Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([O:14][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:20].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(OCC)(=O)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([F:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(O[Si](C)(C)C)CC1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Reaction time: 1.25 h
Yield: 91 %

Procedure:
To a stirred solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydro-4-(trimethylsilyloxy)pyridine (400 g, 14.7 mmol) in anhydrous acetonitrile (160 mL) under nitrogen was added Selectfluor™ reagent (5.74 g, 16.2 mmol) and the mixture was stirred for 75 min. The mixture was poured into ethyl acetate (600 mL), washed with diluted brine (300 mL), then saturated NaCl solution (100 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (alumina, 0-5% MeOH/EtOAc) to afford 2.91 g (91%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 1.50 (9H, s), 2.52-2.64 (2H, m), 3.22-3.38 (2H, m), 4.18 (1H, m), 4.45 (1H, m), 4.83 (1H, m).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C[O:37][C:38]1[CH2:43][CH2:42][CH2:41][C:40](=O)[CH:39]=1.[Br-].[Li+]>C1COCC1.C(#N)C.C(Cl)(Cl)Cl>[OH:37][C:38]1[CH:39]=[C:40]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:9]2=[O:15])[CH:41]=[CH:42][CH:43]=1
Reactant: COC1=CC(=O)CCC1
Reactant: O=C1CCCCCN1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1C(c2cccc(O)c2)CCCCN1Cc1ccccc1
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
A solution of hexahydro-1-phenylmethyl-2H-azepin-2-one (5.68 g) in dry THF was added at -10° C. to lithium diisopropylamide (0.032 mm) prepared from diisopropylamine (4.4 ml) and butyl lithium (22.9 ml of 1.4 M solution in hexane). The mixture was stirred for 30 minutes and then treated with a solution of 3-methoxy-2-cyclohexenone (2.53 g) in THF. After 5 hours at ambient temperature the mixture was poured onto ice-cold concentrated hydrochloric acid (100 ml). After vigorously stirring for 12 hours the solution was shaken with several portions of chloroform. The combined chloroform layers were evaporated to give an orange oil. This was refluxed with cupric bromide (8.95 g) and lithium bromide (1.74 g; 0.02 m) in acetonitrile for 1 hour. Removal of the solvent left a black oil that was triturated with excess 2 N sodium hydroxide solution. The filtrate, after removal of the orange precipitate, was extracted with methylene chloride. The organic layer was acidified (conc.HCl) and the white suspension shaken with several portions of chloroform and were evaporated to leave a dark red oil (1.2 g) that crystallised from ethyl acetate to give the title compound (0.35 g) m.p. 160°-166° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12])=[O:3]>C(Cl)Cl>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([CH:2]([OH:3])[CH3:1])[CH:9]=1
Reactant: COc1ccc(Br)cc1C(C)=O
Solvent: ClCCl
Product: COc1ccc(Br)cc1C(C)O
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
An oven dried 500 mL flask, was charged under nitrogen with (S)-2-methyl-CBS-oxazaborolidine 1M in toluene (2.18 mL) and dissolved in CH2Cl2 (100 mL). Me2-BH3 (13.10 mL, 26.20 mmol) was then added and cooled reaction to −30° C. then stirred for 15 minutes. 5-Bromo-2-methoxyacetophenone (5 g, 21.83 mmol) was dissolved in CH2Cl2 (10 mL) and slowly added via addition funnel to the previous solution. The resulting reaction was stirred at −30° C. for 1 hour. The solution was carefully quenched with MeOH, the solvent was removed in vacuo and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to provide the desired product (5 g, 100%) as a clear oil. 1H NMR (400 MHz, CDCl3): δ 1.47 (d, J=6.41 Hz, 3H), 2.44 (d, J=5 Hz, 1H), 3.84 (s, 3H), 5.03–5.11 (m, 1H), 6.74 (d, J=8.7 Hz, 1H), 7.33 (dd, J=8.7, 2.5 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H).
Reaction SMILES: [O:1]1[C:5]([C:6](OC)=[O:7])=[CH:4][C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(OCC)(=O)C>O1CCCC1>[OH:7][CH2:6][C:5]1[O:1][CH:2]=[C:3]([C:10]([O:12][CH3:13])=[O:11])[CH:4]=1
Reactant: COC(=O)c1coc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1coc(CO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.7 %

Procedure:
408 mg of dimethyl furan-3,5-dicarboxylate [see J. Chem. Soc., Perkin I, 1130 (1973)] was dissolved in 4 ml of anhydrous tetrahydrofuran, and 59 mg of lithium aluminium hydride was added. The mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and ethyl acetate was added to extract it. The extract was worked up in a customary manner and purified by silica gel column chromatography [Wakogel C-200, 20 g; eluting solvent: hexane/ethyl acetate=2/1] to give 44 mg (yield 13%) of methyl 5-hydroxymethylfuran-3-carboxylate as a colorless oil.
Reaction SMILES: CP(C1N=C(OC)C(N)=NC=1)(C)=O.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:36]([O:37][CH3:38])=[N:35][C:34]([P:39]([CH3:42])([CH3:41])=[O:40])=[CH:33][N:32]=2)[C:27]([Cl:43])=[CH:26][N:25]=1.[N:44]1([CH:50]2[CH2:55][CH2:54][N:53]([C:56]3[S:60][C:59]([NH2:61])=[N:58][N:57]=3)[CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[N:44]1([CH:50]2[CH2:55][CH2:54][N:53]([C:56]3[S:60][C:59]([NH:61][C:24]4[N:29]=[C:28]([NH:30][C:31]5[C:36]([O:37][CH3:38])=[N:35][C:34]([P:39]([CH3:42])([CH3:41])=[O:40])=[CH:33][N:32]=5)[C:27]([Cl:43])=[CH:26][N:25]=4)=[N:58][N:57]=3)[CH2:52][CH2:51]2)[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1
Reactant: COc1nc(P(C)(C)=O)cnc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1nnc(N2CCC(N3CCCCC3)CC2)s1
Agent: COc1nc(P(C)(C)=O)cnc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1nc(P(C)(C)=O)cnc1Nc1nc(Nc2nnc(N3CCC(N4CCCCC4)CC3)s2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 5-(dimethylphosphoryl)-3-methoxypyrazin-2-amine (prepared In example 33) with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine. 2,5-dichloro-N-[5-(dimethylphosphoryl)-3-methoxypyrazin-2-yl]pyrimidin-4-amine is then reacted with 5-(1,4′-bipiperidin-1′-yl)-1,3,4-thiadiazol-2-amine according to the procedure described in Example 321.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].I[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>C1COCC1.C(OCC)(=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[N:2]2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(CI)cc1
Reactant: OCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(COCCn2ccnn2)cc1
Reaction time: 0.75 h
Yield: 27.4 %

Procedure:
To a solution of 2-[1,2,3]triazol-1-yl-ethanol (5.98 g, 52.84 mmol) in dry THF (150 ml) at −50° C. sodium hydride (1.27 g, 52.84 mmol) was added and the mixture stirred for 45 min. followed by the addition of 1-iodomethyl-4-nitro-benzene (13.9 g, 52.84 mmol). The mixture was refluxed for 2 h, water (100 ml) and ethyl acetate (150 ml) were added and the resulting precipitate removed by filtration. The filtrate was concentrated and the residue purified by flash column chromatography (ethyl acetate 100%) yielding 3.6 g (27%) 1-[2-(4-nitro-benzyloxy)-ethyl]-1H-[1,2,3]triazole.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:7][O:8][C:9]=1[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=O)=[O:4].S(=O)(=O)(O)O>>[CH3:1][N:2]1[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:10][C:9]2[O:8][N:7]=[C:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:5]=2[C:3]1=[O:4]
Reactant: CNC(=O)c1c(-c2ccccc2)noc1CC(=O)c1ccc(C)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(-c2cc3onc(-c4ccccc4)c3c(=O)n2C)cc1

Procedure:
A mixture of 26.1 g. (0.0815 mole) of N-methyl-5-(4-methylphenacyl)-3-phenyl-4-isoxazole carboxamide and 261 ml. of 2M sulfuric acid is refluxed for 24 hours. The mixture is cooled and extracted with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether and then recrystallized from ethanol to give 5-methyl-3-phenyl-6-(p-tolyl)-isoxazolo[4,5-c]pyridin-4(5H)-one; m.p. 155° to 156° C.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:14]=[C:13]4I)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:32]=[N:31][CH:30]=[C:29]([Sn](CCCC)(CCCC)CCCC)[N:28]=1>CN(C=O)C.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.[Cu]I>[Cl:26][C:27]1[N:28]=[C:29]([C:13]2[C:12]3[C:16](=[CH:17][CH:18]=[C:10]([C:8]4[CH:7]=[N:6][CH:5]=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:9]=4)[CH:11]=3)[N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:14]=2)[CH:30]=[N:31][CH:32]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Reactant: Ic1nn(C2CCCCO2)c2ccc(-c3cncc(C4CC4)n3)cc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Clc1cncc(-c2nn(C3CCCCO3)c3ccc(-c4cncc(C5CC5)n4)cc23)n1
Temperature: 105 °C
Yield: 35.5 %

Procedure:
A glass microwave reaction vessel was charged with 5-(6-cyclopropylpyrazin-2-yl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (140 mg, 0.31 mmol), 2-chloro-6-(tributylstannyl)pyrazine (190 mg, 0.47 mmol), Pd(PPh3)4 (18 mg, 0.016 mmol) and CuI (6 mg, 0.031 mmol) in DMF (1 mL). Argon was bubbled through the mixture for 5 min. The tube was sealed and the mixture was heated to 105° C. for 2 h. The reaction was diluted with EtOAc and water and filtered through celite. The crude was purified by silica gel chromatography, eluting with a gradient of 0-50% EtOAc in hexanes, to provide 3-(6-chloropyrazin-2-yl)-5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (48 mg, 0.11 mmol, 35% yield) as a light-yellow solid. MS (ESI, pos. ion) m/z: 433.0 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])=O.[CH:38]([O:41][NH2:42])([CH3:40])[CH3:39]>>[CH:38]([O:41][N:42]=[CH:1][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][N:7]([C@@H:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)[C:8]([C:10]1[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=1[C:22]([OH:24])=[O:23])=[O:9])([CH3:40])[CH3:39]
Reactant: CC(C)ON
Reactant: O=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1
Product: CC(C)ON=Cc1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 76E and O-isopropylhydroxylamine were processed as described in Example 76F to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=O)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:17][O:18][C:19]([C:21]1[N:22]([CH3:27])[N:23]=[C:24]([NH2:26])[CH:25]=1)=[O:20].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+]>CO.Cl>[CH3:17][O:18][C:19]([C:21]1[N:22]([CH3:27])[N:23]=[C:24]([NH:26][CH2:13][C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][O:10][C:11]=2[CH3:15])[CH:25]=1)=[O:20]
Reactant: COC(=O)c1cc(N)nn1C
Reactant: Cc1onc(-c2ccc(F)cc2)c1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: COC(=O)c1cc(NCc2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 27 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carbaldehyde (1.32 g, 6.44 mmol) and the 5-amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester hydrochloride (1.0 g, 6.44 mmol) in methanol (30 mL) at room temperature was added potassium carbonate (890 mg, 6.44 mmol) and then the reaction mixture was heated under reflux for 2 h. After cooling to room temperature sodium borohydride (487 mg, 12.9 mmol) was added and then the mixture heated under reflux for 12 h. The mixture was then cooled and treated with hydrochloric acid (1 N, 10 drops) and evaporated. Water was then added and the mixture extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (2 N) and then extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulfate, filtered and evaporated to afford 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (27%) which was obtained as a white solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([N:10]1[C:23]2[C:18](=[CH:19][C:20]([OH:28])=[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]3=2)[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])[CH3:8].CI.O>CN(C=O)C>[C:7]([N:10]1[C:23]2[C:18](=[CH:19][C:20]([O:28][CH3:1])=[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]3=2)[S:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc2c(c3ccccc13)N(C(C)=O)c1ccccc1S2
Reaction time: 0.25 h

Procedure:
Potassium tert-butoxide (800 mg) was added to a solution of 12-acetyl-5-hydroxy-12H-benzo[a]phenothiazine (950 mg) (from Example 3) and methyl iodide (1.5 ml) in DMF (10 ml) and stirred for 15 minutes. Water (80 ml) was added to the reaction mixture and the precipitate was filtered to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:28][C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)OC(=O)C(F)(F)F)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:37])[C:5]([O:28][C:29]1[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=1)([CH3:36])[CH2:6][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1cccc(C)c1)C(OC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C)c1
Reaction time: 20 h

Procedure:
3-(4-Benzyloxyphenyl)-2-methyl-2-m-tolyloxy-3-(2,2,2-trifluoroacetoxy)propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: Cl[C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.CN(C=O)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>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.[Cu]I.C(N(CC)CC)C>[CH3:19][Si:20]([C:23]#[C:24][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1)([CH3:22])[CH3:21]
Reactant: CCOC(=O)Cc1nccnc1Cl
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1nccnc1C#C[Si](C)(C)C
Temperature: 90 °C
Yield: 72 %

Procedure:
A mixture of the ethyl 2-(3-chloropyrazin-2-yl)acetate (I99) (0.410 g, 2.04 mmol), DMF (6 mL), triethylamine (2 mL), bis(triphenylphosphine)palladium(II) chloride (72 mg, 5 mol %) and copper(I) iodide (19 mg, 5 mol %) in a Schlenk tube was degassed with three vacuum/nitrogen cycles, then trimethylsilylacetylene (0.866 mL, 6.13 mmol) was added under nitrogen. The tube was flushed with nitrogen, sealed and heated to 90° C. After 18 hours the mixture was cooled and poured into water (50 mL). Saturated ammonium chloride (50 mL) was added, and the mixture was extracted with diethyl ether (3×100 mL). The combined ether phases were washed with brine, dried (sodium sulphate) and evaporated. The residue was chromatographed (40 g silica cartridge, 0-30% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I100) (0.386 g, 72% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.47-8.41 (m, 2H), 4.20 (q, J=7.1 Hz, 2H), 4.05 (s, 2H), 1.26 (t, J=7.1 Hz), 0.28 (s, 9H). LCMS Method C: rt 6.20 min; m/z 263.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Reactant: c1ccc2c(c1)CCN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCc3ccccc32)c1
Temperature: 99 °C
Yield: 89.8 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (70 mg, 0.20 mmol) and indoline (25 μL, 0.22 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively sodium tert-butoxide (29 mg, 0.3 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (3.7 mg, 4.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 6.9 mg, 12 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed to 98-100° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc, and the solution was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by CC (SiO2, CH2Cl2/EtOAc 4:1, then 1:1). The product (71 mg, 90%) was obtained as a bright yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.19 (s, 1H), 7.91 (s, 1H), 7.20-7.00 (m, 4H), 6.79 (t, 1H, J=6.8 Hz), 4.11 (m, 2H), 3.90-3.86 (m, 3H), 3.41 (m, 2H), 3.13 (t, 2H, J=8.4 Hz), 2.02 (m, 3H), 1.86 (m, 1H), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 155.6, 146.0, 141.4, 132.1, 131.5, 130.1, 129.1, 127.3, 125.3, 120.0, 109.4, 108.7, 68.5, 56.1, 51.9, 47.1, 46.8, 28.9, 28.6, 28.2, 24.0.
Reaction SMILES: [Cl-].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12]Cl)=[C:7]([NH+:9]([CH3:11])[CH3:10])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[NH:26][C:25](=[S:27])[NH:24][C:23](=[O:28])[CH:22]=1>CN(C)C(=O)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:12][S:27][C:25]2[NH:24][C:23](=[O:28])[CH:22]=[C:21]([CH3:20])[N:26]=2)=[C:7]([N:9]([CH3:11])[CH3:10])[CH:8]=1
Reactant: C[NH+](C)c1cc(Br)ccc1CCl
Reactant: Cc1cc(=O)[nH]c(=S)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(=O)[nH]c(SCc2ccc(Br)cc2N(C)C)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 49.4 %

Procedure:
1.0 g (3.5 mmol) of (5-bromo-2-chloromethylphenyl)dimethylammonium chloride (m.p.: 118°-120° C.) and 0.97 g (7.0 mmol) of anhydrous potassium carbonate are added to the solution of 0.45 g (3.2 mmol) of 6-methyl-2-thiouracil in 15 ml of N,N-dimethylacetamide and the reaction mixture is stirred in an oil bath of 100° C. temperature for 3 hours. After cooling to room temperature the inorganic salts are filtered and the filtrate is evaporated under reduced pressure. The evaporation residue is shaken with the mixture of 5 ml of water and 5 ml of chloroform and after separation the organic phase is extracted 4 times with 5 ml of chloroform each. The combined organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated. The oily residue is purified by chromatography on a silica gel column by using a 4:1 mixture of ethyl acetate/benzene as eluent. The pure fractions are evaporated under reduced pressure and the residue is recrystallized from ethanol to give 0.56 g (49.5%) of the title compound as a white crystalline product, m.p.: 163°-164° C.
Reaction SMILES: Br[C:2]1[C:7]2[C:8]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:12])=[CH:9][O:10][C:6]=2[C:5]([Br:21])=[CH:4][C:3]=1[OH:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:25]>CS(C)=O>[Br:21][C:5]1[C:6]2[O:10][CH:9]=[C:8]([C:11](=[O:12])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7]=2[C:2](=[O:25])[C:3](=[O:22])[CH:4]=1
Reactant: COc1ccc(C(=O)c2coc3c(Br)cc(O)c(Br)c23)cc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: COc1ccc(C(=O)c2coc3c2C(=O)C(=O)C=C3Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of compound 7d (50 mg, 0.12 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (100 mg, 0.24 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 min and poured into ice water (2 mL). The resulting precipitate was filtered, washed with water, and dried under high vacuum to obtain compound SKC-BF-07 (25 mg, 55%) as a red solid. TLC Rf=0.45 (petroleum ether-EtOAc, 6:4); 1H NMR (CDCl3) δ 7.89 (s, 1H), 7.85 (d, J=8.7 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 6.78 (s, 1H), 3.89 (s, 3H); MS (ES) m/z 362 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[C@H:13]2[C@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14]2)=[C:6]([NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:5]=1.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>>[OH:18][C@@H:17]1[C@H:16]([OH:19])[C@@H:15]([CH2:20][O:21][CH3:22])[O:14][C@H:13]1[N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:4]([CH2:3][CH2:2][NH:1][S:44]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:46])=[O:45])=[N:5][C:6]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Yield: 56.2 %

Procedure:
The title compound was prepared by a similar method to example 3 using (2R,3R,4S,5R)-2-{2-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (example 11) (200 mg, 0.40 mmol), benzenesulphonyl chloride (70 mg, 0.40 mmol) and triethylamine (0.15 ml, 1.08 mmol) to afford the title compound as a solid (145 mg). MS: 645 (MH+).