Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18]Cl)[N:17]=1)(=[O:11])[CH3:10]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C)C=O>[C:9]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][N:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]2=[O:8])[N:17]=1)(=[O:11])[CH3:10]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC(=O)Nc1nc(CCl)cs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(Cn2cc(Cl)cnc2=O)cs1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
A stirred suspension of 5-chloropyrimidin-2-one (653 mg), 2-acetylamino-4-chloromethylthiazole (1.430 g) anhydrous sodium carbonate (1.060 g) and benzyltrimethylammonium chloride (20 mg) in dry N,N-dimethylformamide (25 ml) was heated at 90° C. After 11/2 h the reaction mixture was evaporated to dryness and then the residue was suspended in ethyl acetate (250 ml) and washed with water (3×70 ml), dried (MgSO4) and evaporated to a yellow foam. The foam was subjected to p.l.c. on silica developing with chloroform-ethanol, 19:1 (three runs). The major band was eluted with ethyl acetate to give a foam which was crystallised from acetone to give off white crystals of the title pyrimidinone (170 mg), m.p. 209°-211° C., λmax (EtOH) 227 nm (ε 11,960), 267 nm (ε 8,540), 334 nm (ε 3,420).
Reaction SMILES: [CH2:1]([NH:4][C:5]([CH2:7][CH2:8][C:9]1[CH:25]=[CH:24][C:12]([O:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:10]=1)=O)[CH2:2][CH3:3].Cl.C(N)C>O1CCCC1>[CH2:1]([NH:4][CH2:5][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][C:14]([CH3:23])([CH3:22])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:24][CH:25]=1)[CH2:2][CH3:3]
Reactant: CCCNC(=O)CCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Agent: CCN
Agent: Cl
Solvent: C1CCOC1
Product: CCCNCCCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-[4-[2-(N-n-propylaminocarbonyl)ethyl]phenoxy]-2-methylpropionate (4.0 g, 11.4 mmol) was dissolved in tetrahydrofuran (10 mL). 1.0M Borane-tetrahydrofuran complex in tetrahydrofuran solution (34.3 mL, 34.3 mmol) was added dropwise, the mixture was stirred for three hours at 50° C. Concentrated hydrochloric acid was added under ice-cooling, the mixture was stirred for three hours at room temperature. Aqueous 80% ethylamine solution was added dropwise under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (2.3 g, 59%).
Reaction SMILES: [CH3:1]C(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[OH:14][C@@H:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[C@H:28]([NH:34][C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36])[CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:43]([OH:45])=[O:44])[CH2:16]1.O>CC(C)=O>[O:14]=[C:15]1[CH2:32][CH2:31][C@@:30]2([CH3:33])[C@@H:17]([CH2:18][CH2:19][C@@H:20]3[C@@H:29]2[C@H:28]([NH:34][C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36])[CH2:27][C@@:25]2([CH3:26])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C:43]([O:45][CH3:1])=[O:44])[CH2:16]1
Reactant: CC(C)=O
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]2(C)[C@@H](C(=O)O)CC[C@@H]12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C

Procedure:
Jones reagent was added dropwise to a stirred solution of the product of Preparation 3 (0.3 g) in acetone (20 ml) until the reagent colour was not discharged. Water (150 ml) was added and the precipitate obtained was collected by filtration, washed with water, dried and crystallised from ethyl acetate/petrol to give the title compound (0.19 g), m.p. 208°-209° C., [α]D +41°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]#[C:7][C:8]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([OH:20])=[CH:10][CH:9]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:11]([OH:20])=[CH:10][CH:9]=1
Reactant: COC(=O)CCC#Cc1ccc(O)c(CCC(=O)OC)n1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCc1ccc(O)c(CCC(=O)OC)n1
Yield: 65.6 %

Procedure:
Under the conditions of example 14 A, a solution of 1 g of 5-[3-hydroxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-4-pentynoic acid methyl ester in 10 ml of methanol is hydrogenated in the presence of 100 mg of 10% palladium catalyst on activated carbon and worked up. The crude product is chromatographed on silica gel with hexane/0-50% ethyl acetate. 665 mg of 5-[3-hydroxy-2-(2-methoxycarbonylethyl)-6-pyridyl]-pentanoic acid methyl ester of melting point 92°-95° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:5]([OH:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:1][C:2]1([CH3:23])[CH:5]([OH:6])[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:3]1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1.[C:33]1([NH:39][C:40](=[O:6])[O-:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccccc1
Agent: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C([O-])Nc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of Example 62 (150 mg) in toluene (2.3 mL) at r.t., was added diisopropylethylamine (160 μL) and phenylisocyanate (100 μL ). The mixture was refluxed for 4 hr, cooled to r.t. and diluted with EtOAc and H2O. The organic phase was washed with HCl 1N, brine, dried (MgSO4) and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (80:20 to 60:40)) to give the title compound as a white solid, m.p. 85.5°-87° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:10]([NH2:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[S:10]([NH2:13])(=[O:11])=[O:12])[CH:3]=[CH:2]1
Reactant: NS(=O)(=O)c1cccc2c1NCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a slurry of activated manganese dioxide (20 g) in methylene chloride (200 ml) was added indoline-7-sulfonamide (4.3 g). The mixture was stirred at 25° C. for 24 hours. The solid was removed by filtration and the filtrate concentrated and hexane added until crystallization occurred. The pure product (TLC) was isolated by filtration (2.9 g, m.p. 125°-127° C.).
Reaction SMILES: [N:1]#[C:2]Br.[N:4]1([CH2:11][C:12]2[S:13][C:14]([C:17]([NH:19][NH2:20])=[O:18])=[CH:15][CH:16]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C>[NH2:1][C:2]1[O:18][C:17]([C:14]2[S:13][C:12]([CH2:11][N:4]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)=[CH:16][CH:15]=2)=[N:19][N:20]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Solvent: CCO
Product: Nc1nnc(-c2ccc(CN3CCCCCC3)s2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
2.5 g (23.57 mmol) of cyanogen bromide was added to 250 ml of ethanol solution containing 5.43 g (21.43 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, and the mixture was stirred at room temperature for 2 hours and then at 50° C. for 7 hours. The reaction solution was concentrated under a reduced pressure, saturated sodium bicarbonate aqueous solution and chloroform were added to the resulting residue. Then, the resulting organic layer was separated, washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was recrystallized from ethyl acetate to give 2.43 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][CH:5]([CH2:7][OH:8])[CH:4]([CH2:9][OH:10])[O:3]1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:11])[O:3][CH:4]([CH2:9][OH:10])[CH:5]([CH2:7][O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:6]1
Reactant: ClCc1ccccc1
Reactant: CC1(C)OC(CO)C(CO)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)OC(CO)C(COCc2ccccc2)O1

Procedure:
Alternatively, benzyl ethers may be used to protect --OH groups. For example, 2,2-dimethyl-4,5-di(hydroxymethyl)-1,3-dioxolane (8 g, 0.2 mol) is heated at reflux with benzyl chloride (25 g, 0.2 mol) and K2CO3 (25 g, 0.2 mol) in 100 mL ethanol. The product is added to aqueous NaOH, extracted with ether, and purified by silica gel chromatography to yield 2,2-dimethyl-4-hydroxymethyl-5-benzyloxymethyl-1,3-dioxolane.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[N-]=[C:20]=[S:21]>>[OH:18][CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N:1]=[C:20]=[S:21])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCO)CC2)cc1
Reactant: [N-]=C=S
Product: OCCN1CCN(c2ccc(N=C=S)cc2)CC1

Procedure:
This compound was prepared from 4-(4-nitrophenyl)-1-piperazine-ethanol (Bionet Research Ltd.) using the hydrogenation and isothiocyanate-forming reactions used in Example 4.
Reaction SMILES: CC([Mg]Cl)C.Br[C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)[C:10]([OH:12])=[O:11].CN([CH:25]=[O:26])C.Cl>C(OCC)C.C1COCC1>[CH:25]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:26]
Reactant: O=C(O)c1cc(Br)cc(S(F)(F)(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1

Procedure:
With ice bath cooling, 11.5 ml (23 mmol) of a 2 M solution of 2-propylmagnesium chloride in diethyl ether were added dropwise to a solution of 3.0 g (9.17 mmol) of the compound of Example 15A in 1.6 ml of abs. THF. After the addition had ended, stirring was continued without cooling for another 30 min 1.76 ml (22.9 mmol) of DMF were added with ice bath cooling, and the mixture was stirred without cooling for a further 30 min. 20 ml of 1 M hydrochloric acid were then added, and the mixture was extracted with 100 ml of ethyl acetate. The organic phase was washed with 1 M hydrochloric acid and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness on a rotary evaporator. The residue was suspended in 50 ml of dichloromethane/pentane (1:1) and the solid was filtered off and dried. Any contaminations present were removed by preparative HPLC (Method 22). This gave 780 mg (31% of theory) of the title compound.
Reaction SMILES: [Cl-].[Cl-].[Ca+2].[CH3:4][C:5]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:24])[CH2:22][CH3:23])=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.[OH-].[Na+]>CCCCCC.C(OCC)C.C(Cl)Cl>[O:33]1[C:21]([CH3:24])([CH2:22][CH3:23])[CH:20]1[CH2:19][CH2:18][C:5]([CH3:4])=[CH:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(C)=CCCC(C)=CCOc1ccc2c(c1)OCO2
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCCCCC
Product: CCC1(C)OC1CCC(C)=CCOc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 2 l., four-necked flask (with stirrer, thermometer, CaCl2 -tube and stopper) is placed a solution of 162 g. of the 3,7-dimethyl-1-(3,4-methylenedioxyphenoxy)-2,6-nonadiene in 1.1 l. of methylene chloride. The flask is immersed in an ice-salt bath (-5°C.). When the vigorously stirred solution is cooled to 0°C., 125 g. of pulverized 85% m-chloroperbenzoic acid is added in ca 5 g. portions at such a rate to keep the reaction temperature at 1°-3° (2 hours). After complete addition, the white suspension is stirred for 2 hours, at 0°-1°C. The cold suspension is then poured on a mixture of 600 ml. of 2N sodium hydroxide solution and 300 g. of ice. After partitioning, the brown aqueous layer is extracted with two 250 ml. portions of methylene chloride. The combined organic solution is washed successively with three 250 ml. portions of cold 2N sodium hydroxide solution, 600 ml. of ice water and two 400 ml. portions of brine. The solution is dried (Na2SO4) and concentrated at reduced pressure to give 172 g. of a yellow oil. This crude epoxide is dissolved in 400 ml. of n-hexane-diethyl ether (10:1 parts by volume) and applied on a column (diameter 13 cm) containing 2 kg. of silica gel (E. Merck, AG 70-325 mesh) in n-hexane-diethyl ether (10:1 parts by volume). Elution (700 ml. cuts) with this mixture gives 6,7-epoxy-3,7-dimethyl-1-(3,4-methylenedioxyphenoxy)-2-nonene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]([CH2:13][C:14]([O:16]C)=[O:15])[C:11](=[O:12])[C:3]=12>Cl.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]([CH2:13][C:14]([OH:16])=[O:15])[C:11](=[O:12])[C:3]=12
Reactant: COC(=O)Cn1sc2nc(C)cc(C)c2c1=O
Agent: Cl
Solvent: O
Product: Cc1cc(C)c2c(=O)n(CC(=O)O)sc2n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 100.6 %

Procedure:
Ester 7 (160 mg, 0.63 mmol) was suspended in conc. HCl (4 mL) and heated with stirring at 100° C. for 5 h until hydrolysis completed. The mixture was cooled to room temperature, diluted with water (500 mL), and the precipitate was collected to give the title compound (151 mg, 100% yield). C10H10N2O3S; white solid; mp 355° C. (decomposed); 1H NMR (400 MHz, CD3OD) δ 7.13 (1H, s), 4.60 (2H, s), 2.71 (3H, s), 2.59 (3H, s); 13C NMR (100 MHz, CD3OD) δ 170.2, 165.7, 164.2, 163.3, 151.3, 123.3, 115.1, 45.2, 24.7, 17.9; ESI-HRMS (negative mode) calcd for C10H9N2O3S: 237.0334. found: m/z 237.0329 [M−H]−.
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[CH2:20][C@H:19]([OH:23])[C@@H:18]2[CH3:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O)(=O)C>C1COCC1.O>[CH2:25]([C@H:20]1[C@H:19]([OH:23])[C@H:18]([CH3:24])[N:17]([C:15]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([Cl:8])[CH:16]=2)[C:21]1=[O:22])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@@H](O)[C@H](Cc2ccccc2)C(=O)N1c1ccc(C#N)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of diisopropylamine (0.150 mL) in THF (8 mL) was cooled to −78° C., and n-butyllithium-hexane solution (0.648 mL, 1.6 mol/L) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of 2-chloro-4-[(2S,3S)-3-hydroxy-2-methyl-5-oxopyrrolidin-1-yl]benzonitrile (100 mg) in THF (2.5 mL) was added dropwise, and the mixture was further stirred at −78° C. for 30 min. A solution of benzyl bromide (0.16 mL) in THF (1.5 mL) was added dropwise at −78° C., and the mixture was further stirred at −78° C. to −30° C. for 1 hr. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/2) to give the title compound as a colorless solid (yield: 40.8 mg, 30.0%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[Si:17](Cl)([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:1]([N:5]([Si:17]([CH3:20])([CH3:19])[CH3:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Nc1ccccc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)N(c1ccccc1)[Si](C)(C)C
Temperature: 40 °C
Reaction time: 24 h
Yield: 70.5 %

Procedure:
To a solution of 1a (0.972 g, 6.51 mmol) in THF (10 mL) was added nBuLi (1.6 M solution in hexanes) (4.3 mL, 6.9 mmol) at −78° C. After 30 min stirring of the reaction mixture at the same temperature, Me3SiCl (0.89 mL, 7.0 mmol) was added at room temperature and the reaction mixture was stirred at 40° C. for 24 h. After evaporating all the volatiles by vacuum, pentane (50 mL) was added. After 20 min stirring of the mixture, stirring was stopped. The supernatant solution was transferred to another flask by a canula. Evaporation of the solvent gave 3a (1.016 g, 70.2%) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) 7.32-7.08 (m, 3H), 7.05-6.95 (m, 2H), 1.20 (s, 9H), 0.03 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 148.1, 133.6, 127.9, 124.9, 55.0, 32.1, 4.3. HRMS-ESI (m/z): [M+H]+ calcd for C13H23NSi, 222.1673. found, 222.1670.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=O.[CH:12](=[O:15])[CH2:13][CH3:14]>>[CH3:14][CH:13]([CH2:3][CH:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:12]=[O:15]
Reactant: CC(C=O)Cc1ccccc1
Reactant: CCC=O
Product: CC(C=O)CC(C)Cc1ccccc1

Procedure:
The 2,4-dimethyl-5-phenylpentan-1-yl derivatives in accordance with the present invention can be prepared by a variety of ways. For example, by an Aldol condensation between 2-methyl-3-phenylpropanal and proprionaldehyde, followed by hydrogenation of the resulting α,β-unsaturated aldehyde to form the saturated aldehyde, 2,4-dimethyl-5-phenylpentanal as described above. This aldehyde is the direct precursor for the alcohol, 2,4-dimethyl-5 -phenylpentan-1-ol via reduction with, e.g. sodium borohydride, as well as the nitrile, 2,4-dimethyl-5-phenyl-pentanitrile via oxidation dehydration chemistry by reaction of hydroxylamine/formic acid as described above.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].[Br:11][CH2:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Br:11][CH2:12][CH2:13][CH2:14][O:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrCCCBr
Reactant: COc1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(C)ccc1OCCCBr
Temperature: 85 °C
Yield: 42.1 %

Procedure:
To a solution of 2-methoxy-4-methylphenol (500 mg, 3.62 mmol) in acetonitrile (20 mL) was added 1,3-dibromopropane (3.65 g, 201.89 mmol) followed by cesium carbonate (2.35 g, 7.24 mmol). The resulting solution was heated at 85° C. for 48 h, then cooled to rt. The solution was filtered through a Celite® pad. The Celite® was washed with acetone, and the combined filtrates were concentrated under reduced pressure to give the title compound as a white solid (395 mg, 42%). GC/MS (EI) m/z 258 (M)+, RT 7.94 min.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[NH2:16])=[C:11]2[C:3]=1[C:4]1[CH2:5][CH2:6][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][C:9]=1[NH:10]2.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:15]([C:12]1[CH:13]=[CH:14][C:2]([C:25]2[C:24]([F:23])=[CH:29][CH:28]=[CH:27][C:26]=2[F:30])=[C:3]2[C:11]=1[NH:10][C:9]1[CH2:8][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][C:4]2=1)(=[O:17])[NH2:16]
Reactant: OB(O)c1c(F)cccc1F
Reactant: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCc2c([nH]c3c(C(N)=O)ccc(-c4c(F)cccc4F)c23)C1
Yield: 45.6 %

Procedure:
A mixture of ethyl 5-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate (Intermediate 47-1, 20 mg, 0.055 mmol), 2,6-difluorophenylboronic acid (17.3 mg, 0.110 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (4.5 mg, 11.0 mmol), potassium carbonate (15.1 mg, 0.110 mmol) and tris(dibenzylideneacetone)dipalladium (5.0 mg, 0.005 mmol) in THF (2 mL) was purged with nitrogen for 2 min, then was heated in a sealed tube overnight. The mixture was filtered and concentrated, and the residue was purified by preparative HPLC. The appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases were washed with water, dried and concentrated to provide ethyl 8-carbamoyl-5-(2,6-difluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-2-carboxylate as a light yellow solid (10 mg, 44%). 1H NMR (400 MHz, chloroform-d) δ 10.10 (1H, br. s.), 7.31-7.44 (2H, m), 6.95-7.06 (3H, m), 4.10-4.22 (2H, m), 2.96-3.12 (2H, m), 2.80 (1H, dddd, J=17.52, 5.99, 3.08, 2.86 Hz), 2.27-2.41 (1H, m), 2.15-2.27 (1H, m), 2.04-2.14 (1H, m), 1.69-1.85 (1H, m), 1.26 (3H, t, J=7.25 Hz). Mass spectrum m/z 399.1 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([CH2:12][C:13]([OH:15])=O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[O:28]=[C:29]1[N:35]2[CH2:36][CH2:37][CH2:38][C@H:34]2[C:33]2=[C:39]([C:42]([NH:44][NH2:45])=[O:43])[N:40]=[CH:41][N:32]2[C:31]2[CH:46]=[CH:47][S:48][C:30]1=2>CN(C)C=O>[O:11]=[C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7](=[O:8])[N:9]1[CH2:12][C:13]([NH:45][NH:44][C:42]([C:39]1[N:40]=[CH:41][N:32]2[C:31]3[CH:46]=[CH:47][S:48][C:30]=3[C:29](=[O:28])[N:35]3[CH2:36][CH2:37][CH2:38][C@H:34]3[C:33]=12)=[O:43])=[O:15]
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)NNC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
A solution of 1.0 g (4.9 mmol) of N-phthaloylglycine in 8 ml of dimethylformamide was treated at room temperature with 0.83 g is (5.11 mmol) of 1,1'-carbonyldiimidazole and the mixture was subsequently heated to 50°. After 30 minutes the mixture was cooled to room temperature, 1.5 g (5 mmol) of (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide were added thereto and the mixture was stirred at room temperature for 12 hours. The suspension obtained was filtered and the colourless powder obtained was washed with ethanol and diethyl ether. There were obtained 2.2 g (100%) of (S)-N'-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-ylacetyl)-8-oxo-10,11,12,12a-tetrahydro-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylic acid hydrazide of m.p. >260°.