Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.[CH3:10][O:11][C:12](=[O:17])[CH2:13][CH:14](I)[CH3:15].[I-].COC(C(C)C[Zn+])=O.[Cl-].[Li+].[I:29][C:30]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([CH:38]=[O:39])[N:31]=1>O1CCCC1.ClCCl.[Cl-].[NH4+].[Zn].[Cu+]>[CH3:10][O:11][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH:38]([OH:39])[C:32]1[N:31]=[C:30]([I:29])[C:35]([O:36][CH3:37])=[CH:34][CH:33]=1
Reactant: COC(=O)CC(C)I
Reactant: COc1ccc(C=O)nc1I
Agent: [Cu+]
Agent: COC(=O)C(C)C[Zn+]
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)CCCC(O)c1ccc(OC)c(I)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
680 mg of zinc foil cut into small sections (Aldrich 0.25 mm thickness, 99.999%) in 1 ml of absolute tetrahydrofuran is heated to 65° C. with 80 mg of 1,2-dibromoethane for 1 minute, cooled to 25° C., mixed with 40 μl of chlorotrimethylsilane and stirred for 15 minutes. A solution of 2.3 g of 3-iodobutyric acid methyl ester in 5 ml of absolute tetrahydrofuran is instilled in this activated zinc at 30° C., and the mixture is stirred for 16 hours at 35°-40° C. 4.3 ml of the thus obtained 2-methoxycarbonylpropylzinc iodide solution is instilled at -20° C. in a solution of 430 mg of copper(I) dyanid and 430 mg of lithium chloride in 1 ml of tetrahydrofuran. The reaction mixture is stirred for 5 minutes at 0° C., cooled again to -20° C., mixed with a solution of 1.1 g of 2-iodo-3-methoxypyridine-6-aldehyde in 2 ml of tetrahydrofuran and 2 ml of dichloromethane and 1.9 ml of boron trifluoride-ethyl ether complex, stirred for three hours at 0° C. and 20 hours at room temperature. The reaction mixture is poured in saturated ammonium chloride solution, the precipitate is suctioned off on diatomaceous earth, the filter residue is washed with ethyl acetate, the organic phase is separated and the water phase is also shaken out three times with ethyl acetate. The organic phase is dried on sodium sulfate, concentrated by evaporation and the crude product is chromatographed on silica gel with hexane/0-20% ethyl acetate. 1.11 g of (5RS)-5-hydroxy-5-(2-iodo-3-methoxy-6-pyridyl)-pentanoic acid methyl ester is obtained as oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32]C)=[C:6]([C:8]2([CH2:11][C:12]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:13][NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH2:25][OH:26])=[N:20]4)[CH2:10][CH2:9]2)[CH:7]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]([C:8]2([CH2:11][C:12]([C:28]([F:29])([F:30])[F:31])([OH:27])[CH2:13][NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][C:19]([CH2:25][OH:26])=[N:20]4)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: COc1ccc(F)cc1C1(CC(O)(CNc2cccc3nc(CO)ccc23)C(F)(F)F)CC1
Agent: BrB(Br)Br
Product: OCc1ccc2c(NCC(O)(CC3(c4cc(F)ccc4O)CC3)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 38, 100 mg (0.22 mmol) of 3-[1-(5-fluoro-2-methoxyphenyl)cycloprop-1-yl]-1-(2-(hydroxymethyl)quinolin-5-ylamino)-2-(trifluoromethyl)propan-2-ol is reacted with 4.40 ml (4.40 mmol) of a 1 M boron tribromide solution. After working-up and purification on silica gel with hexane-ethyl acetate (0–100%) as well as with ethyl acetate-methanol (0–20%), 50 mg (50% of theory) of the product is obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.CN.C(O)(=O)C.[B-][C:44]#[N:45].[Na+]>O1CCCC1.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][NH:45][CH3:44])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: [B-]C#N
Agent: CN
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CNCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.0 g), methylamine (2M tetrahydrofuran solution, 3.2 mL), acetic acid (0.13 g), ethanol (20 mL) and tetrahydrofuran (20 mL) was stirred at room temperature for 2 hrs. Sodium cyanotrihydroborate (0.20 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give N-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methyl)-N-methylamine as colorless crystals (0.15 g, yield 14%) from a fraction eluted with ethyl acetate-methanol (10:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][N:12]1[C:18]2=[C:19]3[C:24](=[N:25][C:26]4=[CH:27][CH:28]=[CH:29][C:16](=[C:17]24)[O:15][CH2:14][C:13]1=O)[CH2:23][CH2:22][CH2:21][CH2:20]3>O1CCCC1>[CH3:11][N:12]1[C:18]2=[C:19]3[C:24](=[N:25][C:26]4=[CH:27][CH:28]=[CH:29][C:16](=[C:17]24)[O:15][CH2:14][CH2:13]1)[CH2:23][CH2:22][CH2:21][CH2:20]3
Reactant: CN1C(=O)COc2cccc3nc4c(c1c23)CCCC4
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CN1CCOc2cccc3nc4c(c1c23)CCCC4
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
To a solution of lithium aluminum hydride in tetrahydrofuran (1.0M, 15.82 ml) and dry tetrahydrofuran (32 ml) was added aluminum chloride (2.10 g) in portions. The mixture was stirred for five mins, 1,3,9,10,11,12-hexahydro-1-methyl-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.24 g) was added and the mixture was stirred at room temperature overnight. The reaction mixture was quenched with ethyl acetate (150 ml), 10% sodium hydroxide solution was added, and the organic layer was separated. The organic layer was washed wit brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was adhered to silica (methanol) and flash chromatographed (30-50% ethyl acetate/Hexane) to yield 3.61 g (89.6%) of product, mp 97°-98° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[N:20]=2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1.CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([OH:31])=[O:30])[N:20]=2)=[CH:34][CH:35]=1)=[O:12]
Reactant: CCOC(=O)Cn1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Yield: 87.1 %

Procedure:
575 mg (1.24 mmol) ethyl 2-[3-[4-(2-naphthamido)benzyl]-1H-indazol-1-yl]acetate was dissolved in a mixed solution of 10 mL tetrahydrofuran and 3 mL methanol, in an ice bath 10 mL aqueous solution dissolving 333 mg (7.93 mmol) lithium hydroxide monohydrate was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, the pH value was adjusted to be acidic with diluted hydrochloric acid. A solid precipitated, it was filtered, dried to obtain a white solid 470 mg (1.08 mmol), at a yield of 87.1%.
Reaction SMILES: [C:1]([C:5]1[NH:10][C:9]2[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:12]=[N:13][C:8]=2[C:7](=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:37]>>[C:1]([C:5]1[N:6]=[C:7]([Cl:37])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2nnc3c(=O)nc(C(C)(C)C)[nH]c32)cc1
Solvent: CCN(CC)c1ccccc1
Product: COc1ccc(Cn2nnc3c(Cl)nc(C(C)(C)C)nc32)cc1

Procedure:
A mixture of 5-tert-butyl-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(4H)-one (50.0 mg, 160 μmol) and N,N-diethylaniline (50.8 μL, 319 μmol) in POCl3 (1000 μL, 10.9 mmol) was refluxed for 4 h under N2 atmosphere. The reaction mixture was concentrated in vacuo, diluted with EtOAc, washed with cold H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 5-tert-butyl-7-chloro-3-(4-methoxy benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine. The residue was used for the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[F:50][C:51]1[CH:77]=[C:76]([F:78])[CH:75]=[CH:74][C:52]=1[O:53][CH:54]1[CH2:59][CH2:58][N:57]([C:60]2[N:61]=[C:62]3[CH2:73][CH2:72][NH:71][CH2:70][C:63]3=[N:64][C:65]=2[NH:66][CH:67]([CH3:69])[CH3:68])[CH2:56][CH2:55]1>CC(N(C)C)=O>[F:50][C:51]1[CH:77]=[C:76]([F:78])[CH:75]=[CH:74][C:52]=1[O:53][CH:54]1[CH2:55][CH2:56][N:57]([C:60]2[N:61]=[C:62]3[CH2:73][CH2:72][N:71]([C:7](=[O:9])[C@@H:3]4[CH2:4][CH2:5][CH2:6][N:2]4[CH3:1])[CH2:70][C:63]3=[N:64][C:65]=2[NH:66][CH:67]([CH3:69])[CH3:68])[CH2:58][CH2:59]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(C(=O)[C@@H]1CCCN1C)C2
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
A solution of (S)-1-methylpyrrolidine-2-carboxylic acid (16.8 mg, 0.130 mmol) in DMA (0.4 mL) was treated with HATU (49.6 mg, 0.130 mmol) and DIPEA (45.6 μL, 0.261 mmol) at room temperature. To this was added a solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (45 mg, 0.087 mmol) in DMA (0.47 mL). The reaction mixture was stirred at 60° C. for 45 min. The reaction mixture was allowed to cool to room temperature and was purified directly directly by HPLC Method B, with the exception that a Phenomenex Gemini® C18, 5 μm, ID 30×75 mm column was used, using a 25% to 60% ACN gradient to give the title compound, as a TFA salt, as a white solid (2.8 mg, 5.1%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.26 (dd, J=6.6, 4.5 Hz, 6H), 1.97 (m, 4H), 2.09 (m, 3H), 2.24 (m, 1H), 2.76 (m, 3H), 2.93 (app d, J=7.6 Hz, 3H), 3.03 (m, 2H), 3.20 (m, 1H), 3.40 (m, 2H), 3.69-4.19 (m, 4H), 4.48 (m, 2H), 4.66 (m, 2H), 6.87 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 515.6.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][CH:7]([CH3:14])[C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11].CS(C)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][CH:9]([C:8](=[O:13])[CH:7]([CH3:14])[CH3:6])[C:10](=[O:12])[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: CC(=O)CC(=O)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: CS(C)=O
Solvent: CC#N
Product: CC(=O)C(Cl)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
Chlorotrimethylsilane (13.4 ml, 105 mmol) was added dropwise to a stirred pale yellow solution of tetrabutylammonium iodide (566 mg, 1.53 mmol) in dry acetonitrile (100 ml) at room temperature under nitrogen. The resulting solution was cooled in ice and 5-methylhexane-2,4-dione (4.50 g, 35.1 mmol) and then dry dimethylsulphoxide (7.47 ml, 105 mmol) were added dropwise over 5 minutes producing a yellow solution which was allowed to warm slowly to room temperature with stirring over 1 hour. Tetrabutylammonium bromide (566 mg, 1.75 mmol) was then added in one portion and the reaction was stirred at room temperature for 2 hours. The mixture was diluted with water (200 ml), stirred for 10 min and then extracted with ether (3×100 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow oil. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (98:2, by volume) to provide the title compound (2.00 g) as a colourless oil.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[N:11]=2)=[N:6][CH:5]=1.[OH-].[K+].Cl>CO>[CH3:15][C:12]1[N:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][N:6]=2)[O:14][N:13]=1
Reactant: COC(=O)c1ccc(-c2nc(C)no2)nc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(-c2ccc(C(=O)O)cn2)n1
Temperature: 70 °C

Procedure:
To a solution of 6-(3-methyl-[1,2,4]oxadiazol-5-yl)-nicotinic acid methyl ester (54 mg, 0.246 mmol) in methanol (5 mL) was added an aqueous solution of KOH (3M, 0.49 mL, 1.48 mmol) and the mixture was heated at 70° C. for 12 h. The reaction mixture was neutralized under ice cooling with 2M HCl solution. The solvents were evaporated under reduced pressure, co-evaporated three times with toluene and dried under high vacuum. The acid was used crude for the next reaction. MS ISN (m/e): 204.2 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[O:29][N:28]=[C:27]([C:30]([NH2:32])=O)[N:26]=2)([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[C:19]3[C:14](=[C:15]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[N:12]2)([C:25]2[O:29][N:28]=[C:27]([C:30]#[N:32])[N:26]=2)[CH2:9][CH3:10])=[CH:6][CH:7]=1
Reactant: CCC(c1ccc(Cl)cc1)(c1nc(C(N)=O)no1)n1ncc2c(NS(C)(=O)=O)cccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCC(c1ccc(Cl)cc1)(c1nc(C#N)no1)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 37 step F above (6.8 mg, 0.014 mmol) in pyridine (1.0 mL) was added POCl3 (32.8 mg, 0.28 mmol) at 0° C. After stirring at RT overnight, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=457.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:56]([C:58]1[C:59]([C:64](O)=[O:65])=[N:60][CH:61]=[CH:62][CH:63]=1)[CH3:57]>CC(N(C)C)=O>[CH2:56]([C:58]1[C:59]([C:64]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:65])=[N:60][CH:61]=[CH:62][CH:63]=1)[CH3:57]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: CCc1cccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCc1cccnc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 69.1 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (100 mg, 0.315 mmol) obtained in Example 1, (3), HATU (180 mg, 0.473 mmol), triethylamine (132 μL, 0.945 mmol), and 3-ethylpicolinic acid (71 mg, 0.473 mmol) were stirred at room temperature for 2 hours in anhydrous dimethylacetamide (10 mL). The reaction mixture was post-treated in a conventional manner to give the title compound (98 mg, yield 69%).
Reaction SMILES: S(=O)(=O)(O)O.N[C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].N([O-])=O.[Na+].[I-:27].[K+]>C(OCC)(=O)C.O.C(O)(=O)C>[I:27][C:7]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10]
Reactant: [I-]
Reactant: Nc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1I
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a suspension of water 6.0 mL, acetic acid 10 mL and concentrated sulfuric acid 0.95 mL of 2-amino-4-phenoxybenzoic acid 2.0 g was added water 2.0 mL solution of sodium nitrite 0.66 g at 4° C., and it was stirred at same temperature for 30 minutes. The reaction mixture was added dropwise to water 30 mL solution of potassium iodide 3.2 g at same temperature, and it was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate:acetic acid=80:20:1] to give 2-iodo-4-phenoxybenzoic acid 1.6 g of red solid.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][C:6]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[CH:16][C:17](N)=[N:18][CH:19]=1.[OH2:21].[OH-].[Na+]>S(=O)(=O)(O)O>[CH3:5][C:6]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:7]=1[C:14]1[N:15]=[CH:16][C:17]([OH:21])=[N:18][CH:19]=1
Reactant: O
Reactant: CSc1ccc(-c2cnc(N)cn2)c(C)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CSc1ccc(-c2cnc(O)cn2)c(C)c1
Temperature: 45 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
Sodium nitrite (77 mg, 1.109 mmol) was added portionwise to concentrated sulfuric acid (2 mL) at 0° C. The mixture was stirred at 45° C. until homogeneous, cooled to 0° C., and charged with a solution of 5-[2-methyl-4-(methylthio)phenyl]-2-pyrazinamine (190 mg, 0.821 mmol) in sulfuric acid (3 mL) at 0° C. The mixture was warmed to ambient temperature, stirred at ambient temperature for 15 min, then at 45° C. for 5 h. The mixture was cooled to ambient temperature, poured into water, and the pH was adjusted to ˜4 with 10N NaOH. The resulting precipitate was filtered, washed with water, and air-dried to give 100 mg (52%) of 5-[2-methyl-4-(methylthio)phenyl]-2-pyrazinol (and tautomers thereof) as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 12.61-12.37 (m, 1H), 8.08 (d, 1H, J=1.0 Hz), 7.72-7.45 (m, 1H), 7.30 (d, 1H, J=8.1 Hz), 7.22-7.06 (m, 2H), 2.48 (s, 3H), 2.30 (s, 3H); LRMS (ESI), m/z 233 (M+H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[NH:6][C:7](=[O:17])[CH2:8][S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[Cl:22][C:19]1[CH:18]=[C:5]2[C:4]([C:3]([OH:2])=[C:8]([S:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7](=[O:17])[NH:6]2)=[CH:21][CH:20]=1
Reactant: COC(=O)CCCSCC(=O)Nc1cc(Cl)ccc1C(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCSc1c(O)c2ccc(Cl)cc2[nH]c1=O
Reaction time: 0.5 h

Procedure:
2.0 g (5.6 mmol) of 4-chloro-N-(3-methoxycarbonylpropylthio)acetyl-anthranilic acid methyl ester are placed in 20 ml of tetrahydrofuran at 0° , and 16.8 ml of a 1M solution of sodium bis-trimethylsilylamide are added dropwise thereto. The mixture is then stirred for 30 minutes at 0° and the reaction mixture Is then poured into 2N hydrochloric acid/ice. The resulting white suspension is filtered with suction and the resulting colourless crystals are dried under a high vacuum at 60°. The dried product is made into a suspension in ethyl acetate and stirred for 30 minutes. The suspension is filtered, and the colourless crystals are dried under a high vacuum at 70°, yielding 7-chloro-4-hydroxy-3-(3-methoxycarbonyl-propylthio)-2(1H)-quinolone in the form of colourless crystals having a melting point of 183°-185° (decomp.).
Reaction SMILES: [BH4-].[Na+].[Na].C(=O)=O.[C@@H:7]1([N:15]2[C:19]3[N:20]=[CH:21][NH:22][CH2:23][C@@H:24]([OH:25])[C:18]=3[N:17]=[CH:16]2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[CH2:8]1>C(O)C>[C@H:7]1([N:15]2[C:19]3[N:20]=[CH:21][NH:22][CH2:23][C@@H:24]([OH:25])[C:18]=3[N:17]=[CH:16]2)[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[CH2:8]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c2N=CNC[C@H]3O)C[C@@H]1O
Agent: O=C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC[C@H]1O[C@H](n2cnc3c2N=CNC[C@H]3O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 25 mg. of 6,7-dihydro-3-[3,5-di-O-(p-toluoyl)-60 ,β-D-erythro-pentofuranosyl]imidazo[4,5-d][1,3]diazepin-8(3H)-one in 5 ml. of ethanol is treated with 10 mg. of sodium borohydride and stirred at room temperature for 15 minutes. About 5 mg. of sodium is then added, the solution is stirred at room temperature for 15 minutes, then neutralized with carbon dioxide. The mixture is evaporated at reduced pressure and the residue is partitioned between 10 ml. of ether and 10 ml. of water. The aqueous phase is separated and evaporated at reduced pressure. The residue is applied to the top of a 1 × 10 cm. column of Dowex 50×2 resin (a strongly acidic cation exchange resin) in the ammonium form. The resin is eluted with 25 ml. of 0.01N aqueous ammonia and the eluate is evaporated at reduced pressure to give a residue consisting of a mixture of the four possible isomers, one of which is (R)-3-(2-deoxy-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (pentostatin).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]=[CH2:11])[C:5]([N+:12]([O-])=O)=[CH:4][CH:3]=1.Cl.[Sn](Cl)Cl>[OH-].[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]=[CH2:11])[C:5]([NH2:12])=[CH:4][CH:3]=1
Reactant: C=CCNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: C=CCNc1nc(Cl)ccc1N
Temperature: -5 °C
Reaction time: 1 h

Procedure:
6-Chloro-3-nitro-N-(prop-2-en-1-yl)pyridin-2-amine (71-2, 11.07 g, 51.8 mmol, 1.0 equiv) was added to concentrated HCl (106 mL) to give a suspension. The resulting reaction contents were cooled to −5° C. Tin(II) chloride dehydrate (70.2 g, 311 mmol, 6.0 equiv) was then added in seven 10-g portions while maintaining an internal temperature below 0° C. Following the addition, the reaction mixture was then transferred to a 90° C. bath. After 1 h at 90° C., the reaction contents were cooled to RT and added dropwise to 10N NaOH (300 mL) at 0° C. with vigorous stirring. Following the addition, the mixture was warmed to RT and stirred for 10 min. The aqueous layer was then extracted with 3×100 mL EtOAc and the combined organics were dried over Na2SO4, filtered and concentrated to give a thick, purple oil. The crude material was carried onward without further purification. LRMS (M+H)+: observed=189.0, calculated=183.6.