Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:47][C:48]1[N:52]([CH3:53])[N:51]=[N:50][CH:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:47][C:48]3[N:52]([CH3:53])[N:51]=[N:50][CH:49]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cn1nncc1CCl
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Cl
Product: Cn1nncc1Cn1nc2nc(C(C)(C)C)nc(N3CC(F)(F)C(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as yellow gum. MS (m/e): 414.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([C:20]([OH:22])=O)[CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[OH:47][CH2:48][CH2:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[C:15]([C:20]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][OH:47])[CH2:51][CH2:52]2)=[O:22])[CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:24]
Reactant: OCCN1CCNCC1
Reactant: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccc(C(=O)O)cc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccc(C(=O)N3CCN(CCO)CC3)cc21
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
In a similar manner to Step 1 of Example 20, Compound 158 (20.0 mg, 0.0587 mmol) was dissolved in DMF (1 mL), and the solution was treated with EDCI (23 mg, 0.12 mmol), HOBT monohydrate (7.9 mg, 0.059 mmol) and 1-(2-hydroxyethyl)piperazine (31 mg, 0.24 mmol). The mixture was added with water and ethyl acetate, and then extracted with 1 mol/L hydrochloric acid. The aqueous layer was added with sodium carbonate to adjust the pH to 9 and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in chloroform, and the solution was added with hexane and stirred for 30 minutes. The solid was collected by filtration, washed with hexane and dried under reduced pressure to obtain Compound 160 (16.6 mg, yield 62%).
Reaction SMILES: [CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[C:12]([CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:5][CH:4]=1)[CH3:2]>[O-2].[O-2].[Mn+4].ClCCl>[CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([CH:17]=[O:18])[C:11]=3[CH:10]=[CH:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Cn2ccc3c(CO)cccc32)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1ccc(Cn2ccc3c(C=O)cccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
To a mixture of 1.00 g of 1-(4-ethylbenzyl)-4-(hydroxymethyl) indole prepared in Example 34 and 2.31 g of activated manganese dioxide (~85%), there was added 30 ml of dichloromethane and the resulting mixture was stirred at room temperature for 4 hours. The reaction solution was filtered, followed by washing with dichloromethane (50 ml×2). The solvent was distilled off, under reduced pressure, from the resulting filtrate to give 0.92 g of 1-(4-ethylbenzyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 93%.
Reaction SMILES: [Mg].[Cl-].[Ce+3].[Cl-].[Cl-].Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.CO[C:14](=[O:31])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:26][C:25](=[O:27])[C:24]3=[CH:28][CH:29]=[CH:30][N:23]3[N:22]=2)=[CH:17][CH:16]=1>C1COCC1>[OH:31][C:14]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[NH:26][C:25](=[O:27])[C:24]4=[CH:28][CH:29]=[CH:30][N:23]4[N:22]=3)=[CH:19][CH:20]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: BrCCCCBr
Reactant: COC(=O)c1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(C3(O)CCCC3)cc2)nn2cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 15 ml reaction vial is flushed with nitrogen and charged with dry THF (2.5 ml), magnesium turnings (55.5 mg, 2.28 mmol) and cerium(III) chloride (20.5 mg, 0.084 mmol). The suspension is cooled to 0° C., 1,4-dibromobutane (157 μl, 1.33 mmol) is added. The suspension is allowed to reach room temperature, stirred for 30 minutes at this temperature and again cooled to 0° C. Then, a solution of 4-(4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-benzoic acid methyl ester (113 mg, 0.42 mmol) in THF (1 ml) is added dropwise. The reaction mixture is stirred for 30 minutes at room temperature. The reaction mixture is quenched with saturated ammonium chloride solution and partitioned between ethyl acetate and water. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-[4-(1-hydroxy-cyclopentyl)-phenyl]-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as white solid; HPLC/MS 1.75 (C), [M+H] 296; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 11.92 (s, 1H), 7.98-7.89 (m, 2H), 7.67 (dd, J=2.7, 1.7 Hz, 1H), 7.65-7.59 (m, 2H), 6.94 (dd, J=4.3, 1.7 Hz, 1H), 6.60 (dd, J=4.3, 2.6 Hz, 1H), 4.94 (s, 1H), 1.95-1.85 (m, 6H), 1.83-1.74 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]1[C:10]([CH:11]([NH:15][CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(#N)C.[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[CH2:1]([O:3][CH:4]([O:17][CH2:18][CH3:19])[C:5]1[C:10]([CH:11]([N:15]([CH3:16])[C:36](=[O:37])[CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:12]([CH3:13])[CH3:14])=[CH:9][N:8]=[CH:7][N:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ncncc1C(NC)C(C)C
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(OCC)c1ncncc1C(C(C)C)N(C)C(=O)Cc1ccccc1
Yield: 70.3 %

Procedure:
8.3 g (0.031 mol) of [1-(4-diethoxymethylpyrimidin-5-yl)-2-methylpropyl]methylamine and 6.4 g (46 mmol) of potassium carbonate were added to 100 ml of acetonitrile, and then 5.8 g (0.038 mol) of phenylacetyl chloride was dropwise added at room temperature and reacted for 2 hours. After completion of the reaction, the product was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution, water and an aqueous sodium chloride solution in this order, dried and concentrated, and the obtained oily product was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5 to ethyl acetate), to obtain 8.4 g (yield: 70%) of N-[1-(4-diethoxymethylpyrimidin-5-yl)-2-methylpropyl]-N-methyl-2-phenyl acetamide as colorless viscous liquid (nD2=1.5253)
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[S:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:19][C:20]3[CH:32]=[CH:31][C:23]4[C:24]([C:28]([OH:30])=O)=[C:25]([CH3:27])[O:26][C:22]=4[CH:21]=3)[CH:11]=2)=[O:9])[CH2:4]1.C(Cl)(=O)C(Cl)=O.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>>[CH:39]1([NH:42][C:28]([C:24]2[C:23]3[CH:31]=[CH:32][C:20]([O:19][C:16]4[CH:15]=[CH:14][N:13]=[C:12]5[CH:11]=[C:10]([C:8]([N:5]6[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]6)=[O:9])[S:18][C:17]=45)=[CH:21][C:22]=3[O:26][C:25]=2[CH3:27])=[O:30])[CH2:41][CH2:40]1
Reactant: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)O)c(C)oc5c4)c3s2)C1
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Product: COC1CCN(C(=O)c2cc3nccc(Oc4ccc5c(C(=O)NC6CC6)c(C)oc5c4)c3s2)C1
Yield: 33.1 %

Procedure:
This material was prepared from 6-[2-(3-methoxypyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-benzofuran-3-carboxylic acid 89e (37 mg, 0.08 mmole) by treatment with oxalyl chloride (15 μl, 0.17 mmole) and cyclopropylamine (56 μl, 0.81 mmole) in a manner as previously described for example 16d to give a white solid (13 mg, 33%). 1H NMR (DMSO-d6) δ 8.57 (1H, d, J=5.1 Hz), 8.19 (1H,s), 8.06 (1H, bs), 7.74 (1H, d, J=6.1 Hz), 7.65 (1H, s), 7.24 (1H, d, J=6.1 Hz), 6.71 (1H, d, J=1.8 Hz), 4.10–3.80 (3H, m), 3.70–3.35 (2H, m), 3.25 (3H, d, J=13.1 Hz), 2.86 (1H, m), 2.59 (3H, s), 2.25–1.95 (2H, m), 0.71 (2H, m), 0.60 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C.O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][N:6]=1
Reactant: CCCCCCBr
Reactant: Nc1nnc(S)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCSc1nnc(N)s1
Reaction time: 2 h
Yield: 77.1 %

Procedure:
In 190 ml of ethanol and 240 ml of water, 81.5 g of 2-amino-5-mercapto-1,3,4-thiadiazole and 26.9 g of sodium hydroxide were added. To this solution, 99 g of 1-bromohexane was added and the resulting mixture was warmed to 60°~70° C. and stirred for 2 hours. After cooling, water was added to the reaction mixture, and the resulting solution was filtered. The residue was washed with water and dried under reduced pressure. The dried residue was recrystallized from an ethanol/hexane mixture, and thus 100.5 g of 2-amino-5-hexylthio-1,3,4-thiadiazole was obtained. m.p. 113°~115° C. Yield 77%.
Reaction SMILES: [C:1]([C:6]1[C:17]([O:18][CH3:19])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([CH2:13][OH:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Mn]([O-])(=O)(=O)=[O:21].[K+]>>[C:1]([C:6]1[C:17]([O:18][CH3:19])=[CH:16][C:9]2[N:10]([CH3:15])[C:11]([C:13]([OH:21])=[O:14])=[N:12][C:8]=2[CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCCC(=O)c1cc2nc(CO)n(C)c2cc1OC
Agent: [K+]
Product: CCCC(=O)c1cc2nc(C(=O)O)n(C)c2cc1OC

Procedure:
In a manner analogous to that described in Example 12, 5.2 g of 5-butyryl-6-methoxy-1-methyl-benzimidazole-2-methanol are oxidised with 4.5 g of potassium permanganate to give 5-butyryl-6-methoxy-1-methyl-benzimidazole-2-carboxylic acid with a melting point above 85° (decomposition)
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)=[CH:5][N:4]=1.[ClH:17].O1CCOCC1>>[ClH:17].[CH3:16][N:14]1[CH:15]=[C:11]([C:6]2[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=2)[CH:12]=[N:13]1
Reactant: COc1ncc(-c2cnn(C)c2)c(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cc(-c2c[nH]c(=O)[nH]c2=O)cn1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
2,4-bis(methyloxy)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine (Prep28, 483.7 mg, 1.977 mmol) was suspended in 4M solution of HCl in 1,4-dioxane (10 mL, 40.0 mmol) to give a white suspension. After 1 h at 90° C., 5 ml of 4M solution of HCl in 1,4-dioxane (5 mL, 20.0 mmol) were then added and the reaction mixture was vigorously stirred at 90° C. Again, 5 ml of 4M solution of HCl in 1,4-dioxane (5 mL, 20.0 mmol) were added and the reaction mixture was vigorously stirred at 90° C. overnight. The solvent was evaporated to obtain 508.4 mg of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:6]1[S:10][C:9]([NH:11][CH3:12])=[N:8][N:7]=1)([CH3:5])[CH3:4].[C-:13]#[N:14].[Na+]>CS(C)=O>[C:13]([CH2:2][C:3]([C:6]1[S:10][C:9]([NH:11][CH3:12])=[N:8][N:7]=1)([CH3:5])[CH3:4])#[N:14]
Reactant: [C-]#N
Reactant: CNc1nnc(C(C)(C)CCl)s1
Agent: [Na+]
Solvent: CS(C)=O
Product: CNc1nnc(C(C)(C)CC#N)s1

Procedure:
A 20.5 g. portion of the intermediate prepared in Example 1 and 10 g. of NaCN were added to 50 ml. of dimethylsulfoxide and heated at 110°C. for 2 hours. The reaction mixture was then cooled and poured into 300 ml. of water, which was then extracted with a total of 1 liter of ethyl ether. The combined ether extracts were dried over anhydrous Na2SO4, filtered, and evaporated to dryness yielding a dark oil. The oil was chromatographed on a silica gel column, eluting with ethyl acetate. The desired intermediate product, 5-(2-cyano-1,1-dimethylethyl)-2-methylamino-1,3,4-thiadiazole, m.p. 65°-67°C., was isolated in the amount of 750 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH2:21][C:22]([OH:24])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:32][NH:33][OH:34].C(N(CC)CC)C.Cl>C(Cl)Cl.CN(C)C=O.O1CCCC1.O.C(OCC)(=O)C>[OH:34][N:33]([CH3:32])[C:22](=[O:24])[CH2:21][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)/[C:7](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:6]=1[CH3:20]
Reactant: CNO
Reactant: CSc1ccc(/C=C2/C(C)=C(CC(=O)O)c3cc(F)ccc32)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(/C=C2/C(C)=C(CC(=O)N(C)O)c3cc(F)ccc32)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of (Z)-5-fluoro-2-methyl-1-(4-methylthiobenzylidene) inden-3-ylacetic acid (U.S. Pat. No. 3,647,858; U.S. Pat. No. 3,654,349; J.O.C. Vol 42, 1914-1919 (1977) (130 mg, 0.38 mmol) in methylene chloride (3 mL) at room temperature there was added oxalyl chloride (96.5 mg, 0.76 mmol) and one drop of N, N-dimethylformamide (DMF). When gassing had subsided another drop of DMF was added and stirring was continued for 30 minutes. This solution was added, at 0° C., to a mixture of N-methyl hydroxylamine hydrochloride (125 mg, 1.5 mmol) and triethylamine (253 mg, 2.5 mmol) in tetrahydrofuran (THF) (5 mL). After 30 minutes at 0° C., the mixture was diluted with water and ethyl acetate and acidified with 1N aqueous HCl. The crude product from the organic extract was crystallized from a mixture of ethyl acetate and hexane to afford the title product as yellow-orange crystals, mp: slow decomp. from 118° C.
Reaction SMILES: [C:1]([NH2:12])(=O)[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.S(Cl)(Cl)=O>C(OCC)(=O)C>[C:1](#[N:12])[C:2]1[CH:3]=[C:4]([OH:5])[C:6]([OH:7])=[C:8]([OH:9])[CH:10]=1
Reactant: NC(=O)c1cc(O)c(O)c(O)c1
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: N#Cc1cc(O)c(O)c(O)c1
Temperature: 90 °C
Yield: 86 %

Procedure:
A reaction mixture containing 23.5 g. of gallamide, 180 ml. of ethyl acetate and 35 ml. of thionylchloride was refluxed for about 18 hours. The volatile contents were removed by evaporation in vacuo and the resulting residue dissolved in 215 ml. of water. This aqueous solution was heated to about 90° C. until the evolution of gas had ceased. The aqueous solution was filtered through charcoal and the water removed from the filtrate by evaporation. 18 g. of gallonitrile were obtained melting at about 219° C. with decomposition (86% yield). Other nitriles useful as starting materials can be prepared similarly.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.O>C(#N)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:4]2[N:3]=[C:2]([Cl:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)nc3[nH]cnc23)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
2,6-Dichloropurine [CAS No. 5451-40-1] (5.0 g) was dissolved in acetonitrile (70 mL), and then piperazine-1-carboxylic acid t-butyl ester (4.93 g) and triethylamine (4.1 mL) were added to this solution, and the reaction solution was stirred at room temperature for 22 hours. Water (200 mL) was added to the reaction solution, and this was stirred at room temperature for one hour, and then the white precipitate was collected by filtration. The white solid obtained was washed with water and hexane to give the title compound (8.5 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32]([CH3:40])C(=O)OC(C)(C)C)=[CH:27][C:26]=3Cl)=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C1(C=CC(=[O:59])C=CC2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-].[K+].C(O)(C(F)(F)F)=O>O1CCOCC1.[Pd]>[NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][NH:32][CH3:40])=[CH:27][C:26]=3[OH:59])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4Cl)o3)n2)cc1
Reactant: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)c(O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]-3-chloro-phenyl]methyl]-N-methyl-carbamate (130 mg, 0.2170 mmol) in dioxane (3 mL) was added of 1,5-diphenylpenta-1,4-dien-3-one; palladium (6.239 mg, 0.01085 mmol), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (13.82 mg, 0.03255 mmol) and potassium hydroxide (434.0 μL of 1 M, 0.4340 mmol). The resulting mixture was heated to 100° C. for 2 h. Additional 1,5-diphenylpenta-1,4-dien-3-one; palladium (6.239 mg, 0.01085 mmol), ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (13.82 mg, 0.03255 mmol) and potassium hydroxide (434.0 μL of 1 M, 0.4340 mmol) were added and the resulting mixture heated for a further 2 h at 100° C. The reaction mixture was evaporated to dryness and the residue purified by column chromatography on silica eluting with 20% EtOAc/ petroleum ether. Product fractions were combined and concentrated in vacuo. This mixture was dissolved in DCM (10 mL) and TFA (247.4 mg, 167.2 μL, 2.170 mmol) added. The resulting mixture was stirred at room temperature for 1 h and then concentrated in vacuo to an oil. This was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The product fractions were collected and lypholised to give the product as a yellow solid (24.0 mg, 18% yield); 1H NMR (400.0 MHz, DMSO) d 1.31 (m, 6H), 2.80 (s, 3H), 3.43 (m, 1H), 4.27 (s, 2H), 7.23 (m, 1H), 7.30 (m, 1H), 8.04 (m, 2H), 8.19 (m, 1H), 8.41 (m, 2H) and 8.95 (s, 1H) ppm; MS (ES+) 481.2
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=3[Cl:42])=[O:32])[CH2:17][C@@H:18]([OH:29])[CH2:19][O:20][P:21]([O:26]CC)([O:23]CC)=[O:22])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si](I)(C)(C)C>C(#N)C>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:44])[O:14][CH2:15][C@@H:16]([N:30]([CH3:43])[C:31]([NH:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=3[Cl:42])=[O:32])[CH2:17][C@@H:18]([OH:29])[CH2:19][O:20][P:21]([OH:26])([OH:23])=[O:22])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOP(=O)(OCC)OC[C@H](O)C[C@@H](COC(=O)Nc1cc(-c2ccccc2)no1)N(C)C(=O)NCc1cccc(F)c1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc(-c2ccccc2)no1)C[C@@H](O)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a mixture of (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(diethoxyphosphoryloxy)-4-hydroxypentyl 3-phenylisoxazol-5-ylcarbamate (56 mg, 0.085 mmol, 1.0 equiv.) in acetonitrile (5 mL) was added TMSI (0.115 mL, 0.85 mmol, 10.0 equiv.) at ° C. After stirring at RT for 10 min, the reaction was quenched with MeOH. The solvent was removed, and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O (with 0.1% TFA buffer). The fractions of product was concentrated, dissolved in a mixture of methanol and water (2:1), followed by addition of HCl (4 N in 1,4-dioxane, 2 mL). The mixture was concentrated to give (2S,4R)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4-hydroxy-5-(phosphonooxy)pentyl 3-phenylisoxazol-5-ylcarbamate (48 mg, 94%) as a white solid. LRMS (M+H+) m/z 601.5.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[C:25]([O:27]C)[C:24]([O:29]C)=[C:23]([O:31]C)[CH:22]=3)=[CH:14][C:13]=2[N+:34]([O-:36])=[O:35])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10].B(Br)(Br)Br.O>C(Cl)Cl.CO>[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:33])[CH2:20][C:21]3[CH:26]=[C:25]([OH:27])[C:24]([OH:29])=[C:23]([OH:31])[CH:22]=3)=[CH:14][C:13]=2[N+:34]([O-:36])=[O:35])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: COc1cc(CC(=O)Nc2ccc(-c3cc(C(=O)O)c(C)o3)c([N+](=O)[O-])c2)cc(OC)c1OC
Agent: BrB(Br)Br
Agent: N#N
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1oc(-c2ccc(NC(=O)Cc3cc(O)c(O)c(O)c3)cc2[N+](=O)[O-])cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 73.4 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid (60) (33 mg, 0.07 mmol) in anhydrous DCM (1.0 mL), cool the solution to −78° C. and add dropwise BBr3 (66 μL, 0.70 mmol). Stir the reaction mixture for 10 min at −78° C. and after slowly warming up for additional 2 h at rt. Cool reaction mixture to 0° C., add dropwise water and DCM followed by MeOH to homogenize the mixture and remove solvent. Suspend the crude product in MeOH and filtrate it through a short pad of celite to obtain 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trihydroxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid (61) (22 mg, 72%) as a brown solid. 1H NMR (400 MHz, CD3OD): 2.62 (s, 3H); 3.53 (s, 2H); 6.40 (s, 2H); 6.88 (s, 1H); 7.73 (d, 1H, J=8.6 Hz); 7.80 (dd, 1H, J1=8.6 Hz, J2=2.0 Hz); 8.24 (d, 1H, J=2.0 Hz).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[N:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9](Cl)=[CH:8][C:7]=1Cl.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1.C(=O)([O-])[O-].[Rb+].[Rb+]>>[N:28]1([C:9]2[CH:10]=[C:11]3[C:6]([CH:5]=[CH:4][N:3]3[N:2]([CH3:14])[CH3:1])=[CH:7][CH:8]=2)[CH:32]=[CH:31][CH:30]=[CH:29]1
Reactant: c1cc[nH]c1
Reactant: CN(C)N=CCc1ccc(Cl)cc1Cl
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Rb+]
Product: CN(C)n1ccc2ccc(-n3cccc3)cc21

Procedure:
6-(1-pyrrolyl)-1-(dimethylamino)indole was prepared in the same manner as in Example 12 except that 2,4-dichlorophenylacetaldehyde N,N-dimethylhydrazone was used in place of 2,6-dichlorophenylacetaldehyde N,N-dimethylhydrazone, tri(t-butyl)phosphine was used in place of 1-(N,N-dimethylaminomethyl)-2-(di-t-butylphosphino)ferrocene, pyrrole was used in place of piperazine, and rubidium carbonate was used in place of t-butoxysodium. (Yield: 2′%).