Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Br[CH2:13][CH3:14].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:13][CH3:14])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCBr
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)Cc1ccc(Cl)cc1
Reaction time: 18 h
Yield: 623.3 %

Procedure:
A solution of 25 grams (0.147 mole) of 4-chlorophenylacetic acid in 250 ml of acetonitrile was stirred and 15.0 grams (0.0147 mole) of bromoethane, followed by 22.0 grams (0.147 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene, were added. Upon completion of addition the reaction mixture was cooled in a water bath while being stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to one-half volume and then was added to 50 ml of water. The mixture was extracted with two portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 18.2 grams of ethyl (4-chlorophenyl)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11](=[O:24])[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:31]1(=O)[O:36][C:34](=[O:35])[CH2:33][CH2:32]1>CN(C)C=O>[CH2:17]([N:12]1[C:13](=[O:16])[C:14]2[NH:15][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([N:1]4[C:34](=[O:35])[CH2:33][CH2:32][C:31]4=[O:36])=[CH:30][CH:29]=3)=[N:8][C:9]=2[N:10]([CH2:25][CH2:26][CH2:27][CH3:28])[C:11]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1CCC(=O)O1
Reactant: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Solvent: CN(C)C=O
Product: CCCCn1c(=O)n(Cc2ccccc2)c(=O)c2[nH]c(Cc3ccc(N4C(=O)CCC4=O)cc3)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 36 %

Procedure:
To a solution of 8-(4-amino-benzyl)-1-benzyl-3-butyl-3,7-dihydro-purine-2,6-dione (60 mg) (prepared as described in example 64) in N,N-dimethylformamide (2 mL) was added succinic anhydride (Aldrich) (20 mg) and the mixture stirred at RT under argon for 48 h. The reaction mixture was concentrated in vacuo and acetyl chloride (Aldrich) (2 mL) added to the residue. After stirring at RT for an additional 70 h saturated aqueous sodium bicarbonate (5 mL) was added cautiously to the reaction mixture. The mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purified by crystallization from methanol/water to give the desired product as a pale yellow solid (36%). Mp=208–212° C. MS, m/z(M+)=485.2064.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].[BH4-].[Na+].CO>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)CN
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)CNCc1ccc(F)cc1
Reaction time: 18 h
Yield: 75.7 %

Procedure:
A mixture of 4-fluorobenzaldehyde (6.0 mL, 55.93 mmol), and isobutylamine (3.72 g, 50.85 mmol) in toluene (30 mL) was heated at reflux using Dean-Stark apparatus of 5 hours. The mixture was stood at ambient temperature for 18 hours then cooled in an ice-bath. Sodium borohydride (2.89 g, 76.28 mmol) was added followed by MeOH (5 mL). After 1 hour at 0° C. the reaction was quenched with 1M HCl, basified with a saturated solution of NaHCO3 and extracted into EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-10% MeOH in DCM) afforded the title compound (6.98 g, 76%) as a colourless oil. 1H NMR (300 MHz, CDCl3) δ 7.28 (m, 2H), 7.00 (m, 2H), 3.74 (s, 2H), 2.42 (d, J=6.8 Hz, 2H), 1.76 (m, 1H), 0.91 (d, J=6.6 Hz, 6H).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1
Reactant: Fc1ncccc1-c1ccncc1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncccc2-c2ccncc2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 2-fluoro-3-(pyridin-4-yl)pyridine (1.0080 g, 5.787 mmol), 4-aminophenol (0.7102 g, 5.793 mmol), and cesium carbonate (2.387 g, 6.945 mmol) in dimethyl sulfoxide at 90° C. The reaction was monitored by LCMS to completion. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (3×10 mL), satd sodium chloride solution (3×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (40M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 4-(3-(pyridin-4-yl)pyridin-2-yloxy)benzenamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C>C1COCC1>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1)=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCN
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(NCCCCCCCCCCNC(=O)OC(C)(C)C)nc(OCC(F)(F)F)n2)cc1
Temperature: 70 °C
Yield: 67.7 %

Procedure:
To a suspension of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (600 mg) in THF (20 mL) was added tert-butyl 10-aminodecylcarbamate (451 mg) and iPr2NEt (0.578 mL). The mixture was heated at 70° C. for 16 hours. The solvent was removed under vacuum. The residue was purified by silica gel column (EtOAC/Hexanes=4:1) to give methyl 4-(4-(10-(tert-butoxycarbonylamino)decylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.67 g).
Reaction SMILES: CO.[NH:3]1[C:7](=[O:8])[CH2:6][CH2:5][C@H:4]1[C:9]([OH:11])=[O:10].OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Na+].[Na+].[C:24]([O-])(O)=O.[Na+]>>[CH3:24][O:10][C:9](=[O:11])[C@@H:4]1[CH2:5][CH2:6][C:7](=[O:8])[NH:3]1
Reactant: O=C([O-])O
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
Methanol (62 L, 1.155 mol), L-pyroglutamic acid (20 kg, 154.9 mol) and H2SO4 (97%, 0.87 L, 15.5 mol) were introduced into a reactor. The suspension was warmed to 60° C. and stirred until the pyroglutamic acid concentration dropped below 10%. The temperature of the reactor jacket was lowered to 0° C., and when the internal temperature reached 30° C., 9.7 kg (68.1 mol) of Na2SO4 was added and stirred for 15 min, then 8.1 kg (96.4 mol) of NaHCO3 was added. When pH 7 was reached (about 10 min), the suspension was filtered over a pad of celite. The filtrate was reintroduced into the reactor, and the methanol was distilled off at a pressure of 90-160 mbar and a jacket temperature of 50° C. Ethyl acetate (53 L) was then added with stirring, the mixture cooled to 0° C., and the mixture stirred for 16 hr. Unreacted pyroglutamic acid crystallized out and was removed by filtration. Removal of the ethyl acetate by evaporation under reduced pressure provided the title product as a viscous yellow oil, which was taken to the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[O:17][CH3:18].[N+:19]([O-])([OH:21])=[O:20]>ClCCl.C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([N+:19]([O-:21])=[O:20])[C:7]=1[O:17][CH3:18]
Reactant: CCOC(=O)c1ccc(OCCCCl)c(OC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OCCCCl)c(OC)c1[N+](=O)[O-]
Yield: 82 %

Procedure:
WO 02/36587 describes a process for preparing a 5-alkoxy-4-halogenoalkoxy-2-nitrobenzoic acid compound from a 3-alkoxy-4-hydroxybenzoic acid compound. For example, ethyl vanillate (i.e., ethyl 4-hydroxy-3-methoxybenzoate) is reacted with 3-bromo-1-chloropropane in an aqueous potassium carbonate solution in the presence of N-butyl-ammonium bromide to produce ethyl 4-(3-chloropropoxy)-3-methoxybenzoate, and the ethyl 4-(3-chloropropoxy)-3-methoxybenzoate is reacted with 70% nitric acid in a mixture of dichloromethane and acetic acid, to give ethyl 4-chloropropoxy-3-methoxy-2-nitrobenzoate in 82% yield (based on the amount of ethyl vanillate).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=O)[CH3:25])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)CCc1ccc(Cl)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-chloro-phenyl)-butan-2-one.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:20][C:21]1[N:30]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:22]=1>>[NH2:30][C:21]1[N:22]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[CH2:6][C:5]=2[N:20]=1
Reactant: COc1ccccc1C1CC(=O)C(C(C)=O)C(=O)C1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Product: COc1ccccc1C1CC(=O)c2c(C)nc(N)nc2C1

Procedure:
The title compound was prepared from 2-acetyl-5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (872 mg, 3.35 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3) except that the title compound was further purified by recrystallisation in methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[N:13]([O-])=O.[Na+]>C(O)(=O)C.[OH-].[NH4+]>[CH3:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1)[NH:9][N:13]=[CH:8]2
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Reactant: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])c2[nH]ncc2c1
Reaction time: 12 h
Yield: 8.8 %

Procedure:
4,6-Dimethyl-2-nitro-phenylamine (10.6 g, 64.08 mmol) prepared in Step A was dissolved in acetic acid (150 mL). Sodium nitrite (5.3 g, 76.90 mmol) was added in drops thereto, and the mixture was stirred for 12 h. After completion of the reaction, the reaction mixture was diluted with ammonium hydroxide, extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (1.0 g, Yield 9%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([OH:12])=O)=[CH:2]1.C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]([Cl:16])=[O:12])=[CH:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1coc2ccccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1coc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzofuran-3-carboxylic acid (1.00 g, 6.17 mmol) was suspended in methylene chloride (20 mL), and oxalyl chloride (1.08 mL, 12.34 mmol) was added dropwise. To this reaction liquor, a catalytic amount of DMF (one drop) was added, and the reaction liquor was stirred for one hour at room temperature. The solvent was distilled off under reduced pressure, to obtain benzofuran-3-carboxylic acid chloride as a solid. The obtained acid chloride was suspended in 1,2-dichloroethane (20 mL), and (4-amino-3-chlorophenyl)acetic acid ethyl ester hydrochloride (1.54 g, 6.17 mmol) was added. The mixture was heated and stirred for 20 hours. The mixture was left to cool naturally to room temperature, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by flash column chromatography (Flash Chromatography System from Biotage AB, column size: 40S, elution solvent: n-hexane:ethyl acetate=95:5 to 75:25), to obtain the title compound (2.08 g, 94%) as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:6].NC(N)=O.[N+:19]([O-])([O-:21])=[O:20].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][CH2:3][CH2:4][N:5]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=1)[CH3:6]
Reactant: COCCN(C)c1ccc(OC)cc1
Reactant: O=[N+]([O-])[O-]
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COCCN(C)c1ccc(OC)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
To a stirred solution of 600 mg (3.07 mmol) (2-methoxy-ethyl)-(4-methoxy-phenyl)-methyl-amine in 1.3 ml concentrated sulfuric acid at room temperature was added 222 mg (3.69 mmol) urea. After stirring for 1 h at room temperature, a solution of 342 mg (3.38 mmol) potassium nitrate in 0.6 ml concentrated sulfuric acid was added dropwise and stirring continued for a further 16 h. The mixture was then poured onto water amd extracted five times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/9 ethyl acetate/hexane) afforded 260 mg (35%) (2-methoxy-ethyl)-(4-methoxy-3-nitro-phenyl)-methyl-amine as an orange oil. ES-MS m/e (%): 241 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.F[C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[C:14]([C:13]1[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=1[O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)#[N:15]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: N#Cc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccccc1Oc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of 4-hydroxybenzoic acid (7 g, 50 mmol) and 2-fluorobenzonitrile (7.36 g, 60 mmol) in dimethylsulfoxide (40 mL) was added potassium carbonate (20 g, 150 mmol). The reaction mixture was stirred at 120° C. for 4 hours. After the reaction, the temperature was allowed to cool to room temperature, then the mixture was poured into ice water (100 mL). The mixture was neutralized to pH=3 with concentrated hydrochloric acid and then extracted with ethyl acetate (15 mL×3). The combined organic phase was dried by sodium sulfate, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give 4-(2-cyanophenoxy)benzoic acid as a white solid (5.80 g, 48.5%). LRMS (M+H)− m/z: calcd 239.06. found 239. 1H NMR (300 MHz, d6-DMSO): δ 12.94 (s, 1H), 7.99-7.91 (m, 3H), 7.71 (t, J=8.4 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.17-7.14 (m, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](Cl)=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)[C:2]#[C:3][CH3:4].[OH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(O)C>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:9][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(C)c(=O)c21
Reactant: CCOC(=O)CO
Solvent: CCO
Product: CC#CCn1c(N2CCNCC2)nc2nc(OCC(=O)OCC)n(C)c(=O)c21

Procedure:
Ethyl [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetate trifluoroacetate and [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetic acid trifluoroacetate [MS m/e (ESI) 361 (MH+-CF3COOH)] were obtained by treating t-butyl 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate using ethyl 2-hydroxyacetate, instead of ethanol, by the same method as used in Example 11. Ethyl [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetate trifluoroacetate was purified by chromatography using NH-silica gel. Thus, ethyl [7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetate [1H-NMR (CDCl3) δ 1.29 (t, J=7.22 Hz, 3H) 1.83 (t, J=2.4 Hz, 3H) 3.02-3.06 (m, 4H) 3.38-3.41 (m, 4H) 3.55 (s, 3H) 4.22 (q, J=7.2 Hz, 2H) 4.90 (q, J=2.4 Hz, 2H) 5.03 (s, 2H); MS m/e (ESI) 389 (MH+)] was obtained from the fraction eluted with ethyl acetate-methanol (20:1)
Reaction SMILES: [C:1]([S:20][CH2:21][C@@H:22]([C:24]([NH2:26])=[O:25])[NH2:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([S:48](Cl)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([NH:23][C@H:22]([C:24]([NH2:26])=[O:25])[CH2:21][S:20][C:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1
Reactant: NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccc(S(=O)(=O)N[C@@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Part C: To a solution of 2.93 grams (8.1 mmol) of S-trityl-L-cysteine amide in 50 mL of dry methylene chloride was added 2 equivalents of triethylamine followed by 2.29 grams (8.1 mmol) of 4-(4′-methoxyphenyl)phenylsulfonyl chloride. The solution was stirred at room temperature for one hour, then concentrated on a rotory evaporator. The resulting slurry was partitioned between ethyl acetate and water. The organics were washed with 5% potassium hydrogen sulfate, saturated sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to give 4.2 grams of crude product. The crude material was purified by silica gel chromatography using 1:1 ethyl acetate:hexane as the eluent to yield 3.36 grams of pure N-(4-(4′methoxyphenyl)-benzenesulfonyl-S-trityl-L-cysteine amide as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C@H:11]1[CH2:30][C@@:29]2([CH3:31])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13][C@@H:12]1[OH:34])=[O:4].[I-:35].[Na+]>CC(C)=O>[OH:34][C@@H:12]1[C@@H:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:3](=[O:4])[CH2:2][I:35])[CH2:30][C@@:29]2([CH3:31])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:28]2[C:27](=[O:32])[CH2:26][C@@:25]2([CH3:33])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C:22](=[O:24])[CH3:23])[CH2:13]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCOC(=O)CCl)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCCCOC(=O)CI)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Yield: 87.7 %

Procedure:
2β-(4'-Chloroacetoxy-n-butoxy)-3α-hydroxy-5α-pregnane-11,20-dione (450 mg.) was dissolved in acetone (30 ml.) and sodium iodide (460 mg.) added to this solution. The mixture was refluxed for 1 hour, a white precipitate forming in this time. The mixture was filtered and the filtrate evaporated to a yellowish solid which was partitioned between ether and water. The ethereal solution was dried over anhydrous sodium sulphate and evaporated in vacuo to give the title compound (467 mg.) as a pale yellow foam which almost immediately collapsed to a gun. This unstable product was used immediately for the following Examples 50 and 51
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 29; the configuration of the stereocenter is arbitrarily assigned) and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 7. LC (method 4): tR=1.02 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[Li]CCCC.CON(C)[C:30](=[O:34])[CH2:31][CH2:32][CH3:33]>C1COCC1>[Si:15]([O:14][CH:13]1[C:6]2=[CH:5][C:4]3[CH:3]=[C:2]([C:30](=[O:34])[CH2:31][CH2:32][CH3:33])[CH:10]=[CH:9][C:8]=3[N:7]2[CH2:11][CH2:12]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CCCC(=O)N(C)OC
Reactant: CC(C)(C)[Si](C)(C)OC1CCn2c1cc1cc(Br)ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc2c(c1)cc1n2CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a solution of 7-bromo-1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indole (4.1 g, 11.2 mmol) in THF (60 mL), cooled to −78° C., was added n-BuLi (7.7 mL, 1.6M, 12.3 mmol) dropwise. The reaction mixture was allowed to stir at −78° C. for 5 minutes before N-methoxy-N-methylbutyramide (1.6 g, 12.3 mmol) was added. The resulting orange solution was allowed to slowly warm to room temperature then quenched with the addition of a saturated solution of NH4Cl. The reaction mixture was poured into H2O (100 mL) and extracted with Et2O (2×100 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound as a white solid (4.0 g, 99%).