Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]#[N:10])=[CH:4][C:3]=1[O:11][C:12]1[C:13]([F:37])=[C:14]([CH2:19][NH:20][C:21]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[N:25][C:24]=2[Cl:36])=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].N(OC(C)(C)C)=O>C(#N)C.CCOC(C)=O>[Cl:36][C:24]1[N:25]=[CH:26][N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:23]=1[C:21]([NH:20][CH2:19][C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([O:11][C:3]2[CH:2]=[CH:7][C:6]([F:8])=[C:5]([C:9]#[N:10])[CH:4]=2)[C:13]=1[F:37])=[O:22]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)c(F)cc2N)c1F
Agent: CC(C)(C)ON=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2ccc(F)c(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of N-({3-[(2-amino-5-cyano-4-fluorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (110 mg, 0.194 mmol) in Acetonitrile (8 ml) was added tert butyl nitrite (0.046 ml, 0.387 mmol) and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-4-fluorophenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (49 mg, 0.089 mmol, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (t, 1H), 7.98 (s, 1H), 7.42-7.59 (m, 3H), 7.29-7.42 (m, 2H), 5.49 (s, 2H), 4.48 (d, 2H), 3.38 (t, 2H), 0.75 (t, 2 H), −0.09 (s, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].[C:5]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[C:6]1[CH3:7]>O>[C:5]([NH:3][NH2:4])(=[O:12])/[C:6](=[CH:8]\[C:9]([OH:11])=[O:10])/[CH3:7]
Reactant: NN
Reactant: CC1=CC(=O)OC1=O
Agent: Cl
Solvent: O
Product: C/C(=C/C(=O)O)C(=O)NN
Temperature: 10 °C

Procedure:
To a solution of 210 g of hydrazine dihydrochloride in 2 liters of water there was added, in one portion, 224 g of citraconic anhydride. When the mixture was heated to boiling with stirring, a homogeneous solution was first obtained and then a white precipitate started to form in the mixture. After 30 minutes at reflux, the mixture was allowed to cool with stirring. It was then cooled to 10° C. and the solid was separated by filtration and dried in a vacuum oven overnight to give citraconic hydrazide melting at about 281-283.5° C. with decomposition.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][C:28]1([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:34]([C:28]5([O:27][CH3:26])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[O:35])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: COC1(C(=O)O)CCCCC1
Agent: Cl
Product: COC1(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)CCCCC1

Procedure:
The title compound, white solid (22.2 mg, 57.7%), MS (ISP) m/z=471.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (30 mg, 0.0818 mmol) and 1-Methoxycyclohexane-1-carboxylic acid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[C:10]1[N:11]=[CH:12][C:13]([C:16]([NH:18][C:19]2[NH:20][N:21]=[C:22]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=3)[CH:23]=2)=[O:17])=[N:14][CH:15]=1>CS(C)=O>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:22]2[CH:23]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[N:11][C:10]([N:6]4[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]4)=[CH:15][N:14]=3)=[O:17])[NH:20][N:21]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(Cl)cn3)[nH]n2)cc(OC)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CS(C)=O
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4C[C@@H](C)N[C@@H](C)C4)cn3)[nH]n2)cc(OC)c1
Temperature: 100 °C
Reaction time: 18 h
Yield: 35.2 %

Procedure:
(2S,6R)-2,6-Dimethylpiperazine (228 mg, 2.00 mmol) was added in one portion to 5-chloro-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (388 mg, 1.00 mmol) in anhydrous dimethylsulfoxide (1.00 ml) at 25° C. The resulting solution was stirred at 100° C. for 18 h. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (164 mg, 35%) as a cream solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[CH3:15][NH:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][N:16]([CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])[CH3:17]
Reactant: CNC
Reactant: N#Cc1cccc([N+](=O)[O-])c1CBr
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1c(C#N)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a stirred mixture of 2-(bromomethyl)-3-nitrobenzonitrile (1.10 g, 4.56 mmol) (prepared according to the method described in Tetrahedron 40: 1863-1868 (1984)) and dimethylamine hydrochloride (0.74 g, 9.13 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.85 g, 18.25 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (3×50 mL). The EtOAc solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 2-((dimethylamino)methyl)-3-nitrobenzonitrile (0.75 g, 80%) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.93 (br d, 1H, J=8.0 Hz), 7.85 (dd, 1H, J=8.0, 1.4 Hz), 7.55 (t, 1H, J=8.0 Hz), 3.94 (s, 2H), 2.24 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]([OH:21])[CH3:20]>O.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]([CH2:18][CH:19]([OH:21])[CH3:20])[N:4]=1
Reactant: CC(O)CBr
Reactant: COc1n[nH]cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1nn(CC(C)O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 33.6 %

Procedure:
To a suspension of 3-methoxy-4-nitro-1H-pyrazole (2.00 g, 14.0 mmol, 1.00 eq) and cesium carbonate (13.7 g, 41.9 mmol, 3.0 eq) was added 1-bromo-2-propanol (2.70 mL, 22.4 mmol, 1.60 eq, 70% purity) and the reaction mixture was heated at 60° C. After 3.5 hr, an additional portion of 1-bromo-2-propanol (2.70 mL, 22.4 mmol, 1.60 eq, 70% purity) was added. After a further 12 hr, the reaction mixture was cooled to ambient temperature and diluted with water (100 mL) and EtOAc (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (4×50 mL). The combined organics were washed with water (50 mL) and brine (50 mL), dried (Na2SO4), concentrated, and purified via flash chromatography on silica gel eluting with a gradient of 0-50% EtOAc in heptane to give the title compound (945 mg, 34% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.09 (s, 1H), 4.32-4.22 (m, 1H), 4.06 (s, 3H), 4.05 (dd, J=5.0, 13.0 Hz, 1H), 3.87 (dd, J=8.0, 13.0 Hz, 1H), 2.60 (br. s., 1H), 1.29 (d, J=6.4 Hz, 3H). m/z (APCI+) for C7H12N3O4 201.9 (M+H)+.
Reaction SMILES: C[Si](OP(=O)=O)(C)C.[Br:9][C:10]1[CH:11]=[C:12]([C:26](O)=O)[C:13]([C:16]2[C:17](=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)[C:18](O)=O)=[CH:14][CH:15]=1.[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35].C([O-])(O)=O.[Na+]>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:17]=2[C:18]2[NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:36]=2)=[C:12]([C:26]2[NH:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[N:36]=2)[CH:11]=1
Reactant: O=C(O)c1cc(Br)ccc1-c1ccc(Br)cc1C(=O)O
Reactant: Nc1ccccc1N
Agent: C[Si](C)(C)OP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Brc1ccc(-c2ccc(Br)cc2-c2nc3ccccc3[nH]2)c(-c2nc3ccccc3[nH]2)c1
Temperature: 160 °C
Yield: 53.9 %

Procedure:
To the PPSE solution was added 15.0 g of 4,4'-dibromodiphenic acid, 8.11 g of o-phenylene diamine (recrystallized from methylene chloride and charcoal). This mixture was rapidly heated to 160° C. and maintained there for 20 hours. The solution was cooled, then poured into 2 1 of 10% NaHCO3 solution. The product was filtered, washed with 300 ml of hot methylene chloride, then extracted using a Soxhlet extractor using 10% NaHCO3 overnight. The product was dried then recrystallized from ethanol to give 11 g of white crystals, mp 326° C.-328° C. Analysis calculated for C26H16N4Br2 : C, 57.38; H, 2.96; N, 10.29. Found: C, 57.81; H, 3.04, N, 10.30.
Reaction SMILES: [CH3:1][C:2]([CH:9]1[CH:18]2[CH2:19][CH:20]=[CH:21][CH:17]2[C:16]2[CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=[CH:12][C:11]=2[NH:10]1)([CH3:8])[CH2:3][S:4]C(=O)C>CO.O1CCCC1.[OH-].[Na+]>[CH3:8][C:2]([CH:9]1[CH:18]2[CH2:19][CH:20]=[CH:21][CH:17]2[C:16]2[CH:15]=[C:14]([N+:22]([O-:24])=[O:23])[CH:13]=[CH:12][C:11]=2[NH:10]1)([CH3:1])[CH2:3][SH:4]
Reactant: CC(=O)SCC(C)(C)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(CS)C1Nc2ccc([N+](=O)[O-])cc2C2C=CCC21
Temperature: 50 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
The compound of Example 76 (134 mg) was dissolved in 15 ml of a mixed solution of methanol and tetrahydrofuran, and 15 ml of a 2 mol/l sodium hydroxide solution was added. After overnight stirring at 50° C., the reaction mixture was concentrated under reduced pressure. The resulting residue was acidified with saturated ammonium chloride solution and 2 mol/l hydrochloric acid solution, and then ethyl acetate was added. The ethyl acetate layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvents: hexane:ethyl acetate 4:1˜hexane:ethyl acetate=2:1˜hexane:ethyl acetate=1:1) to obtain 34 mg of the captioned compound. Its physical properties are shown below.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:28](O)[CH3:29]>>[C:1]1([CH:7]([C:13]2[C:14](=[O:23])[C:15]([CH3:22])=[C:16]([CH3:21])[C:17](=[O:20])[C:18]=2[CH3:19])[CH2:8][CH2:9][C:10]([O:12][CH2:28][CH3:29])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC1=C(C)C(=O)C(C(CCC(=O)O)c2ccccc2)=C(C)C1=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCC(C1=C(C)C(=O)C(C)=C(C)C1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
4-Phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)butanoic acid (1.2 g) was dissolved in ethanol (50 ml), and thionyl chloride (0.4 ml) was added to the solution, followed by stirring at room temperature for 4 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in isopropyl ether, and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and the object compound was eluted with isopropyl ether to give ethyl 4-phenyl-4-(3,5,6-trimethyl-1,4-benzoquinon -2-yl)butanoate (1.1 g, 84%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this example, the Compound No. 42 was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:24]O.O>C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][S:17](=[O:24])[C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Reactant: OO
Solvent: O=CO
Solvent: O
Product: Cc1cc2c(s1)S(=O)CCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Temperature: 5 °C

Procedure:
To a solution of 1.0 g of 2-(4-chlorophenyl)-9-methyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one in 50 ml of formic acid is added 0.3 ml of 35% aqueous hydrogen peroxide solution with stirring at 5° C. and the mixture is stirred for 10 minutes at the same temperature. To the mixture is further added 0.3 ml of aqueous hydrogen peroxide solution and the mixture is stirred for 20 minutes. Then, the mixture is poured into water, extracted with chloroform three times and the extract is washed with water and dried over magnesium sulfate. After the chloroform is distilled off under reduced pressure, the resulting crystals are recrystallized from a mixed solvent of chloroform and ethanol to give 1.0 g of 2-(4-chlorophenyl)-9-methyl-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one 7-oxide as white crystals, melting at 174°-175° C. with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:13]>C1C=CC=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1cccc(Br)c1
Reaction time: 168 h
Yield: 69.7 %

Procedure:
A solution of 2-(3-bromophenyl)acetic acid (2.64 g, 12.28 mmol) in 8:2 benzene/methanol (50 mL) was cooled to 0° C., then treated with the dropwise addition of 2.0 M TMS-diazomethane in hexanes (6.14 mL, 12.28 mmol) over 10 minutes. The mixture was allowed to come to room temperature and stirred for 7 days. The mixture was concentrated in-vacuo, and the residue was purified over silica gel, eluting with 10% ethyl acetate/hexanes to yield the title compound (1.96 g, 8.56 mmol, 69.7% yield) as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:11]([O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:13])[CH3:12].Cl>C(Cl)Cl>[C:11]([O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:19][CH:18]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OCCc1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)OCCc1ccc(C(=O)C(C)C)cc1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
Isobutyryl chloride (114 g, 1.07 mol) is added drop wise at −5 to 0° C. over 40 minutes to 295 g (2.21 mol) of anhydrous aluminum chloride in 160 ml of methylene chloride. Stirring is continued for 30 min, and 2-phenylethyl acetate (164.2 g, 1.00 mol) is then added drop wise at −5 to 0° C. over 2 hours. The mixture is stirred an additional 4 hours at −5 to 0° C., and then poured into a mixture of concentrated hydrochloric acid and ice. The organic layer is washed with water, dried and concentrated to give 190.5 g of crude 2-(4-isobutyrylphenyl)ethyl acetate, a colorless liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([C:16](=[O:18])[CH3:17])[C:6]1=[O:19].[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:9][CH:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]([C:16](=[O:18])[CH3:17])[C:6]1=[O:19]
Reactant: COCCn1cc(-c2ccccc2)n(C(C)=O)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCN1CC(c2ccccc2)N(C(C)=O)C1=O

Procedure:
Approximately 3.9 g. of 1-(2-methoxyethyl)-3-acetyl-4-phenyl-4-imidazolin-2-one and 400 mg. of 10% palladium on carbon in 30 ml. of ethanol is hydrogenated in the Parr Shaker apparatus at 30 psig of hydrogen. After one hour the catalyst is filtered and washed with 50 ml. of ethanol. The combined filtrate is concentrated to yield the title compounds as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27].[N:31]1C=CC=CC=1.[OH-].[NH4+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:1][O:2][C:3](=[O:24])[CH2:4][O:5][C:6]1[C:7]2[C:14]([C:25](=[O:29])[C:26]([NH2:31])=[O:27])=[C:13]([CH2:15][CH3:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Agent: CCc1cc2c(OCC(=O)OC)ncnc2n1Cc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)ncnc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of 831 mg (2.55 mmol) of [[6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 20 mL of chloroform was added 0.67 mL of oxalyl chloride followed by 0.30 mL of pyridine. The reaction was stirred for 18 hours at ambient temperature then poured into a solution prepared from 2.0 mL of concentrated ammonium hydroxide and 8.0 mL of water. The reaction was partitioned by the addition of 20 mL of methylene chloride and 10 mL of water. The organic phase was dried with sodium sulfate and concentrated. The residue was purified by flash chromatography (100 g of silica, ethyl acetate) to provide 420 mg (51%) of [[6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester and 455 mg (45%) of [[5-(aminooxoacetyl)-6-ethyl-7-(phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a white solid. nmr (500 MHz, CDCl3) δ1.13 (t, J=7.5 Hz, 3H), 2.95 (q, J=7.5 Hz, 2H), 3.77 (s, 3H), 5.06 (s, 2H), 5.53 (s, 2H), 6.28 (s, 1H), 6.70 (s, 1H), 7.13 (d, J=6.7 Hz, 2H), 7.27 (m, 3H), 8.46 (s, 1H)
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([B:11]([OH:13])[OH:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[N+:14]([O-])([OH:16])=[O:15]>C(OC(=O)C)(=O)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([B:11]([OH:13])[OH:12])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1ccc(B(O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-isobutyl-phenylboronic acid (0.9 g, 5.05 mmol) in acetic anhydride (9 mL) at -10° C., fuming nitric acid (0.4 mL) was added over 10 minutes. The mixture was stirred for 1 hour, warmed to room temperature and stirred for an additional 1.5 hours. The clear orange solution was added to 100 mL of ice, stirred for 3 hours and azeotroped with water (4×100 mL). The residue was partitioned between 25 mL each of ether and water and the ether layer was dried and evaporated to provide 0.75 g of yellow solid. The solid was dissolved in ethyl acetate (25 mL) and the solution was extracted with 1N aqueous sodium hydroxide (2×25 mL). The combined aqueous extracts were acidified to pH 2 using 2N aqueous hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed once with water, dried and evaporated to provide 0.63 g of light yellow solid. Reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 76% solvent A (90% MeOH, 10% H2O, 0.1% TFA) and 24% solvent B (10% MeOH, 90% H2O, 0.1% TFA) provided 0.16 g of compound A as light yellow solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:12]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].S(=O)(=O)(O)[O-:30].[Na+]>O1CCCC1.O>[OH:30][C:2]1[N:7]=[C:6]([N:8]2[C:12]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:11][N:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])O
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(F)n2)CC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nnnn2-c2cccc(O)n2)CC1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
Part C″: To a solution of tert-butyl 4-(1-(6-fluoropyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (0.349 g, 1.00 mmol) in 20 mL of tetrahydrofuran at 25° C. was added a solution of lithium hydroxide monohydrate (0.084 g, 2.00 mmol) in 5 mL of water, and the resulting mixture was stirred at 25° C. for 11 days. The reaction mixture was diluted with water, the pH of the solution was adjusted to ˜pH 6 employing aqueous sodium bisulfate solution, and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-50% diethyl ether/methylene chloride) to afford tert-butyl 4-(1-(6-hydroxypyridin-2-yl)-1H-tetrazol-5-yl)piperazine-1-carboxylate (0.090 g); Mass Spec.: m/e: 348.24 (M+H)+ [calc'd: 348.18]; 1H NMR (300 MHz, CDCl3) δ 7.84 (m, 1H), 7.21 (m, 1H), 6.89 (m, 1H), 3.52 (m, 4H), 3.32 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]Br)=[CH:6][C:5]=1[OH:14].[C:16]1([C:22](=[N:24][OH:25])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:14][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][O:25][N:24]=[C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: COC(=O)c1ccc(OCCBr)cc1O
Reactant: CC(=NO)c1ccccc1
Product: CC(=NOCCOc1ccc(C(=O)O)c(O)c1)c1ccccc1

Procedure:
2-Hydroxy-4-[2-({[1-phenylethylidene]amino}oxy)ethoxy]benzoic acid was prepared as a white solid (0.712 g, 27%) from 4-(2-bromo-ethoxy)-2-hydroxy-benzoic acid methyl ester and 1-phenyl-ethanone oxime using a procedure similar to that of step 1 of example 6. 1H NMR (400 MHz, DMSO-d6); δ 13.60 (bs, 1H), 11.50 (bs, 1H), 7.66 (m, 3H), 7.40 (m, 3H), 6.53 (dd, 1H), 6.52 (s, 1H), 4.44 (t, 2H), 4.32 (t, 2H), 2.18 (m, 2H).
Reaction SMILES: [Cl-].[NH4+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH3:36])[C:17]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[N:30]=3)=[C:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[CH:21]=3)[C:12]=2[C:11]1=[O:37])=[O:9])([CH3:6])([CH3:5])[CH3:4].O>O1CCOCC1.[Zn]>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13]2[N:16]([CH3:36])[C:17]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH2:35])[N:30]=3)=[C:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=3)[C:12]=2[C:11]1=[O:37])=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: Cn1c2c(c(Cc3cccc([N+](=O)[O-])c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c2c(c(Cc3cccc(N)c3)c1-c1ccnc(N)n1)C(=O)N(C(=O)OC(C)(C)C)CC2
Yield: 100 %

Procedure:
Zn (0.041 g, 0.632 mmol) and ammonium chloride (0.034 g, 1.58 mmol) were added to a solution of 2-(2-Amino-pyrimidin-4-yl)-1-methyl-3-(3-nitro-benzyl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.075 g, 0.158 mmol) was dissolved in dioxane (5 ml) and purite water (1.0 ml) and the reaction mixture was stirred at 75° C. for 2 hours. A solution of Na2HPO4 (10 ml) was then added and the water layer was extracted with EtOAc (3×10 ml). The organic layers were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure yielding 3-(3-Amino-benzyl)-2-(2-amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo-[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (0.071 g, 0.158 mmol, 100%).