Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:5])C=O.[N-]=[N+]=[N-].[Na+].[CH2:10]([O:12][CH:13]([O:17][CH2:18][CH3:19])[CH2:14]CCl)[CH3:11]>C(O)C.[Pd]>[CH2:10]([O:12][CH:13]([O:17][CH2:18][CH3:19])[CH2:14][CH2:5][NH2:2])[CH3:11]
Reactant: CN(C)C=O
Reactant: CCOC(CCCl)OCC
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CCN)OCC
Temperature: 60 °C
Reaction time: 96 h
Yield: 63 %

Procedure:
To 500 ml of dimethylformamide (DMF) containing NaN3 (26.0 g, 400 mmol) was added 3-chloropropionaldehyde diethyl acetal (33.3 g, 200 mmol). The solution was warmed to 60° C., and the reaction was monitored by GC (50° C., 1 min to 250° C. at 15° C./min, DB5-15 m). (Retention time (tR) of starting material 5.1 min, product 6.5 min). The reaction mixture was diluated with 1 L of ice water and extracted with ether (3×500 mL). The combined ether extracts were washed with water (2×500 mL) and then dried over MgSO4. Removal of solvent afforded a crude product, which was dissolved in 500 mL of ethanol containing Pd/C (10%, 2.03 g, 2 mmol). The suspension was degassed, saturated with H2, and stirred under an H2 balloon for four days at which time GC analysis of the product amine (tR 5.4 min) indicated a complete reaction. The solution was degassed and filtered through Celite 545, and the solvent was removed under reduced pressure. The residue was diluted with 25 mL of 12N KOH and extracted with ether (2×50 mL). The ether layer was filtered through glass wool/Na2CO3 and dried over Na2CO3. The solvent was removed under water aspirator vacuum, and the residue was distilled to yield 3-aminopropanal diethylacetal (18.6 g, 126 mmol, 63%): bp17 80°-81.5° C. bp20 68°-70° C. agreed with b.p. in Becke, F. German Patent 845,348, 1952, Chem. Abstr. 47 (1952) 542); 1H--NMR (200 MHz CDCl3) δ 1.21 (t, 6 H, CH3), 1.58 (s, 2 H, NH2), 1.78 (q, 2 H CH2), 2.81 (t, 2 H, NCH2), 3.53 and 3.66 (m, 4 H, OCH2), 4.62 (t, 1 H, CH). Anal. Calcd for C7H17NO2 : C, 57.1; H, 11.6. Found: C, 57.1; H, 11.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[C:11]([Cl:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][OH:19])=[CH:16][C:15]2[C:10](=[C:11]([Cl:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=Cc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl

Procedure:
Prepared according to Procedure B using 2-(2-chlorophenyl)-8-chloroquinoline-3-carbaldehyde (1.18 g, 3.9 mmol), and sodium borohydride (0.222 g, 5.86 mmol, 1.5 eq) in THF (20 mL). (2-(2-chlorophenyl)-8-chloroquinolin-3-yl)methanol was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (1H, s), 8.10 (1H, dd, J=8.2, 1.2 Hz), 7.94 (1H, dd, J=7.6, 1.4 Hz), 7.63 (2H, t, J=7.8 Hz), 7.44-7.59 (3H, m), 5.54 (1H, t, J=5.3 Hz) Mass Spectrum (ESI) m/e=304.0 and 306.1 (M+1)
Reaction SMILES: [F:1][CH:2]1[C:8](=[O:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[OH-].[Na+].OO>C1COCC1.CO.O>[F:1][C@H:2]1[C@H:8]([OH:9])[CH2:7][CH2:6][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)CC1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H](F)CC1
Temperature: -5 °C
Reaction time: 20 h

Procedure:
To a tert-butyl 4-fluoro-5-oxoazepane-1-carboxylate (20.0 g, 86.5 mmol) was dissolved in THF (430 mL) solution and the solution was cooled to −5° C. L-selectride (112 mL, 112 mmol, 1.0 M in THF) was added via syringe. The mixture was gradually warmed to ambient temperature over 3 hours and stirred for an additional 20 hours. The resulting cloudy mixture was diluted with 110 mL of MeOH which was followed by the addition of NaOH (355 mL, 355 mmol, 1.0M aqueous). The mixture was cooled in a water bath, and H2O2 (80.4 mL, 709 mmol, 30% aqueous) was added carefully via addition funnel over 30 minutes. The mixture was stirred vigorously for 1 hour, then diluted with water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with water and 1N KHSO4 (2×150 mL), and the combined aqueous phases were back-extracted with EtOAc (200 mL). The combined organic layers were washed with saturated aqueous NaHCO3, then dried over Na2SO4, filtered and concentrated. The crude product was purified via column chromatography (15% to 60% EtOAc/hexanes) to provide the product as a thick colorless oil which slowly became a white solid (13.9 g, 69%; diastereomeric ratio (dr): ˜7:1 trans:cis).
Reaction SMILES: [N:1]([C@H:4]1[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:8]=2[CH2:7][CH2:6][CH2:5]1)[CH2:15][N:14](C(=O)C(F)(F)F)[CH2:13][CH2:12]3)=[N+:2]=[N-:3].[OH-].[Na+]>C1COCC1.CO.O>[N:1]([C@H:4]1[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:8]=2[CH2:7][CH2:6][CH2:5]1)[CH2:15][NH:14][CH2:13][CH2:12]3)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc3c(cc21)CCN(C(=O)C(F)(F)F)C3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1CCCc2cc3c(cc21)CCNC3

Procedure:
A solution of (R)-1-(6-azido-3,4,6,7,8,9-hexahydrobenzo[g]-isoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone (972 mg, 3.0 mmol) and NaOH (240 mg, 6 mmol) in 21 mL of THF/MeOH/H2O (10/10/1) was stirred at RT for 5 h. The solvent was evaporated and the residue was submitted to flash chomatograph (SiO2, EtOAc/MeOH=100:10 to 100:20 to 100:30) to give (R)-6-azido-1,2,3,4,6,7,8,9-octahydrobenzo[g]isoquinoline as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[C:17]([O:18][CH3:19])=[C:16]([O:20][CH3:21])[CH:15]=[CH:14][C:6]=1[N:7](C(=O)C)C(=O)C)([O:3]C)=[O:2].[OH-].[Na+].C>C(O)(=O)C>[CH3:21][O:20][C:16]1[C:17]([O:18][CH3:19])=[C:5]([C:1]([OH:3])=[O:2])[C:6]([NH2:7])=[CH:14][CH:15]=1
Reactant: COC(=O)c1c(N(C(C)=O)C(C)=O)ccc(OC)c1OC
Agent: C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N)c(C(=O)O)c1OC
Yield: 60.1 %

Procedure:
A mixture of 36.8 g (130 mmol) of 2-carbomethoxy-N,N-diacetyl-3,4-dimethoxyaniline and 500 mL of 2N NaOH was prepared and heated to reflux to obtain a clear brown solution. After refluxing for 5 hours, the reaction mixture was treated with Darco and filtered through a Hyflo bed to give a clear yellow solution. Glacial acetic acid (65 mL) was added and the reaction mixture was extracted with 2×500 mL of methylene chloride. Drying over sodium sulfate and rotary evaporation gave 19.5 g (76%) of crude white product. Recrystallization from ethyl acetate-hexane gave 15.4 g (60%) of the product as a white crystalline solid, mp 92.5°-95.0° C. NMR (CDCl3) δ 3.78 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 6.45 (d, 1H, J=10 Hz, ArH), 7.00 (d, 1H, J=10 Hz, ArH), 7.60 (br s, 3 H, CO2H and NH2).
Reaction SMILES: O1C2C(=CC=CC=2)C(=O)C=C1C1C=CC=CC=1.O1CC1C[O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](=[O:38])[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29]2)=[CH:24][CH:23]=1>>[OH:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](=[O:38])[CH:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29]2)=[CH:24][CH:23]=1
Reactant: O=c1cc(-c2ccccc2)oc2cc(OCC3CO3)ccc12
Agent: O=c1cc(-c2ccccc2)oc2ccccc12
Product: O=c1cc(-c2ccccc2)oc2cc(O)ccc12

Procedure:
7-2,3-Epoxypropoxy)flavone is useful as an intermediate for the preparation of 7-[3-(alkylamino)-2-hydroxypropoxy]flavones, which aminated flavones are disclosed in U.S. Pat. No. 4,495,198 to be particularly useful as antihypertensives. This patent shows the preparation of 7-(2,3-epoxypropoxy)flavone in low yields by reaction of 7-hydroxyflavone and an epihalohydrin in the presence of either sodium hydroxide and ethanol (59% yield) or potassium carbonate and acetone (68% yield after refluxing for 2 days).
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: ClC1=NN(c2ccccc2)CC1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Clc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Yield: 36.9 %

Procedure:
3-Chloro-4,5-dihydro-1-phenylpyrazole (1.8 g) and 4-chloroaniline (3.8 g) were fused under N2 at 140° for 20 minutes. The melt was cooled and the solid dissolved in CH2Cl2, washed with 1% HCl (×3), water, dried (Na2So4), then absorbed into silica and column chromatographed using first 1:1 petrol:ether and then ether to give the title product as a yellow powder (1.0 g), (37%), m.p. 144°-7°.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:21]3[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Fc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1Cl
Yield: 41.2 %

Procedure:
1-Benzyl-5-(3-chloro-4-fluorophenyl)-1H-indole was prepared by coupling 1-benzyl-5-bromo-1H-indole (1.46 g, 5.10 mmol), and 3-chloro-4-fluorophenylboronic acid (1.08 g, 6.19 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.209 g, 0.256 mmol), potassium carbonate (1.44 g, 10.4 mmol) in dioxane (51 mL) and water (5 mL), following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant and drying 60° C. furnished the title compound as a light brown gum (0.706 g, 41%). 1HNMR (200 MHz, DMSO-d6) δ 7.8-7.9 (m, 2H), 7.6-7.7 (m, 1H), 7.4-7.6 (m, 3H), 7.15-7.4 (m, 6H), 6.55 (d, 1H, J=2.5 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:25]=[C:24]4[C:20]([C:21]([CH3:34])([CH3:33])[CH2:22][N:23]4[C:26](=[O:32])[CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])=[CH:19][CH:18]=3)[C:10]2=[O:35])[CH:5]=[CH:4][N:3]=1.[NH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1.CC1(C)C2C=CC(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=2OC2C1=CC=C(P(C1C=CC=CC=1)C1C=CC=CC=1)C=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:29]([NH:28][CH2:27][C:26]([N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([N:11]3[C:12](=[O:16])[C:13]([CH3:15])([CH3:14])[N:9]([CH2:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([NH:36][C:37]5[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=5)[CH:7]=4)[C:10]3=[O:35])[CH:25]=2)[C:21]([CH3:34])([CH3:33])[CH2:22]1)=[O:32])([CH3:31])[CH3:30]
Reactant: CC(C)NCC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Cl)c4)C(C)(C)C3=O)cc21
Reactant: Nc1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2ccc(P(c3ccccc3)c3ccccc3)cc2Oc2cc(P(c3ccccc3)c3ccccc3)ccc21
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)NCC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc(Nc5cccnc5)c4)C(C)(C)C3=O)cc21
Temperature: 140 °C
Yield: 12.6 %

Procedure:
To a solution of 249 mg of 1-[(2-chloropyridin-4-yl)methyl]-3-[1-(N-isopropylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage a) below in 3 mL of N-methylpyrrolidinone are successively added, under argon, 94 mg of 3-aminopyridine, 29 mg of (9,9-dimethyl-9H-xanthene-3,6-diyl)bis(diphenylphosphine) (Xantphos), 22 mg of palladium acetate and 652 mg of caesium carbonate. The reaction mixture is heated at 140° C. for 1 hour by microwave, cooled to room temperature, diluted with 20 mL of dichloromethane and filtered, and the filtrate is concentrated under reduced pressure. The residue is triturated in 40 mL of water and the precipitate formed is filtered off and purified by chromatography on a column of silica, eluting with a mixture of dichloromethane and methanol (93/7 by volume) to give 35 mg of 3-[1-(N-isopropylglycyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl]-5,5-dimethyl-1-{[2-(pyridin-3-ylamino)pyridin-4-yl]methyl}imidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Br:10][C:11]1[CH:16]=[C:15]([C:17]([O-:19])=O)[CH:14]=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH:49]1[C:57]2[CH:56]=[CH:55][CH:54]=[C:53]([CH2:58][NH2:59])[C:52]=2[CH:51]=[CH:50]1.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[Br:10][C:11]1[CH:16]=[C:15]([C:17]([NH:59][CH2:58][C:53]2[CH:54]=[CH:55][CH:56]=[C:57]3[C:52]=2[CH:51]=[CH:50][NH:49]3)=[O:19])[CH:14]=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Br
Reactant: NCc1cccc2[nH]ccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
Diisopropylethylamine (2.3 mL, 13.2 mmol) was added dropwise to a solution of 2-bromo-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 2; 861 mg, 3.32 mmol), HBTU (1.39 g, 3.65 mmol), 1H-indole-4-methanamine hydrochloride salt (Example 11; 528 mg, 3.98 mmol), and HOBT (493 mg, 3.65 mmol) in N,N-dimethylformamide (6.5 mL) at 0° C. The solution warmed to room temperature and stirred for 24 h. The solvent was concentrated under vacuum to remove most of the N,N-dimethylformamide. The residue was diluted with ethyl acetate (50 mL) and washed with 1 M HCl (10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, evaporated and flash chromatographed (silica, 25-35% ethyl acetate/petroleum ether) to give 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid, methyl ester (900 mg, 70%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([C:5](Cl)=[O:6])[CH2:4][CH2:3]1.[F:8][C:9]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=1.CCN(CC)CC.CCOC(C)=O>C(Cl)Cl>[F:8][C:9]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:5]([C:2]2([CH3:1])[CH2:4][CH2:3]2)=[O:6])[CH:13]=1
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Yield: 24 %

Procedure:
Add the solution of the above 1-methylcyclopropanecarbonyl chloride in DCM slowly to a solution of 4-(2-fluoro-4-nitro-phenoxy)pyridin-2-amine (500 mg, 2.0 mmol) and Et3N (505 mg, 5.0 mmol) in DCM (15 mL) at 0° C. Stir the reaction at room temperature for 15 hrs. TLC (EtOAc:PE=1:1) shows the reaction is complete. Concentrate the mixture to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the target compound (160 mg, 24%). MS: (M+1): 332.2.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH2:24][CH2:25][CH3:26])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[C:10]([O:21]C)[N:11]2[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([NH2:23])[N:6]=1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:23][C:7]1[N:6]=[C:5]([O:4][CH2:3][C:2]([CH3:1])([CH3:27])[CH2:24][CH2:25][CH3:26])[N:13]=[C:12]2[C:8]=1[NH:9][C:10](=[O:21])[N:11]2[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CCCC(C)(C)COc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCC(C)(C)COc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a solution of 2-[(2,2-dimethylpentyl)oxy]-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (116 mg) in dry MeOH (14.5 mL) was added 4N HCl in 1,4-dioxane (2.48 mL). The mixture was stirred at room temperature for 3 h. The reaction was neutralised to pH 7 with 2M sodium hydroxide solution and was concentrated in vacuo to give and off-white solid. The solid was triturated with water (30 mL) and was filtered under reduced pressure to give the title compound as an off-white solid (76 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.O(C1C=CC(C[N:20]2[CH:35]=[C:23]3[C:24](=[O:34])[N:25]([CH3:33])[C:26]4[N:27]([CH2:28][C:29]([CH3:32])([CH3:31])[N:30]=4)[C:22]3=[N:21]2)=CC=1)C1C=CC=CC=1.C(S(O)(=O)=O)(F)(F)F.O>C(Cl)Cl>[CH3:33][N:25]1[C:24](=[O:34])[C:23]2=[CH:35][NH:20][N:21]=[C:22]2[N:27]2[CH2:28][C:29]([CH3:32])([CH3:31])[N:30]=[C:26]12
Reactant: CN1C(=O)c2cn(Cc3ccc(Oc4ccccc4)cc3)nc2N2CC(C)(C)N=C12
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)c2c[nH]nc2N2CC(C)(C)N=C12
Temperature: 25 °C
Yield: 79.9 %

Procedure:
TFA (600 mL) is added into a suspension of 2-(4-phenoxybenzyl)-7,8-dihydro-5,7,7-trimethyl-[2H]-imidazo-[1,2-a]pyrazolo[4,3-e]pyrimidin-4(5H)-one (103 g, 257 mmol) in methylene chloride (210 mL) to give a tan solution, and then TFMSA (168 mL) is added. The reaction mixture is stirred at room temperature until the starting material disappears. The mixture is poured into cold water (3 L). After filtration, the filter cake is washed with water twice, and then basified with ammonium hydroxide aqueous solution, followed by adding ethyl acetate with stirring. The precipitated solids are filtered, washed successively with water three times, ethyl acetate twice and methanol once, and then dried under vacuum to give 45 g of product (yield: 80%). MS (ESI) m/z 220.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[NH2:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CC(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[NH:13][C:14](=[O:16])[CH3:15]
Reactant: COc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])cc(Br)c1NC(C)=O
Temperature: 0 °C

Procedure:
A solution of 23 g of 2-bromo-6-methoxy-4-nitrophenylamine in 125 mL of acetic anhydride and 100 mL of AcOH was refluxed at 110° C. Following reflux for 5 h, mixture was dumped into 1.5 L of ice water. A precipitate formed, and was collected via filtration. The precipitate was then placed in EtOH and refluxed for 15 min. 9 mL of conc. NH4OH was then added to the hot mixture. The solution was then cooled, and a precipitate formed and collected again via filtration. The solid was washed with ethanol(2×) and ether, and allowed to air dry. 21.5 g of title compound as a tan powder was collected.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.SC[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][CH2:10][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(SCCc2ccccn2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in dioxane. ES-MS m/e (%): 335 (M{37Cl}+H+, 30), 333 (M{35Cl}+H+, 100).
Reaction SMILES: [CH:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21]C)[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])([CH3:3])[CH3:2]>CO.Cl.O>[CH:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C@@H:13]4[C:18]([CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])=[CH:17][C:16](=[O:21])[CH2:15][CH2:14]4)([CH3:3])[CH3:2]
Reactant: COC1=CCC2=C(CC[C@@H]3[C@@H]2CC[C@]2(C(C)C)[C@@H](O)CC[C@@H]32)C1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 2 h

Procedure:
Dissolve 13β-isopropyl-3-methoxy-gona-2,5(10)-dien-17β-ol in methanol (36 cc.), concentrated hydrochloric acid (2.4 cc.) and water (1.6 cc.) and allow the mixture to stand at room temperature for 2 hours. Add water and collect the product in ether. Wash, dry and evaporate the ethereal solution and chromatograph the residue on alumina (30 g.). Elute with benzene containing 30% ether and evaporate the solvent to obtain 13β-isopropyl-17β-hydroxy-gon-4-en-3-one as a gum; infrared absorption peak at 5.99 μ; ultraviolet absorption peak at 240 mμ (ε12,000).
Reaction SMILES: C([NH:4][C@@:5]([CH3:17])([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])(=O)C.[ClH:18]>>[ClH:18].[NH2:4][C@@:5]([CH3:17])([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1ccc([C@](C)(NC(C)=O)C(=O)O)cc1
Agent: Cl
Product: COc1ccc([C@](C)(N)C(=O)O)cc1
Yield: 92 %

Procedure:
A suspension of (S)-(+)-α-acetamido-4-methoxy-α-methylbenzeneacetic acid (30 g, 126 mmol) in 4N HCl (300 mL) was refluxed for 2 hours and evaporated in vacuo to dryness. The residue was repeatedly dissolved in EtOH and evaporated again to dryness (4 liters of EtOH were used). The final solid was washed with tert-butyl methyl ether (4×100 mL) and finally with acetone (2×125 mL), dried in vacuo at 40° C. in presence of P2O5 to yield 26.92 g of (S)-α-amino-4-methoxy-α-methylbenzeneacetic acid, hydrochloride salt (92%, mp: >260° C.). αD : 70.4° (1N HCl, c=1).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([CH:10]([CH2:22][CH:23]=[CH2:24])[CH2:11][O:12][SiH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH:8]=[CH2:9]>C1(C)C=CC=CC=1>[CH2:7]([CH:10]([CH2:22][CH:23]=[CH2:24])[CH2:11][O:12][SiH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH2:1])=[CH:16][CH:15]=1)[CH:8]=[CH2:9]
Reactant: CC(C)(C)[O-]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(C=O)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCC(CC=C)CO[SiH2]c1ccc(C=C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Firstly, PPh3MeI (317 mg, 0.78 mmol: Me=methyl) was added with dist. toluene (4 mL). The resultant mixture was then added with KOt-Bu (88 mg, 0.78 mmol) at 0° C., and then was stirred under a nitrogen atmosphere at 0° C. for 30 minutes to obtain a mixture. Subsequently, the obtained mixture was added dropwise with a mixed solution (2 mL) of 4-(diallylethoxysilyl)benzaldehyde (204.2 mg, 0.78 mmol) obtained in Example 12 and dist. toluene under a nitrogen atmosphere at 0° C. The resultant mixture was stirred under a nitrogen atmosphere at 0° C. for 1.5 hours, and then was stirred at room temperature for 17 hours to obtain a reaction mixture. After that, a salt contained in the reaction mixture was removed through a celite filtration process. The organic layer thus obtained was then concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=20/1) to obtain 4-(diallylethoxysilyl)styrene (134.3 mg, 66% yield).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH:28]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[CH2:28][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN(C)CC3)c2c1

Procedure:
The title compound was prepared as a solid by the method of Example 59 step iv) using product of Example 59 step iii) and 1-methylpiperazine.