Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=O.COCCO[AlH2-]OCCOC.[Na+].O.Cl>C1(C)C=CC=CC=1>[CH2:25]([CH:22]1[CH2:21][CH2:20][CH:19]([CH:18]=[CH:17][C:14]2[CH:13]=[CH:12][C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH:3]=[O:2])[CH2:10][CH2:9]3)=[CH:16][CH:15]=2)[CH2:24][CH2:23]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC1CCC(C=Cc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(C=Cc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Temperature: -40 °C

Procedure:
Vitride (3.3M in toluene, 10 eq, 26.6 ml, 87.7 mmol) was added with syringe to a flask filled with Argon gas at 0° C., and morpholine (10 eq, 7.67 ml, 87.7 mmol) was added slowly dropwise with syringe. Then, toluene (a half of morpholine mmol, 44 ml) was added dropwise with syringe to produce vitride solution. 88 ml of a solution including cyclohexane carboxylate compound (3.48 g, 8.77 mmol) obtained in Example 4-1 in toluene a solution was added to another 2-neck flask filled with argon gas, and vitride solution was added slowly dropwise at −70° C. for 30 minutes. Then, the solution was stirred with maintaining −30 to −50° C. for 6 hours and water was added very slowly dropwise to the flask. 1M HCl was slowly added to the flask to neutralize the reaction solution. White precipitate was filtered under reduced pressure and the filtrate was extracted by toluene (20 ml×three times). The organic layer was collected, washed by distilled water (10 ml×two times), dried with anhydrous Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane:ether=5:1, Rf=0.32) to produce 1.77 g (55%) of trans-4-{4-[2-(4-pentylcyclohexyl)ethenyl]phenyl}cyclohexane carbaldehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]([CH3:12])=[CH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8]
Reactant: CC(C)=Cc1cccc(C#N)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=Cc1cccc(CN)c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
3-(2-Methylpropenyl)benzonitrile described in Preparation Example 136 (0.44 g, 2.8 mmol) was dissolved in tetrahydrofuran (5 mL), lithium aluminum hydride (0.16 g, 4.2 mmol) was added under stirring at room temperature, the solution was heated to 70° C., followed by stirring for 2 hours. The reaction solution was cooled on an ice bath, then, water (0.16 mL), an aqueous solution of 15% sodium hydroxide (0.16 mL) and water (0.48 mL) were sequentially added, then, the solid was filtered, and washed with tetrahydrofuran (10 mL). The filtrate and the washings were combined, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo, and the title compound (0.40 g, 2.48 mmol, 88.7%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([NH2:11])[N:3]=1.Cl.[CH3:13]O>>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:13])=[O:9])[CH:5]=[C:4]([NH2:11])[N:3]=1
Reactant: Nc1cc(C(=O)O)nc(N)n1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(N)nc(N)n1
Yield: 100 %

Procedure:
2,6-diamino pyrimidine-4-carboxylic acid (G. D. Davies, F. Baiocchi, R. K. Robins and C. C. Cheng, J. Org Chem 26 (1961) 2755-2759) was esterified with HCl/MeOH using the procedure of Preparation 4, step (a) in 100% yield. 1HNMR δ(DMSO) 3.90(3H,s), 6.72 (1H,s), 8.57 (broad), 8.93 (broad).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].C(OCC)C.[BH4-].[Na+].Cl>CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C@H:15]3[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(-c2ccc(C3CCC(=O)CC3)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: N#Cc1ccc(-c2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Reaction time: 3 h

Procedure:
A suspension of 10 g of 4-(4'-cyano-4-biphenylyl)cyclohexanone, 30 ml of diethyl ether and 270 ml of methanol was treated portionwise at 0° C. with 1.8 g of sodium borohydride. After 3 hours the reaction mixture was made acid (pH 1-2) with 25% hydrochloric acid. The reaction mixture was extracted three times with 50 ml of dichloromethane each time. The combined organic phases were washed twice with 500 ml of water each time and subsequently dried over magnesium sulfate, filtered and concentrated. Recrystallization from methanol gave 3.5 g of trans-4-(4'-cyano-4-biphenylyl)cyclohexanol.
Reaction SMILES: O1CCCC1.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C([Li])CCC.[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]=[O:21]>CCCCCC>[F:17][C:18]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:19]=1[CH:20]([OH:21])[C:7]1[S:8][CH:9]=[CH:10][N:11]=1
Reactant: O=Cc1cc(F)ccc1F
Reactant: Brc1nccs1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1nccs1)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (10 ml) solution of 2-bromothiazole (180 μg, 2 mmol) was added dropwise a hexane solution of n-butyl lithium (1.57M, 1.40 ml, 2.2 mmol) at −78° C. After stirring for 10 minutes, 2,5-difluorobenzaldehyde (238 μl, 2.2 mmol) was added and while stirring, the temperature of the mixture was gradually raised to 0° C. The reaction was then quenched by the addition of an aqueous solution of ammonium chloride, followed by the addition of ether. The ether layer was washed with water and brine, and then, dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1), whereby the title compound (358 mg, 79%) was obtained as an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:18])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([O:16]C)=[O:15])[S:11][C:12]=1[CH3:13])[CH3:2].[OH-].[Na+]>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:18])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([OH:16])=[O:15])[S:11][C:12]=1[CH3:13])[CH3:2]
Reactant: CCc1cnn(C)c1-c1cc(C(=O)OC)sc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cnn(C)c1-c1cc(C(=O)O)sc1C
Yield: 100 %

Procedure:
A solution of methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (145 mg, 0.55 mmol) in 6N sodium hydroxide (1.8 ml, 10.97 mmol) and tetrahydrofuran (4.8 ml) was stirred at 60° C. in a sealed tube for 12 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (137 mg, 0.55 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 250 (M+H)+.
Reaction SMILES: [P:1]([O:16][C:17]1C=CC=C[CH:18]=1)([O:9][C:10]1C=CC=C[CH:11]=1)[O:2][C:3]1C=CC=C[CH:4]=1.P(OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)(OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C)OC1C=CC(C(C)(C)C)=CC=1C(C)(C)C>>[P:1]([O:16][CH2:17][CH3:18])([O:9][CH2:10][CH3:11])[O:2][CH2:3][CH3:4]
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Agent: CC(C)(C)c1ccc(OP(Oc2ccc(C(C)(C)C)cc2C(C)(C)C)Oc2ccc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Product: CCOP(OCC)OCC

Procedure:
(PhO)3P, diphenylmono(2-ethylhexyl) phosphite: (PhO)2(MeC3H6CH(Et)CH2O)P, tris(2,4-di-tert-butylphenyl) phosphite:
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1.[Br:32][C:33]1[C:41]([C:42]#[N:43])=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][C@@H:37]2O.C(P(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:31])[CH2:20][C@H:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][C@H:37]3[C:38]4[C:34](=[C:33]([Br:32])[C:41]([C:42]#[N:43])=[CH:40][CH:39]=4)[CH2:35][CH2:36]3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: N#Cc1ccc2c(c1Br)CC[C@@H]2O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reaction time: 0.5 h

Procedure:
A solution of di-tert-butyl azodicarboxylate (3.30 g) in tetrahydrofuran (5 mL) is added dropwise over 45 min to a solution of (S)-(6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (for preparation see WO 2008001931; 2.10 g), (S)-4-bromo-1-hydroxy-indan-5-carbonitrile (2.40 g) and tri-n-butyl-phosphine (3.8 mL) in tetrahydrofuran (25 mL) at −10° C. The resulting solution is stirred for 30 min and then diluted with ethyl acetate. The resulting solution is washed with water and brine and dried (MgSO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→70:30) to give the title compound. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=428/430 (Br) [M+H]+.
Reaction SMILES: N[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([CH3:10])[N:3]=1.[BrH:11].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:11][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1nc(N)c(Cl)cc1Cl
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Br)c(Cl)cc1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
2-Amino-3,5-dichloro-6-methylpyridine (3.54 g, 20 mmol) was suspended in aqueous 48% HBr solution at rt and the mixture was cooled to −20° C. This suspension was maintained at −20° C. while bromine (2.87 mL, 56 mmol) was added dropwise. The resultant paste was stirred for 30 minutes at this temperature before the dropwise addition of a cooled solution of sodium nitrite (3.59 g, 52 mmol) in water (5 mL). At this point the reaction mixture was allowed to warm to rt. After stirring for a further 60 minutes, the mixture was again cooled to −20° C. and treated with a solution of sodium hydroxide (16 g, 0.4 mol) in water (20 mL). This mixture was extracted with ethyl acetate and the organic layer washed with water and then brine solution. The organic solution was dried over MgSO4, filtered and the residue obtained from solvent evaporation was purified using silica gel chromatography [eluent: 10% ethyl acetate in hexane]. 2-Bromo-3,5-dichloro-6-methylpyridine 1-4 (2.14 g, 45%) was obtained as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.Cl.[NH2:10]O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:1][C:2]1[S:6][C:5]([C:7]([NH2:10])=[O:8])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(C=O)s1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C(N)=O)s1
Reaction time: 4 h
Yield: 82 %

Procedure:
5-Methyl-2-thiophenecarbaldehyde (2.6 g, 0.1 M), hydroxylamine hydrochloride (8.3 g, 0.12 M), and sodium acetate (9.8 g, 0.12 M) were added to. acetic acid (50 ml) and the mixture was refluxed for 13 to 15 hours. After disappearance of the starting material was confirmed by high performance liquid chromatography (HPLC retention time ca 13 min.), the reaction mixture was concentrated under reduced pressure to about one-half of its volume. To this concentrate was added concentrated hydrochloric acid (100 ml) and the reaction was allowed to proceed at 60° C. for 4 hours. The reaction mixture was then diluted with 100 ml of water and stirred under ice-cooling for 30 minutes. The resulting crystals were recovered by filtration and rinsed with 100 ml of iced water to provide 5-methyl-2-thiophenecarboxamide (HPLC retention time ca 4 min.)
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:5][CH:6]([O:15][CH2:16][CH3:17])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH3:4].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:3]([O:5][CH:6]([O:15][CH2:16][CH3:17])[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH:2][CH3:1])=[CH:9][CH:8]=1)[CH3:4]
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(OCC)c1ccc(CNC)cc1
Temperature: 20 °C
Yield: 96 %

Procedure:
2M methylamine in MeOH (288.1 mL, 576.2 mmol) was diluted with methanol (1.000 L) and stirred at ˜20° C. 4-(Diethoxymethyl)benzaldehyde (100 g, 480.2 mmol) was added dropwise over 1 minute and the reaction stirred at ambient temperature for 1.25 hours. Sodium borohydride (29.07 g, 30.76 mL, 768.3 mmol) was added portionwise over 20 minutes while maintaining the temperature between 20 and 30° C. with an ice-water bath. The reaction solution was stirred at ambient temperature overnight then quenched by the dropwise addition of NaOH (960.4 mL of 1.0 M, 960.4 mmol) over 20 minutes. The reaction was stirred for 30 minutes and concentrated in vacuo to remove MeOH. The reaction was partitioned with MTBE (1.200 L) and the phases separated. The organic phase was washed with water (300.0 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound as a yellow oil (102.9 g, 96% Yield); 1H NMR (400 MHz, CDCl3) δ 1.25 (t, 6H), 2.46 (s, 3H), 3.45-3.65 (m, 4H), 3.75 (s, 2H), 5.51 (s, 1H), 7.32 (d, 2H) and 7.44 (d, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.[CH:28](O)=[O:29]>>[CH:28]([O:24][CH2:23][C:22]#[C:21][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=1)=[O:9])=[C:19]2[OH:20])=[O:29]
Reactant: O=CO
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Product: O=COCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 25 °C
Yield: 44 %

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example No. 53 (0.15 g) in 6 mL formic acid is heated at 100° C. for 6 hours. Once the reaction is cooled to room temperature, it is partitioned between CH2Cl2 and water. The organic layer is washed with water, saturated NaHCO3, and water again. The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure to give a residue which is crystallized with CH2Cl2 /hexanes to give the product (0.070 g, 44%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([N:11]3[CH2:15][CH2:14][O:13][C:12]3=[O:16])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[N:34][NH:35]3)O1>>[NH:35]1[C:36]2[C:32](=[C:31]([C:2]3[N:3]=[C:4]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:5]4[S:10][C:9]([N:11]5[CH2:15][CH2:14][O:13][C:12]5=[O:16])=[CH:8][C:6]=4[N:7]=3)[CH:39]=[CH:38][CH:37]=2)[CH:33]=[N:34]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: O=C1OCCN1c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: O=C1OCCN1c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl) oxazolidin-2-one (46 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via Procedure A. The product was purified by reverse phase HPLC to yield 8.6 mg of 3-(2-(1H-indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl) oxazolidin-2-one. MS (Q1) 423 (M)+
Reaction SMILES: Cl.C([N:5]([CH2:9][CH3:10])[CH:6]([CH3:8])[CH3:7])(C)C.Cl[C:12]1[CH:16]=CS[C:13]=1C(OCC1C=CC=CC=1)=O>O1CCOCC1>[NH:5]1[C:6]2[C:7](=[CH:13][CH:12]=[CH:16][CH:8]=2)[CH2:10][CH2:9]1
Reactant: O=C(OCc1ccccc1)c1sccc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(c1)CCN2
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
HCl (6 mL of a 4.0 M solution in 1,4-dioxane) was added to a solution of (2,3-dihydroindole)-3-[BOC-L-LeuΨ[COCH2]-L-Phe-L-(Tr-Gln)]-E-propenamide (0.204 g, 0.233 mmol, 1 equiv) in 1,4-dioxane (8 mL). The reaction mixture was stirred at 23° C. for 2.5 hours and then concentrated. The resulting oil was dissolved in CH2Cl2 (8 mL), and N,N-diisopropylethylamine (0.081 mL, 0.465 mmol, 2.0 equiv) and benzyl chlorothiolformate (0.042 mL, 0.279 mmol, 1.2 equiv) were added sequentially. The reaction mixture was stirred for 2 hours at 23° C. and then partitioned between water (100 mL) and a 1:1 mixture of EtOAc and hexanes (2×100 mL). The combined organic layers were dried over Na2SO4 and concentrated to provide crude (2,3-dihydroindole)-3-[BnSCO-L-LeuΨ[COCH2-L-Phe-L-(Tr-Gln)]-E-propenamide as an off-white foam. This material was dissolved in CH2Cl2 (5 mL), and triisopropylsilane (0.075 mL), and trifluoroacetic acid (5 mL) were added sequentially producing a bright yellow solution. The reaction mixture was stirred for 30 minutes at 23° C., then carbon tetrachloride (4 mL) was added, and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (5% CH3OH in CH2Cl2) to afford (2,3-dihydroindole)-3-(BnSCO-L-LeuΨ[COCH2]-L-Phe-L-Gln)-E-propenamide (0.016 g, 10%) as a white foam: Rf=0.51 (10% CH3OH in CH2Cl2); 1H NMR (CDCl3) δ 0.92 (d, 6H, J=6.2), 1.11-1.25 (m, 1H), 1.33-1.36 (m, 1H), 1.49-2.17 (m, 4H), 2.25 (s, br, 2H), 2.58 (d, 1H, J=17.1), 2.70-2.72 (m, 1H), 2.94-3.17 (m, 4H), 4.01-4.04 (m, 2H), 4.11 (s, 2H), 4.5-4.58 (m 2H), 5.47 (s, br, 1H), 6.13 (d, 1H, J=13.4), 6.29 (s, br, 1H), 6.41 (s, br, 1H 6.66)s, br, 1H), 7.00-7.05 (m, 1H), 7.17-7.29 (m, 13H), 8.25 (d, 1H, J=7.2).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16]OS(C)(=O)=O)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:22][CH3:23])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=O.C([O-])(O)=O.[Na+]>CC#N>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:16][C:28]4[NH:27][CH:31]=[CH:30][N:29]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:22][CH3:23])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(COS(C)(=O)=O)nc(=O)c1-2
Reactant: CC(=O)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ncc[nH]3)nc(=O)c1-2
Temperature: 0 °C
Yield: 29.8 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(methylsulfonyloxymethyl)pyrazolo[3,4-d]pyrimidin-4-one (1.8 g, 15.3 mmol), 1-(methylcarbonyl)imidazole (640 mg, 5.8 mmol) and CH3CN (36 mL) was heated at reflux for 6 hours. The solvent was stripped, ice water and saturated NaHCO3 were added and the mixture was extracted with ethyl acetate, dried over MgSO4, filtered and stripped. The product was combined with that from a similar experimental run and the mixture was recrystallized from ethyl acetate. The product was then treated with 2N HCl, extracted with ethyl acetate and the aqueous layer was neutralized with NaHCO3, extracted with ethyl acetate, dried over MgSO4, filtered and stripped. The residue was recrystallized from ethyl acetate to afford 0.54 g of 1-cyclopentyl-3-ethyl-6-(1-imidazolylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 252°-253° C.
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[OH:8][C@@H:9]([C@H:11]1[C:17](=[O:18])[N:16]2[CH:12]1[S:13][C:14](=[S:32])[CH:15]2[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])[CH3:10].ICC>O1CCCC1>[CH2:1]([S:32][C:14]1[S:13][CH:12]2[N:16]([C:17](=[O:18])[C@@H:11]2[C@H:9]([OH:8])[CH3:10])[C:15]=1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=S)SC12
Solvent: CCI
Solvent: C1CCOC1
Product: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)C2S1
Reaction time: 16 h

Procedure:
To 0.200 ml of diisopropylamine was added to 0.426 g of 4-nitrobenzyl 6(S)-[1(R)-hydroxyethyl]-7-oxo-3-thioxo-4-thia-1-azabicyclo[3,2,0]heptane-2-carboxylate in dry tetrahydrofuran with stirring. 0.252 ml of iodoethane was then added and stirring was continued for 16 hours at room temperature. The reaction mixture was then evaporated to dryness and chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures, to give the title product as a mixture of 5R and 5S isomers.
Reaction SMILES: C(=O)([O-])[O:2][C:3](C1C2C=CC=CC=2C2C1=CC=CC=2)(C)[CH:4]1[N:8]2[C:9](=[O:18])[C:10]3[N:16]=[CH:15][C:14]([Br:17])=[CH:13][C:11]=3[N:12]=[C:7]2[CH2:6][CH2:5]1.CCN(CC)CC>C(Cl)Cl>[OH:2][CH2:3][CH:4]1[N:8]2[C:9](=[O:18])[C:10]3[N:16]=[CH:15][C:14]([Br:17])=[CH:13][C:11]=3[N:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(OC(=O)[O-])(C1c2ccccc2-c2ccccc21)C1CCc2nc3cc(Br)cnc3c(=O)n21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2ncc(Br)cc2nc2n1C(CO)CC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.1 %

Procedure:
To a solution of (9H-fluoren-9-yl)methyl(3-bromo-10-oxo-6,7,8,10-tetrahydropyrido[3,2-d]pyrrolo[1,2-a]pyrimidin-8-yl)methyl carbonate (1.4 g, 4.7 mmol) in DCM (50 mL) was added Et3N (4 mL). The mixture was stirred for 5 h at room temperature. The reaction mixture was then concentrated and purified by column chromatography to give 0.6 g of the desired product. MS (ESI): 296, 298 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=O)C.C(OC(=O)C)(=[O:17])C>[Cr].[Co]>[OH:17][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][C:5](=[O:4])[CH:14]=[CH:13]2
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Oc1ccc2ccccc2c1
Agent: [Co]
Agent: [Cr]
Product: O=C1C=Cc2cc(O)ccc2C1
Temperature: -50 °C

Procedure:
These examples further illustrate the process of the invention. In each of the examples, a 300 cc Hastelloy C autoclave was charged with a quantity of 2-naphthyl acetate. In Examples 7, 8 and 9, one mole of acetic anhydride per mole of 2-naphthyl acetate was also charged with the 2-naphthyl acetate. The autoclave was cooled to -50° C. and evacuated to 150 mm Hg whereupon a quantity of anhydrous hydrogen fluoride was transferred from a cylinder to the autoclave at such a rate that the temperature did not exceed 0° C. The contents were warmed to reaction temperature and stirred for a predetermined period of reaction during which time a pressure of ca. 40 psig was generated. At the end of the run, the hydrogen fluoride was vented through a caustic scrubber and the contents of the autoclave were poured onto ca. 30 g of ice. The pH of the mixture was adjusted to 6.5 using a solution of 50% potassium hydroxide and the mixture was then extracted with 75 mL of ethyl acetate (3×). The organic solution was dried over anhydrous MgSO4, filtered, and the solvent was removed using a rotary evaporator to yield the 6-hydroxy-2-naphthone.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[CH3:31])[CH2:26][NH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[N:13]=[CH:12][C:11]2=[O:21])[CH2:6][CH2:7]1
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Reactant: Cc1ccc(C=O)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1ccc(CNC2CCN(CCn3c(=O)cnc4ccc(F)cc43)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To 10 mL of a chloroform solution containing 383 mg of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one and 160 mg of 3-fluoro-4-methylbenzaldehyde, 76 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 437 mg of sodium triacetoxyborohydride was added, and stirred overnight. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; ethyl acetate:hexane=1:1] to give 429 mg of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-fluoroquinoxalin-2(1H)-one as a pale yellow solid.