Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[CH:4]=1.[Li+].CC([N-]C(C)C)C.[CH2:38](Br)[CH:39]=[C:40]([CH3:42])[CH3:41]>C1COCC1>[CH3:1][O:2][C:3]1[C@:10]2([CH2:13][CH:14]=[C:15]([CH3:16])[CH3:17])[C:11](=[O:12])[C@@H:6]([C@:7]([CH3:28])([CH2:22][CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C@@H:8]([O:18][CH2:19][O:20][CH3:21])[CH2:9]2)[C:5](=[O:29])[C:4]=1[CH2:38][CH:39]=[C:40]([CH3:42])[CH3:41]
Reactant: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Reactant: CC(C)=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C(CC=C(C)C)=C2OC)[C@]1(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
A 1 dram vial equipped with a stir bar is charged with 12.6 mg (0.031 mmol, 1 equiv.) of starting material 50 followed by 660 μL of THF. The solution is cooled to −78° C. prior to the addition of 124 μL of LDA (0.50 M, 0.062 mmol, 2 equiv.). The mixture was then stirred for 20 minutes followed by the addition of 18 μL (0.155 mmol, 5 equiv.) of prenyl bromide. Stirring was continued for an additional 20 minutes at which time the reaction was quenched by the addition of 500 μL of saturated aqueous ammonium chloride. The reaction was transferred to a separatory funnel in diethyl ether, and the organic layer was washed twice with water, dried with MgSO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (Rf=0.25 in 9:1 hexane:ethyl acetate), affording 7.5 mg (51% yield) of 54 as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 5.07 (t, J=7.0 Hz, 1H), 5.04-4.94 (m, 2H), 4.58 (dd, J=7.0, 47.1 Hz, 2H), 3.95 (s, 3H), 3.60 (dd, J=5.3, 11.4 Hz, 1H), 3.33 (s, 3H), 3.25 (s, 1H), 3.13 (d, J=6.4 Hz, 2H), 2.50 (dd, J=6.2, 14.7 Hz, 1H), 2.42-2.28 (m, 2H), 2.25 (dd, J=5.2, 13.4 Hz, 1H), 1.96-1.84 (m, 1H), 1.77 (dd, J=11.5, 13.3 Hz, 1H), 1.71-1.61 (m, 18H), 1.58-1.51 (m, 2H), 1.30-1.23 (m, 2H), 1.18 (dt, J=4.3, 12.8 Hz, 2H), 0.91 (s, 3H). HRMS-ESI (m/z): [M+H]+ calculated for C29H44O5, 473.3262. found 473.3250.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]1([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN([CH:24]=[O:25])C>>[C:6]1([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH:24]=[O:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccccc2)[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of DMF (11.0 mL, 142 mmol) and phosphorous oxychloride (3.63 mL, 39 mmol) is stirred at 0° C. for 1 h, a 0.2 mL portion is pipetted into a solution of 2-phenylindole (96 mg, 0.5 mmol) in DMF at 5° C. This reaction mixture is stirred at 5°-10° C. for 1 h, quenched with water, stored at −200 for 16 h and filtered. The filtercake is washed with water and dried in vacuo to afford the 2-phenylindole-3-carboxaldehyde intermediate. A suspension of the thus-obtained 2-phenylindole-3-carboxaldehyde (44.2 mg, 0.2 mmol) in isopropanol and concentrated HCl (50 μL) is treated with aminoguanidine bicarbonate (27 mg, 0.2 mmol), heated at 80° C. for 2 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to afford the title product, 28 mg (20% yield), identified by mass spectral and HPLC analyses (M+H) 277; retention time 3.76 min.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]4[CH2:28][O:27]4)[N:21]=3)[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]>O.CS(C)=O>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]([OH:1])[CH2:28][OH:27])[N:21]=3)[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]
Reactant: CCOc1ccc(-c2nc(-c3cccc(C4CO4)n3)cs2)cc1OCC
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccc(-c2nc(-c3cccc(C(O)CO)n3)cs2)cc1OCC
Temperature: 100 °C
Reaction time: 7 h
Yield: 47.7 %

Procedure:
A solution of 505 mg of potassium hydroxide dissolved in 30 ml of water was added to a solution of 700 mg of 2-(3,4-diethoxyphenyl)-4-(6-oxiranyl-2-pyridyl)thiazole dissolved in 30 ml of dimethyl sulfoxide. The mixture was stirred at 100° C. for 7 hours. The reaction mixture was subjected to extraction three times with 50 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol=20/1) and then recrystallized from ethyl acetate-n-hexane to obtain 350 mg of 2-(3,4-diethoxyphenyl)-4-[6-(1,2-dihydroxyethyl)-2-pyridyl]-thiazole.
Reaction SMILES: [CH2:1]([N:8]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([O:20]CC)=[O:19])[NH:15][C:14]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:23]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[NH:15][C:14]=12)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Yield: 21.5 %

Procedure:
A mixture of ethyl 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Reference Example 3) (500 mg, 1.30 mmol), 2 M sodium hydroxide solution (6 mL), tetrahydrofuran (3 mL) and ethanol (3 mL) was refluxed for 2 h. The mixture was neutralized by addition of 1 M hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was crystallized from ethyl acetate to give 7-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (100 mg, 22%) as pale brown amorphous solid. Additional material (348 mg, 75%; 97% overall yield) was obtained from the mother liquid: Rf 0.01 (silica gel, ethyl acetate); mp 114-120° C.; 1H NMR (300 MHz, DMSO-d6) δ4.82 (4H, br s), 7.18-7.35 (12H, m), 7.68 (1H, d, J=6.0 Hz); ESI MS m/z 358 [C22H19N3O2+H]+; HPLC (Method A) 98.8% (AUC), tR=17.7 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CCCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-propyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J36) (239 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow oil (180 mg, 44%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]#[C:9][CH2:10][OH:11].C(NCC)C.BrC1C=CC=CN=1>[Cu]I.C(OCC)C>[C:2]1([C:8]#[C:9][CH2:10][OH:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: C#CCO
Agent: [Cu]I
Agent: Brc1ccccn1
Solvent: CCOCC
Solvent: CCNCC
Product: OCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.7 g (1 mmol) of bis-triphenylphosphinepalladium dichloride and 0.38 g (2 mmols) of copper (I) iodide is added, with stirring, to 31.6 g (200 mmols) of bromobenzene, 16.8 g (300 mmols) of 1-propyn-3-ol and 300 ml of diethylamine. The reaction mixture is stirred in an argon atmosphere at room temperature (20°-25° C.), and within one hour the mixture heats up to about 30° C. A precipitate commences to occur, and after a reaction time of 6 hours, no further bromopyridine can be detected according to chromatographic analysis. 200 ml of diethyl ether are added to the reaction mixture and this is then filtered. The filtrate is washed with 200 ml of water, dried over magnesium sulfate, and concentrated by evaporation to leave a solid residue. Recrystallisation from diethyl ether yields 1-(phenyl)-propyn-3-ol. 1H-NMR Spectrum 100 MHz (CDCl3, TMS) δ in ppm: 2.4(s); 4.5(s); 7.2-7.5(m) in the ratio of 1:2:5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([CH3:24])[C:16]=3[N+:21]([O-:23])=[O:22])[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[CH2:27].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:31]1[CH:32]=[CH:33][C:28](/[CH:26]=[CH:27]/[C:13]2[CH:14]=[C:15]([CH3:24])[C:16]([N+:21]([O-:23])=[O:22])=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])=[CH:29][CH:30]=1
Reactant: C=Cc1ccncc1
Reactant: Cc1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(/C=C/c2ccncc2)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-8-bromo-6-methyl-5-nitroquinazolin-4-ol (65 mg) in N,N-dimethylformamide (2 mL) was added 4-vinylpyridine (0.040 mL), followed by palladium acetate (14 mg), tri-o-tolylphosphine (30 mg) and N,N-diisopropylethylamine (0.44 mL). The mixture was heated at 120° C. for 22.5 h, then was cooled to room temperature. The supernatant was concentrated in vacuo to a dark oil which was triturated with a 50% (v/v) methanol/dichloromethane (5 mL). The solid product was isolated by filtration, washed with 50% (v/v) methanol/dichloromethane (5 mL) and dried to give the title compound (12 mg). 1H NMR (300 MHz, DMSO-d6) δ11.55 (s, 1H), 9.23, 8.59 (d, J=4.5 Hz, 2H), 8.43 (d, J=2.4 Hz, 1H), 8.21 (s, 1H), 8.08 (d, J=16.8 Hz, 1H), 7.62-7.31 (m, 5H), 2.26 (s, 3H). HPLC (Method B) 9.3 min. MS (APCI+): m/z 468.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.Br[C:13]1[CH:14]=[CH:15][C:16]2[N:22]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH2:21][CH2:20][C:19]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][C:17]=2[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]([C:13]2[CH:14]=[CH:15][C:16]3[N:22]([S:23]([C:26]([F:27])([F:29])[F:28])(=[O:24])=[O:25])[CH2:21][CH2:20][C:19]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:18][C:17]=3[CH:35]=2)=[CH:4][CH:5]=1
Reactant: Cc1ccc(OB([O-])[O-])cc1
Reactant: CCOC(=O)C1=Cc2cc(Br)ccc2N(S(=O)(=O)C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=Cc2cc(-c3ccc(C)cc3)ccc2N(S(=O)(=O)C(F)(F)F)CC1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
In water/ethanol/toluene (1:1:10, 36.0 ml) 4-methylphenyl borate (194 mg) and ethyl 7-bromo-1-[(trifluoromethyl)sulfonyl]-2,3-dihydro-1-benzazepine-4-carboxylate (510 mg) were dissolved, and to the mixture was added potassium carbonate (395 mg). The mixture was stirred under argon atmosphere for 30 minutes, and to the mixture was added tetrakistriphenylphosphine palladium (138 mg). Under argon atmosphere, the mixture was refluxed for 17 hours, and the mixture was diluted with ethyl acetate (150 ml) and washed with water (50 ml) and saturated brine (50 ml). The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (50g, hexane/ethyl acetate=9:1) to give ethyl 7-(4-methylphenyl)-1-[(trifluoromethyl)-sulfonyl]-2,3-dihydro-1-benzazepine-4-carboxylate (469 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.CI.[CH3:25]COC(C)=O.O>CN(C=O)C.CC([O-])(C)C.[K+]>[NH2:1][C:2]1[C:3]([C:21]#[N:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH3:25])[CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(-c2nc(C#N)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile (58 mg) was dissolved in DMF (1 ml). To the solution were added 1M MeI solution in DMF (0.22 ml) and 0.1M t-BuOK solution in DMF (2.2 ml). The mixture was stirred at 20-30° C. for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO4. Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only-EtOAc:MeOH=93:7, v/v) to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile, which was crystallized from EtOAc (18 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II.[CH3:10][C:11]([CH3:13])=O>>[NH:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=[CH:11][CH2:13]1
Reactant: CC(C)=O
Reactant: Nc1ccccc1
Agent: II
Product: C1=Cc2ccccc2NC1
Yield: 18 %

Procedure:
1,2-dihydroquinolines are key intermediates in the preparation of a number of steroid receptor modulating compounds, and are prepared by a multi-step route culminating in the treatment of an aniline with acetone and iodine at elevated temperatures in a process known as the Skraup reaction, as shown below. See R. H. F. Manske et al., Organic Reactions 7: 59-98 (1953), and W. R Vaughan, Org. Synth. Coll. Vol III, 329-332 (1955). ##STR1## Many 1,2-dihydroquinolines are themselves steroid receptor modulating compounds. See, for example, PCT Int'l Publ. No. WO 96/19458; U.S. Pat. No. 5,693,647. Application of the traditional Skraup reaction to the synthesis of many of these 1,2-dihydroquinolines is problematic in that large quantities of a number of tarry by-products are formed that must be removed prior to use in further synthetic transformations, and the yields are generally low (15-50%). For example, as shown in U.S. Pat. No. 5,693,647, treatment of a polycyclic aniline, such as the amino-chloro-benzocoumarin shown below, with acetone and iodine at 130-135° C. affords only an 18% yield of the corresponding 1,2-dihydroquinoline. Furthermore, purification is very difficult due to the aforementioned by-product formation. ##STR2##
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10](=[O:13])[CH2:11][NH2:12].Br[CH2:15][CH2:16][S:17][CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:21]([O:20][P:19]([CH2:18][S:17][CH2:16][CH2:15][NH:12][CH2:11][C:10]([O:9][CH3:8])=[O:13])([O:23][CH2:24][CH3:25])=[O:26])[CH3:22]
Reactant: COC(=O)CN
Reactant: CCOP(=O)(CSCCBr)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CSCCNCC(=O)OC)OCC

Procedure:
A suspension of potassium carbonate (0.42 g, 3 mmol) in anhydrous dimethylformamide (3 ml) is treated with glycine methyl ester hydrochloride (0.25 g, 2 mmol) and stirred under nitrogen. After 5 minutes diethyl (2-bromoethyl)thiomethylphosphonate (Example G) (0.28 g, 1.08 mmol) is added as a solution in dimethylformamide (0.5 ml). After stirring 48 hours, the dimethylformamide is removed in vacuo, and the residue is dissolved in water and extracted with chloroform (2×30 ml). The organic layer is separated, dried over sodium sulfate, filtered, evaporated, and the residue is purified by silica gel chromatography (60:1 chloroform:methanol as eluant) to give methyl N-[2-[[(diethoxyphosphinyl)methyl]thio]ethyl]glycinate.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][O:9][C:10]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([S:21]([O-:24])(=[O:23])=[O:22])=[C:14]([N+:25]([O-:27])=[O:26])[CH:13]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+]>O.CO>[S:21]([C:15]1[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]([C:10]([O:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:11])=[CH:13][C:14]=1[N+:25]([O-:27])=[O:26])([OH:24])(=[O:23])=[O:22]
Reactant: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(S(=O)(=O)[O-])c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(OCCC1CCCCC1)c1cc([N+](=O)[O-])c(S(=O)(=O)O)c([N+](=O)[O-])c1

Procedure:
11.20 parts of sodium 4-(2-cyclohexylethoxycarbonyl)-2,6-dinitrobenzenesulfonate was dissolved in 60.0 parts of ion-exchanged water and 60 parts of methanol. The solution was passed thrice through a column filled with 32.07 parts of ion-exchange resin (Duolite C20 H type, manufactured by Sumitomo Chemical Co., Ltd.). After concentrating to eliminate methanol, the concentrate was freeze-dried to obtain 9.87 parts of 2-cyclohexylethyl 4-sulfo-3,5-dinitrobenzoate.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].[Si]([O:16][CH2:17][C@@H:18]([N:27]1[CH:31]=[C:30]([C:32](OC)=[O:33])[N:29]=[CH:28]1)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C(C)(C)C)(C)C.O>CO.CN(C=O)C>[OH:16][CH2:17][C@@H:18]([N:27]1[CH:31]=[C:30]([C:32]([NH:7][C:6]([NH2:8])=[NH:5])=[O:33])[N:29]=[CH:28]1)[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1cn([C@@H](CCc2ccccc2)CO[Si](C)(C)C(C)(C)C)cn1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: N=C(N)NC(=O)c1cn([C@H](CO)CCc2ccccc2)cn1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 28.6 %

Procedure:
A solution of 28% NaOMe in methanol (583 mg) was added to an ice cooled solution of guanidine hydrochloride (307 mg) in DMF (5 ml). After 10 minutes, methyl (S)-1-[1-(tert-butyl-dimethylsilyloxy)-4-phenyl-2-butyl]imidazole-4-carboxylate (obtained in Example 6) (250 mg) in DMF (2 ml) was added to the mixture and the resulting mixture was stirred at 100° C. for 5 hours. After cooling, the reaction mixture was poured into water (30 ml) and the solution was washed with ethyl acetate. The aqueous layer was purified by HP-20 (40 cc) column chromatography eluting with water/2-propanol (9:1) and lyophilized to give (S)-1-[1-hydroxy-4-phenyl-2-butyl]imidazole-4-carbonylguanidine (55.4 mg)
Reaction SMILES: [Br:1]/[C:2](/[C@@H:22]([OH:30])[C@@H:23]([CH3:29])[CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:3]/[C@@H:4]1[C@H:11]([O:12]C(=O)C2C=CC=CC=2)[CH2:10][C@H:9]2[C@@H:5]1[CH2:6][C:7](=[O:21])[O:8]2.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[Br:1]/[C:2](/[C@@H:22]([OH:30])[C@@H:23]([CH3:29])[CH2:24][C:25]#[C:26][CH2:27][CH3:28])=[CH:3]/[C@@H:4]1[C@H:11]([OH:12])[CH2:10][C@H:9]2[C@@H:5]1[CH2:6][C:7](=[O:21])[O:8]2
Reactant: CCC#CC[C@H](C)[C@H](O)/C(Br)=C\[C@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC#CC[C@H](C)[C@H](O)/C(Br)=C\[C@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
3.12 g of (1S,5R,6R,7R)-6-[(E)-(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-7-benzoyloxy-2-oxa-bicyclo[3.3.0]octan-3-one was dissolved in 18 ml of reagent-grade methanol, mixed with 290 mg of finely powdered potassium carbonate and allowed to stir for 3 hours at 25° C. By adding a 50% hydrochloric acid, it was adjusted to pH 7 and concentrated by evaporation at 30° C. in a water jet vacuum. The residue was taken up in methylene chloride, filtered on magnesium sulfate and Celite, again concentrated by evaporation in a water jet vacuum and chromatographed under pressure on about 200 ml of fine silica gel by using a gradient of hexane/ethyl acetate. 2.00 g (82%) of the title compound was isolated as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]1([C:24]([O-])=O)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:10]([C:11]3([CH3:24])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:1][C:2]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)[O-])CC1
Reactant: Nc1cc(F)ccc1O
Product: CC1(c2nc3cc(F)ccc3o2)CCNCC1

Procedure:
Starting from 2-amino-4-fluorophenol and mono-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (V-9) may be prepared and purified analogously to (V-8) (see 45.1).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.[C-:15]#[N:16].[Na+].O>CS(C)=O>[C:15]([CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1)#[N:16]
Reactant: COc1ccc2c(c1)C(CCBr)CC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(CCC#N)CC2
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
To a solution of 1-(2-bromoethyl)-6-methoxyindan (1.75 g, 6.86 mmol) in dimethyl sulfoxide (80 ml) was added sodium cyanide (0.35 g, 7.20 mmol). This mixture was stirred for 40 minutes at 60° C. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with brine and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (hexane/ethyl acetate, 85:15) to give 1.28 g (yield 93%) of the above-titled compound as an oily-product.
Reaction SMILES: C([S:4][CH:5]([CH3:18])[CH2:6][C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH:5]([CH3:18])[CH2:6][C:7]([N:9]1[CH2:16][C:15](=[O:17])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SC(C)CC(=O)N1CC(=O)C[C@H]1C(=O)O
Agent: N
Product: CC(S)CC(=O)N1CC(=O)C[C@H]1C(=O)O

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia to yield (S)-1-(3-mercapto-3-methyl-1-oxopropyl)-4-oxo-L-proline.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]2[N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:17][C:3]=12.Cl.[CH:25]12[O:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][NH:27][CH2:26]2.C(N(CC)CC)C>C(O)C>[CH:29]12[O:32][CH:25]([CH2:31][CH2:30]1)[CH2:26][N:27]([C:2]1[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=3)[N:5]=[C:4]3[N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:16]=[CH:17][C:3]=13)[CH2:28]2
Reactant: C1CC2CNCC1O2
Reactant: Oc1cccc(-c2nc(Br)c3cnn(-c4ccccc4)c3n2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1cccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(-c4ccccc4)c3n2)c1
Temperature: 180 °C

Procedure:
A Smith process vial was charged with a suspension of 3-(4-bromo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (0.15 g, 0.41 mmol) and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (approximately 1 mmol) in ethanol (5 mL). The suspension was treated with triethylamine (500 μL, 3.8 mmol) and was then heated in the microwave reactor for 10 minutes at 180° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 15% acetonitrile/88% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile to provide 3-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenol. MS (ES+): 400.1 (M+H)+