Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:18]([OH:20])=O.C(N1C=CN=C1)([N:23]1C=CN=C1)=O>O1CCOCC1>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:18]([NH2:23])=[O:20]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1c(C(=O)O)oc2ccc(Cc3cccnc3)cc12
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)oc2ccc(Cc3cccnc3)cc12
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A mixture of 3-methyl-5-(3-pyridylmethyl)benzofuran-2-carboxylic acid (0.28 g.), carbonyldiimidazole (0.28 g.) and dioxan (5 ml.) was heated on a steam bath for 2 hours and then evaporated. The residue was dissolved in a concentrated solution of ammonia in ethanol (10 ml.), the solution was allowed to stand for 30 minutes and then evaporated. The residue was chromatographed on silica gel. Elution with chloroform first gave a small amount of impurity followed by pure product. Evaporation of the product-containing fractions gave a solid which was crystallized from isopropanol/petrol (b.p. 60°-80°) to give 3-methyl-5-(3-pyridylmethyl)benzofuran-2-carboxamide (0.16 g.), m.p. 175°-177° C.
Reaction SMILES: C(OC(=O)CCN[C:13](=[O:41])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:40])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH:15]=1)C1C=CC=CC=1.NC1C=C(C=CC=1)C(O)=[O:48]>>[CH2:33]([O:32][C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([OH:41])=[O:48])=[O:40])=[O:31])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(CCCCCCCNC(=O)OCc1ccccc1)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1
Reactant: Nc1cccc(C(=O)O)c1
Product: O=C(CCCCCCCNC(=O)OCc1ccccc1)Nc1cccc(C(=O)O)c1

Procedure:
The ester starting material (m.p. 123°-124° C.) is obtained by coupling 8-[1-(benzyloxy)formamidooctanoic acid and 3-aminobenzoic acid to give m-[8-[1-(benzyloxy)formamido]octanamido]benzoic acid, m.p. 167°-168° C., and reacting the latter with β-alanine benzyl ester p-toluenesulphonate.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:23]=[C:22]([CH3:24])[O:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:38]([C:37]3[CH:36]=[CH:35][C:34]([CH2:33][N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:41][CH:40]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)no1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc(CN2CCN(c3c(Br)cnc4[nH]c(-c5ccc(Cn6cccn6)cc5)nc34)CC2)no1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-bromo-4-[4-(5-methyl-isoxazol-3-ylmethyl)-piperazin-1-yl]-3-nitro-pyridin-2-ylamine (0.040 g, 0.10 mmol) and EtOH (3.5 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.024 g, 0.13 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.40 ml, 0.40 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 3%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.020 g, 38%). 1H-NMR (500 MHz, DMSO-d6) 2.40 (s, 3H, isoxazole 5-CH3), 2.63 (br s, 4H, piperazine N(CH2)2), 3.60 (s, 2H, NCH2 isoxazole), 3.66 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.24 (s, 1H, isoxazole 4-H), 6.30 (t, J=2.0 Hz, 1H, pyrazole 4-H), 7.35 (d, J=8.3 Hz, 2H) and 8.14 (d, J=8.2 Hz, 2H) (3,5-C6H4 and 2,6-C6H4), 7.49 (d, J=1.4 Hz, pyrazole-H), 7.86 (d, J=2.0 Hz, 1H, pyrazole-H), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.50 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C([N:4]1[C:8]2[S:9][C:10]([C:12]#[N:13])=[CH:11][C:7]=2[CH:6]=[N:5]1)(=O)C.Cl>C(O)C.[OH-].[Na+]>[NH:4]1[C:8]2[S:9][C:10]([C:12]#[N:13])=[CH:11][C:7]=2[CH:6]=[N:5]1
Reactant: CC(=O)n1ncc2cc(C#N)sc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc2cn[nH]c2s1
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
To a suspension of 215 mg of 1-acetyl-1H-thieno[2,3-c]pyrazole-5-carbonitrile in 8 mL of ethanol, 1 mL of 5N sodium hydroxide aqueous solution was added at room temperature, and stirred at this temperature for 10 minutes. Then the solution was neutralized with 5N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 168 mg of the title compound as colorless crystals.
Reaction SMILES: [N+:1]([CH:4]([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[C:9]1(=[O:14])[O:13][CH2:12][CH:11]=[CH:10]1>>[N+:1]([C:4]([CH:11]([CH2:10][CH2:9][OH:14])[CH2:12][OH:13])([N+:6]([O-:8])=[O:7])[CH3:5])([O-:3])=[O:2].[C:9]1(=[O:13])[O:14][CH2:5][CH:4]=[CH:10]1
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Agent: O=C1C=CCO1
Product: CC(C(CO)CCO)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
The reaction sequences for preparing these branched polynitroalkyl diols can be summarized as follows: ##STR6## where Z is --C(NO2)3, --CF(NO2)2, --C(NO2)2CH3, or --N(NO2)CH3. The reaction of one mole of trinitromethane with one mole of gamma-crotonolactone under the reaction conditions of example 1 produces 4-hydroxy-3-(trinitromethyl)butyric acid, gamma-lactone which is reduced by borane-tetrahydrofuran to produce 2-(trinitromethyl)-1,4-butanediol as shown in example 3. Similarly, the reaction of one mole of fluorodinitromethane with gamma-crotonolactone under the reaction conditions of example 2 produces 4-hydroxy-3-(fluorodinitromethyl)butric acid, gamma-lactone which is reduced by borane-tetrahydrofuran to produce 2-(fluorodinitromethyl)-1,4-butanediol as shown in example 4. Using the same procedure, 1,1-dinitroethane and gamma-crotonolactone can be used to produce 2-(1,1-dinitroethyl)-1,4-butanediol and methyl nitramine and gamma-crotonolactone can be used to produce 2-(methylnitraza)-1,4-butanediol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH:36]1[CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:36]1([O:8][C:7]2[CH:6]=[CH:5][C:4]([N:9]3[C:14](=[O:15])[C:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:18]=4)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]3[CH3:34])=[CH:3][C:2]=2[F:1])[CH2:38][CH2:37]1
Reactant: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 48 h

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclopropane (1.8 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (3.60 g), and the mixture was stirred at 150° C. for 2 days. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.15 g, 14%).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[NH:28][C:27]([O:29][C@@H:30]3[CH2:34][O:33][C@@H:32]4[C@:35]([CH2:39][CH:40]=[O:41])([OH:38])[CH2:36][O:37][C@H:31]34)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[OH2:42]>C(Cl)(Cl)(Cl)Cl.C(#N)C.O.[Ru](Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]2[NH:28][C:27]([O:29][C@@H:30]3[CH2:34][O:33][C@@H:32]4[C@:35]([CH2:39][C:40]([OH:42])=[O:41])([OH:38])[CH2:36][O:37][C@H:31]34)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1
Reactant: O
Reactant: O=CC[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(O)C[C@@]1(O)CO[C@@H]2[C@H](Oc3nc4nc(-c5ccc(-c6ccccc6)cc5)c(Cl)cc4[nH]3)CO[C@@H]21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium periodate (41.5 mg, 0.194 mmol) and ruthenium (III) chloride hydrate (1.5 mg, 6.65 μmol) were added to a stirred solution of 2-[(3R,3aR,6R,6aS)-3-[[6-chloro-5-(4-phenylphenyl)-1H-imidazo[4,5-b]pyridin-2-yl]oxy]-6-hydroxy-3,3a,5,6a-tetrahydro-2H-furo[3,2-b]furan-6-yl]acetaldehyde (32.4 mg, 0.066 mmol) in carbon tetrachloride (0.2 ml), acetonitrile (0.2 ml), and water (0.26 ml). The reaction mixture was stirred at room temperature. After 6 hours, the reaction mixture was placed in the refrigerator overnight. In the morning, the reaction mixture was removed from the refrigerator and allowed to warm to room temperature. After 4 hours, the reaction mixture was partitioned between EtOAc (40 ml) and water (40 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, dried over MgSO4, filtered, and evaporated under reduced pressure to give an off-white residue. This material was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 20%-100% acetonitrile/water+0.05% TFA gradient followed by a 100% acetonitrile+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C26H22ClN3O6 507.12 observed m/e: 508.21 (M+H)+ (Rt 1.17/2 min); 1H NMR δ (ppm) (CD3OD): 7.97 (s, 1H), 7.74-7.77 (m, 4H), 7.70 (d, J=7.8 Hz, 2H), 7.48 (t, J=7.7 Hz, 2H), 7.38 (t, J=7.3 Hz, 1H), 5.58 (qt, J=5.4 Hz, J=10.8 Hz, 1H), 4.99 (t, J=5.4 Hz, 1H), 4.41 (d, J=4.9 Hz, 1H), 4.15-4.21 (m, 2H), 3.83 (abqt, J=8.9 Hz, J=69.3 Hz, 2H), 2.58-2.65 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9](O)[C:10](=O)[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C(OC=C)(=O)C.[OH-].[Na+].Cl.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.[Cl-].[Na+].O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[CH:11]=[CH:10][NH:9]2
Reactant: CC(=O)N(O)c1cc(F)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C=COC(C)=O
Product: Fc1cc(Cl)c2cc[nH]c2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 43.2 %

Procedure:
N-(3-Chloro-5-fluoro-phenyl)-N-hydroxy-acetamide (200 mg, 982 μmol) was dissolved in vinyl acetate (1.81 mL, 19.6 mmol), and Li2PdCl4 (25.7 mg, 98 μmol) was added. The reaction mixture was stirred for 3 hr at 60° C. The reaction mixture was diluted with EtOAc and brine; the organic layer was separated and concentrated under reduced pressure to give a solid, which was dissolved in 8 mL of MeOH. 1N aqueous NaOH (1.89 mL, 1.89 mmol) was added, and the reaction was stirred for two hours at room temperature. The reaction mixture was quenched by addition of 2 N aqueous HCl (0.95 mL, 1.9 mmol), followed by addition of 300 mg of Na2CO3. After addition of 50 mL of EtOAc, the organic layers were separated, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (12 g SiO2; EtOAc/heptane in a gradient from 0/100 to 1/4) to yield the title compound as a liquid (72 mg, 45% over 2 steps). 1H-NMR (DMSO-d6): 11.52 (brs, 1H), 7.45 (d, 1H), 7.20 (d, 1H), 7.05 (d, 1H), 6.45 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.[P:6]([OH:9])([OH:8])[OH:7].P(Cl)(Cl)Cl>O>[CH3:1][N:2]([CH3:5])[CH:3]([P:6]([OH:9])(=[O:7])[OH:8])[P:6]([OH:9])(=[O:8])[OH:7]
Reactant: CN(C)C=O
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Solvent: O
Product: CN(C)C(P(=O)(O)O)P(=O)(O)O
Yield: 76 %

Procedure:
73.1 parts of dimethyl formamide were mixed with 41 parts by phosphorous acid and this mixture was reacted with 137.3 parts of phosphorus trichloride at about 70°C. A viscous mass was formed, which after about an hour was treated with 180 parts of water. The solution so obtained was filtered and treated with acetone. A precipitate was formed which was further treated as described in Example 1. N,N-dimethyl-1-aminomethane-1,1-diphosphonic acid was obtained in a yield of 76%, based on PCl3.
Reaction SMILES: [CH2:1]([C:3](=[CH:17][CH3:18])[CH:4]=[CH:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=1)=[O:9])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1>[CH2:17]([C:3](=[CH:1][CH3:2])[CH:4]=[CH:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][C:13]([NH:16][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:14][CH:15]=1)=[O:9])[CH3:18]
Reactant: CC=C(C=CCNC(=O)c1ccc(N)nc1)CC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC=C(C=CCNC(=O)c1ccc(NS(C)(=O)=O)nc1)CC

Procedure:
A solution of N-(4-ethyl-2,4-hexadien-1-yl)-6-amino-3-pyridinecarboxamide (3.0 g) and methanesulfonyl chloride (1.54 g) in pyridine (25 ml) was stirred at 50° C. for 3 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 0.5N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (3% methanol-chloroform) to give N-(4-ethyl-2,4-hexadien-1-yl)-6-methansulfonamido-3-pyridinecarboxamide.
Reaction SMILES: [CH3:1][C@H:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:14])[CH3:13])[CH2:3]/[CH:4]=[CH:5]/[C:6](=[O:8])[CH3:7].[H][H]>C(OCC)(=O)C.[Ni]>[CH3:1][C@H:2]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7]
Reactant: [H][H]
Reactant: CC(=O)/C=C/C[C@H](C)CCC=C(C)C
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(=O)CCC[C@H](C)CCCC(C)C
Yield: 23.6 %

Procedure:
A solution of 33.6 g (3E,6R)-6,10-dimethyl-3,9-undecadien-2-one in one liter of ethyl acetate was hydrogenated over Raney-Nickel (2 g) during 21 hours (hydrogen uptake 10.7 l). Thereafter, the catalyst was filtered off and the filtrate was concentrated. According to gas chromatography the crude product (34) contained 77% (R)-6,10-dimethyl-2-undecanone. 15 g of the crude product (44% of the total amount) were chromatographed on silica gel (n-hexane/ethyl acetate). After distillation of the pure fractions there were obtained 8.1 g (R)-6,10-dimethyl-2-undecanone (99.8% purity according to gas chromatography). The enantiomeric purity was 96.6% ee, as determined by gas chromatographic diastereomer analysis of an acetal derivative with an optically active diol. This enantiomeric purity corresponds to that of the used starting material.
Reaction SMILES: [C:1]([Mg]Br)([CH3:4])([CH3:3])[CH3:2].[Cu](C#N)C#N.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][N:24]=2)[C:21]=1[CH3:22])=[O:16])[CH3:13].[OH-].[NH4+]>O1CCCC1>[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][C:26]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:25][N:24]=2)[C:21]=1[CH3:22])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1cnn(-c2ccc(Br)cn2)c1C
Reactant: CC(C)(C)[Mg]Br
Agent: N#C[Cu]C#N
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2ccc(C(C)(C)C)cn2)c1C
Reaction time: 0.33 h

Procedure:
tert-Butyl magnesium bromide (2M tetrahydrofuran solution; 35 ml) was added to a suspension of copper cyanide (3.1 g) in tetrahydrofuran (35 ml) at −78° C., stirred for 20 minutes, and then 1-(5-bromopyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (3.1 g) described in Reference example 24(2) was added and the mixture was stirred at −78° C. for two hours. It was further stirred at room temperature for 16 hours. Ammonium hydroxide was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(5-tert-butylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (320 mg) as a yellow oil.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C)C)[C:6](=[O:28])[N:5]([CH3:29])[C:4]=2[N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][CH:36]=1)[O:37][C:2]1[N:10]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][CH2:18][CH2:19][OH:20])[C:6](=[O:28])[N:5]([CH3:29])[C:4]=2[N:3]=1
Reactant: CC(C)CCn1c(Br)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: Oc1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Oc2cccc(F)c2)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
8-Bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.03 mmol, intermediate 82), 3-fluorophenol (0.098 mL, 1.08 mmol) and potassium carbonate (0.29 g, 2.06 mmol) were combined in DMF (8 mL) and heated at 90° C. for 15 h. The reaction was cooled to room temperature and acidified with 6N HCl to pH=1. The reaction was stirred for 1 h then diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N LiCl (2×100 mL), dried with magnesium sulfate, filtered and the solvent was removed under reduced pressure to yield a golden oil. The oil was purified using a 24 g silica gel flash column eluted with a gradient of 20% ethyl acetate/hexanes to 100% ethyl acetate to give 8-(3-fluorophenoxy)-1-(3-hydroxypropyl)-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.20 g, 48% yield) as a white solid. LCMS retention time=3.524 min and 96% purity, LCMS MH+=405.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[S:14][C:8]=2[C:7]=1[OH:27])=[O:5])[CH3:2].[Br:28]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([Br:28])[C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:19]=3)[S:14][C:8]=2[C:7]=1[OH:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2nc(-c3cnn(Cc4ccccc4)c3)sc2c1O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)c1nc(Br)c2nc(-c3cnn(Cc4ccccc4)c3)sc2c1O

Procedure:
A suspension of 2-(1-benzyl-1H-pyrazol-4-yl)-7-hydroxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester, example 91(c)(0.48 g, 1.26 mmol), N-bromosuccinimide (0.24 g, 1.32 mmol), and benzoyl peroxide (30.5 mg, 0.126 mmol) in 4.2 mL of benzene was heated at reflux temperature for 5 h. The reaction mixture was washed successively with saturated sodium bicarbonate, brine, saturated ammonium chloride solution, and brine. The organic solution was dried, filtered, and concentrated. The crude product was purified by flash chromatography eluting from silica gel with a gradient of 0-100% ethyl acetate in hexanes to produce 0.44 g of a white solid. MS: (+) m/z 459.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)([O-])=O>C(O)C.[Pd]>[NH:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([NH2:1])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2[nH]nc(-c3ccc[nH]3)c2c1
Yield: 62.2 %

Procedure:
5-Nitro-3-(1H-pyrrol-2-yl)-1H-indazole (37 mg) (from Example 22) was hydrogenated using 5% Pd/C (20 mg) in ethanol (5 mL) for 2 hours. The reaction was filtered and the filtrate was concentrated to give 20 mg of the titled compound.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].C(O)(=O)C.C(O)(=O)C.[Cl:64][C:65]1[CH:70]=[CH:69][C:68]([Bi](C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2)=[CH:67][CH:66]=1.C(O)(=O)C.C(=O)(O)O.ClC1C=CC([Bi](C2C=CC(Cl)=CC=2)C2C=CC(Cl)=CC=2)=CC=1>C(Cl)Cl.C([O-])(O)=O.[Na+].CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][C:68]3[CH:69]=[CH:70][C:65]([Cl:64])=[CH:66][CH:67]=3)[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: Clc1ccc([Bi](c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(Oc4ccc(Cl)cc4)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 40 °C

Procedure:
To a stirred mixture of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxy-cyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (150 mg, 0.189 mmol, 1 eq) and Cu(OAc)2 (6.1 mg, 0.033 mmol, 0.17 eq) in CH2Cl2 (2.5 ml) in a round bottom flask equipped with a magnetic stir-bar is added tri(4-chlorophenyl) bismuth diacetate [prepared immediately prior to use by addition of acetic acid (0.075 ml, 1.3 mmol, 6.9 eq) to a suspension of tri(4-chlorophenyl) bismuth carbonate (200 mg, 0.331 mmol, 1.75 eq) in CH2Cl2 (2.5 ml)]. The reaction flask is then fitted with a reflux condensor and the mixture warmed to 40° C. After sufficient time the reaction mixture is cooled, diluted with saturated aqueous NaHCO3 (10 mL) and extracted times with CH2Cl2. The organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The product is separated and purified by preparative TLC on silica gel to give 17-ethyl-1,14-dihydroxy-12-[2' -(3"-(4'"-chlorophenyloxy)-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.