Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[N:4][NH:5][C:6](=[O:16])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH3:15])([CH3:3])[CH3:2].Cl[O:18][N:19]=[CH:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=1.C(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>O>[CH3:28][C:23]1[CH:22]=[C:21]([C:20]2[N:4]([NH:5][C:6](=[O:16])[C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=3[CH3:15])[C:1]([CH3:3])([CH3:2])[O:18][N:19]=2)[CH:26]=[C:25]([CH3:27])[CH:24]=1
Reactant: Cc1cc(C)cc(C=NOCl)c1
Reactant: COc1cccc(C(=O)NN=C(C)C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cccc(C(=O)NN2C(c3cc(C)cc(C)c3)=NOC2(C)C)c1C
Reaction time: 24 h
Yield: 37.5 %

Procedure:
3-Methoxy-2-methyl-benzoic acid isopropylidene-hydrazide (1.71 g, 7.77 mmol) and 3,5-dimethyl-benzaldehyde chlorooxime (2.29 g, 12.4 mmol), both as CHCl3 solutions (total volume 40 mL), were added to a 250 mL round bottom flask equipped with a magnetic stirrer. An aqueous K2CO3 solution (5 g in 30 mL) was added, the vessel was placed in a 50° C. water bath, and the reaction was stirred vigorously for 24 hours. The reaction was monitored by 1H NMR. Chloroform (100 mL) and water (50 mL) were added, and the mixture was shaken in a separatory funnel. The organic phase was separated, dried, and the solvent was removed in vacuo. Column chromatography on silica gel using a gradient of 10-30% ethyl acetate in hexane yielded 1.07 g of N-[3-(3,5-dimethyl-phenyl)-5,5-dimethyl-[1,2,4]oxadiazol-4-yl]-3-methoxy-2-methyl-benzamide (32%). An analytical sample was obtained by crystallization from CH2Cl2/hexane under refrigeration. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.4 (s, 2H), 7.1 (t, 1H), 7.07 (s, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 3.78 (s, 3H), 2.30 (s, 6H), 2.07 (s, 3H), 1.65 (s, 6H).
Reaction SMILES: [C:1]([N:11]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@@H:24]([CH2:26][N:27]=[N+]=[N-])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[C:1]([N:11]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH2:27])[O:23][C:22]3=[O:30])=[CH:17][C:16]=2[F:31])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 3 h

Procedure:
To a stirred solution of (S)-(−)-N-carbobenzyloxy-3-[2-fluoro-4-[5-azidomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 7, 1.63 g, 3.84 mmol) in dry THF (20 mL) was added triphenylphosphine (1.11 g, 4.23 mmol). After 3 hr, water (0.69 mL, 38.4 mmol) was added and the reaction stirred for 2 days at which time the solvents were evaporated. The residue was chromatographed over silica gel (150 g, 40-60 μm) eluting with 5-10% methanol-chloroform. The title compound was isolated as a viscous colorless oil. FAB-HRMS: theory 400.1672 (M+1); meas. 400.1676.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.[CH3:10][C:11]([C@H:15]([OH:19])[C:16]([OH:18])=[O:17])([CH2:13][OH:14])[CH3:12]>>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1.[O:14]=[CH:13][C:11]([CH2:12][OH:4])([CH3:10])[C@@H:15]([OH:19])[C:16]([OH:18])=[O:17]
Reactant: CC1(C)COC(=O)C1O
Reactant: CC(C)(CO)[C@H](O)C(=O)O
Product: CC(C=O)(CO)[C@@H](O)C(=O)O
Product: CC1(C)COC(=O)C1=O

Procedure:
Burkholderia caryophylli Lu681 (or other strains from Tab. 1) were grown in 25 ml of complex medium (for example HFP=1% peptone, 1% tryptone, 0.5% yeast extract, 0.3% NaCL) for 1 to 3 days, harvested, washed in Tris-HCl buffer (50 mM, pH 7.0) and resuspended (5 ml of 50 mM Tris/HCl, pH 7.0) and incubated with 50 mM ketopantolactone at 30° C. for 3 h. After removal of the cells, the concentrations of ketopantolactone, ketopantoic acid, D,L-pantolactone, D,L-, D-, and L-pantoic acid were determined by HPLC analysis (Tab. 1a). All the listed strains apart from Beauveria amorpha Lu7953 were able to reduce to pantoic acid the ketopantoic acid resulting from spontaneous hydrolysis of ketopantolactone. Since, however, D-pantoic acid was formed with all the strains instead of the L-pantoic acid described in Example 1, the conversion of pantolactone to L-pantoic acid cannot be produced by an oxidation-reduction process (via ketopantolactone and ketopantoic acid). No dependence of the L-pantolactone hydrolysis on cofactors was found in the dialyzed crude extract from Lu681 or Lu5351 and on use of the purified enzymes from Lu681 and Lu5351 either. The enzymatic activity can thus be attributed to a hydrolytic enzyme.
Reaction SMILES: O.[C:2](Cl)(=[O:6])[C:3](Cl)=O.Cl.[F:9][C:10]([F:22])([F:21])[C:11]1[N:20]=[CH:19][C:14]2[CH2:15][NH:16][NH:17]C[C:13]=2[CH:12]=1.C([N:25](CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:9][C:10]([F:22])([F:21])[C:11]1[N:20]=[CH:19][C:14]2[CH2:15][NH:16][NH:17][CH:3]([C:2]([NH2:25])=[O:6])[C:13]=2[CH:12]=1
Reactant: FC(F)(F)c1cc2c(cn1)CNNC2
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)C1NNCc2cnc(C(F)(F)F)cc21
Reaction time: 4 h
Yield: 10.3 %

Procedure:
To a solution of Intermediate 2 (250 mg, 0.712 mmol) in DCM (100 mL), was added 2M oxalyl chloride in DCM (0.427 μL, 0.854 mmol) and DMF (˜50 μL). The reaction mixture was stirred for 4 hr, and concentrated. The residue was put on high vacuum for 2 hr and dissolved in DCM (10 mL). The formed acid chloride was added into a solution of the product from Step D (267 mg, 0.854 mmol) and triethylamine (456 L, 3.28 mmol) in DCM (10 mL) at 0° C. The reaction mixture was stirred for 16 hr and concentrated. The residue was purified by flash column chromatography (silica gel, 8% [aq. NH4OH/MeOH 1/9]/DCM ) first and then by preparative TLC (100 micron) (developed by 5% MeOH/DCM) to yield the 7-(trifluoromethyl)-1,2,3,4-tetrahydropyrido[3,4-d]pyridazine amide (39.5 mg, 10.3%) and another structural isomer (42.3 mg, 11.1%). LC-MS calc. For C24H30F6N4O3: 536.22; Found: 537 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:12]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl>CC(C)=O>[C:17]([O:16][C:14](=[O:15])[CH2:13][N:12]1[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]=[C:8]1[S:7][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[O:26][CH3:25])([CH3:19])([CH3:20])[CH3:18]
Reactant: COc1ccccc1CCl
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1CSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A suspension of K2CO3 (31.4 mg, 0.23 mmol) in acetone (3 ml) containing tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 30 mg, 0.11 mmol) and 2-methoxybenzyl chloride (17.8 mg, 15.8 μl, 0.11 mmol) is stirred at rt overnight. Filtration over Celite and evaporation of the solvent in vacuo affords the pure title compound (27 mg) in 62% yield as a yellow oil: tR=7.47 min (LC-1), MS (pos.): m/z 385.20 [M+H]+; 1H NMR (DMSO-d6): δ (ppm) 1.37 (s, 9H, tBu), 3.90 (s, 3H, OCH3), 4.53 (s, 2H, SCH2), 4.92 (s, 2H, CH2CO2), 6.87 (t, 1Harom), 7.03 (d, 1Harom), 7.21 (m, 2Harom), 7.28 (t, 1Harom), 7.40 (d, 1Harom), 7.50 (m, 1Harom), 7.64 (m, 1Harom).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.[N:42]([CH2:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][CH:47]=1)=[N+:43]=[N-:44]>C1COCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:52][C:49]2[CH:48]=[CH:47][C:46]([CH2:45][N:42]=[N+:43]=[N-:44])=[CH:51][CH:50]=2)=[CH:37][CH:36]=1
Reactant: [N-]=[N+]=NCc1ccc(CO)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(COc2ccc(Cl)cc2)cc1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (4.33 g, 16.5 mmol) was dissolved in dry THF (20 mL) under an atmosphere of argon. After cooling to −40° C., diisopropyl-azodicarboxylate (DIAD, 3.2 mL, 16.5 mmol) was added and the mixture was stirred at −40° C. for 10 min. A solution of 4-chlorophenol (2.12 g, 16.5 mmol) and (4-azidomethyl-phenyl)-methanol (2.45 g, 15 mmol) in dry THF (10 mL) was added dropwise. After addition, the cooling bath was removed and stirring was continued for 1 h. The solution was diluted with Et2O (150 mL) and washed with pH-7-phosphate buffer solution (1×50 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (2-3% EtOAc in hexane) to give the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:37][C@H:34]([CH2:35][OH:36])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: NC[C@H](O)CO
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.3 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (338 mg, 0.759 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (S)-(−)-3-amino-1,2-propanediol (105 mg, 1.15 mmol), WSCI.HCl (220 mg, 1.15 mmol) and 4-dimethylaminopyridine (185 mg, 1.51 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (265 mg, yield 68%) as a white solid.
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O.C(#N)C.[C:18]([O:34][CH2:35][CH3:36])(=[O:33])[CH2:19][C:20]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([C:22]([O:24]CC)=[O:23])[OH:21]>C(#N)C>[C:28]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:27][C:20]([CH2:19][C:18]([O-:34])=[O:33])([C:22]([O-:24])=[O:23])[OH:21].[C:28]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:27][C:20]([CH2:19][C:18]([O:34][CH2:35][CH3:36])=[O:33])([C:22]([O-:24])=[O:23])[OH:21]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)[O-]
Product: CCOC(=O)CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Citric acid and its ethyl esters (mono, di and tri) were quantitatively analyzed on a Hewlett-Packard 1090 HPLC using a reversed phase C18 column (Novapak, 3.9 mm×150 mm) held at 40° C. Water/acetonitrile (ACN) mixtures, buffered at pH=1.3, were used as mobile phase (1.0 ml/min) in a gradient mode (0% ACN (t=0) to 60% ACN (t=20 min) to 90% ACN (t=25 min) to 0% ACN (t=28 min)), and species were quantified by UV detection (Hitachi L400H) at a wavelength of 210 nm. Citric acid (CA) and triethyl citrate (TEC) were identified and quantified by comparing HPLC retention time and peak area with their respective calibration standard. Standards for monoethyl citrate (MEC) and diethyl citrate (DEC) could not be obtained commercially. On a mass basis, the response factor values for CA and MEC were found to be the same; therefore MEC and DEC were each assigned the same response factor value as corresponding to TEC. Using these response factor values, the carbon balance for each reaction sample, based on citric acid and its esters, was in the range of ±10%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[C:34]([O:45][CH3:46])(=[O:44])[C:35]1[CH:43]=[CH:42][CH:41]=[C:37]([C:38]([O-])=[O:39])[CH:36]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([CH:32]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[C:35]([C:34]([O:45][CH3:46])=[O:44])[CH:36]=3)=[CH:25][C:24]=2[O:30][CH3:31])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reactant: COC(=O)c1cccc(C(=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(C(=O)Oc2ccc(-c3ccc4c(c3COc3cc(F)ccc3C)N(C)C(=O)C(C)(C)N4)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 8-(5-fluoro-2-methylphenoxymethyl)-7-(4-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 11, 25.3 mg, 0.0562 mmol), monomethyl isophthalate (20.5 mg, 0.114 mmol), N,N-diisopropylethylamine (38.8 μL, 0.223 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (43.4 mg, 0.114 mmol) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (15 mL). The mixture was washed with water (15 mL) and saturated brine (15 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (22.0 mg) as a colorless solid. (Yield 64%)
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[N:9](CC3C=CC(OC)=CC=3OC)[CH2:10][C:6]=2[C:5]([F:23])=[C:4]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(=O)OC(C)(C)C)[N:3]=1.[CH3:39][C:40]1[N:41]=[CH:42][NH:43][CH:44]=1.C([O-])([O-])=O.[K+].[K+].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(#N)C>[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52].[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:4]1[N:3]=[C:2]([N:43]2[CH:44]=[C:40]([CH3:39])[N:41]=[CH:42]2)[C:7]2[C:8](=[O:22])[NH:9][CH2:10][C:6]=2[C:5]=1[F:23]
Reactant: Cc1c[nH]cn1
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Cl)c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2nc(N[C@@H]3CCCC[C@@H]3N)c(F)c3c2C(=O)NC3)cn1
Temperature: 80 °C
Yield: 23 %

Procedure:
In a 10 mL sealed cap glass vial, tert-butyl (1S,2R)-2-(4-chloro-2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (50 mg, 0.091 mmol), 4-methyl-1H-imidazole (22.43 mg, 0.273 mmol) and K2CO3 (50.3 mg, 0.364 mmol) were dissolved in ACN (2 mL). The cap was sealed and the mixture was reacted at 100° C. for 16 h. The reaction mixture was subsequently filtered through a Buchner funnel to remove un-dissolved solids. The solids were washed with ACN (2×5 mL) and the filtrate was evaporated to give a residue, which was treated with TFA (4 mL) and heated at 80° C. for 1 h to remove the protecting groups. Next, TFA was evaporated from the reaction mixture. The resulting residue was reconstituted in DMSO (5 mL) and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (15-65% gradient, 0.035% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (7.2 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.65 (m., 8 H), 3.65-3.79 (m, 5 H), 4.15 (s, 2 H), 6.40 (d, 1 H), 6.51 (d, 1 H), 6.73 (m, 1 H), 6.97 (d, 1 H), 7.26 (d, 1 H), 8.68 (br s, 1 H). [M+H] calc'd for C17H21FN6O, 345; found, 345.
Reaction SMILES: [H-].[Na+].C1COCC1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][S:13][CH2:12][CH2:11][NH:10]1.Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1>O.CCOC(C)=O>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][N:10]1[C:9](=[O:8])[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH2:14][S:13][CH2:12][CH2:11]1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NC1CSCCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1CSCCN(Cc2ccc3ccccc3c2)C1=O
Yield: 191.2 %

Procedure:
81 mg of sodium hydride as a 60% suspension in oil (2.03 μmol) are introduced at room temperature into a 25 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of THF and 500 mg of 26 (2.03 mmol). The medium is stirred for 1 hour and 449 mg (2.03 mmol) of 2-(bromomethyl)naphthalene are then added. The medium is stirred for 16 hours, 20 ml of EtOAc and 20 ml of water are added to the reaction medium and, after separation of the phases by settling, the organic phase is washed with 10 ml of water. The organic phase is dried, filtered and then evaporated to dryness to give 1.5 g of crude product, which product is chromatographed on a silica cartridge (25 g) with a 90/10 heptane/EtOAc mixture. 510 mg of product 42 are recovered (yield=65%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[C:13]1[Se:14][CH:15]=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)=O.C([O:28][P:29](OCC)([O:31]CC)=[O:30])C.[OH-].[Na+]>>[C:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][O:12][P:29]([OH:31])([OH:30])=[O:28])[O:7][C@H:6]1[C:13]1[Se:14][CH:15]=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=1)(=[O:3])[CH3:2]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CC(=O)O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1c1nc(C(N)=O)c[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)O[C@@H]1[C@H](O)[C@@H](COP(=O)(O)O)O[C@H]1c1nc(C(N)=O)c[se]1

Procedure:
2-(2-O-Acetyl-β-D-ribofuranosyl)selenazole-4-carboxamide is treated with 1 to 5 equivalents of phosphoryl chloride in the presence of triethylphosphate at 0 decrees C. After complete dissolution is obtained, the solution is poured over crushed ice and adjusted with sodium hydroxide solution to pH 7, extracted with chloroform, and placed on a column of ion exchange resin (Dowex AG 1×8, formate). The column is first washed with water, then the product is eluted with a gradient of water-formic acid. The fractions containing pure product are pooled and evaporated to dryness. The residue is recrystallized from ethanol-water to provide the free acid of the title compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=CC=C(C#N)[N:3]=1.[CH3:10][Mg]I.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:15][CH:14]=[C:13]([C:17](=[O:16])[CH3:10])[N:3]=1
Reactant: N#Cc1cccc(Cl)n1
Reactant: C[Mg]I
Reactant: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cccc(Cl)n1

Procedure:
A solution of 2-chloro-6-cyanopyridine (50 g) in THF (400 ml) is cooled to −5° C. and a solution of methylmagnesium iodide in diethyl ether (3 M, 200 ml) is added. After 1 h at 0° C. the ether is destilled off and the THF-mixture is heated to 60° C. for 1 h. The THF is evaporated and the residue is treated with ice water and acidified with 2 M hydrochloric acid. The water phase is extracted with dichloromethane and after drying and evaporation of the organic phase, the residue is purified by silica-gel flash chromatography. The title compound is obtained as an oil (11.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[NH3:11].C[Si]([C:16]#[N:17])(C)C.CCCCCC.CCOC(C)=O>CO>[NH2:11][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[CH:3]=1)[C:16]#[N:17]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[Si](C)(C)C#N
Reactant: N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: N#CC(N)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Through a solution of 3,4-difluorobenzaldehyde (25.0 g, 0.176 mol) in MeOH (500 mL) in a round bottom flask, was bubbled ammonia gas for two hours at room temperature. The flask was then cooled to 0° C. and trimethylsilyl cyanide was then added slowly. The reaction mixture was stirred for 2 h, at which time TLC analysis indicated that the reaction was complete (Rf=0.35, 3:2 hexane/EtOAc). The solvent was removed in vacuo and the residue was subjected to flash column chromatography on silica gel to obtain the desired product, which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].CS([C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([S:31](Cl)(=[O:33])=[O:32])[CH:30]=1)(=O)=O>C(Cl)Cl.N1C=CC=CC=1>[CH3:12][S:9]([C:26]1[CH:25]=[CH:30][C:29]([S:31]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:32])=[O:33])=[C:28]([O:35][CH3:36])[CH:27]=1)(=[O:11])=[O:10]
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Reactant: COc1ccc(S(C)(=O)=O)cc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(S(C)(=O)=O)ccc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.4 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-amino-phenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 5-methanesulfonyl-2-methoxybenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (10 mL). The organic phase was washed with 10% aqueous HCl (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 330 mg of benzo[b]thiophene-2-sulfonic acid [2-(4-methanesulfonyl-2-methoxy-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.06 min; MS: 553.8 (M+1)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:31])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:63][CH:60]5[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]5)=[O:27])=[C:24]([F:31])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)c(F)c3)ncc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)cc2F)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluorobenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.74 (m, 11 H) 1.86-2.09 (m, 5 H) 2.15 (s, 3 H) 2.63-2.81 (m, 2 H) 3.57-3.79 (m, 1 H) 3.94-4.16 (m, 2 H) 4.81 (t, J=8.1 Hz, 1 H) 7.32-7.46 (m, 1 H) 7.51 (t, J=8.6 Hz, 1 H) 7.85 (br. s., 1 H) 7.88 (dd, J=4.3, 2.3 Hz, 1 H) 8.30 (s, 1 H) 9.88 (s, 1 H). [M+H] calc'd for C26H32F3N7O2, 532; found 532.