Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C:5](=O)[CH2:4]1)[CH3:2].Cl.[CH:22]1([CH2:25][O:26][NH2:27])[CH2:24][CH2:23]1>CCO>[CH:22]1([CH2:25][O:26][N:27]=[C:5]2[CH2:6][C@H:7]([C:8]3[N:12]4[C:13]5[CH:19]=[CH:18][NH:17][C:14]=5[N:15]=[CH:16][C:11]4=[N:10][N:9]=3)[C@H:3]([CH2:1][CH3:2])[CH2:4]2)[CH2:24][CH2:23]1
Reactant: CC[C@@H]1CC(=O)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Reactant: NOCC1CC1
Agent: Cl
Solvent: CCO
Product: CC[C@@H]1CC(=NOCC2CC2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
To a solution of (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.05 g, 0.19 mmol, Example #AA.1.59) in EtOH (1 mL) was added TEA (0.04 mL, 0.28 mmol) and O-(cyclopropylmethyl)hydroxylamine hydrochloride (0.02 g, 0.19 mmol, Huhu Technologies). The reaction mixture was stirred for about 18 h at ambient temperature. Additional O-(cyclopropylmethyl)hydroxylamine hydrochloride (0.02 g, 0.19 mmol, Huhu Technologies) was added. The reaction was stirred at ambient temperature for about 5 h. The solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 1-10% MeOH in DCM to afford (3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone O-cyclopropylmethyl oxime (0.051 g, 80%): LC/MS (Table 1, Method a) Rt=1.94 min; MS m/z: 339 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=O)[CH2:3][CH2:4][C:5](=[O:9])[NH:6]OC.[Cl:13][C:14]([Cl:22])([Cl:21])[CH2:15][O:16][C:17]([NH:19][NH2:20])=[O:18]>>[NH2:1][C@H:2]([C:10]([NH:20][NH:19][C:17]([O:16][CH2:15][C:14]([Cl:22])([Cl:21])[Cl:13])=[O:18])=[O:12])[CH2:3][CH2:4][C:5](=[O:9])[NH2:6]
Reactant: CONC(=O)CC[C@H](N)C(=O)O
Reactant: NNC(=O)OCC(Cl)(Cl)Cl
Product: NC(=O)CC[C@H](N)C(=O)NNC(=O)OCC(Cl)(Cl)Cl
Yield: 46.4 %

Procedure:
According to the process of H. Watanabe et al, Chemical Pharmaceutical Bulletin, vol. 22, p. 1889 (1974), 4 g of Gln(OMe) is reacted with 4 g of β,β,β-trichloroethyloxycarbonylhydrazine (hereinafter referred to as "TrocNHNH2 ") to obtain 3 g of GlnNHNH-Troc.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[Cl:11][C:4]1[S:3][C:2]([NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COC(=O)c1cc(Cl)sc1N
Product: CCOC(=O)C(=CNc1sc(Cl)cc1C(=O)OC)C(=O)OCC

Procedure:
Reaction of methyl 2-amino-5-chlorothiophene-3-carboxylate with diethyl ethoxymethylenemalonate is a similar manner to that used in Reference Example 10 yields diethyl (5-chloro-3-methoxycarbonylthienyl)aminomethylenemalonate as crystals melting at 89.5°-90.5° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].[OH:27][CH2:28][CH2:29][C:30](O)=[O:31]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][C:28](=[O:27])[CH2:29][CH2:30][OH:31])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C
Reactant: O=C(O)CCO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNC(=O)CCO)cc3)no2)cc1C
Yield: 5 %

Procedure:
The title compound (3 mg) is prepared in analogy to Example 163 by coupling 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylamine (50 mg, 135 μmol) with 3-hydroxypropionic acid (18 mg, 202 μmol); LC-MS: tR=0.71 min; [M+1]+=442.76.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][C:5]([NH:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])=[O:6]>O.C(O)(C)C>[NH:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[O:11][CH2:4][C:5]1=[O:6]
Reactant: O=C(CCl)Nc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C1COC(=O)c2ccccc2N1
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of sodium hydroxide (2 g, 50 mole) in water (12 ml) was added to a stirred slurry of 2-chloroacetamidobenzoic acid (10.3 g, 48 mmole) in isopropanol (22.5 ml) and water (87.5 ml). The mixture was stirred until a solution formed and then heated at 80° C. for 4 hours. The solution was cooled to 0° C. and the crystalline solid collected, washed with water and dried in vacuo at 50° C. to give the product (7.4 g, 87%), m.p. 200°-201° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.[CH2:19](N(CC)CC)[CH3:20].BrCC>C(#N)C>[O:1]=[C:2]1[CH2:11][CH2:10][CH:9]2[CH:4]([CH2:5][CH:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: COC(=O)N1CC2CCC(=O)CC2CC1C(=O)O
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: CCBr
Product: CCOC(=O)C1CC2CC(=O)CCC2CN1C(=O)OC
Temperature: 50 °C

Procedure:
In Scheme VI, Step A, 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylic acid (Pg is as herein defined above) is esterified by reaction with a compound of formula R5-Br (where R5 is as herein defined) to provide the 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylate intermediate of compound (2). For example 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid is dissolved in acetonitrile and treated with triethylamine and bromoethane. The reaction is heated at 50° C. for about 3 hours, cooled and partitioned between 50:50 ethyl acetate/heptane and 1N HCL. The organic phase is isolated and washed 3 times with water, saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide ethyl 6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate, a compound of structure (2). This crude material may then be purified under standard conditions well known in the art. For example, the crude material is dissolved in 10% ethyl acetate/heptane and applied to a plug of silica gel (10 g in 10% ethyl acetate/heptane). The plug is eluted with, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25% ethyl acetate/heptane. The eluents are combined and concentrated under vacuum to provide the purified compound of structure (2).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:28]=[N:27][C:26]([O:29][CH3:30])=[C:25]([C:31](=O)[CH3:32])[CH:24]=2)=[CH:18][C:17]=1[CH3:34].C(O)(=O)C>CC(N(C)C)=O>[NH:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:32]=[C:31]1[C:25]1[CH:24]=[C:23]([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([OH:15])=[C:17]([CH3:34])[CH:18]=2)[N:28]=[N:27][C:26]=1[O:29][CH3:30]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1C(C)=O
Reactant: Nc1ccccc1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccccc2[nH]1
Temperature: 140 °C

Procedure:
205 mg of 2-bromoaniline and 72 mg of anhydrous magnesium sulfate are suspended in 7 ml dimethylacetamide. 325 mg of 1-[6-(4-Hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-ethanone and 86.6 μl acetic acid are added and the reaction is degassed with argon. 330 mg of tripotassium phosphate and 61 mg of bis(tri-tert-butylphosphine) palladium (0) are added and the reaction is degassed with argon. The reaction is heated to 140° C. for 5 h. The solution is poured into water and extracted with ethyl acetate. The solvent is removed under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 105 mg. LC-MS (ES+) 346 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH2:5]([O:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]([C:20]([O-:22])=O)=[C:13]([OH:23])[C:12]=2[CH2:11]1)=[O:9])[CH3:6]>>[CH2:5]([O:7][C:8]([N:10]1[CH2:19][CH2:18][C:17]2[N:16]=[CH:15][C:14]([C:20](=[O:22])[NH:4][CH2:1][CH2:2][CH3:3])=[C:13]([OH:23])[C:12]=2[CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)N1CCc2ncc(C(=O)[O-])c(O)c2C1
Reactant: CCCN
Product: CCCNC(=O)c1cnc2c(c1O)CN(C(=O)OCC)CC2

Procedure:
Reaction of N-propylamine with 6-ethoxycarbonyl-4-hydroxy-5,6,7,8-tetrahydro[1,6]naphthyridine-3-carboxylate yields 6-ethoxycarbonyl-4-hydroxy-5,6,7,8-tetrahydro-3-(N-propylcarbamoyl)[1,6]-naphthyridine, mp 199°-201°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH:24]([C:26]([O:28]C)=O)[CH2:23][C:22]=4[CH:30]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.CN.[CH:34]([N:37](C(C)C)CC)(C)C>CO.O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]([F:16])=[CH:14][N:13]=[C:12]([NH:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH:24]([C:26]([NH:37][CH3:34])=[O:28])[CH2:23][C:22]=4[CH:30]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(F)c(F)c4)n3)ccc2O1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4ccc(F)c(F)c4)n3)ccc2O1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, methylamine Hydrogen Chloride (5 equivalents) and diisopropylethylamine (5 equivalents) in MeOH was shaken in a sealed tube at 80° C. for 24 h. The resulting solution was diluted with water and the precipitate obtained was filtered, washed with water, dried and analyzed to afford (±)-N4-(3,4-difluorophenyl)-5-fluoro-N2-[2,3-dihydro-2-(N-methylamino)carbonylbenzofuran-5-yl]-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.46 (s, 1H), 9.07 (s, 1H), 8.05 (m, 3H), 7.48 (m, 2H), 7.35 (m, 1H), 7.22 (m, 1H), 6.72 (d, 1H, J=8.1 Hz), 5.07 (dd, 1H, J=6.6 and 6.3 Hz), 3.40 (dd, 1H), 3.15 (dd, 1H), 2.60 (d, 3H, J=4.5 Hz); LCMS: purity: 98%; MS (m/e): 416 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[N:13]1([CH2:18][CH2:19][NH2:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:20][CH2:19][CH2:18][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: NCCN1CCCC1
Product: COc1cc([N+](=O)[O-])ccc1NCCN1CCCC1
Temperature: 75 °C
Yield: 23.6 %

Procedure:
A neat mixture of 1-chloro-2-methoxy-4-nitrobenzene (2.0 g, 10.7 mmol) and 2-pyrrolidin-1-ylethanamine (2.5 g, 22 mmol) was heated to 75° C. overnight, then chromatographed on silica gel with ethanol (100%) to give a yellow solid (0.67 g, 24%).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][N:5]1[NH:9][CH:8]=[C:7]([C:10]2[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=2)[S:6]1.N1CC[CH2:22][CH2:21][CH2:20]1>O1CCOCC1>[N:4]1([N:5]2[NH:9][CH:8]=[C:7]([C:10]3[N:11]([CH3:18])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=3)[S:6]2)[CH2:22][CH2:21][CH2:20][CH2:2][CH2:3]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(NCCO)S1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCCCC2)S1

Procedure:
A mixture composed of 7.4 g. of 2-(2-chloro-5-thiadiazolyl)-1-methyl-5-nitroimidazole (Example 16), 6 g. of piperidine, and 200 ml. of dioxane is stirred at room temperature for 24 hours, and then taken to dryness under reduced pressure. The residue is shaken with 100 ml. of water and the insoluble portion collected and dried. Recrystallization from 150 ml. of 2-methoxyethanol gives 7.6 g. of the subject compound melting at 212°-213° C.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][C:8](=[O:10])[CH2:7]1)=[O:4].[BH4-].[Na+]>C(Cl)Cl.CO>[F:42][C:2]([F:1])([F:43])[C:3]([NH:5][C:6]1([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:9][CH:8]([OH:10])[CH2:7]1)=[O:4]
Reactant: O=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)CC(O)C1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a mixture of 2,2,2-trifluoro-N-(3-oxo-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (25 mg, 0.043 mmol) in CH2Cl2 (1 mL) and MeOH (1 mL) was added NaBH4 (2.0 mg, 0.052 mmol) at −78° C., and the mixture was stirred at −78° C. for 1 hour. The mixture was quenched with sat. NH4Cl, extracted with CHCl3, washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give 2,2,2-trifluoro-N-(3-hydroxy-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-3). MS (M+H)+: observed=581, calculated=581.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[NH:5][N:4]=1.Br[CH:16]([C:18]1[O:19][C:20](=[O:34])[C:21]2[C:26]([C:27]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:17]>>[NH2:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:5]([CH:16]([C:18]3[O:19][C:20](=[O:34])[C:21]4[C:26]([C:27]=3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:17])[N:4]=[C:3]([C:2]([F:13])([F:1])[F:14])[C:11]=12
Reactant: Nc1ncnc2[nH]nc(C(F)(F)F)c12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(C(F)(F)F)c2c(N)ncnc21
Yield: 14.9 %

Procedure:
The title compound was made in a similar way as that of the compound of example 1 using 3-(trifluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G16, 45 mg, 0.222 mmol) 3-(1-bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 72.9 mg, 0.222 mmol). to give the title compound (15 mg, 0.033 mmol, 15.0% yield) as white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:18][C@@H:19]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([NH:22][CH3:23])=[O:21])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-N,3,3-trimethyl-butanamide, (CAN 89226-12-0) as starting materials, LC-MS (UV peak area/ESI) 96%, 360.2272 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:29][C@H:28]([CH2:30][O:31]C(=O)C4C=CC=CC=4)[C@@:23]([CH3:40])([O:24]C(=O)C)[C@H:13]3[O:14]C(=O)C3C=CC=CC=3)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO>[NH2:1][C:2]1[NH:3][C:4](=[O:41])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:29][C@H:28]([CH2:30][OH:31])[C@@:23]([CH3:40])([OH:24])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)O[C@]1(C)[C@@H](COC(=O)c2ccccc2)O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@]1(O)[C@@H](CO)O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@@H]1O
Reaction time: 16 h
Yield: 73.9 %

Procedure:
Nucleoside triester 116 (100 mg, 0.172 mmol) was dissolved in methanol (5 mL) and K2CO3 (28.6 mg, 0.207 mmol) was added. The reaction progressed for 16 h. The reaction was neutralized with acetic acid (24.8 mg, 0.412 mmol). Then the solvent removed by rotary vacuum and the solid submitted to HPLC purification (MeCN—H2O) yielding 42 mg (74%) of white solid: 1H NMR (400 Mz, d6-DMSO) δ 11.20 (s, 1H), 6.89 (br s, 2H), 5.80 (d, J=8.0, 1H), 5.36 (d, J=6.0, 1H), 4.77 (t, J=8.0, 1H), 4.62 (s, 1H), 4.48 (m, 1H), 3.75 (m, 1H), 3.58-3.44 (m, 2H), 1.19 (s, 3H); Analysis calc'd for C14H14N4O6S.0.125H2O.0.125HCO2H: C, 39.33; H, 4.34; N, 16.43; S, 9.40. Found: C, 39.77; H, 4.81; N, 15.02; S, 9.69; [M+H]+ m/z 331.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:26])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([S:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:12]=1)[C:5]#[N:6].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[Cl:26][C:8]1[CH:7]=[C:4]([C:5]2[N:27]=[N:28][NH:29][N:6]=2)[CH:3]=[C:2]([Cl:1])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([S:18]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:20])=[O:19])[CH:12]=1
Reactant: N#Cc1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)N3CCCC3)c2)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: O=S(=O)(c1cc(Oc2c(Cl)cc(-c3nn[nH]n3)cc2Cl)ccc1O)N1CCCC1
Temperature: 143 °C

Procedure:
4-[2,6-Dichloro-4-(2H-tetrazol-5-yl)-phenoxy]-2-(pyrrolidine-1-sulfonyl)-phenol was prepared from 3,5-dichloro-4-[4-hydroxy-3-(pyrrolidine-1-sulfonyl)-phenoxy]-benzonitrile according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (4.0 equiv) and ammonium chloride (4.0 equiv) were used, and the reaction was heated to 143° C. for 40 hours. After the reaction had been acidified and the crude product collected by filtration, the solid was dissolved in MeOH, filtered, and the filtrate was concentrated. The residue was purified by preparative TLC (methanol:water:chloroform=19:1:47) to afford the title product of Example 2. MS (APCI−) Calc.: 455.0, Found: 454.2 (M−1).
Reaction SMILES: [CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH2:14].[Cl-].[C:16]([O:27][CH3:28])(=[O:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21]([O-])=[O:22])=[CH:19][CH:18]=1.Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH:1]1[C:12]2=[C:13]3[CH:8]([CH2:9][CH2:10][CH2:11]2)[CH2:7][CH2:6][CH2:5][C:4]3=[CH:3][C:2]=1[NH:14][C:21]([C:20]1[CH:24]=[CH:25][C:17]([C:16]([O:27][CH3:28])=[O:26])=[CH:18][CH:19]=1)=[O:22]
Reactant: Nc1cc2c3c(c1)CCCC3CCC2
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4CCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
A solution of 5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.260 g) in anhydrous benzene (10 ml) and pyridine (3 ml) was added with monomethyl terephthalate chloride (0.304 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.460 g, yield: 95%) as colorless needles (melting point: 217-218° C.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH:12]=[O:13])=[C:7]([OH:14])[CH:6]=[CH:5][C:4]=2[N:3]=1.OC1C=C2C(C(C)=C([C:27]3[CH:43]=[CH:42][C:30]([C:31]([NH:33][CH2:34][CH2:35][N:36]4[CH2:41][CH2:40]OC[CH2:37]4)=[O:32])=[CH:29][CH:28]=3)C(=O)O2)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C.O>[OH:14][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([C:28]3[CH:27]=[CH:43][CH:42]=[C:30]([C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH3:37])[CH2:41][CH2:40]4)=[O:32])[CH:29]=3)[CH:11]=[CH:10][C:9]=2[C:8]=1[CH:12]=[O:13]
Reactant: Cc1c(-c2ccc(C(=O)NCCN3CCOCC3)cc2)c(=O)oc2cc(O)ccc12
Reactant: O=Cc1c(O)ccc2nc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CN1CCN(C(=O)c2cccc(-c3ccc4c(C=O)c(O)ccc4n3)c2)CC1

Procedure:
A mixture of 2-chloro-6-hydroxyquinolin-5-carbaldehyde (3) (104 mg, 0.5 mmol), 3-(4-methylpiperazine-1-carbonyl)phenylboronic acid (6) (198 mg, 0.7 mmol) and K2CO3 (174 mg, 1.25 mmol) in a mixture of i-PrOH and water (6 mL 10:1) was purged with Argon for five minutes in a microwave vessel. A tablet of PdOAc2(Sphos)4 (Aldrich, Cat, No. 694088) was added under an Argon atmosphere then the vessel was sealed and irradiated for 45 min at 165° C. Upon cooling, the reaction mixture was filtered through a silica plug using MeOH. The solution was evaporated and purified by Flash chromatography using 0-5% MeOH in CH2Cl2. The product was recrystallized from CH2Cl2/hexanes to afford the title compound, MS (ESI): 376 (M+H)+. 1H NMR (δ, DMSO (2.5 ppm)): 10.74 (s, 1H), 9.44 (d, 1H), 8.30 (dd, 1H), 8.27 (d, 1H), 8.24 (s, 1H), 8.23 (d, 1H), 7.61 (t, 1H), 7.49 (d, 1H), 7.47 (dd, 1H), 3.60, 3.40, 2.40 and 2.30 (4 broad s, 4×2H), 2.23 (s, 3H).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@@H:11]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]#[C:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:12]2=[O:25])=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].CO>ClCCl>[OH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]#[C:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:12]1=[O:25]
Reactant: O=C(O[C@@H]1CCN(CC#CCN2CCCC2)C1=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C1[C@H](O)CCN1CC#CCN1CCCC1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
A mixture of 1.6 g of (R)-3-[(4-Nitrobenzoyl)-oxy]-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone, 1.6 g of potassium carbonate and 60 ml of methanol was stirred for 2 hours, diluted with dichloromethane and filtered. The filtrate was concentrated to dryness. The residue was chromatographed (alumina) to give 0.8 g of the desired product as an off white solid; mp 81°-85° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH:20]=[C:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:29][CH3:30])[C:8]=2[C:7]1=[O:31].[H-].[Na+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][N:6]1[CH:20]=[C:19]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:39]([CH3:38])(=[O:41])=[O:40])[C:18]2[N:11]3[CH2:12][CH2:13][N:14]([CH3:17])[C:15](=[O:16])[C:10]3=[C:9]([O:29][CH3:30])[C:8]=2[C:7]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c2n(c3c(NC(=O)OC(C)(C)C)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2n(c3c(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cn(Cc4ccc(F)c(Cl)c4)c(=O)c13)CCN(C)C2=O
Reaction time: 1 h

Procedure:
A cold (0° C.) solution of 2-(3-chloro-4-fluorobenzyl)-10-methoxy-4-(N-tert-butoxylcarbonyl-amino)-8-methyl-7,8-dihydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]pyrazine-1,9(2H,6H)-dione (0.74 g, 1.70 mmol) in anhydrous DMF (3 mL) was treated with sodium hydride (7 mg, 0.30 mmol). The resultant mixture was stirred at the same temperature for 30 minutes, and treated with methanesulfonyl chloride (34 mg, 0.30 mmol). After stirring at 0° for 1 hour, the product mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 20% methanol in ethyl acetate. Collection and concentration of appropriate fractions provided the titled compound.