Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1B1OC(C)(C)C(C)(C)O1.[Cl:21][C:22]1[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=1.C(=O)(O)O.[K]>CCO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])[N:25]=[CH:24][N:23]=1
Reactant: COc1cc([N+](=O)[O-])ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)O
Agent: [K]
Solvent: CCO
Product: COc1cc([N+](=O)[O-])ccc1-c1cc(Cl)ncn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
2-(2-methoxy-4-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2 g, 7.17 mmol) was dissolved in 20 ml of EtOH and the resulting solution was concentrated to ˜15 ml and diluted with EtOH (30 ml). To this solution was added 4,6-dichloropyrimidine (1.495 g, 10.03 mmol), Bis(triphenylphosphine)palladium(II) chloride (0.075 g, 0.107 mmol) and aqueous potassium hydrogenbicarbonate (2.152 g, 21.50 mmol) (in 10 ml of water) at rt. The resulting mixture was stirred at 80° C. for 2 h. The reaction was concentrated under vacuum. The residue was partitioned between EtOAc/aqueous sodium bicarbonate. The aqueous layer was extracted with EtOAc (3×20 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2×20 ml) and brine (20 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified via Biotage Horizon system (25 g column of Thomson Single Step, EtOAc/Hexane, Griadient: 0%˜30%) to get 0.66 g (35%) of product as white solid. LC-MS (M+H)+=266.1. 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 3H) 7.90 (d, J=2.26 Hz, 1H) 7.98 (dd, J=8.53, 2.26 Hz, 1H) 8.09 (d, J=1.00 Hz, 1H) 8.26 (d, J=8.53 Hz, 1H) 9.10 (d, J=1.25 Hz, 1H).
Reaction SMILES: [Br:1]Br.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([N:11]1[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:4]2>C(O)(=O)C>[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH:5]([N:11]1[CH:20]=[C:19]([Br:1])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:4]2
Reactant: BrBr
Reactant: O=c1c2ccccc2ccn1C1CN2CCC1CC2
Solvent: CC(=O)O
Product: O=c1c2ccccc2c(Br)cn1C1CN2CCC1CC2

Procedure:
A solution of Br2 (1.0M) in glacial acetic acid (0.8 mL) was added to a solution of (RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)-l(2H)-isoquinolinone (0.20 g; 0.787 mmol), from Example 2, in glacial acetic acid (5.0 mL). Thesolvent was removed under pressure and the residue was partitioned between methylene chloride (100 ml) and sodium carbonate (2.0M, 30 ml). The organic phase was separated and dried over anhydrous sodium sulfate. The mixture was then filtered and concentrated under reduced pressure. The solid residue was dissolved in ethyl alcohol (2 ml) and the solution acidified with hydrochloric acid (10%). A small amount of ethyl ether was added and crystals were collected and dried in vacuo to give (RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)-4-bromo-1(2H)-isoquinolinone (0.0832 g, 0.248 mmol), m.p. 208°-209° C.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[CH2:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[S:17][C:18]([C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:14])[CH:10]=[CH:9][N:8]=1.O>CN(C=O)C>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:20]=[C:16]([NH:15][C:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][O:4][CH3:3])[CH:12]=2)=[O:14])[S:17][C:18]=1[C:26]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccnc(CCl)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under ice-cooling, 60% sodium hydride (10.0 mg, 0.250 mmol) was dissolved in DMF (1.0 mL), methanol (110 μL, 2.72 mmol) was slowly added dropwise thereto, and the mixture was stirred at 0° C. for 10 min. Then, 2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide (81.0 mg, 0.189 mmol) obtained in step 1 of Reference Example 6, which was dissolved in DMF (1.0 mL), was slowly added dropwise thereto, and the mixture was stirred at room temperature for 5 hr. To the mixture were added water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50), and recrystallized from ethanol-water to give compound (IJ) (45.0 mg, 56%) as white crystals.
Reaction SMILES: C1C2C(COC([NH:18][C:19]([CH3:69])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44]([NH:46][C@H:47]([C:55]3[S:56][CH:57]=[CH:58][N:59]=3)[CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[S:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1>ClCCl.C(NCC)C>[CH3:20][C:19]([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:65]([CH3:68])[CH2:66][CH3:67])[C@H:33]([O:63][CH3:64])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:61][CH3:62])[C@@H:43]([CH3:60])[C:44]([NH:46][C@H:47]([C:55]1[S:56][CH:57]=[CH:58][N:59]=1)[CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[S:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])([CH3:69])[NH2:18]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: ClCCl
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)c1nccs1)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Yield: 59.9 %

Procedure:
According to general procedure A, from #33 (55 mg, 0.055 mmol, 1 eq.) in dichloromethane (6 mL, 0.009 M) and diethylamine (4 mL) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to give #34 (25 mg, 60%) as a solid. HPLC (Protocol A): m/z 759.4 [M+H+], retention time=7.088 minutes, (purity >75%). 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.54 (br d, J=8 Hz) and 10.81 (br d, J=8 Hz), total 1H], 8.01-8.08 (m, 1H), [7.80 (d, J=3.1 Hz) and 7.83 (d, J=3.3 Hz), total 1H], [7.65 (d, J=3.2 Hz) and 7.69 (d, J=3.2 Hz), total 1H], 7.29-7.33 (m, 2H), 7.20-7.27 (m, 2H), 7.13-7.19 (m, 1H), 6.27-6.35 and 6.40-6.48 (2 m, total 1H), [4.49 (dd, J=9, 8 Hz) and 4.56 (dd, J=9, 8 Hz), total 1H], 3.24 and 3.25 (2 s, total 3H), 3.17 and 3.21 (2 s, total 3H), 2.92 and 2.99 (2 br s, total 3H), 1.20 and 1.21 (2 s, total 3H), 1.12 and 1.13 (2 s, total 3H), 0.75-0.81 (m, 3H).
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/C(O)=O.[NH:9]([C:11]1[N:16]=[N:15][C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]=2[CH:12]=1)[NH2:10].[OH-].[Na+].C(Cl)(Cl)Cl>CC(C)=O.N>[C:2](=[N:10][NH:9][C:11]1[N:16]=[N:15][C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:13]=2[CH:12]=1)([CH3:3])[CH3:1]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: NNc1cc2c(nn1)CCCCCCCCCC2
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)=NNc1cc2c(nn1)CCCCCCCCCC2

Procedure:
1.5 g of 3-hydrazino-5,6,7,8,9,10,11,12,13,14-decahydrocyclododeca[c]pyridazine fumarate are heated in 20 cc of acetone, to which a few drops of concentrated aqueous ammonia solution have been added, on a water bath for 1 hour. The mixture is cooled with ice, and the resulting crude title compound is divided between 5 cc of concentrated aqueous caustic soda solution and 20 cc of chloroform. The chloroform phase is concentrated, whereby a yellowish foam results, from which the title compound is obtained by recrystallization from absolute ethanol. M.P. 165°-166° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N+]([O-])=O)\[CH3:10])=[C:4]([F:14])[CH:3]=1.[N+:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[C-:16].C1COCC1>CC(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:10])=[CH:16][NH:15][C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([F:14])[CH:3]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C/C(=C\c1ccc(Cl)cc1F)[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.2 %

Procedure:
To a suspension of (E)-4-chloro-2-fluoro-1-(2-nitroprop-1-enyl)benzene (5 g, 23.2 mmol) and ethyl 2-isocyanoacetate (2.65 mL, 24.4 mmol) in a mixture of dry THF (20 mL) and i-PrOH (20 mL) was added 2.6 mmol TBD/g polymer (9.8 g, 25.5 mmol). The suspension was stirred at room temperature for 5 d. The reaction mixture was filtered off and the residue was washed with i-PrOH/THF (1:1, 30 mL). The filtrate was concentrated to give the desired product (5.7 g, 87%) as a yellow oil.
Reaction SMILES: [CH:1]1[C:11]([Br:12])=[CH:10][C:9]2[C:3](=[N:4][C:5]([NH:7][N+:8]=2[O-:13])=O)[CH:2]=1.O=P(Cl)(Cl)[Cl:16]>>[Br:12][C:11]1[CH:1]=[CH:2][C:3]2[N:4]=[C:5]([Cl:16])[N:7]=[N+:8]([O-:13])[C:9]=2[CH:10]=1
Reactant: O=c1nc2ccc(Br)cc2[n+]([O-])[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: [O-][n+]1nc(Cl)nc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A solution of 7-bromo-1-oxy-benzo[1,2,4]triazin-3-ol (11 g, 46 mmol) in POCl3 (50 mL) was heated under reflux for 16 h, cooled to rt, poured into ice-water and stirred for 30 min. The mixture was filtered, washed with water and dried to afford 7-Bromo-3-chloro-benzo[1,2,4]triazine 1-oxide (5 g, 42%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=O.CO.[NH2:17][OH:18].Cl.[OH-].[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]1[CH2:13][CH:6]([CH2:7]1)[C:5]2=[N:17][OH:18]
Reactant: NO
Reactant: O=C1c2cc(Br)c(F)cc2C2CC1C2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: ON=C1c2cc(Br)ccc2C2CC1C2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
Into a 20-L 4-necked round-bottom flask was placed 6-Bromo-7-fluoro-2,3-dihydro-1H-1,3-methano-naphthalen-4-one (920 g, 3.88 mol, 1.00 equiv), methanol (7.5 L), tetrahydrofuran (2.5 L), NH2OH.HCl (538.2 g, 2.00 equiv), and KOH (655.2 g, 3.00 equiv, 50%). The resulting solution was stirred at 80° C. for 2.5 h and cooled to 25° C. The solids were filtered out and washed with 3×1 L of DCM. The filtrate was concentrated under vacuum and the residue was diluted with 5 L of H2O and 8 L of EA. The pH value of the solution was adjusted to 7 with HCl (3 M). The organic layer was washed with 1×2 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 980 g (crude) of 6-Bromo-2,3-dihydro-1H-1,3-methano-naphthalen-4-one oxime as a dark red solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])=[O:9].[Br:18]N1C(=O)CCC1=O.ClCCl>FC(F)(F)C(O)=O>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([Br:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])=[O:9]
Reactant: COC(=O)c1sccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sulfuric acid (98% strength; 12 mL) was added to a solution of 3-nitrothiophene-2-carboxylic acid methyl ester (Barker et al., Synth. Commun. 1995, 25, 3729; 20.8 g) in trifluoroacetic acid (60 mL). At 0° C., N-bromosuccinimide (21.9 g) was added in portions over a period of 45 minutes. After a further 30 minutes, the mixture was warmed to room temperature and poured into ice-water. The organic phase obtained by extraction with dichloromethane was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product with the molecular weight of 266.07 (C6H4BrNO4S) was obtained in this way; MS (ESI): 266 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=2[N+:20]([O-])=O)[C:15]#[N:16])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[S]>C(OCC)(=O)C>[NH2:20][C:19]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[NH:11][C:9]1[N:8]=[C:7]2[C:3]([NH:4][C:5](=[O:29])[N:6]2[CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[C:2]([Cl:1])[N:10]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Nc2nc(Cl)c3[nH]c(=O)n(C4CCOCC4)c3n2)c1
Agent: [S]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(Nc2nc(Cl)c3[nH]c(=O)n(C4CCOCC4)c3n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
Pale yellow solid. 86% yield on 0.49 mmol scale. In a typical procedure, to 3-(6-chloro-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purin-2-ylamino)-4-nitrobenzonitrile (0.49 mmol) was added ethyl acetate (20 mL) and Pt catalyst, 0.5% sulfur (Alfa Aesar) (95.5 mg 5% on activated carbon, 4.8 mg, 0.025 mmol, 0.05 equiv.) with stirring at room temperature under hydrogen (1 atm) for 18 h (HPLC monitoring). Filtration of the reaction mixture over a small plug of celite, thorough washing with ethyl acetate and methanol, evaporation of solvent and drying provided the desired product, which was used in the next step without further purification. Yield quantitative on 2.95 mmol scale. The catalyst was washed with 12-15 portions of 100 mL of a 1/1 (v) solution of methylene chloride/isopropanol to recover desired product. MS (EI) m/z 386.1 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9](I)[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Cu](C#N)[C:15]#[N:16]>CN(C=O)C>[C:15]([C:9]1[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=[C:5]([CH:8]=1)[CH:6]=[O:7])#[N:16]
Reactant: N#C[Cu]C#N
Reactant: COc1cc(C=O)cc(I)c1OC
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(C#N)c1OC
Temperature: 25 °C
Yield: 99.6 %

Procedure:
3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (4.40 g, 15.07 mmole), copper cyanide (13.5 g, 150.7 mmole) and dry DMF (45 ml) were stirred under an argon atmosphere for 18 hours at 140° C. The reaction was cooled to room temperature, filtered through celite, and the filtrate concentrated to an oil in vacuo. The dark brown oil was purified through a short flash silica column using 11 hexane/ethyl acetate as eluent to yield 2.87 g (69%) of a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.[C:37]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])([CH3:40])([CH3:39])[CH3:38]>CO.ClCCl>[C:37]([NH:41][C:42](=[O:45])[CH2:43][CH2:44][NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:4]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: C=CC(=O)NC(C)(C)C
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Solvent: CO
Solvent: ClCCl
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNCCC(=O)NC(C)(C)C)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
(2R,3R,4S,5R)-2-{2-(Aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 1) (250 mg, 0.48 mmol) was dissolved in stirred methanol (10 ml) and N-(tert-butyl)acrylamide (62 mg, 0.48 mmol) added. The reaction mixture was stirred for 24 hr at room temperature and then heated at reflux for 120 hr, at which time all solvent had evaporated. The residual reaction mixture was dissolved in dichloromethane and the solvent removed under reduced pressure, this procedure was repeated twice more and then the product purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (94:4:0.2) increasing in polarity to (93:7:0.3) to give the title compound (143 mg) as a foam. MS: 618 (MH+).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=O)[CH2:25][CH3:26])=[CH:23][C:18]=2[N:17]=[CH:16]1.O>CO>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[N:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24](=[N:2][OH:3])[CH2:25][CH3:26])=[CH:23][C:18]=2[N:17]=[CH:16]1
Reactant: NO
Reactant: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccc2c(c1)ncn2C1CCCCO1
Yield: 89.1 %

Procedure:
Hydroxylamine hydrochloride (54 mg, 0.78 mmol) and sodium acetate (100 mg, 1 mmol) were added to a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one (100 mg, 0.39 mmol) in MeOH (5 mL). The mixture was refluxed overnight. The mixture was poured into water and extracted with EtOAc. The organics were washed sequentially with water and brine, then (Na2SO4). Removal of solvent followed by SiO2 chromatography afforded 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one oxime (95 mg, 90% yield) as a light yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:23])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]21OCC[O:19]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([CH3:23])[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(CCCCOCc2ccccc2)CCCCC12OCCO2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC1(CCCCOCc2ccccc2)CCCCC1=O
Yield: 92.6 %

Procedure:
A mixture of the 2-(4'-benzyloxybutyl)-1,1-ethylenedioxy-2-methylcyclohexane (32.5 g, 0.10 mol), acetone (375 ml), H2O (50 ml) and 0.002 N H2SO4 (125 ml) is refluxed for 18 hours under a nitrogen atmosphere. The reaction mixture is cooled, the acetone is evaporated under reduced pressue and the aqueous layer extracted with ether (3×500 ml). The combined organic layers are washed with satd. NaHCO3 (2×300 ml), satd. NaCl (2×500 ml) and dried (MgSO4). The solvents are removed under reduced pressure and the crude product (29 g) is chromatographed on SilicAR CC-7 (500 g) in hexane. Elution with 5% ethyl acetate/hexane gives 2-(4'-benzyloxybutyl)-2-methylcyclohexanone as a colorless oil (25.4 g, 91%): ir (neat) 1705 cm-1 (CO); nmr (CDCl3) δ1.03 (s, 3H, CH3), 2.35 (m, 2H, OC-- CH2 --CH2), 3.5 (t, 2H, O--CH2 --CH2), 4.44 (s, 2H, O--CH2 --Ph), 7.3 (s, 5H, aromatic).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH:20]3[CH2:22][CH2:21]3)[CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1Br.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[C:33]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]3)O1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH:20]3[CH2:22][CH2:21]3)[CH3:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][C:7]=1[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[NH:36][CH2:35][CH2:34]2
Reactant: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(Br)n2)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)CCNC3=O)OC1(C)C
Product: CN(C1CC1)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1
Yield: 85 %

Procedure:
General method C was applied to 4-(5-amino-6-bromopyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide (383 mg, 1.00 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (300 mg, 1.1 mmol) to provide 4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-cyclopropyl-N-methylbenzenesulfonamide (382 mg, 85% yield) after purification by preparatory HPLC. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (s, 1H), 8.26 (d, J=8.5 Hz, 2H), 8.03 (br. s., 1H), 7.97 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.5 Hz, 2H), 7.74 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 3.42 (t, J=5.3 Hz, 2H), 2.99 (t, J=6.4 Hz, 2H), 2.67 (s, 3H), 1.77-1.86 (m, 1H), 0.61-0.81 (m, 4 H); MS (EI) m/z=450.5 [M+1]+.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:27])=[C:5]([C:18]([O:25]C)=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:22][O:21][C:20]1[C:3](=[O:2])[C:4]([CH3:27])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH3:17])=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:18](=[O:25])[C:19]=1[O:23][CH3:24]
Reactant: COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)O
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)O)c2)=C(C)C1=O
Yield: 99.9 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-methoxybenzoic acid (0.257 g, 0.684 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (0.937 g, 1.71 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.237 g, 0.683 mmol, 99%).
Reaction SMILES: P(O[CH2:10][CH3:11])(OCC)(OCC)=O.Br[CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C@H:20]2[CH2:25][CH2:24][Si@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]2)[CH2:16][CH2:15]1>C1COCC1.[Cu]I>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:10][CH2:11][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([C@H:20]3[CH2:25][CH2:24][Si@H:23]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[CH:15][CH:16]=1)[CH3:21]
Reactant: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CBr)CC2)CC1
Reactant: CCOP(=O)(OCC)OCC
Agent: [Cu]I
Solvent: C1CCOC1
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCCCc3ccc(CC)cc3)CC2)CC1

Procedure:
22.7 g (0.1 mol) of 4-(3-bromopropyl)-1-ethylbenzene was dropped in a mixture of 2.5 g (0.11 mols) of magnesium and 300 ml of THF to obtain a Grignard reagent. The resultant solution was further dropped in a solution, in 500 ml of THF, of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 31.7 g (0.1 mol) of trans-4-(trans-4-bromomethylcyclohexyl)-1-propyl-1-silacyclohexane. The resultant product was subjected to ordinary aftertreatments to obtain trans-4-(trans-4-(4-(4-ethylphenyl)butyl)cyclohexyl)-1-propyl-1-silacyclohexane. After ordinary aftertreatments, the product was purified through chromatography to obtain 31.7 g (yield: 82%) of the trans isomer product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:14]([NH:18][S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11])[CH2:15][CH2:16][CH3:17]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCN
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Yield: 86.3 %

Procedure:
4-Nitrophenylsulfonyl chloride (3.0 g, 13.5 mmol) was dissolved in THF and a catalytic amount of 4-dimethylaminopyridine and 1-butylamine (4.0 mL, 41 mmol) was added and the mixture was refluxed for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (100 mL) and washed with water (50 mL) and a 10% aqueous solution of sodium hydrogen carbonate (50 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to afford 3.01 g (86%) of N-butyl-4-nitrobenzenesulfonamide as a solid.