Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([C:25]([C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)=[O:26])[CH:20]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([C:25]([C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:1]4[CH2:2][CH2:3][CH:4]([C:7]5[C:8](=[O:17])[NH:9][C:10]6[C:15]([CH:16]=5)=[CH:14][CH:13]=[CH:12][CH:11]=6)[CH2:5][CH2:6]4)[CH:20]=3)=[O:26])=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC(c4cc5ccccc5[nH]c4=O)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60 mg (0.26 mmol) 3-piperidin-4-yl-1H-quinolin-2-one, 80 mg (0.26 mmol) 6-(6-chloropyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.86 mmol) DIPEA were combined in 3 mL DMF and stirred overnight at RT. The reaction mixture was added to water and the precipitate formed was suction filtered, washed with MeOH and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.CS(C)=O.[I:13]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[F:8][C:5]1[CH:6]=[C:7]([I:13])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Nc1ncc(F)cc1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a mixture of 2-amino-5-fluoropyridine (2.0 g, 17.8 mmol) and dimethyl sulfoxide (50 mL) was added N-iodosuccinimide (4.8 g, 21.4 mmol), which was stirred for 1 hour at room temperature. A suitable amount of acetic acid was added to this mixture, which was stirred for 1 hour at the same temperature, and then stirred for another 3 hours at 55° C. This reaction mixture was cooled to room temperature, after which a saturated sodium hydrogencarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (751 mg, 18%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15]O)[O:13][CH:14]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:17])[CH:11]=[C:12]([CH2:15][Cl:22])[O:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(COc2coc(CO)cc2=O)cc1
Solvent: C1CCOC1
Product: COc1ccc(COc2coc(CCl)cc2=O)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
5-p-Methoxybenzyloxy-2-hydroxymethyl-4-pyrone, 24 g, was dissolved in 120 ml of dry tetrahydrofuran. The solution was cooled to 5° C. and 15 ml of thionyl chloride was dropwise added to the solution over 30 minutes. The reaction solution was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction liquid was concentrated to approximately 20 ml and the concentrate was added to 50 ml of water and 100 ml of dichloromethane. Under ice cooling, the pH was adjusted to 7.0 with saturated sodium hydrogencarbonate aqueous solution and the organic phase was washed with 20 ml of water. After drying over anhydrous magnesium sulfate, the organic phase was concentrated under reduced pressure and crystallized with ethyl acetate-ether. The formed crystals were taken out by filtration and dried under reduced pressure to give 20 g of the title compound.
Reaction SMILES: C([O:8][C:9]1([CH3:30])[CH2:18][CH2:17][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:29])[N:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[N:21]=[C:12]3[C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>CN(C=O)C.CCO>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:19](=[O:29])[C:13]3=[CH:14][NH:15][C:16]4[CH2:17][CH2:18][C:9]([OH:8])([CH3:30])[CH2:10][C:11]=4[C:12]3=[N:21]2)=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC1(O)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
8-Benzyloxy-2-p-chlorophenyl-8-methy-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one (4 g) is dissolved in 200 mL of a 1:1 mixture of DMF/EtOH and subjected to catalytic hydrogenation with 5% palladiium on carbon (1 g) for 24 hours under 1 atm. of hydrogen. After the reaction is over, the catalyst is filtered off, the filtrate is evaporated, and the dried residue is triturated with EtOH to yield 2-p-chlorophenyl-8-hydroxy-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[C:16]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=3)[C:17]2=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O-])([O-])=O.[Cs+].[Cs+].CI>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[C:16]2[CH2:24][C:23]3[C:18](=[CH:19][C:20]([C:25]([O:27][CH3:29])=[O:26])=[CH:21][CH:22]=3)[C:17]2=[O:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=C2Cc3ccc(C(=O)O)cc3C2=O)CC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(=O)C(=CCC1CCN(C(=O)OC(C)(C)C)CC1)C2

Procedure:
A slurry of 2-1 (4.5 g, 11.7 mmol) in CH3OH (120 mL) was treated with Cs2CO3 (1.9 g, 5.85 mmol) to give a homogenous solution. The solvent was removed in vacuo and the resulting solid was dissolved in DMF (120 mL) and treated with methyliodide (0.72 mL, 11.7 mmol) at room temperature for 18 h. The solution was diluted with EtOAc and washed with H2O, sat. NaHCO3 and brine. The organic layer was dried (MgSO4), filtered, concentrated, and chromatographed (30% EtOAc/Hexanes) to give 2-2 as a white solid. Rf (30% EtOAc/Hexanes) 0.15 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.28 (d, 1H), 7.58 (d, 1H), 6.94 (m, 1H), 4.1 (bd, 2H), 3.93 (s, 3H), 3.7 (s, 2H), 2.7 (bt, 2H), 2.28 (t, 2H), 1.7 (m, 3H), 1.45 (m, 9H), 1.2 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][C@@H:22]4[CH2:24][C@H:19]3[CH2:20][O:21]4)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[N:18]1[CH2:23][C@@H:22]3[CH2:24][C@H:19]1[CH2:20][O:21]3)[CH2:9][NH:8][CH2:16]2
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3C[C@@H]4C[C@H]3CO4)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(cc1N1C[C@@H]3C[C@H]1CO3)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-chloro-6-(1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Brown oil. MS (m/e): 253.1 ([{37Cl}M+H]+, 26%), 251.1 ([{35Cl}M+H]+, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH:28]12[O:37][CH:32]([O:33][CH:34]1[CH2:35][OH:36])[CH2:31][NH:30][CH2:29]2>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:30]2[CH2:31][CH:32]3[O:37][CH:28]([CH:34]([CH2:35][OH:36])[O:33]3)[CH2:29]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Reactant: OCC1OC2CNCC1O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CC4OC(CO)C(C3)O4)sc2Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (400 mg; 0.96 mmol; 1 eq), is dissolved in anhydrous DCM (40 ml). The reaction is put under nitrogen. Triethylamine (0.67 ml; 4.81 mmol; 3 eq) and (6,8-Dioxa-3-aza-bicyclo[3.2.1]oct-7-yl)-methanol (349.2 mg; 2.41 mmol; 2.5 eq) are added successively and the reaction mixture is stirred overnight at room temperature. It is then washed with water, NH4Cl sat., brine and dried over MgSO4, affording the title compound (450 mg; 77%).
Reaction SMILES: N1C=CC=C(OCC2CC3N(C(OC(C)(C)C)=O)C2CC3)N=1.[CH3:23][N:24]1[C:28]([O:29][CH2:30][CH:31]2[CH2:36][CH:35]3[N:37](C(OC(C)(C)C)=O)[CH:32]2[CH2:33][CH2:34]3)=[CH:27][CH:26]=[N:25]1>>[CH3:23][N:24]1[C:28]([O:29][CH2:30][CH:31]2[CH2:36][CH:35]3[NH:37][CH:32]2[CH2:33][CH2:34]3)=[CH:27][CH:26]=[N:25]1
Reactant: Cn1nccc1OCC1CC2CCC1N2C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N1C2CCC1C(COc1cccnn1)C2
Product: Cn1nccc1OCC1CC2CCC1N2

Procedure:
Prepared analogous to Example 53 Step B substituting (±)-tert-butyl 2-((pyridazin-3-yloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate the title compound of Step A. MS (ESI) mass calcd. for C11H17N3O, 207.1; m/z found 208.0 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH3:17][Si](C=[N+]=[N-])(C)C.CCCCCC>C1C=CC=CC=1.CO>[C:1]([NH:4][C:5]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:17])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(C)=O
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a stirred solution of 2-acetylamino-4-nitrobenzoic acid (1.28 g, 5.71 mmol) in benzene-MeOH (4:1, v/v, 25 mL), was added trimethylsilyldiazomethane (2.0 M solution in n-hexane, 4.28 ml, 8.56 mmol) at 0° C. The stirring was continued for 18 hours at rt. The reaction was poured into hexane, and the resulting precipitate was collected by filtration to give methyl 2-acetylamino-4-nitrobenzoate (1.32 g, 97%) as a white solid; mp no data; 1H-NMR (400 MHz, CDCl3) δ2.30 (s, 3 H), 4.00 (s, 3 H), 7.88 (m, 1 H), 8.18 (dd, J=2.0 Hz, 8.8 Hz, 1 H), 9.60 (t, J=2.2 Hz, 1 H), 11.10 (s, 1 H); MS (ESI) m/z 238 (M+).
Reaction SMILES: O(C1C=CC=CC=1B(O)O)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][C:24]1[NH:25][C:26](=[O:47])[C:27]2[C:28](=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[NH:31][C:32]=2[CH3:33])N=1.[Cl-].[Na+]>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.COCCOC>[CH3:33][C:32]1[NH:31][C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:28]2[CH2:23][CH2:24][NH:25][C:26](=[O:47])[C:27]=12
Reactant: Cc1nc2c(-c3ccccc3Oc3ccccc3)[nH]c(C)c2c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1Oc1ccccc1
Solvent: COCCOC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1[nH]c(-c2ccccc2Oc2ccccc2)c2c1C(=O)NCC2
Temperature: 25 °C
Yield: 53 %

Procedure:
A 2 mL microwave reaction vessel equipped with stirbar was charged with Example 92f (0.010 g, 0.044 mmol), 2-phenoxyphenylboronic acid (0.023 g, 0.109 mmol), 2 M aqueous sodium carbonate (0.218 mL, 0.437 mmol) and bis(triphenylphosphine)palladium(II) dichloride (3.06 mg, 4.37 μmol) in ethanol (0.200 mL)/DME (0.200 mL) and sealed. The mixture was heated at 120° C. for 30 minutes in a Biotage Initiator 2 monomode microwave reactor, then cooled to ambient temperature. The mixture was shaken in a separatory funnel with 75 mL ethyl acetate and 50 mL saturated aqueous sodium chloride. The organics were dried over anhydrous sodium sulfate. After filtration and solvent removal the residue was purified by reverse phase HPLC (C18, 0-100% CH3CN/water (0.1% TFA)) to afford the title compound (7.3 mg, 53%). 1H NMR (300 MHz, CD3OD) δ 10.74 (bds, 1H), 7.42 (dd, J=1.9, 7.6 Hz, 1H), 7.31-7.18 (m, 4H), 7.02-6.96 (m, 2H), 6.85 (m, 2H), 3.36 (m, 2H), 2.73 (m, 2H), 2.44 (s, 3H). MS (ESI+) m/z 319.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].Br[CH2:30][CH2:31][CH2:32][CH2:33][Cl:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:34][CH2:33][CH2:32][CH2:31][CH2:30][O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: ClCCCCBr
Reactant: CCCCCCCCCCCCCCCCCC(=O)N1CCCCC1CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCCCC1CCOCCCCCl

Procedure:
1-[2-(2-Hydroxyethyl)piperidino]octadecan-l-one and 1-bromo-4-chlorobutane are reacted in acetone in the presence of potassium carbonate at reflux temperature to obtain 2-[2-(4-chlorobutoxy)ethyl]-1-octadecanoylpiperidine.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:8][C:5]=1[CH:6]=[O:7]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:3][C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]([F:14])([F:15])[F:16])=[CH:8][C:5]=1[C:6]([OH:1])=[O:7]
Reactant: [OH-]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1O
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a stirring solution of NaOH (8.15 g, 203.8 mmol) in water (35 mL, 5.8 M) was added an aq solution of silver nitrate (17.3 g, 101.9 mmol, 35 mL water, 2.9 M). A brownish solid formed. The flask was placed in an ice bath and to the stirring suspension was added 2-hydroxy-5-trifluoromethoxy-benzaldehyde in 500 mg portions (10.0 g, 48.5 mmol). After addition was complete and the reaction was stirred for 10 min in an ice bath, the mixture was filtered and the brownish precipitate was washed with hot water. The combined washings were acidified with conc HCl to pH 1 and the precipitate was collected by vacuum filtration. This solid was then dissolved in ethyl acetate. The ethyl acetate was washed with saturated aq NaCl, dried over Na2SO4, and filtered. The aqueous layer was also extracted with ethyl acetate. This organic layer was washed with saturated aq NaCl, dried over Na2SO4, filtered and concentrated to provide 2-hydroxy-5-trifluoromethoxy-benzoic acid (9.8 g, 91%) as a white solid: Rf 0.38 (20% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 10.30 (bs, 1 H), 7.79 (d, J=3.0 Hz, 1 H), 7.41 (dd, J l=9.3 Hz, J2=3.0 Hz, 1 H), 7.05 (d, J=9.0 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([OH:22])=O.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[C:27]2[Br:33].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Br:33][C:27]1[C:26]2[C:30](=[CH:31][CH:32]=[C:24]([NH:23][C:20]([C:13]3[CH:12]([C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[F:1])[CH2:17][C:16](=[O:18])[NH:15][C:14]=3[CH3:19])=[O:22])[CH:25]=2)[NH:29][N:28]=1
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Br)c3c2)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
The product of Example 21, Step 2 (200 mg, 0.63 mmol, 1.00 equiv), 5-amino-3-bromoindazole (134 mg, 0.63 mmol, 1.0 equiv), and EDC (145 mg, 0.757 mmol, 1.20 equiv) were suspended in 1.75 mL DMF. Et3N (0.106 mL, 0.757 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (10-80% CH3CN/H2O—NH4OH to pH 10 over 17 minutes, retention time 12.59 min) to provide 65 mg (20%) of the title compound as a white solid. MS (ES+) m/e 511 [M+H]+
Reaction SMILES: C(N(CC)[CH:5]([CH3:7])[CH3:6])(C)C.[C:10]1([CH:16]([O:23][C:24]([C:26]2[N:31]3[C:32](=[O:44])[C@@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@H:30]3[S:29][CH2:28][C:27]=2[SH:45])=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[O:25]=[C:24]1[CH:7]=[C:5]([CH2:6][S:45][C:27]2[CH2:28][S:29][C@@H:30]3[C@H:33]([NH:34][C:35](=[O:43])[CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:32](=[O:44])[N:31]3[C:26]=2[C:24]([O:23][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:25])[CH2:16][O:23]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(S)CS[C@H]12
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCC3=CC(=O)OC3)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N,N-Diisopropylethylamine (0.15 ml) was added to a stirred solution of diphenylmethyl-3-mercapto-7β-phenylacetamidoceph-3-em-4-carboxylate (500 mg) and 4-bromomethyl-2(5H)-furanone1 (200 mg) in tetrahydrofuran (10 ml). After stirring at room temperature for 90 mins. the mixture was partitioned between ethyl acetate and aqueous citric acid solution. The organic phase was separated and washed three times with water, then brine, dried over magnesium sulphate and evaporated. The title compound (474 mg) was isolated by column chromatography of the residue using gradient elution (Kieselgel 1:1 ethyl acetate:hexane going to neat ethyl acetate), m.p. 172°-176° C. from ethyl acetate/hexane. (Found: C, 64.24; H, 4.69; N, 4.51; S, 10.48; C33H28N2O6S2 requires; C, 64.69; H, 4.61; N, 4.57; S, 10.47); υmax (CHCl3) 3400, 1785, 1750, 1680 cm-1. δH (CDC13) 3.23 (1H, d, J 17.0Hz), 3.38 (1H, d, J 17.1Hz), 3.41 (H, d, J 15.2Hz), 3.53 (1H, d, J 15.1Hz), 3.66 (2H, s), 4.62 (2H, s), 4.98 (1H, d, J 4.6Hz), 5.76 (1H, dd, J 4.6 and 8.8Hz), 5.89 (1H, s), 6.56 (1H, d, J 8.8Hz) 6.91 (1H, s) 7.2-7.4 (15H, m).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([O:21]CC)=[O:20])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O.C1COCC1.CO>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=2)[C:19]([OH:21])=[O:20])[N:10]=3)=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(-c2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(-c2ccc3nc(NC(=O)C4CC4)sc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
Ethyl 3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoate (870 mg, 2.37 mmol) was dissolved in the mixture of water (3.0 mL), THF (3.0 mL) and methanol (3.0 mL) followed by the addition of lithium hydroxide monohydrate (497 mg, 11.85 mmol). The reaction mixture was stirred at room temperature for 16 h and was neutralized with 1N aqueous HCl until pH=6 (monitored with pH paper). Upon removal of the organic solvent in vacuo the resulting brown solid was collected and dried to give 620 mg (87% yield) of 3-(2-(cyclopropanecarboxamido)thiazolo[5,4-b]pyridin-5-yl)benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:24][C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]([OH:23])=O)[C:15]=2[CH:14]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:58][C:59]([CH3:63])([CH3:62])[CH2:60][OH:61]>CN(C)C=O>[OH:61][CH2:60][C:59]([NH:58][C:21]([C:20]1[C:15]2[CH:14]=[C:13]([C:6]3[C:5]4[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=4)[N:8]([CH3:12])[CH:7]=3)[NH:24][C:16]=2[N:17]=[CH:18][CH:19]=1)=[O:23])([CH3:63])[CH3:62]
Reactant: COc1ccc2c(c1)c(-c1cc3c(C(=O)O)ccnc3[nH]1)cn2C
Reactant: CC(C)(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(-c1cc3c(C(=O)NC(C)(C)CO)ccnc3[nH]1)cn2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(5-methoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine-4 carboxylic acid [32 mg, Example 41(a)] in dry dimethylformamide (10 mL), under nitrogen, was treated with diisopropylethylamine (35 μL) followed by O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (38 mg). After stirring at room temperature for 1 hour this mixture was treated with a solution of 2-amino-2-methyl-1-propanol (10.5 μL) in dry dimethylformamide (1 mL) and stirring was then continued for a further 2 hours. The reaction mixture was evaporated and the residue was treated with saturated aqueous sodium bicarbonate solution (15 mL). This mixture was stirred for 1 hour and the resulting yellow solid was filtered, then washed well with water and then dried at 100° C. under vacuum to give the title compound (34 mg) as a yellow solid, m.p. 210-212° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28]Cl)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)=[CH:27][CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Product: CC(C)(C)OC(=O)N1CCCC(OCc2ccc(-c3ccc(Cl)cc3)cc2)C1
Yield: 83.6 %

Procedure:
Using 1-(tert-butoxycarbonyl)-3-hydroxypiperidine (403 mg, 2.00 mmol) and 4′-chloro-4-chloromethylbiphenyl (474 mg, 2.00 mmol), the same procedure was followed as in Step 6a of Example 6 to give 672 mg (84%) of the desired compound as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[C:25]1([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]1([CH2:31][CH2:32][CH2:33][C:34]([NH:18][C:15]2[CH:16]=[N:17][C:12]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=4[C:2]([F:1])([F:23])[F:24])[CH2:11][CH2:10]3)=[CH:13][CH:14]=2)=[O:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCc1ccccc1)Nc1ccc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}pyridin-3-amine (225 mg, 0.7 mmol), 4-phenylbutyric acid (131 mg, 0.8 mmol), HATU (380 mg, 1.5 mmol) and DIPEA (465 μL, 2.7 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. After dilution with water, the mixture was extracted with EtOAc. The EtOAc extract was washed with diluted brine, dried (Na2SO4) and concentrated. CombiFlash chromatography (10 g, 40-70% EtOAc in hexanes in 20 min, 20 mL/min, 15 mL/fraction) gave a light brown gum which solidified on standing. Swishing with hexanes-Et2O (1:1) gave the title compound as a white powder.