Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH:27]([CH3:29])[CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:30]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:26][CH:27]([CH3:29])[CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CNCC(C)C
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CC(C)CN(Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1)CC(C)C
Yield: 76.1 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 0.97 g (7.5 mmol) of diisobutylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 1.07 g (76%) of (S)-8-chloro-1-(5-diisobutylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 125°-140°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([Cl:22])[CH:15]=2)[N:11]([CH3:23])[N:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([Cl:22])[CH:15]=2)[N:11]([CH3:23])[N:10]=1
Reactant: COc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(O)c(Cl)c1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To benzene (300 ml) are added the crude product of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-methoxyphenyl)-1-methyl 1H-1,2,4-triazole (70.5 g) and anhydrous aluminum chloride (80.0 g), which are heated under reflux for 3 hours with stirring. After cooling to room temperature, the reaction mixture is poured into ice water and extracted with toluene. The organic layer is washed with water, extracted with aqueous solution of 20% NaOH, and the aqueous layer is acidified by adding a concentrated sulfuric acid little by little while cooling with ice and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 64.2 g of desired compound.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[OH2:13]>>[O:13]=[O:1].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=O
Reaction time: 7 h

Procedure:
In preparing the NMR samples, the MVo-glucose reaction was run in 98% D2O (deuterium oxide). The reaction proceeded at a slower rate compared to corresponding reactions conducted in H2O. Closer examination showed that after approximately 3 hours (approximately 60% oxidation of glucose), a nearly two-fold slower reaction had occurred in D2O compared to the same reaction conducted in H2O. For reactions conducted over 6-8 hours, a O2/glucose ratio value of 5.7 (6.0 is expected for complete oxidation of glucose) and 3.7 were obtained in H2O and D2O, respectively, indicating that D2O severely retarded the final stages of glucose oxidation by air. The isotope effect from oxidizing glucose in D2O is consistent with data obtained from anaerobic oxidation of glucose, i.e., that ionization of a proton with a pKa of approximately 10 works more effectively.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4][CH2:5][C:6]([CH3:15])=[C:7]2[C:11]([O:13][CH3:14])=[O:12].C(N(CC)CC)C.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:15][C:6]1[CH2:5][S:4][CH:3]2[N:8]([C:9](=[O:10])[CH:2]2[NH:1][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1=C(C)CSC2C(N)C(=O)N12
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1=C(C)CSC2C(NC(=O)Cc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Methyl 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1126) (801 mg, 3.51 mmol) was dissolved in dry dichloromethane (DCM) (20 mL), cooled to ˜0° C. in an ice bath before adding triethylamine (0.587 mL, 4.21 mmol) followed by phenylacetyl chloride (0.514 mL, 3.86 mmol) in Dichloromethane (DCM) (5 mL) slowly over 5-10 mins. The reaction was then allowed to warm up to RT and stirred for 4 hours then left to stand overnight. LCMS run, desired material seen. Diluted with DCM (40 ml), washed with saturated sodium bicarbonate solution (45 ml). Aqueous layer extracted with DCM (2×30 ml). Combined extracts were washed with brine (45 ml), dried over Na2SO4, filtered and evaporated to afford a red gum of crude material. Purified on a SNAP 100 cartridge, eluting with DCM (3CV) to 100% 10% MeOH in DCM (12CV). Compound identified and solvent removed to afford an orange gum of desired product in 972 mg.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:38]C(OC(C)(C)C)=O)[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1>C(O)=O>[S:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:34])([CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:11]=2)=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2cncs2)cc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: O=CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C

Procedure:
742 mg (1.16 mmol) of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane and 12 ml of formic acid are stirred at room temperature for 7 hours and then concentrated by evaporation. Sat. NaHCO3 solution and ethyl acetate are added to the residue; the aqueous phase is separated off and extracted with ethyl acetate. The organic phases are treated with water and brine, dried (Na2SO4) and concentrated by evaporation, yielding the title compound which is used further directly.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:19][CH:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[CH:23][CH:22]=3)[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:29]1([CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH:18]3[CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C@@H:8]([NH2:7])[CH3:9])=[CH:15][CH:14]=4)[CH2:19]3)=[CH:22][CH:23]=2)[CH2:30][CH2:31]1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1ccc(N2CC(Oc3ccc(OCC4CC4)cc3)C2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
130 mg (0.30 mmol) (1-{4-[3-(4-cyclopropylmethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester are added to 2 mL DCM and the mixture is cooled to 0° C. 0.03 mL TFA is added and stirring is continued for 1 h at 0° C. The solution as such is used directly for subsequent reactions.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[S:26]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:45]/[C:38]3[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=4)(=[O:28])=[O:27])[CH:37]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.697 g, 2.00 mmol) obtained in Example A16, Step 1 in methanol (10 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.599 g, 2.00 mmol) synthesized in Step 1 and piperidine (0.0170 g, 0.200 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.470 g, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15]OS(C)(=O)=O)[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:29].C([NH3+])(C)(C)C>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][CH2:15][F:29])[CH2:12][N:11]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[C:10](=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCOS(C)(=O)=O
Agent: CC(C)(C)[NH3+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2cccc(Cl)c2)C[C@@H]1CCF

Procedure:
4-tert-Butoxycarbonyl-1-(3-chlorophenyl)-5(S)-(2-methylsulfonyloxyethyl)-piperazin-2-one (0.433 g, 1.00 mmol) and tert-butylammonium fluoride (3.0 mL, 1M in THF) were stirred at room temperature in acetonitrile (5 mL) for 72 h. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic extracts were dried, concentrated and purified by column chromatography using 20% ethyl acetate in hexane. The title compound was obtained as a thick oil.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH:6]=1.[OH-].[Na+]>CO>[C:26]1([CH:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:24][N:15]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH2:14][CH2:13][CH2:12][O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:38])=[O:2])[CH:10]=[CH:9][CH:8]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(Cl)c2)CC(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1cccc(OCCCN(Cc2cccc(Cl)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of (3-{3-[(2,2-Diphenyl-ethyl)-(3-chloro-benzyl)-amino]-propoxy}-phenyl)-acetic acid methyl ester (4h). (0.15 g, 0.0003 mol) in methanol (3 mL) was treated with 2N NaOH (2 mL) and the mixture stirred overnight at ambient temperature. After concentration to dryness, the residue was dissolved in EtOAc (15 mL) and water was added (5 mL), the solution acidified to pH 3 with concentrated hydrochloric acid, then extracted into EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4, and then concentrated in vacuo to provide the carboxylic acid as waxy oil, which was purified by flash chromatography (9:1 CH2Cl2/MeOH) to give the desired product as oil 0.11 g in 73% yield. 1H NMR (CD3OD) δ 7.22 (m, 8H), 7.18 (t, 4H), 7.16 (s, 1H), 7.12 (t, 1H), 7.04 (d, 1H), 6.88 (d, 1H), 6.67 (s, 1H), 6.63 (d, 1H), 4.26 (t, 1H), 3.67 (s, 2H), 3.63 (t, 2H), 3.59 (s, 2H), 3.14 (d, 2H), 2.68 (t, 2H), 1.86 (t, 2H); 13C NMR (CD3OD) δ 175.8, 160.5, 145.0, 143.3, 137.4, 135.0, 130.6, 130.2, 130.1, 129.4, 129.3, 128.4, 128.0, 127.3, 122.4, 116.5, 114.1, 66.4, 60.9, 59.7, 51.5, 51.1, 42.3, 27.9. Anal. Calcd for C23H32ClNO3.H2O: C, 72.23; H, 6.06; N, 2.63; Cl, 6.67. Found: C, 72.53; H, 6.09; N, 2.96; Cl, 7.08.
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9](=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:18]1([CH2:30][C:31]([NH2:33])=[O:32])[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1>>[C:18]1([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:17])[C:4]=2[C:6]2[C:14]3[C:9](=[C:10]([C:15]#[N:16])[CH:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1
Reactant: COC(=O)C(=O)c1c[nH]c2c(C#N)cccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: N#Cc1cccc2c(C3=C(c4cn5c6c(cccc46)CCC5)C(=O)NC3=O)c[nH]c12

Procedure:
Beginning with 7-cyanoindole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH2:37].O>CN(C=O)C.C(=O)(O)[O-].[NH4+]>[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH:37][C:17]([C:16]1[C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[CH:13]=[N:14][CH:15]=1)=[O:19]
Reactant: COC(=O)CN
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.08 h

Procedure:
A suspension of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (2.95 g, 11.5 mmol) in DMF (25 mL) was treated with CDI (1.51 g, 12.0 mmol). The mixture turned to a dark brown clear solution in 5 minutes, and then a solid precipitate formed. Additional DMF (10 mL) was added to assist stirring. The mixture was stirred for 1 hour. A solution of glycine methyl ester hydrochloride (2.42 g, 14.9 mmol) in DMF (5 mL) was added. After 18 hours, the mixture was poured into water (200 mL) and diluted with saturated aqueous ammonium bicarbonate (50 mL). The solid was collected by filtration to afford {[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-acetic acid methyl ester as a light brown solid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.BrC1C=CN2C(C(NC3[CH:23]=[C:24](C=CC=3F)[C:25]([OH:27])=[O:26])=O)=CN=C2C=1>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:8]=2)[CH:7]=1
Reactant: O=C(O)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: Nc1ccc(I)cn1
Product: O=C(O)c1cnc2ccc(I)cn12

Procedure:
The title compound was prepared from 5-iodopyridin-2-amine analogously to 7-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (Intermediate 1A step 2 and step 3); LC-MS: Rt 1.07 mins; MS m/z 317 [M+H]+; Method 2minLC_v003
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:19]=4[F:32])[CH:14]=3)[N:9](S(C3C=CC=CC=3)(=O)=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO>[C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17](=[O:33])[C:18]4[C:23]([F:24])=[CH:22][CH:21]=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[C:19]=4[F:32])[CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C2=CCCCC2)cn3S(=O)(=O)c2ccccc2)c1F
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C4=CCCCC4)c3c2)c1F
Yield: 100 %

Procedure:
N-(3-cyclohexenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide was subjected to methanol/2M aqueous potassium carbonate (1 mg/1 mL) at 60° C. for 1 hour to give N-(3-cyclohexenyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (100%). m/z (APCI-neg) M−1=473.2, (APCI-pos) M+1=475.1.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8](=[O:13])O[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]1[C@@H:17](C(O)=O)[NH:16][CH2:15]1>CN(C)C=O.C(O)(=O)C>[F:1][C:2]1[C:7]2[C:8](=[O:13])[N:16]3[CH2:17][CH2:14][C@H:15]3[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2cccc(F)c2C(=O)N2CC[C@@H]12
Yield: 49.4 %

Procedure:
A solution of 10 g (55.2 mmol) of 5-fluoro-2H-3,1-benzoxazine-2,4(1H)-dione and 5.66 g (55.2 mmol) of L-azetidine-2-carboxylic acid in 75 ml of dimethylformamide and 15 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 6 g (42%) of (S)-5-fluoro-1,2,4,9,10,10a-hexahydroazeto[2,1-c][1,4]benzodiazepine-4,10-dione as beige needles of m.p. 232°-233.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[S:13][N:12]=[C:11]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([CH3:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:30])([F:29])[F:31])[S:13][N:12]=[C:11]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:27])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
To a solution of tert-butyl 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-2-methyl-benzoate (164 mg) in dichloromethane (1.7 mL) was added trifluoroacetic acid (0.17 mL). The reaction mixture was stirred at room temperature for 6 hours then the solution was concentrated under vacuo. The residue was extracted with water and ethyl acetate. The organic extract was washed with water, dried over sodium sulfate and concentrated to give 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-2-methyl-benzoic acid (140 mg) as a white foam.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13](I)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:40]=[CH:39][C:27]([CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)=[CH:26][CH:25]=2)O1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:24]4[CH:25]=[CH:26][C:27]([CH2:28][N:29]5[CH2:30][CH2:31][CH:32]([C:35]([F:38])([F:36])[F:37])[CH2:33][CH2:34]5)=[CH:39][CH:40]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CC1(C)OB(c2ccc(CN3CCC(C(F)(F)F)CC3)cc2)OC1(C)C
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: FC(F)(F)C1CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 85 °C
Yield: 6.9 %

Procedure:
A degassed mixture of 6-bromo-3-iodo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (0.64 g, 1.7 mmol), 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-4-trifluoromethyl piperidine (1.14 g, 3.1 mmol) and 1,1′-[bis(diphenyl phosphino)ferrocene]dichloropalladium(II) (0.21 g, 0.26 mmol) in 2-methyl-THF (26 mL) and saturated aqueous sodium carbonate solution (12 mL) was heated at 85° C. for 16 h. The cooled reaction mixture was filtered through celite and partitioned between DCM and water and the phases were separated. The organic phase was dried over sodium sulfate, filtered and evaporated then the residue was purified by flash chromatography (silica, 40 g column, ISCO, 0-15% methanol in DCM). Trituration of the resultant residue with acetonitrile afforded the title compound as a tan solid (57 mg, 7%). 1H NMR (CD3OD, 300 MHz): 8.84 (d, J=2.2 Hz, 1H), 8.70-8.67 (m, 2H), 8.27 (d, J=1.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 3.63 (s, 2H), 3.11-3.02 (m, 2H), 2.14-2.02 (m, 3H), 1.94-1.84 (m, 2H), 1.76-1.59 (m, 2H. LCMS (Method B): RT=2.55 min, M+H+=489.
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[OH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:17][CH:18]=1
Reactant: Clc1nccs1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2nccs2)cc1
Reaction time: 6 h
Yield: 27.8 %

Procedure:
A mixture of 2-chlorothiazole (2.0 g), ethyl 4-hydroxybenzoate (2.8 g), potassium carbonate powder (3.5 g) and dimethylformamide (30 ml) is stirred at 135°-140° C for 6 hours. The reaction mixture is treated in the same manner as in Example 1. From the eluate of 30% ether-benzene, ethyl 4-(2-thiazolyloxy)benzoate (1.16 g) is obtained. IR νmaxCCl 4 1730, 1280 cm-1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[OH:4].[C:15](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C)C=O>[F:14][C:2]([F:1])([F:13])[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[O:4][CH3:15]
Reactant: N#Cc1cc(C(O)C(F)(F)F)ccn1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(c1ccnc(C#N)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 46.8 %

Procedure:
To 4 ml of dimethylformamide were added 0.4 g of 4-(2,2,2-trifluoro-1-hydroxyethyl)pyridine-2-carbonitrile, 0.33 g of potassium carbonate and 0.34 g of methyl iodide, and the mixture was stirred at room temperature for 20 hours. Thereafter, an aqueous saturated ammonium chloride solution was added to the reaction solution, the resultant solution was extracted with ethyl acetate three times, the organic layers were combined, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.2 g of 4-(2,2,2-trifluoro-1-methoxyethyl)pyridine-2-carbonitrile.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21](Cl)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[C:26]([N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43](B4OC(C)(C)C(C)(C)O4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1)(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:34][CH2:33][N:32]2[N:35]=[C:36]([NH:38][C:39]3[C:40](=[O:55])[N:41]([CH3:54])[CH:42]=[C:43]([C:21]4[C:18]([CH:19]=[O:20])=[C:17]([N:10]5[N:9]=[CH:8][C:7]6[C:12](=[C:13]([F:15])[CH:14]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=6)[C:11]5=[O:16])[N:24]=[CH:23][CH:22]=4)[CH:44]=3)[CH:37]=[C:31]2[CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: CC(=O)N1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Product: CC(=O)N1CCn2nc(Nc3cc(-c4ccnc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)cc2C1

Procedure:
Following the procedure described in Example 123d, and starting with 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (200 mg, 0.57 mmol) and 124h (343 mg, 0.83 mmol), 124i was obtained as a yellow solid (300 mg, 86%). MS-ESI: [M+H]+ 611.3