Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].[CH2:10]([N:17]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]([CH2:24]Cl)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)CCC.C(Cl)Cl>[CH2:10]([N:17]1[CH2:23][CH2:22][CH2:21][O:20][CH:19]([CH2:24][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCC1CN(Cc2ccccc2)CCCO1
Reactant: Nc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Solvent: ClCCl
Product: c1ccc(CN2CCCOC(CNc3ccccc3)C2)cc1
Temperature: 110 °C

Procedure:
Aniline (2.59 mL, 28.4 mmol) and NaI (4.06 g, 27.1 mmol) were added to a solution of 4-benzyl-2-chloromethyl-1,4-oxazepane (79) (6.49 g, 27.1 mmol) in n-butanol (68 mL, 0.4 M), and the reaction was heated to 110° C. until the reaction was judged complete by TLC (4 h). The reaction was cooled to room temperature, and water and CH2Cl2 were added. The organic layer was removed, and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to achieve (4-benzyl-1,4-oxazepan-2-ylmethyl)-phenyl amine 80, which was used without purification in the next reaction. 1H NMR (partial, CDCl3) 4.08–3.86 (3H, m), 3.80 (1H, d, J=13.3 Hz), 3.73 (1H, d, J=13.3 Hz), 3.22–3.05 (2H, m), 2.95–2.70 (3H, m), 2.64 (1H, dd, J=13.6, 7.6 Hz), 2.1–1.9 (2H, m) ppm. 13C NMR (CDCl3) 148.33, 139.38, 129.28, 129.11, 128.46, 127.23, 117.44, 113.13, 76.70, 67.49, 62.92, 59.35, 54.76,46.93, 30.75 ppm. LRMS: 296.68.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([SH:37])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:37][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]3[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=3[CH:23]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Reactant: COc1ccc(S)cc1OC
Product: COc1ccc(SCCCCOc2cc3c(cc2[N+](=O)[O-])NC(=O)OC3(C)C)cc1OC

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH2:11][C:12]#[CH:13].C[O-].[Na+].[Cl:17][C:18](OC(Cl)(Cl)Cl)=[O:19]>O.C(Cl)(Cl)Cl.CO>[Cl:17][C:18]([O:9][C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:10][CH2:11][C:12]#[CH:13])[CH:5]=1)=[O:19]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C#CCOc1cc(O)ccc1Cl
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: C#CCOc1cc(OC(=O)Cl)ccc1Cl

Procedure:
The sodium salt of 4-chloro-3-propargyloxyphenol as prepared from 14 g of 4-chloro-3-propargyloxyphenol and 28% methanol solution of sodium methylate was dissolved in 300 ml of distilled water and the solution was added dropwise to a solution of 5 ml of trichloromethyl chloroformate in 100 ml of chloroform at a temperature of 10° C. or below. The resulting reaction mixture was allowed to stand for phase separation. The chloroform layer was separated and dried over anhydrous magnesium sulfate, and the solvent was then distilled off. There was obtained 15.5 g of 4-chloro-3-propargyloxyphenyl chloroformate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1.Br[CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:31][CH2:32][C:33]([F:36])([F:35])[F:34])[CH2:20][CH2:21]3)=[CH:11][C:10]=2[F:22])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3F)ncc2Cl)n[nH]1
Reactant: FC(F)(F)CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCN(CCC(F)(F)F)CC4)cc3F)ncc2Cl)n[nH]1
Reaction time: 8 h

Procedure:
The mixture of 5-chloro-N2-(2-fluoro-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (0.12 mmol), 3-bromo-1,1,1-trifluoropropane (85.0 uL, 0.60 mmol) and triethylamine (102.0 uL, 0.60 mmol) in 2 mL of DMF was stirred overnight. The reaction mixture was purified by preparative RP-HPLC to afford 5-chloro-N2-(2-fluoro-5-methyl-4-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine. ESMS m/z 512.2 (M+H+).
Reaction SMILES: [CH:1]([C:5]([CH3:13])([CH:9]([CH3:12])[CH2:10][CH3:11])[C:6]([OH:8])=[O:7])([CH2:3][CH3:4])[CH3:2].S(Cl)([Cl:16])=O.[CH:18]([NH2:21])([CH3:20])[CH3:19]>CCOCC>[CH:1]([C:5]([CH3:13])([CH:9]([CH3:12])[CH2:10][CH3:11])[C:6]([Cl:16])=[O:7])([CH2:3][CH3:4])[CH3:2].[CH:18]([NH:21][C:6](=[O:8])[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])([CH3:13])[CH:9]([CH3:12])[CH2:10][CH3:11])([CH3:20])[CH3:19]
Reactant: O=S(Cl)Cl
Reactant: CC(C)N
Reactant: CCC(C)C(C)(C(=O)O)C(C)CC
Solvent: CCOCC
Product: CCC(C)C(C)(C(=O)Cl)C(C)CC
Product: CCC(C)C(C)(C(=O)NC(C)C)C(C)CC

Procedure:
2-sec-butyl-2,3-dimethylpentanoyl chloride (bp. 108°-110°/17 mm) was prepared in the usual way from 2-sec-butyl-2,3-dimethylpentanoic acid and thionyl chloride. A solution of this acid chloride (2.0 g) in ether (30 ml) was added with stirring to a solution of isopropylamine (2.0 g) in ether (100 ml). After 16 hours the external solution was washed with dilute hydrochloric acid and water, dried (MgSO4), and concentrated to give a white solid. This solid was recrystallized from petroleum ether (bp. 40°-60°) to give N-isopropyl-2-sec-butyl-2,3-dimethylpentanamide, MP. 74°-6°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:23]#[N:24])=[C:11]([NH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.B.C1COCC1.Cl>C1COCC1.O1CCOCC1.CO>[NH2:24][CH2:23][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:14][N:13]2[CH:15]=[CH:16][N:17]=[C:12]2[C:11]=1[NH:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CNc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)CNc1c(CN)c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
In a sealed flask, a solution of 6-(2,4-dichloro-phenyl)-8-isobutylamino-imidazo[1,2-a]pyridine-7-carbonitrile (19.1 mg, 0.053 mmol) in THF (0.5 mL) was cooled to 0° C. (ice bath), treated with BH3.THF complex (1.0 M solution in THF, 0.48 mL, 0.48 mmol) and heated at 40° C. After 1 h, the reaction was not complete according to HPLC. 4.0 M HCl in dioxane (2 drops) and additional BH3.THF complex (1.0 M solution in THF, 0.16 mL, 0.16 mmol) were added, then the reaction mixture was heated at 40° C. for 14 h, cooled to 0° C., and diluted in MeOH (large excess). The resulting mixture was concentrated under vacuum, and the remaining residue was dissolved in TFA. After evaporation to dryness, the remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 7.6 mg, 0.013 mmol, 24%). MS: 363 [M+1]+; HPLC: AtRet=1.47.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]([O:16][C:17]2[C:22]([CH:23]=[CH2:24])=[CH:21][CH:20]=[CH:19][C:18]=2[O:25][CH3:26])C=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[CH3:26][O:25][C:18]1[C:17]2[O:16][CH:13]([CH2:12][OH:11])[CH:24]=[CH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=Cc1cccc(OC)c1OC(C=C)COS(=O)(=O)c1ccc(C)cc1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: COc1cccc2c1OC(CO)C=C2
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 4 h
Yield: 183.5 %

Procedure:
A solution of 2-(2-methoxy-6-vinylphenoxy)but-3-enyl 4-methylbenzenesulfonate (4.4 g, 12 mmol) in dichloromethane (100 mL) was treated with benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (0.9 g) at 23° C. with stirring. After 4 hours, the solvent volume was reduced under reduced pressure (to ca. 10 mL) and the solution was pre-adsorbed on silica gel (5 g). Purification by flash chromatography using a solvent gradient of 10 to 20% ethyl acetate in hexane provided 8-methoxy-2H-1-benzopyran-2-methanol 4-methylbenzenesulfonate (4.0 g, 98%) as a dark oil. MS (ESI) m/z 345.0 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[CH:13][C:5]2[NH:6][C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:8][C:4]=2[C:3]=1[F:16].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:45]1[O:57][C@H:56]([CH3:58])[C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@H:46]1[O:47][C:48](=[O:50])[CH3:49])(=O)C>ClCCCl>[Cl:15][C:14]1[C:2]([Cl:1])=[C:3]([F:16])[C:4]2[N:8]([C@@H:45]3[O:57][C@H:56]([CH3:58])[C@@H:51]([O:52][C:53](=[O:55])[CH3:54])[C@H:46]3[O:47][C:48](=[O:50])[CH3:49])[C:7]([NH:9][CH:10]([CH3:12])[CH3:11])=[N:6][C:5]=2[CH:13]=1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(C)Nc1nc2c(F)c(Cl)c(Cl)cc2[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(NC(C)C)nc2cc(Cl)c(Cl)c(F)c21
Yield: 26 %

Procedure:
5,6-Dichloro-4-fluoro-N-(1-methylethyl)-1H-benzimidazol-2-amine (0.85 g, 3.24 mmol), N,O-bis(trimethylsilyl)acetamide (0.89 mL, 0.73 g, 3.60 mmol), trimethylsilyl trifluromethanesulfonate (0.45 mL, 0.53 g, 2.25 mmol), 1,2,3-tri-O-acetyl-5-deoxy-ribofuranose (1.15 g, 4.42 mmol) and 1,2-dichloroethane were used according to general procedure II. The title compounds were purified by silica gel chromatography using 95:5 dichloromethane-acetonitrile to first provide 5,6-dichloro-4-fluoro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine as a white foam (0.66 g, 44%); 1H NMR (DMSO-d6) δ: 7.49 (s, 1H, Ar—H), 7.05 (d, J=7.4 Hz, 1H, NH), 6.09 (d, J=6.8 Hz, 1H, CH), 5.57 (t, J=7.2 Hz, 1H, CH), 5.24 (dd, J=7.4, 5.3 Hz, 1H, CH), 4.12 (m, 2H, overlapping CH), 2.14 (s, 3H, CH3), 2.01 (s, 3H, CH3), 1.49 (d, J=6.3 Hz, CH3), 1.24 (m, 6H, overlapping CH3). The second fraction provided 5,6-dichloro-7-fluoro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-N-(1-methylethyl)-1H-benzimidazol-2-amine as a white foam (0.39 g, 26%); 1H NMR (DMSO-d6) δ: 7.37 (s, 1H, Ar—H), 7.12 (d, J=7.4 Hz, 1H, NH), 6.08 (d, J=5.4 Hz, 1H, CH), 5.32 (t, J=6.8 Hz, 1H, CH), 4.98 (t, J=7.3 Hz, 1H, CH), 4.10 (m, 2H, overlapping CH), 2.10 (s, 3H, CH3), 2.04 (s, 3H, CH3), 1.41 (d, J=6.2 Hz, CH3), 1.23 (m, 6H, overlapping CH3).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH:12][CH:13]=1.[C:21](OCC)(=[O:27])[C:22]([O:24]CC)=[O:23]>O1CCCC1.O.CCCCCC>[CH2:1]([C:9]1[C:8]([O:7][CH3:6])=[CH:13][CH:12]=[CH:11][C:10]=1[NH:14][C:15](=[O:20])[C:16]([CH3:17])([CH3:19])[CH3:18])[CH3:2].[O:27]=[CH:21][C:22]([O-:24])=[O:23]
Reactant: [Li]CCCC
Reactant: COc1cccc(NC(=O)C(C)(C)C)c1
Reactant: CCOC(=O)C(=O)OCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CCc1c(NC(=O)C(C)(C)C)cccc1OC
Product: O=CC(=O)[O-]
Reaction time: 2 h

Procedure:
Under argon atmosphere and water cooling, 43 ml of a hexane solution of 1.6M n-butyl lithium was added dropwise to a solution of 5.75 g of N-(3-methoxyphenyl)-2,2-dimethyl-propaneamide [synthesized according to R. M. Soll et al., Journal of Organic Chemistry, 53, 2844 (1988)] in 100 ml of tetrahydrofuran. After the mixture was stirred under ice cooling for 2 hours, 18 ml of diethyl oxalate was added to the mixture, and the resulting mixture was stirred at room temperature for additional 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried, the solvent was removed by evaporation. The residue was purified by silica gel column chromatography [hexane-ethyl acetate (5:1)] and recrystallized from ethyl acetate-hexane to afford 2.86 g of ethyl 2-(2,2-dimethylpropanoylamino)-6-methoxybenzene-α-oxoacetate as lightly yellow crystals. Melting point: 99° to 100° C.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].O1C[CH2:11][CH2:10][CH2:9]1.[C:13](=[S:15])=[S:14].C(Br)C=C>O>[CH2:9]([S:15][C:13](=[S:14])[N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:10]=[CH2:11]
Reactant: C1CCOC1
Reactant: CCCNCCC
Reactant: S=C=S
Solvent: C=CCBr
Solvent: O
Product: C=CCSC(=S)N(CCC)CCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
13.4 Grams of dipropylamine was added to 50 ml of tetrahydrofuran, and to this mixture being maintained a temperature at 0°-5° C., was added dropwise 5.0 gr of carbon disulfide over the period of 30 minutes under agitation. Thereafter, the mixture was maintained at a room temperature and 7.3 gr of allyl bromide was added dropwise thereto over the period of 30 minutes. The mixture was agitated at the same temperature for 3 hours to complete the reaction. The reaction mixture was poured into water and the separated organic substance was extracted twice with 30 ml of toluene and washed with diluted hydrochloric acid, followed by further washing with water. After removal of toluene by distillation to obtain 9.7 gr of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:20][CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:6]([CH:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)O)[CH:7]=1.[SH:26][CH:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28](O)=[O:29].C(O)(=O)CC>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:28](=[O:29])[CH:27]([CH2:31][C:32]([OH:34])=[O:33])[S:26][CH:8]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][CH:11]=3)[C:6]=2[CH:7]=1
Reactant: CC(C)(C)CNc1ccc(Cl)cc1C(O)c1cccc2ccccc12
Reactant: O=C(O)CC(S)C(=O)O
Solvent: O
Solvent: CCC(=O)O
Product: CC(C)(C)CN1C(=O)C(CC(=O)O)SC(c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
A stirred mixture of 50.0 g (141 mmol) of (5-chloro-2-neopentylamino-phenyl)-naphthalen-1-yl-methanol, 27.58 g (184 mmol, 1.3 equivalents) of mercaptosuccinic acid, and 340 mL of propionic acid was heated to 130° C. with a nitrogen purge. After 48 hours, the reaction mixture was cooled to room temperature giving a precipitate, treated with 200 mL of water, cooled to -5° C. with stirring, and filtered giving 60.83 g (92% yield) of the title compound as an off white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:10].[BH4-].[Na+].C(O)(=O)C>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[OH:10]
Reactant: O=C(CCCCCCCBr)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: OC(CCCCCCCBr)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of 8-bromo-1-(4-chlorophenyl)octan-1-one (0.95 g) in industrial methylated spirit (10 ml) was added sodium borohydride (0.115 g) at −10° C. After stirring for 1 h, glacial acetic acid (0.2 g) was added and the mixture was poured into water (60 ml) and extracted with diethyl ether. The diethyl ether layer was washed with brine and dried over magnesium sulfate. Removal of the solvent under reduced pressure gave an oil that was chromatographed on silica gel using dichloromethane as eluent. This gave 8-bromo-1-(4-chlorophenyl)-1-hydroxyoctane (0.70 g). 1H-NMR (CDCl3) δ 1.15-1.95 (12H, m), 3.40 (2H, t), 4.65 (1H, t) and 7.2-7.4 (4H, m).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15][Si:16]([CH2:19][CH2:20][O:21][CH2:22]Cl)([CH3:18])[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:22][O:21][CH2:20][CH2:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1c[nH]c2ncc(Br)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Yield: 21.2 %

Procedure:
To a 10 ml round bottom flask, 2-bromo-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (0.450 g, 0.00199 mol) and NaH (0.143 g, 0.00597 mol) were taken in DMF (5 ml) and stirred in cooling for 15 min. SEM-Cl (0.497 g, 0.00298 mol) was added dropwise and stirred at room temperature for 2 hr. After completion of the reaction, the reaction mixture was poured in to water and extracted with ethyl acetate. The combined organics were washed with brine solution. The organic layer was separated and dried over sodium sulphate, concentrated to give the crude product which was purified using column purification by eluting the compound with 10% ethyl acetate in hexanes to yield 150 mg of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde.
Reaction SMILES: Cl.[C:2]1([CH2:12][CH2:13][NH2:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:21]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22]1>O.C(Cl)(Cl)Cl>[C:2]1([CH2:12][CH2:13][NH:14][C:25]([CH:21]2[CH2:24][CH2:23][CH2:22]2)=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NCCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(NCCc1cccc2ccccc12)C1CCC1

Procedure:
0.01 mol of N-[2-(1-naphthyl)ethyl]amine hydrochloride is dissolved in a water/chloroform (40: 60; vol/vol ) mixture, and 0.02 mol of potassium carbonate is then added with magnetic stirring. The reaction mixture is cooled in an ice bath, and 0.01 mol of cyclobutanecarbonyl chloride is then added dropwise with magnetic stirring.
Reaction SMILES: [CH2:1]([NH:8][S:9]([CH2:12][C@:13]12[C:19]([CH3:21])([CH3:20])[C@H:16]([CH2:17][CH2:18]1)[CH2:15][C:14]2=[N:22]O)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.C(N)(C)(C)C>C(O)C.C(OCC)(=O)C>[CH2:1]([NH:8][S:9]([CH2:12][C@:13]12[C:19]([CH3:20])([CH3:21])[C@H:16]([CH2:17][CH2:18]1)[CH2:15][C@H:14]2[NH2:22])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)NCc1ccccc1)C(=NO)C2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(C)(C)N
Product: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)NCc1ccccc1)[C@H](N)C2
Temperature: 0 °C

Procedure:
A solution of (1S,4R)—N-benzyl-2-hydroxyimino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (IXa) (45.0 g, 134 mmol) in ethanol (360 mL) was added dropwise to a solution of sodium acetate (94.5 g, 1150 mmol) and TiCl3 (460 mmol) in 10.5% wt. aq. HCl (320 mL) at −20 to −10° C. The addition was conducted below 0° C., and the reaction mixture was then stirred at 0° C. for an hour prior to addition of neat t-BuNH2.BH3 (29.1 g, 335 mmol) in portions. The mixture was stirred at 0-10° C. for 30 minutes and then at ambient temperature. After the reaction was completed, the solution was diluted with ethyl acetate (675 mL) and was extracted with water (450 mL). Following separation of the layers, the organic layer was washed with sat. aq. NH4Cl (675 mL), 1 M aq. Na2CO3 (900 mL) and finally with 10% aq. NaCl (450 mL). The organic solution was concentrated to give the crude amine product (1S,2R,4R)—N-benzyl-2-amino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (VIa) as light yellow powder. The crude product was dissolved in ethanol (180 mL) at 70-75° C. and was hot-filtered. The filter cake was washed with hot ethanol (45 mL), and the filtrate was slowly cooled allowing recrystallization to occur at about 50° C. After stirring for an hour at 0° C., the white suspension was filtered and washed with cold ethanol (45 mL) to give pure (1S,2R,4R)—N-benzyl-2-amino-7,7-dimethylbicyclo[2.2.1]hept-1-ylmethanesulfonamide (VIa) as a white powder (23.5 g; 54%; >99.9% pure as assessed by HPLC).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([Br:18])=[N:16][NH:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1
Reactant: CN(C)CCN
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2[nH]nc(Br)c2c(=O)n1Cc1ccccc1

Procedure:
A solution of 5-benzyl-3-bromo-6-(1-bromopropyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1-3, 5.0 g, 11.7 mmol, 1 equiv) and N,N-dimethylethylenediamine (2.6 g, 29.3 mmol, 2.5 equiv) in ethanol (25 mL) was heated at reflux for 18 h. The reaction was concentrated, and the residue was purified by flash chromatography. Elution with CH2Cl2 to 25% NH3-EtOH/(CH2Cl2 gave 5-benzyl-3-bromo-6-(1-{[2-(dimethylamino)ethyl]amino}propyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (1-4) as a light green foam. 1H NMR (500 MHz, CDCl3) δ 11.1 (bs, 1H), 7.33 (m, 2H), 7.29 (m, 1H), 7.15 (d, J=7 Hz), 5.97 (d, J=16 Hz), 4.71 (d, J=16 Hz), 3.58 (m, 1H), 2.52 (m, 1H), 2.30 (m, 2H), 2.24 (s, 6H), 1.94 (m, 1H), 1.52 (m, 1H), 1.31 (m, 1H), 0.84 (t, J=7 Hz, 3H).
Reaction SMILES: O1CCCC1.[C:6]([C:8]1([OH:26])[C:19]([CH3:24])([C:20]([F:23])([F:22])[F:21])[CH2:18][C:11]2([O:15][CH:14]([CH3:16])[CH:13]([CH3:17])[O:12]2)[CH:10]=[C:9]1[CH3:25])#[CH:7].[CH2:27]([SnH:31]([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:17][CH:13]1[CH:14]([CH3:16])[O:15][C:11]2([CH2:18][C:19]([CH3:24])([C:20]([F:21])([F:23])[F:22])[C:8](/[CH:6]=[CH:7]/[Sn:31]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:28][CH2:29][CH3:30])([OH:26])[C:9]([CH3:25])=[CH:10]2)[O:12]1
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CC1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](/C=C/C1(O)C(C)=CC2(CC1(C)C(F)(F)F)OC(C)C(C)O2)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.4 %

Procedure:
Under argon, tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.02 mmol) was initially charged in a round-bottom flask that had been dried by heating, and abs. tetrahydrofuran (5 ml) and 8-ethynyl-2,3,7,9-tetramethyl-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-ol (100 mg, 0.33 mmol) were added. Stirring at room temperature for 5 minutes was followed by the addition of tributyltin hydride (0.11 ml, 0.39 mmol). The resulting reaction mixture was stirred at 55° C. for 1 h and, after cooling to room temperature, water was added. The aqueous phase was repeatedly extracted thoroughly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), it was possible to obtain 2,3,7,9-tetramethyl-8-[(E)-2-(tributylstannyl)vinyl]-9-(trifluoromethyl)-1,4-dioxaspiro[4.5]dec-6-en-8-ol (160 mg, 82% of theory) in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.33/6.31 (d, 1H), 5.97/5.92 (d, 1H), 5.51/5.42 (s, 1H), 4.24/3.64 (m, 2H), 2.46/2.35 (d, 1H), 1.92 (br. s, 1H, OH), 1.91/1.87 (d, 1H), 1.64/1.62 (s, 3H), 1.49 (m, 6H), 1.32-1.26 (m, 9H), 1.18 (m, 3H), 0.89 (m, 18H).