[CH3:43][S:44]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:18][CH:19]=2)[O:14][CH2:13][C:12]1([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:30][CH:31]=1)[CH3:25])(=[O:46])=[O:45]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
4-(9-Hydroxynonyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (435 mg, 0.89 mmol) was dissolved in dichloromethane (30 ml), to which were added triethylamine (0.62 ml, 4.47 mmol) and methanesulfonyl chloride (0.34 ml, 4.47 mmol). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, water was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate-7:3) to give the title compound (0.49 g, yield 97%) as a colorless oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:9]([CH3:20])[CH:8]=1.S(=O)=O.[S:24](Cl)([Cl:27])(=[O:26])=[O:25]>O1CCCC1.CCCCCC>[CH3:13][C:11]1[CH:12]=[C:7]([S:24]([Cl:27])(=[O:26])=[O:25])[CH:8]=[C:9]([CH3:20])[C:10]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc(Br)cc(C)c1-c1ccccc1
Agent: O=S=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)Cl)cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
2.5 M n-butyllithium, in tetrahydrofuran, (0.46 ml, 1.17 mmol, 1.1 equiv.) was added dropwise to a solution of 4-bromo-2,6-dimethylbiphenyl (0.28 g, 1.06 mmol, 1.0 equiv.) in dry tetrahydrofuran (5 ml), under nitrogen at −78° C. and the mixture stirred for 15 minutes. This solution was added, by canula, to a solution of sulfur dioxide (3 mL) and tetrahydrofuran (3 ml) under nitrogen at −78° C. The solution was allowed to warm to room temperature while stirring for 16 hours. The solvent was evaporated under reduced pressure and the residue suspended in hexane (4 ml) and dichloromethane (4 ml). The suspension was cooled to 0° C., a solution of sulfuryl chloride (0.14 g, 1.06 mmol, 1.0 equiv.) in hexane (2 ml) was added and the mixture was allowed to warm to room temperature while stirring for 1.5 hours. The hexane and dichloromethane were evaporated under reduced pressure to afford crude 2,6-dimethylbiphenyl-4-sulfonyl chloride, 0.22 g (74% yield) as a red gum, this material was used in the next step without further purification.
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][NH:8][CH2:9][CH2:10][OH:11].[OH-:14].[Na+]>CC(C)=O.O>[OH:11][CH2:10][CH2:9][N:8]1[CH2:7][C:6]([CH3:13])([CH3:12])[NH:5][C:6]([CH3:13])([CH3:12])[C:7]1=[O:14]
Reactant: [OH-]
Reactant: CC(C)(N)CNCCO
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Temperature: 5 °C

Procedure:
244.2 g (2.05 mol) of chloroform are added to 180 g (1.36 mol) of 2-(2-amino-2-methyl-propylamino)ethanol in 1204 ml of acetone. The mixture is cooled to 5° C. under stirring and a solution of 327 g (8.18 mol) of sodium hydroxide in 327 ml of water is slowly added, the temperature of the mixture being maintained at 0°–5° C. during the addition. The mixture is then stirred at this temperature for further 2 hours and at room temperature for 15 hours. Subsequently, the pH of the aqueous solution is corrected to 11 and the mixture is stirred for further 4 hours. Then, the mixture is filtered and the residue is washed with acetone. The filtrate and the acetone of washing are collected and evaporated under vacuum (70° C./24 mbar). The residue is distilled giving a white oil with a boiling point of 115° C. at 2.66 mbar. After cooling a solid product with a melting point of 91°–93° C. is obtained.
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:26]1[O:37][C:36]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]=2[O:27]1.O>CN(C=O)C>[CH2:26]1[O:37][C:36]2[CH:35]=[CH:34][C:30]([C:31]([N:5]3[CH2:6][CH2:7][N:2]([C:8]4[CH:9]=[C:10]5[C:15](=[CH:16][CH:17]=4)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]5)[CH2:3][CH2:4]3)=[O:32])=[CH:29][C:28]=2[O:27]1
Reactant: O=c1ccc2cc(N3CCNCC3)ccc2[nH]1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1ccc2c(c1)OCO2)N1CCN(c2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
6-(1-Piperazinyl)carbostyril hydrobromide (2.0 g) was suspended in 20 ml of DMF. After adding 2.34 ml of triethylamine, a solution of 1.43 g of 3,4-methylenedioxybenzoyl chloride in 2 ml of DMF was added dropwise to the mixture. After completion of addition, the mixture was stirred at room temperature for 30 minutes and the reaction mixture was poured in a large amount of water. Crystals which formed were collected by filtration and dried. Then, the crystals were purified through silica gel column chromatography and recrystallized from chloroform-methanol to give 1.9 g of 6-[4-(3,4-methylenedioxybenzoyl)-1-piperazinyl]carbostyril, m.p. 266°-267° C. (decomp.), yellow powders.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38](O)=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].[C:50]1([C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:57](=[O:89])[O:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][N:67]([CH3:88])[C:68](=[O:87])[CH2:69][CH2:70][NH:71][C:72]2[CH:77]=[CH:76][C:75]([C:78](=[O:86])[N:79]([CH3:85])[CH2:80][CH2:81][CH2:82][NH:83][CH3:84])=[CH:74][CH:73]=2)[CH2:61][CH2:60]1>>[C:50]1([C:90]2[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=2)[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[NH:56][C:57](=[O:89])[O:58][CH:59]1[CH2:60][CH2:61][N:62]([CH2:65][CH2:66][N:67]([C:68](=[O:87])[CH2:69][CH2:70][NH:71][C:72]2[CH:73]=[CH:74][C:75]([C:78](=[O:86])[N:79]([CH2:80][CH2:81][CH2:82][N:83]([C:38](=[O:39])[CH2:37][O:36][C@@H:28]3[C:25]4([CH2:26][CH2:27][N:22]([CH2:21][CH2:20][C@:11]5([C:13]6[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=6)[O:10][CH2:9][N:8]([C:6](=[O:7])[C:5]6[CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:43]=[C:3]([C:2]([F:49])([F:1])[F:48])[CH:4]=6)[CH2:12]5)[CH2:23][CH2:24]4)[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29]3)[CH3:84])[CH3:85])=[CH:76][CH:77]=2)[CH3:88])[CH2:63][CH2:64]1
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: CNCCCN(C)C(=O)c1ccc(NCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCNc1ccc(C(=O)N(C)CCCN(C)C(=O)CO[C@H]2Cc3ccccc3C23CCN(CC[C@@]2(c4ccc(F)cc4)CN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)CO2)CC3)cc1
Yield: 62.2 %

Procedure:
The compound (119 mg, 0.17 mmol) obtained in Example 1j and the compound (98 mg, 0.16 mmol) obtained in Example 94c were used to give the title compound (130 mg; yield, 64%) as a white solid according to the method described in Example 11e.
Reaction SMILES: O=S1[O:6][CH:5]([C@@H:7]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]O1.[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][NH:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][N:34]1[CH2:4][C@@H:5]([OH:6])[C@@H:7]([N:15]1[C:16](=[O:25])[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:23]1=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)C1COS(=O)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Yield: 65 %

Procedure:
A suspension of 0.35 g of the above 83:17 mixture of the two 1:1 mixtures of the (2R,4S) and (2S,4S) and respectively (2R,4R) and (2S,4R) isomers of 2-[(S)-1-[2-oxo-1,3,2-dioxathiolan-4-yl]-2-phenylethyl]-2,3-dihydro-1H-isoindol-1,3-dione, 0.24 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 0.21 g of sodium carbonate in 3.5 ml of isobutyl methyl ketone is heated to reflux for 24 hours, thereafter cooled and filtered. The filtrate is purified on silica gel with hexane/ethyl acetate (4:1). After evaporation and drying there is obtained 0.34 g (65%) of pure N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, IR (KBr): 3388m (OH), 1771m and 1708s (C=O of imide).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]=[O:21])=[CH:14][C:13]=2[F:22])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1OC1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:37]([CH:44]([CH2:47]O)[CH2:45][OH:46])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH:20]3[O:46][CH2:45][CH:44]([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:47][O:21]3)=[CH:14][C:13]=2[F:22])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(CCC=O)cc2F)cc1
Reactant: CCCCCCCC(CO)CO
Agent: O=[Cr](=O)([O-])Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: C1CO1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCC1COC(CCc2ccc(-c3ccc(CCCCC)cc3)c(F)c2)OC1

Procedure:
6 g of 3-(4'-pentyl-2-fluorobiphenyl-4-yl)-propionaldehyde (obtainable by reaction of 4-(2-fluoro-4'-pentylbiphenylyl)-magnesium bromide with ethylene oxide and subsequent oxidation of the resulting alcohol with pyridinium chlorochromate) and 3.5 g of 2-heptylpropane-1,3-diol are heated with a spatula tip of p-toluenesulfonic acid in 100 ml of toluene, using a water separator, until no further water is foamed. After cooling, the mixture is washed with bicarbonate solution and water until neutral and dried over sodium sulfate and the toluene is distilled off. After customary working-up, 1-(4'-pentyl-2-fluorobiphenyl-4-yl)-2-(5-heptyl-1,3-dioxan-2-yl)-ethane is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:3]=1.C([Li])(CC)C.C(O[B:24]1[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]1)(C)C.[Cl-].[NH4+]>O1CCCC1>[CH:12]1([CH2:11][O:10][C:4]2[CH:3]=[C:2]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)[CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[CH2:14][CH2:13]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(Br)cc1OCC1CC1
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OCC1CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 94 %

Procedure:
To 60 ml of dehydrated tetrahydrofuran solution containing 3.64 g (14.2 mmol) of 4-bromo-2-cyclopropylmethoxy-1-methoxybenzene was added dropwise 18.0 ml of tetrahydrofuran solution containing 0.97M sec-butyl lithium at −70° C. under argon atmosphere, and the mixture was stirred at the same temperature for 50 minutes. Then, 3.70 ml (19.2 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane was added to the mixture, and the resulting mixture was raised to room temperature. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and after adjusting a pH thereof to 2 with 1N hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure to obtain 4.78 g (purity: 84.7%) of the title compound as a slightly yellowish oil. (Yield: 94%)