Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]([N:22]3[C:26](=[O:27])[C@@H:25]([CH2:28][C:29]([OH:31])=O)[NH:24][C:23]3=[O:32])[C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:33]([O:35][CH2:36][CH2:37][O:38][NH2:39])=[CH2:34].C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C@@H:13]([N:22]3[C:26](=[O:27])[C@@H:25]([CH2:28][C:29]([NH:39][O:38][CH2:37][CH2:36][O:35][CH:33]=[CH2:34])=[O:31])[NH:24][C:23]3=[O:32])[C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccccc1)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CC(=O)O)C1=O
Reactant: C=COCCON
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)C[C@H]1NC(=O)N([C@H](c2ncc(-c3ccc(I)cc3)[nH]2)[C@@H](C)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of ((R)-1-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2,5-dioxo-imidazolidin-4-yl)-acetic acid; hydrochloride salt (114 mg, 0.21 mmol) (prepared as described in example 8), O-(2-vinyloxy-ethyl)-hydroxylamine (26 mg, 0.25 mmol) (prepared as described in WO 02/06213) and N,N-diisopropylethyl amine (0.11 mL, 0.63 mmol) in N,N-dimethylformamide (2 mL) was added O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uronium hexafluororophosphate (110 mg, 0.25 mmol). The reaction mixture was stirred for 1 hour at room temperature then diluted with ethyl acetate and the organic layer washed successively with saturated aqueous sodium carbonate then brine, dried over sodium sulfate, filtered, concentrated and the residue purified by chromatography over silica gel eluted with ethyl acetate to give 2-((R)-1-{(1S,2S)-1-[5-(4-iodo-phenyl)-1H-imidazol-2-yl]-2-phenyl-propyl}-2,5-dioxo-imidazolidin-4-yl)-N-(2-vinyloxy-ethoxy)-acetamide (81 mg, 61%) as a solid. LC-MS: calcd for C27H28IN5O5 [M+H+] 630. Found 630.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][NH:13][C:11]=3[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].S(OCC)(O[CH2:31][CH3:32])(=O)=O>C(O)(=O)C>[N:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:31][CH3:32])[C:11]=3[N:12]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1c[nH]c2nc(N3CCNCC3)ncc2c1=O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21

Procedure:
To a solution of 1.5 g of 5,8-dihydro-2-(1-piperazinyl)- 5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in 60 ml of a 10% aqueous solution of sodium carbonate was added three 10 ml portions of diethyl sulfate. After completion of the reaction, the resulting mixture was neutralized with acetic acid. The precipitate was collected and recrystallized from dimethylformamide to give 0.8 g of 2-(1-piperazinyl)-5,8-dihydro-8-ethyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (compound 1) m.p. 253° - 255°C. Concentration of the mother liquor to about a half volume gave another solid which was further recrystallized from the same solvent to give 0.6 g of 2-(4-ethyl-1-piperazinyl)-5,8-dihydro-8-ethyl-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (compound 21), m.p. 228° - 230°C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:7].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[O:7]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH2:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:34][CH2:35]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1
Reactant: O=C(CCCCCl)c1ccccc1C(F)(F)F
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccccc1C(F)(F)F

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-[2-(trifluoromethyl)phenyl]-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 473.2 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[C:6]([OH:13])(=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10].C(=O)=O>>[C:6]([O-:13])(=[O:12])/[CH:7]=[CH:8]\[C:9]([O-:11])=[O:10].[Ca+2:5]
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
A solution of maleic acid was prepared by adding 39.2 g of maleic anhydrideto 40 g of water and heating the mixture to 70° C. in a water bath to form a solution of maleic acid. A calcium carbonate filter cake (23.4 g, 0.248 mole calcium carbonate) and 1 g of calcium carbonate was added tothe maleic acid solution at 70° C. and heated for 50 min. Carbon dioxide was stripped off and calcium maleate was formed.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([CH:26]1[CH2:31][CH2:30][N:29]([C:14]([C:10]2[CH:11]=[N:12][O:13][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=2)=[O:16])[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 4-benzylpiperidine (10.5 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (13.4 mg). Calcd for C23H21F3N2O2: 414.1555, found 414.1544.
Reaction SMILES: [C:1]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].II.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C1C=CC=CC=1.BrCC(OCC)=O.Cl>C1C=CC=CC=1.[Zn]>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:1]([OH:3])([CH3:2])[C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5]1)[CH3:20]
Reactant: CCOC(=O)C1(C(C)=O)CC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)C1(C(=O)OCC)CC1
Yield: 95 %

Procedure:
A 61.7 g (0.39 mol) portion of ethyl 1-acetylcyclopropanecarboxylate was dissolved in 500 ml of benzene to which were subsequently added 13 g of zinc powder and a catalytically effective amount of iodine. While heating under reflux, a solution of 56.2 ml (0.51 mol) of ethyl bromoacetate in 100 ml of benzene was added dropwise to the mixture above. When the reaction started to progress, the dropwise addition was suspended, 39 g of zinc powder was added in small portions and then the remaining ethyl bromoacetate benzene solution was added dropwise. After completion of the addition, the reaction solution was heated under reflux for another 2 hours. The reaction solution was cooled spontaneously, mixed with 500 ml of 1N hydrochloric acid and then filtered through celite. The organic layer was separated, washed with saturated brine (500 ml×2) and then dried over anhydrous sodium sulfate. By evaporating the solvent, 90.31 g (95%) of the title compound was obtained as an oily substance.
Reaction SMILES: CS(O[CH2:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)(=O)=O.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.CCOCC>[N:12]([CH2:6][C:7]1([C:10]#[N:11])[CH2:9][CH2:8]1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1(C#N)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1(CN=[N+]=[N-])CC1
Temperature: 120 °C
Yield: 68.5 %

Procedure:
A stirred mixture of (1-cyanocyclopropyl)methyl methanesulfonate (21.52 mmol, 3.77 g) and sodium azide (43.0 mmol, 2.80 g) in N,N-dimethyl formamide (40 mL) was heated to 120° C. for ˜18 hours. The mixture was allowed to cool and was diluted with water and ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to give an oil. This oil was taken up in ether and washed with water, dried and concentrated under reduced pressure to give the intermediate 1-(azidomethyl)cyclopropanecarbonitrile (1.8 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]([CH3:15])[CH2:11][C@@H:12](O)[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@H:12]([CH3:13])[CH2:11][N:10]([CH3:15])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN(C)C
Reactant: Oc1ccc(Br)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@H](CN(C)C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromophenol (0.2 g, 1.16 mmol) and (S)-(+)-1-dimethylamino-2-propanol (0.14 ml, 1.16 mmol) were dissolved in dichloromethane (10 ml). PS-Triphenylphospine (1.74 g, 1.74 mmol) was added, followed by di-tert-butyl azodicarboxylate (0.4 g, 1.74 mmol). The mixture was stirred overnight at room temperature, then filtered and the filtrate washed with sodium hydrogenocarbonate then brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the desired product. Yield: 0.3 g, 100%. LCMS method: 2, RT: 2.62 min; MI: 258-260 [M+1].
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:12]2[CH:13]=[CH:14][C:10]([Cl:9])=[N:11]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: Clc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccn(-c2ncccc2Cl)n1
Temperature: 100 °C

Procedure:
To a mixture of 2,3-dichloropyridine (92.60 g, 0.629 mol) and 3-chloropyrazole (i.e. the product of Step B) (64.44 g, 0.629 mol) in N,N-dimethylformamide (400 mL) was added potassium carbonate (147.78 g, 1.06 mol), and the reaction mixture was then heated to 100° C. for 36 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water. The precipitated solids were filtered and washed with water. The solid filter cake was taken up in ethyl acetate, dried over magnesium sulfate and concentrated. The crude solid was chromatographed on silica gel using 20% ethyl acetate/hexane as eluent to afford the title product as a white solid (39.75 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([O:19]C)=[O:18].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([OH:19])=[O:18]
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2ccc(F)cc2F)CC(=O)N1
Temperature: 60 °C
Yield: 50.4 %

Procedure:
The product from Step 1 (600 mg, 2.13 mmol) was dissolved in methanol (15 mL), and NaOH (5 mL, 2.5 M) was added. This reaction mixture was heated to 60° C. for 18 h. The reaction mixture was concentrated, and then poured into EtOAc (20 mL) and water (5 mL). The aqueous layer was acidified to pH<3 by adding 6N HCl solution, and then extracted with EtOAc (50 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was triturated with 5% ether/hexanes to afford the title compound (287 mg, 50%). MS (ES+) m/e 268 [M+H]+.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]([C:13]2[CH:18]=[N:17][CH:16]=[N:15][CH:14]=2)[CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(C(F)(F)F)cc2)c2cncnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
To a suspension of 40 mg of sodium hydride in 2 ml of N,N-dimethylformamide was added 0.22 g of 5-[(4-nitrophenyl)amino]pyrimidine in small portions. After stirring at room temperature for 30 minutes, 0.24 g of 4-trifluoromethylbenzyl bromide was added thereto, followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to recover crude crystals from the chloroform eluate. Recrystallization of the crude crystals from a mixed solvent of ethyl acetate and ethyl ether yielded 0.19 g of 5-[N-(4-nitrophenyl)-N-(4trifluoromethylbenzyl)amino]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH2:12])=[C:5]2[C:4](=[O:13])[N:3]=1.C[O-].[Na+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+].Cl.N.C(O)C>CO>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][C:10]([CH2:11][NH:12][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:5]2[C:4](=[O:13])[N:3]=1
Reactant: O=Cc1ccccc1
Reactant: NCC1=C2C(=O)N=C(N)N=C2N=C1
Agent: C[O-]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Product: NC1=NC(=O)C2=C(CNCc3ccccc3)C=NC2=N1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
In 5 ml of methanol was dissolved 251 mg of 2-amino-5-aminomethylpyrrolo[2,3-d]pyrimidin-4-one (dihydrochloride). To this solution was added 396 mg of a 28% methanolic solution of sodium methoxide, and under stirring at room temperature, 106 mg of benzaldehyde and, then, 1 g of molecular sieve (Wako Pure Chemical Co. in Japan 3 A 1/16) were added. The mixture was stirred for 30 minutes, after which 25 mg of sodium borohydride was added. The mixture was further stirred at room temperature for 30 min., and 0.3 ml of concentrated HCl and, then, 5 ml of 5.4% ammonia-ethanol were added. The insolubles were filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give 214 mg of the desired compound.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH3:15])[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:14])=[O:13])=[CH:7][CH:6]=1.C([O:19][CH2:20][CH3:21])(=O)C>O1CCCC1>[CH3:15][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:13])[NH:14][C:21]2([NH:14][C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([CH3:15])=[CH:6][CH:7]=3)=[O:13])[C:9]3[C:8](=[CH:7][CH:6]=[CH:5][CH:10]=3)[NH:11][C:20]2=[O:19])=[CH:7][CH:6]=1
Reactant: Cc1ccc(NC(N)=O)cc1
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)NC2(NC(=O)Nc3ccc(C)cc3)C(=O)Nc3ccccc32)cc1
Yield: 36 %

Procedure:
To a solution of 12.0 g of anhydrous aluminum chloride in 150 ml of dry tetrahydrofuran were added successively a solution of 5.79 g of isatin-3,3-dimethylacetal in 150 ml of dry tetrahydrofuran and 9.0 g of p-tolylurea at 0° C. under a nitrogen atmosphere, and the mixture was heated under reflux for 40 minutes. Ethyl acetate was added to the reaction mixture, and the mixture was washed twice with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, followed by concentration. To the residue was added 150 ml of ethyl ether, and insoluble matter was removed by filtration. The filtrate was concentrated and recrystallized from acetone to yield 4.61 g (36%) of the title compound as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[CH:20][C:15]=3[C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])[CH2:9]1)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[NH2:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3[N:17]=[CH:18][N:19]=[CH:20][C:15]=3[C:14]([CH3:21])([CH3:22])[C:13]2=[O:23])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N2C(=O)C(C)(C)c3cncnc32)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2ncncc21
Yield: 86 %

Procedure:
To a solution of tert-butyl(trans-3-(5,5-dimethyl-2-(methylthio)-6-oxo-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate, INTERMEDIATE 63, (0.9 g, 2.378 mmol) in dry tetrahydrofuran (10 mL) was added cautiously palladium 10 wt. % on activated carbon (0.051 ml, 0.476 mmol) followed by triethylsilane (3.04 ml, 19.02 mmol). The mixture was stirred for 15 minutes under nitrogen atmosphere, filtered, and filtrate concentrated to give tert-butyl(trans-3-(5,5-dimethyl-6-oxo-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate. The crude tert-butyl(trans-3-(5,5-dimethyl-6-oxo-5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)cyclobutyl)carbamate was redissolved in dioxane (10 mL) and treated with 4N HCl in dioxane (10 mL). After 30 minutes the reaction mixture was evaporated to dryness under reduced pressure to give the desired crude product 7-(trans-3-aminocyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one hydrochloride (0.55 g, 2.047 mmol, 86% yield). The product was used in next step without further purification. m/z: 233.0 (M+1-HCl).
Reaction SMILES: N[C@H](C=O)CCSC.[C:9]([O:16][CH2:17][CH3:18])(=[O:15])[C:10]([O:12]CC)=O.[C:19]1(=[O:24])[O:23][CH2:22][CH2:21][CH2:20]1.Cl>C(O)C>[O:24]=[C:19]1[CH:20]([C:10](=[O:12])[C:9]([O:16][CH2:17][CH3:18])=[O:15])[CH2:21][CH2:22][O:23]1
Reactant: O=C1CCCO1
Reactant: CCOC(=O)C(=O)OCC
Agent: CSCC[C@H](N)C=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCOC1=O
Temperature: -12.5 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
Metal sodium in an amount of 25.80 g was added to 500 ml of dried ethanol and dissolved therein. Then, 148.21 g of diethyl oxalate were added, and the reaction system was chilled to −15 to −10° C. A solution of 88.79 g of γ-butyrolactone in 60 ml of ethanol was added dropwise to the mixture while maintaining this temperature, and after the resultant mixture was stirred for 2 hours, it was stirred at room temperature for 16 hours. The reaction mixture was poured into 1 liter of ice water, and the pH of the mixture was then adjusted to 4 to 5 with concentrated hydrochloric acid, and the mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product thus obtained was distilled under reduced pressure to give a fraction of 150 to 160° C. (5-6 mmHg) as the intended product. Pale yellow liquid, 156.21 g (yield: 83.1%).
Reaction SMILES: N1CCOCC1.C([Li])CCC.Br[C:13]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH2:24][CH3:25])=[CH:17][C:14]=1[CH:15]=[O:16].[F:26]NS(C1C=CC=CC=1)(=O)=O.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[CH2:24]([O:23][C:18]1[C:19]([O:21][CH3:22])=[CH:20][C:13]([F:26])=[C:14]([CH:17]=1)[CH:15]=[O:16])[CH3:25]
Reactant: CCOc1cc(C=O)c(Br)cc1OC
Reactant: O=S(=O)(NF)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1cc(C=O)c(F)cc1OC
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 2.62 ml of morpholine in 50 ml of THF there was added 11.2 ml of n-butyllithium (2.71 M, hexane solution) at −78° C. under a nitrogen atmosphere, and the mixture was stirred at −40° C. for 30 minutes. To this solution there was added dropwise a solution of 6.5 g of 2-bromo-5-ethoxy-4-methoxybenzaldehyde [CAS No. 56517-30-7] in 40 ml of THF at −78° C., and the mixture was stirred at −78° C. for 1 hour. After further adding 14.8 ml of n-butyllithium (2.71 M, hexane solution) at −78° C., the mixture was stirred at −78° C. for 40 minutes, and then a solution of 15.8 g of N-fluorobenzenesulfonamide in 40 ml of THF was added dropwise at −78° C. and the mixture was stirred overnight while raising the temperature to room temperature. Saturated aqueous ammonium chloride was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (3.33 g) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:26](=[O:28])[CH3:27])[CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:27][C:26]([C:18]2[CH:19]=[C:20]([O:24][CH3:25])[C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=2)=[O:28])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Product: COc1cc(C(=O)C=Cc2cc(O)c(O)c([N+](=O)[O-])c2)cc(OC)c1OC

Procedure:
The procedure described in Example 8 was repeated using 0.55 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 0.63 g of 3',4',5'-trimethoxyacetophenone. Yield 0.50 g (44%), m.p. 213°-216° C.
Reaction SMILES: C([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)C.Br[CH2:42][CH2:43][CH2:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4][CH2:42][CH2:43][CH2:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:18]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CCC(CC)(CCCBr)O[Si](CC)(CC)CC
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(CCCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To a solution of 17-acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (274 mg, 0.454 mmol) and 1-bromo-4-ethyl-4-(triethylsilyloxy)hexane (294 mg, 0.909 mmol) in tetrahydrofuran (2 ml), was added a 1M potassium hydroxide methanol solution (3 ml) under a nitrogen atmosphere, followed by stirring at room temperature for 5 min. The thus obtained reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was purified by column chromatography (hexane:toluene=6:1) to give the titled compound (333 mg, 91%) as a colorless oil.