Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH2:9]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:11][CH3:12]>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C:7]([NH:17][CH2:16][CH2:15][CH2:14][O:13][CH2:9][CH2:10][CH2:11][CH3:12])=[S:8])=[O:5])[CH3:2]
Reactant: CCCCOCCCN
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: CCCCOCCCNC(=S)NC(=O)OCC
Reaction time: 2 h

Procedure:
Again following the procedure of Example 1, to 1.31 parts of the ethoxycarbonyl isothiocyanate in 6 parts of methylene chloride are added 1.31 parts of butoxypropylamine. After 2 hours at room temperature, the methylene chloride is evaporated off. The viscous liquid product N-ethoxycarbonyl-N'-n-butoxypropyl thiourea (2.6 parts) gives the correct IR analysis.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:36])([CH3:35])[CH:33]=[CH2:34])[NH:9]1)=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:19][C:15]1[C:14]([F:20])=[C:13]([CH:12]2[C:11]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([CH3:35])([CH3:36])[CH:33]=[CH2:34])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: C=CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 91 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 80b (1.0 g, 1.7 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-but-3-enyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.0 g, 91%).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11](Cl)(Cl)C(OC)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH3:11][O:8][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccccc1
Temperature: 150 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A mixture of benzoic acid (1.53 g, 0.0125 mole), methyl trichloroacetate (2.22 g, 0.0125 mole), potassium carbonate (0.035 g) and 18-crown-6 cyclic polyether (0.066 g) was placed in a 25 ml round-bottom flask fitted with a stirrer, distillation head, dry ice receiver and trap. The mixture was heated with stirring to 150° C. Gas evolution was observed to begin at about 90° C. After about 3 hours, the heating was discontinued. The trap contained CHCl3 (approx. 1.5 g). Distillation of the remaining mixture gave methylbenzoate identified by gas-liquid chromatography and nuclear magnetic resonance spectroscopy. Purified yield was 85 percent.
Reaction SMILES: [Cl:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=3)=[CH:14][C:6]1=2.[CH3:28][N:29]1[CH2:34][CH2:33][N:32](C2C=C(B3OC(C)(C)C(C)(C)O3)C=CN=2)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH:16]=3)=[CH:14][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(-c4ccnc(Cl)c4)cc32)c1Cl
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Product: CN1CCN(c2cc(-c3cnc4c(c3)N(Cc3c(F)ccc(F)c3Cl)CCN4)ccn2)CC1
Yield: 15 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-(2-chloropyridin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (88 mg) was coupled to 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine as in General Procedure 4B to give the title compound as a light yellow solid (15% yield). LCMS: m/z=471.07 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.36 (3H, s), 2.56 (4H, t, J=4.9 Hz), 3.33 (2H, t, J=4.7 Hz), 3.55 (2H, m), 3.62 (4H, t, J=4.9 Hz), 4.53 (2H, s), 5.23 (1H, bs), 6.72 (1H, s), 6.78 (1H, dd, J=5.3, 1.3 Hz), 7.03 (2H, m), 7.12 (1H, m), 7.77 (1H, d, J=1.8 Hz), 8.18 (1H, d, J=5.1 Hz).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:15]([C:17]([CH3:19])=[O:18])=[CH2:16]>>[C:1]([CH:9]([CH2:16][CH2:15][C:17](=[O:18])[CH3:19])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: C=CC(C)=O
Product: CCOC(=O)C(CCC(C)=O)C(=O)c1ccncc1

Procedure:
3-(4-Pyridinyl)-2-cyclohexen-1-one is obtained by modifying the procedure described in Example B-1 as follows: Ethyl isonicotinoylacetate and methyl vinyl ketone are reacted as in Example B-1 to yield ethyl 2-(isonicotinoyl)-5-oxohexanoate which is then reacted with 35% aqueous sodium hydroixde solution at 25°-30° C. to produce ethyl 3-(4-pyridinyl)-2-cyclohexen-1-one-4-carboxylate and the 4-carboxylate is heated with aqueous sulfuric acid at 95° C. until the evolution of carbon dioxide ceases, thereby producing 3-(4-pyridinyl)-2-cyclohexen-1-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([OH:11])[CH2:7][CH2:6]1.[H-].[Na+].I[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][CH3:16])[CH2:7][CH2:6]1
Reactant: CI
Reactant: COC(=O)C[C@H]1CC[C@@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1CC[C@@H](OC)CC1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 103.9 %

Procedure:
Cis (4-Hydroxy-cyclohexyl)-acetic acid methyl ester (500 mg, 2.90 mmol) were dissolved in 1.5 ml DMF and cooled to 0-5° C. Sodium hydride (190 mg, 4.35 mmol, 55%) and iodomethane (3.62 ml, 23.2 mmol) were added and the reaction mixture stirred for 4 hours at 0-5° C. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with dichloromethane. The organic extract was washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (561 mg, quant.) was obtained as a colourless oil and used without any further purification for the next step.
Reaction SMILES: [NH2:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I:13][CH2:14][C:15](O)=[O:16]>>[I:13][CH2:14][C:15]([NH:1][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:16]
Reactant: O=C(O)CI
Reactant: CCOC(=O)C(N)C(=O)OCC
Product: CCOC(=O)C(NC(=O)CI)C(=O)OCC

Procedure:
Diethyl 2-aminomalonate and iodoacetic acid are treated in the same manner as described in Reference Example 1 to give diethyl 2-[(iodoacetyl)amino]malonate, m.p. 96°-98° C.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=O)[CH3:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].N1C=CC=CC=1.Cl.[CH2:24]([O:26][NH2:27])[CH3:25].O>O1CCOCC1>[CH2:24]([O:26][N:27]=[C:12]([CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:13])[CH3:25]
Reactant: CCON
Reactant: CCC(C)Oc1ccc(OCC(C)=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CCON=C(C)COc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-(1-methylpropoxy)phenoxyacetone (0.70 g, 3.1 mmol) and pyridine (0.50 g, 6.3 mmol) in 10 ml of p-dioxane is added a solution of ethoxyamine hydrochloride (0.70 g, 7.2 mmol) in a minimum amount of water. The reaction mixture is stirred at RT for 16 hours, after which the dioxane is removed in vacuo. The residue is taken up in ether and the organic layer is washed with water. The aqueous phase is extracted with ether, and the combined organic phases are dried, the solvent is evaporated off and the product is purified by column chromatography to give 4-(1-methylpropoxy)phenoxyacetone O-ethyloxime, MS m/e 265 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[O:17][CH2:18][C:19](O)=[O:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:37][C:38]1[NH:42][N:41]=[N:40][N:39]=1>O1CCCC1>[NH:39]1[C:38]([NH:37][C:19](=[O:20])[CH2:18][O:17][C:16]2[CH:22]=[CH:23][CH:24]=[C:14]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH:15]=2)=[N:42][N:41]=[N:40]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(O)COc1cccc(CCNC(=O)OCc2ccccc2)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=C(COc1cccc(CCNC(=O)OCc2ccccc2)c1)Nc1nnn[nH]1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution at 40° C. of 13.1 g. (39.8 mMol) 3-[2-(benzyloxycarbonylamino)-ethyl]-phenoxyacetic acid and 130 ml. anhydrous tetrahydrofuran are added 6.48 g. (39.9 mMol) carbonyl-bis-imidazole, followed by stirring for 30 minutes at 40° C. 3.39 g. (39.9 mMol) anhydrous 5-aminotetrazole are then added thereto and allowed to react for 18 hours at 60° C. After distilling off the tetrahydrofuran, there is obtained a colourless oil which is stirred with 130 ml. 2N hydrochloric acid, crystallisation thereby taking place. The crystals are filtered off with suction, triturated with dilute hydrochloric acid, again filtered off with suction and washed with water. After drying in a vacuum at 80° C. over potassium hydroxide and recrystallising from nitromethane, there are obtained 12.7 g. (50.5% of theory) of the desired product; m.p. 164°-167° C.
Reaction SMILES: [SnH4].C(OC([N:8]1[CH2:12][C@@H:11]([S:13]C(OC(C)(C)C)=O)[CH2:10][C@H:9]1[CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32](=[O:43])[NH:33][C@H:34]([C:39]([O:41][CH3:42])=[O:40])[CH2:35][CH2:36][S:37][CH3:38])[CH:27]=1)(=[O:25])=[O:24])=O)C=C.COC(=O)C(NC(=O)C1C=CC=C(S(=O)(=O)NC[C@@H]2C[C@H](SC(OC(C)(C)C)=O)CN2)C=1)CCSC>O.C(Cl)Cl>[CH3:42][O:41][C:39](=[O:40])[C@@H:34]([NH:33][C:32](=[O:43])[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([S:23](=[O:24])(=[O:25])[NH:22][CH2:21][C@@H:9]2[CH2:10][C@H:11]([SH:13])[CH2:12][NH:8]2)[CH:27]=1)[CH2:35][CH2:36][S:37][CH3:38]
Reactant: C=CCOC(=O)N1C[C@@H](SC(=O)OC(C)(C)C)C[C@H]1CNS(=O)(=O)c1cccc(C(=O)N[C@@H](CCSC)C(=O)OC)c1
Agent: COC(=O)C(CCSC)NC(=O)c1cccc(S(=O)(=O)NC[C@@H]2C[C@H](SC(=O)OC(C)(C)C)CN2)c1
Agent: [SnH4]
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cccc(S(=O)(=O)NC[C@@H]2C[C@H](S)CN2)c1
Reaction time: 0.17 h

Procedure:
Tri-nButyl tin hydride (565 mL, 2.1 mmol) was added to a stirred solution of (15(c)) (1.18 g, 1.8 mmol) and (PPh)3PdCl2 (13 mg. 0.018 mmol) in a mixture of water (0.5 mL) and CH2Cl2 (100 mL). The reaction mixture was left to stir for 10 minutes. dried over MgSO4, filtered and concentrated to a brown oil. This was then purified by flash chromatography on 9385 SiO2, elutins with a gradient of 0-10% EtOAc/i-Hexane to give the desired starting material 15(d) as a white foam: 751 mg (73%).
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]([NH:21]C(OCC1C=CC=CC=1)=O)[CH2:11][S:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)(=[O:14])=[O:13])C1C=CC=CC=1.N#N>[Pd]>[NH2:21][C@@H:10]([CH2:11][S:12]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)(=[O:13])=[O:14])[C:9]([OH:32])=[O:8]
Reactant: O=C(N[C@@H](CS(=O)(=O)N1CCOCC1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: N#N
Product: N[C@@H](CS(=O)(=O)N1CCOCC1)C(=O)O
Reaction time: 16 h
Yield: 150.8 %

Procedure:
To a 1/1 mixture of EtOH/EtOAc (50 mL each) was added concentrated HCl (12 M, 0.83 mL) to produce a 0.10 M solution. Solid 2(R)-benzyloxycarbonylamino-3-(morpholin-4-sulfonyl)-propionic acid benzyl ester (0.764 g, 1.65 mmol) was dissolved in this solution with gentle heating via heat gun until a clear colorless solution resulted. The solution was allowed to cool to rt with N2 aspiration, at which time 10% Pd/C (Aldrich, 0.300 g) was added in one portion to form a dark colored suspension. The reaction mixture was then shaken under an atmosphere of H2 (50 psi) in a Parr hydrogenator for 16 h. The suspension was filtered through a pad of celite, which is then washed with several portions of MeOH. The combined organics were concentrated in vacuo to afford 0.593 g (quant) of 2(R)-amino-3-(morpholin-4-sulfonyl)-propionic acid as its HCl salt as a solid orange foam.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5](=[O:26])[C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@H:13]([CH2:14][C:15](=[O:25])[CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH3:4][C:5]([C@@H:6]1[C@@:23]2([CH3:24])[CH2:22][CH2:21][C@@H:20]3[C@@:18]4([CH3:19])[CH2:17][CH2:16][C@:15]([OH:25])([CH3:1])[CH2:14][C@@H:13]4[CH2:12][CH2:11][C@H:10]3[C@@H:9]2[CH2:8][CH2:7]1)=[O:26]
Reactant: C[Mg]Cl
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 75.9 %

Procedure:
Titanium tetrachloride (350 uL, 3.2 mmol) is added in a dropwise fashion to a solution of titanium tetraethoxide (2.42 g, 10.6 mmol) in tetrahydrofuran (anhydrous, 30 mL) cooled to 0° C. After stirring for 20 min at 0° C., methyl magnesium chloride (3M, 4.3 mL 12.9 mmol) in tetrahydrofuran solution is added dropwise while maintaining the temperature below 5° C. After stirring for an additional 20 minutes at 5° C., 5α-pregnane-3,20-dione (2.53 g, 8 mmol) was added in one portion. The reaction is warmed to 40° C. and stirred for 4 hours. The reaction mixture is quenched with 20 mL of methanol and the solvent removed in vacuo. The reaction mixture is partitioned between 100 ml of 3N HCl and 100 mL of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and brine and the solvent removed in vacuo to afford crude ganaxolone as a white solid of 75.9% pure ganaxolone by HPLC (Table 1, entry 3).
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>>[CH2:17]([C:24]1[CH:25]=[CH:26][C:27]([C:1](=[O:12])[CH2:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:28][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCc1ccccc1
Reactant: O=C1Cc2ccccc2C(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCc1ccc(C(=O)Cc2ccccc2C(=O)O)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of homophthalic anhydride (40 g, 0.24 mole), aluminum chloride (48 g, 0.36 mole) and heptylbenzene (400 ml) is heated (90° C. for 90 minutes). The reaction mixture is poured into a mixture of ice water (800 ml) and concentrated hydrochloric acid (200 g) and stirred overnight. The product is extracted with ether (3×300 ml). The extracts are combined, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from heptane to provide 2-(4-n-heptylphenacyl)benzoic acid (10.4 g) as a white crystalline solid, m.p. 128°-131° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:19]=[CH:18][C:9]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1)=[O:5].[Li][CH3:22].[Cl-].[NH4+]>C1COCC1>[C:4]([C:6]1[CH:19]=[CH:18][C:9]2[CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:12][C:8]=2[CH:7]=1)(=[O:5])[CH3:22]
Reactant: CCOC(=O)c1cc2ccc(C(=O)N(C)OC)cc2s1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(C)=O)cc2s1
Temperature: 25 °C

Procedure:
To a solution of ethyl 6-{[methoxy(methyl)amino]carbonyl}-1-benzothiophene-2-carboxylate (0.07 g, 0.22 mmol) in THF (3 mL) at −78° C. was added MeLi (0.15 mL, 1.6 M in Et2O, 0.24 mmol). The reaction was stirred for 1 h at −78° C. before saturated ammonium chloride solution was added to quench the reaction. At which time the reaction mixture was allowed to warm to room temperature and then extracted with a mixture of hexane:ethyl acetate solution (3:1) (3×). The combined organic layers was dried over Na2SO4, filtered, and concentrated in vacuo. The crude mixture was chromatographed to provide the ketone. 1H NMR (CDCl3, 600 MHz) δ 8.46 (s, 1H), 8.07 (s, 1H), 7.98 (dd, J=8.2, 1.2 Hz, 1H), 7.92 (m, 1H), 4.42 (q, J=7.1 Hz, 2H), 2.69 (s, 3H), 1.42 (t, J=7.2 Hz, 3H). MS: cal'd (MH+) 249, exp (MH+) 249.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:20](OCC)=[O:21])=[C:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].CC(C[AlH]CC(C)C)C.O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([C:5]1[NH:9][C:8]([S:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:7]([CH2:20][OH:21])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(SCc2ccc(OC)cc2)c(C(=O)OCC)[nH]1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCc1nc(CO)c(SCc2ccc(OC)cc2)[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
50 g or 143.5 mmol of ethyl 2-butyl-4-[4-methoxy-benzyl-thio]-1H-imidazole-5-carboxylate[prepared as indicated in the European Patent Application No. 0,465,368] were solubilized in 300 ml of methylene chloride and the mixture was cooled to -78° C. With stirring, 68.3 g (480 mmol) and 2N DIBAH in 400 ml of toluene were added and then the medium was allowed to return to ambient temperature for about 30 minutes. The reaction medium was hydrolyzed with 130 ml of water, filtered, washed with 500 ml of methylene chloride and then 3 times with 500 ml of a methylene chloride/methanol solution (9-1). After evaporation to dryness, 100 g (orange solid) were recovered and 500 ml of methylene chloride/methanol (9-2) were added. The insoluble white product was filtered off and the organic phase was evaporated to dryness to obtain 46.55 g of product (orange-yellow powder) which was purified on a silica column with methanol/methylene chloride (5-95) as eluant to obtain 32.49 g of the expected product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][CH:12]=[CH:13][CH:14]=2)=[C:6]([F:15])[C:5]=1[F:16])[CH3:2].[Li][CH2:18]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH3:18])=[CH:13][CH:14]=2)=[C:6]([F:15])[C:5]=1[F:16])[CH3:2]
Reactant: CCOc1ccc(-c2ccc[se]2)c(F)c1F
Reactant: [Li]CCCC
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: CCOc1ccc(-c2ccc(C)[se]2)c(F)c1F
Temperature: -70 °C
Reaction time: 22 h

Procedure:
6.25 g (20.7 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)selenophene are initially introduced in 50 ml of diethyl ether, and 16.9 ml (26.9 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −70° C. 7.0 ml (0.11 mol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 22 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1→5:1). The further purification is carried out by recrystallisation from n-heptane; 2-(4-ethoxy-2,3-difluorophenyl)-5-methylselenophene is obtained as a colourless solid (m.p. 76° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:28][C@H:27]([CH2:29]O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[CH:9][N:8]([C@@H:25]3[CH2:26][C@H:27]([CH2:29][N:54]4[C:50](=[O:60])[C:51]5[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=5)[C:53]4=[O:55])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3.5 g (8.74 mmol) of cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl)methanol, which is prepared as described in Example 47(b) of WO 97/28161, in 70 ml of dry THF are added under argon 2.75 g (10.5 mmol) of triphenylphosphine and 1.54 g (10.5 mmol) of phthalimide; 1.9 g (1.71 ml; 10.5 mmol) of diethyl azodicarboxylate (96%) are added dropwise thereto. After stirring for 16 h at RT, the solution is concentrated to dryness and the crude compound is purified by flash-chromatography (ethylacetate) to provide cis-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}isoindole-1,3-dione. Analytical HPLC: tR=11.96 min (Grad 1); ES-MS: m/eo=529.9.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([OH:27])[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[C:10](=[O:28])[CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCCC1.C(OCC)(=O)C>[ClH:29].[OH:27][C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[O:28])[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][N:22]=2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(O)CCN(c3ccncn3)CC2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CNCCN1CC1(O)CCN(c2ccncn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-1-[4-hydroxy-1-(4-pyrimidinyl)piperidin-4-ylmethyl]piperazin-2-one (516 mg) in tetrahydrofuran (4 ml) was added a solution of 4N hydrochloric acid in ethyl acetate (4 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated, and the residue was crystallized from tetrahydrofuran to give colorless crystals of 1-[4-hydroxy-1-(4-pyrimidinyl)piperidin-4-ylmethyl]piperazin-2-one hydrochloride (435 mg).
Reaction SMILES: [NH4+].[Cl-].[Br:3][C:4]1[O:12][C:11]2[CH:10]=[CH:9][N:8]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([CH3:22])[CH:14]=3)[C:7](=[O:23])[C:6]=2[CH:5]=1>[Fe].CCO.O>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[CH:9]=[CH:10][C:11]3[O:12][C:4]([Br:3])=[CH:5][C:6]=3[C:7]2=[O:23])=[CH:14][C:15]=1[CH3:22]
Reactant: Cc1cc(-n2ccc3oc(Br)cc3c2=O)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1cc(-n2ccc3oc(Br)cc3c2=O)ccc1N
Yield: 97.2 %

Procedure:
Fe powder (1.30 g, 23.2 mmol) and NH4Cl (69 mg, 1.3 mmol) were added to a suspension of 2-bromo-5-(3-methyl-4-nitrophenyl)furo[3,2-c]pyridin-4(5H)-one (896 mg, 2.58 mmol) in 4:1 EtOH/H2O (60 mL) and the resulting suspension was heated at reflux for 14 h. The suspension was filtered through Celite, while warm, and the filtrate was concentrated to afford 800 mg of crude 5-(4-amino-3-methylphenyl)-2-bromofuro[3,2-c]pyridin-4(5H)-one as a yellow solid.