Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[Br:23])(=[O:15])=[O:14])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:28]=[CH:27][O:26][C:25]=1[C:29]([O:31]CC)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[Br:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:6]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:2]2[C:3]([C:24]3[CH:28]=[CH:27][O:26][C:25]=3[C:29](=[O:31])[NH:1]2)=[CH:4][CH:5]=1)(=[O:15])=[O:14]
Reactant: CCOC(=O)c1occc1-c1ccc(NS(=O)(=O)c2ccc(F)cc2Br)c(C(=O)OC)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1[nH]c(=O)c1occc12
Yield: 78 %

Procedure:
A mixture of ethyl 3-[2-amino-4-(2-bromo-4-fluorobenzenesulfonylamino)-3-methoxycarbonylphenyl]-furan-2-carboxylate (Intermediate 88, 0.960 g) and potassium carbonate (0.736 g) in methanol (50 mL) was heated at reflux overnight. The resultant mixture was concentrated in vacuo and the residue was acidified with 1M HCl and extracted with a mixture of DCM and ethyl acetate. The precipitate from the acidification did not dissolve, therefore the volatiles were removed in vacuo and the aqueous slurry was filtered. The resultant paste was triturated with hot acetonitrile and the solid was collected by filtration and dried under vacuum overnight. The resultant solid was purified by chromatography on silica, eluting with a mixture of ethyl acetate and DCM, with a gradient of 0-100%, followed by methanol and DCM, with a gradient of 0-10% and finally flushing the column with methanol and DCM (50%) to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4-oxo-4,5-dihydrofuro[2,3-c]quinoline-6-carboxylate (0.685 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2)([O-:3])=[O:2].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7](=[O:13])[NH:8]2)([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=C1Cc2c(cccc2[N+](=O)[O-])N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1C(=O)Nc2cccc([N+](=O)[O-])c21
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-nitro-1,3-dihydro-2H-indol-2-one (3.00 g, 16.8 mmol, described in Intermediate 17) in DMF (100 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil; 740 mg, 18.5 mmol) and the resulting mixture was stirred for 30 min. Ethyl bromoacetate (1.87 mL, 16.8 mmol) in DMF (10 mL) was added dropwise over 10 min. The reaction mixture was stirred at 0° C. for 2 h, then quenched with H2O (200 mL). The mixture was extracted with EtOAc (5×200 mL) and the combined organic extracts were washed with brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, followed by crystallization from hexane:EtOAc to give the title compound. MS: m/z=265 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:12]2([OH:22])[CH2:20][CH2:19][CH2:18][C:17]3[N:16]([CH3:21])[N:15]=[CH:14][C:13]2=3)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:23].CC(O)C>>[NH2:23][C:7]1[C:6]2[N:5]([C:4]([C:12]3([OH:22])[CH2:20][CH2:19][CH2:18][C:17]4[N:16]([CH3:21])[N:15]=[CH:14][C:13]3=4)=[N:3][C:2]=2[Br:1])[CH:10]=[CH:9][N:8]=1
Reactant: Cn1ncc2c1CCCC2(O)c1nc(Br)c2c(Cl)nccn12
Reactant: N
Solvent: CC(C)O
Product: Cn1ncc2c1CCCC2(O)c1nc(Br)c2c(N)nccn12
Temperature: 120 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 4-(1-bromo-8-chloroimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (860 mg, 2.26 mmol) in NH3/i-PrOH (2N, 25 ml) was added in a sealed tube, and then stirred at 120° C. overnight. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated under reduce pressure. The residue was re-dissolved in DCM, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give 4-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (720 mg, 88%). MS-ESI (m/z): 363 (M+1)+ (Acq Method: 0-60AB_2 min; Rt: 0.98 min)
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][Cl:38])[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:70])C=1.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:57][O:58][CH:59]([F:61])[F:60])[C:27]([NH:29][CH:30]2[C:55](=[O:56])[N:32]3[C:33]([C:39]([O:41][CH:42]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[O:40])=[C:34]([CH2:37][Cl:38])[CH2:35][S:36](=[O:70])[C@H:31]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)C(=NOC(F)F)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A mixture of benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (35 g), m-chloroperbenzoic acid (8.64 g) and ethyl acetate (300 ml) was stirred for 30 minutes at 0° to 5° C. and then, water (300 ml), sodium bisulfite and sodium bicarbonate were added thereto. The organic layer was separated, washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated. The residue was triturated with diisopropyl ether to give benzhydryl 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (syn isomer) (29.93 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([OH:15])([CH3:14])[CH2:12][O:13][S:17]([CH3:16])(=[O:19])=[O:18])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@@](O)(COS(C)(=O)=O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 4 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
(S)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 16 (4.05 g, 16.9 mmol) was dissolved in pyridine (8 ml), and this solution was cooled to 4° C. Methanesulfonyl chloride (1.6 ml, 20.28 mmol) was added dropwise to the solution below 15° C. followed by stirring at the same temperature for 1 hour. 6N hydrochloric acid (33 ml) was added to the mixture below 30° C. The reaction mixture was extracted with methylene chloride (20 ml) three times. The organic phases were combined, washed with water (20 ml) and a saturated saline solution (20 ml), dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. Toluene (10 ml) was added to the residue, and the resulting precipitates were filtered off to afford (S)-2-chloro-1-(2-hydroxy-2-methyl-3-methanesulfonyloxypropyl)-4-nitroimidazole (3.04 g, yield 57%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([CH3:38])[N:37]=1)[C:32](Cl)=[O:33].CO>C1COCC1.ClCCl>[Cl:28][C:29]1[CH:30]=[C:31]([CH:35]=[C:36]([CH3:38])[N:37]=1)[C:32]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:33]
Reactant: Cc1cc(C(=O)Cl)cc(Cl)n1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3cc(C)nc(Cl)c3)nc12
Temperature: 5 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a stirred suspension of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine (13.3 g, 50.1 mmol) in THF (700 ml) was added N-ethyldiisopropylamine (21.3 ml, 125 mmol). The mixture was then cooled to 5° C. and a solution of 2-chloro-6-methyl-isonicotinoyl chloride (10.5 g, 55.1 mmol) in dichloromethane (350 ml) was added dropwise over 2 hours. The reaction mixture was then stirred overnight at 20° C. To this mixture was added methanol (40 ml) and stirring continued for ten minutes. The mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic phases were then dried over Na2SO4 and the solvent evaporated. The crude product was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/MeOH (98:2), the product fractions were pooled and the solvent evaporated, to afford the title compound as a brown solid (16.0 g, 76% yield), MS: m/e=421 (M{37Cl}+H+), 419 (M{35Cl}+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.CN1CCOCC1.N1C(Cl)=NC(Cl)=NC=1Cl.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CC(C)=O>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:23][CH3:24])(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])=[CH:44][CH:43]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)O)cc21
Reactant: Nc1ccc(Cl)cc1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (30 mg, 0.082 mmol) in acetone (0.9 ml) was treated with N-methylmorpholine (0.025 ml, 2.4 equiv.) and cyanuric chloride (18 mg, 0.098 mmol, 1.2 equiv.) and stirred at room temperature for 2 hours. 4-Chloro-phenyl-amine (12 mg, 0.098 mol, 1.2 equiv.) was then added, and the mixture was stirred for 12 hours at room temperature. The solvent was evaporated, and the residue dissolved in methanol (2.5 ml) and purified by preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid). 1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-chloro-phenyl)-amide was obtained as a white solid, 10.6 mg (27%). MS (ISP): m/e=474.9, 477.8 (M−H), δH (300 MHz; d6-DMSO) 10.33 (1H, s), 7.86 (1H, d), 7.79 (2H, d), 7.71 (1H, s), 7.69 (1H, d), 7.60 (1H, d), 7.40 (2H, d), 7.35 (1H, d), 7.21 (1H, d), 4.10 (2H, t), 3.66 (3H, s), 3.12 (2H, t).
Reaction SMILES: C(OC(=O)[N:7]([CH2:27][C:28](=[O:30])[CH3:29])[C:8]1[S:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:12]=1)(C)(C)C.Cl>O1CCOCC1>[C:22]1([CH3:26])[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][C:15]2[N:14]=[C:13]([C:10]3[S:9][C:8]([NH:7][CH2:27][C:28](=[O:30])[CH3:29])=[CH:12][CH:11]=3)[CH:18]=[CH:17][N:16]=2)[CH:21]=1
Reactant: CC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2ccnc(Nc3cccc(C)c3)n2)s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)CNc1ccc(-c2ccnc(Nc3cccc(C)c3)n2)s1
Yield: 10.6 %

Procedure:
(2-Oxo-propyl)-[5-(2-m-tolylamino-pyrimdin-4-yl)-thiophen-2-yl]-carbamic acid tert-butyl ester (0.078 mmol) was treated with 1 mL 4N HCl in dioxane. After 1½ hours, the mixture was concentrated in vacuo and redissolved in EtOAc. The organics were washed with saturated NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by prep LCMS to afford title compound (2.8 mg, 10.5% yield for 2 steps). %). MS: m/z 339 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.15 (s, 3H), 2.318 (s, 3H), 4.077 (d, J=5.5 Hz, 2H), 5.94 (d, J=4 Hz, 1H), 6.73 (d, J=8 Hz, 1H), 7.02 (d, J=5.5 Hz, 1H), 7.13 (t, J=8 Hz, 1H), 7.41 (t, J=6 Hz, 1H), 7.52 (br d, J=9 Hz, 1H), 7.59 (d, J=4 Hz, 1H), 7.75 (br s, 1H), 8.19 (d, J=5.5 Hz, 1H), 9.27 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[C:4]([OH:19])[CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[N:30]1([C:36]([O:19][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[N:6][C:5]=2[O:8][C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH:16]2[CH2:18][CH2:17]2)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1OC(=O)N1CCOCC1
Yield: 99.2 %

Procedure:
To 19.0 g (68.8 mmol) of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol were added 51.3 g of acetone and 10.5 g (75.7 mmol) of potassium carbonate, and the resultant mixture was stirred at 30° C. To the mixture was added dropwise 11.3 g (75.7 mmol) of morpholinecarbonyl chloride over one hour. The reaction mixture was subjected to reaction at 30° C. for 5 hours. After completion of the reaction, pure water was added to the reaction mixture to deposit solids, and then the solids were taken out by filtration. The resultant solids were dried under a reduced pressure, and the solids were quantitatively determined by an HPLC internal standard analysis method, which showed that 26.6 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinyl morpholine-4-carboxylate (yield: 99%) was obtained.
Reaction SMILES: F.[CH3:2][N:3]([CH3:27])[C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=3[N+:24]([O-:26])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[CH:6][N:5]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1B(O)O>>[CH3:2][N:3]([CH3:27])[C:4]1[N:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:29]4[O:28][CH:32]=[CH:31][CH:30]=4)=[CH:19][C:18]=3[N+:24]([O-:26])=[O:25])[CH:13]=[CH:14][CH:15]=2)=[CH:6][N:5]=1
Reactant: OB(O)c1ccco1
Reactant: CN(C)c1ncc(-c2cccc(Nc3ccc(I)cc3[N+](=O)[O-])c2)cn1
Agent: F
Product: CN(C)c1ncc(-c2cccc(Nc3ccc(-c4ccco4)cc3[N+](=O)[O-])c2)cn1
Yield: 89 %

Procedure:
N-(3-(2-(Dimethylamino)pyrimid-5-yl)phenyl)-4-(2-furanyl)-2-nitroaniline (7m) was prepared analogously from 6h (Example 10) and 2-furanylboronic acid in 89% yield. Mp 160-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1.CS(O[C@H:18]([C@@H:20]1[CH2:24][C:23](=[O:25])[N:22]([C@@H:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH3:27])[CH2:21]1)[CH3:19])(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C@@H:18]([C@H:20]2[CH2:21][N:22]([C@@H:26]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[CH3:27])[C:23](=[O:25])[CH2:24]2)[CH3:19])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@H](C)OS(C)(=O)=O)CC2=O)cc1
Reactant: Cc1cnn2cc(Cl)cc(O)c12
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(C)c34)CC2=O)cc1

Procedure:
This reaction was conducted in an analogous fashion to step 1 in General Procedure 6A, beginning with 6-chloro-3-methylpyrazolo[1,5-a]pyridin-4-ol and mesylate 1.30 to afford (R)-4-((R)-1-((6-chloro-3-methylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.31. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H26ClN3O3: 428.2; found 428.2.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].C(O)(C(F)(F)F)=O.FC1C2OC(C3(O)CCN(C4N=CC(CCC)=CN=4)CC3)CC=2C=C(C2CCNCC=2)C=1>>[CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)N1CCC(C2Cc3cc(C4=CCN(C(=O)OC(C)(C)C)CC4)ccc3O2)CC1
Agent: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCNCC5)cc(F)c4O3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CCCS(=O)(=O)N1CCC(C2Cc3cc(C4=CCNCC4)ccc3O2)CC1

Procedure:
Compound 10C was prepared from Compound 10B and TFA in a similar manner to the procedure described for Compound 1J in Example 1.
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@H:32]1[CH2:34][O:33]1.C(O)C>C(Cl)Cl>[OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:34][C@@H:32]([OH:33])[C:23]2[CH:24]=[CH:25][C:26]3[C:27](=[O:31])[O:28][CH2:29][C:30]=3[C:22]=2[CH3:21])[CH2:6][CH2:5]1
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Solvent: CCO
Solvent: ClCCl
Product: Cc1c([C@H](O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a 20 mL microwave tube charged with 5-[(1R)-1-hydroxy-2-piperazin-1-ylethyl]-4-methyl-2-benzofuran-1(3H)-one (166 mg, 0.600 mmol) and a stir bar was added 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one (171 mg, 0.900 mmol) and ethanol (10 mL). The mixture was heated in a microwave apparatus to 150° C. for 90 minutes. After the reaction cooled down, DCM (5 mL) was added to the tube. The mixture was allowed to sit at RT overnight. A lot of solids precipitated during that time; these were collected by filtration. Chiral HPLC analysis showed the material was over 95% ee pure 5-((1R)-1-hydroxy-2-{4-[(2S)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, DMSO-d6) δ ppm 7.74 (s, 4H), 5.43 (m, 4H), 6.60-5.80 (broad, 2H), 5.33 (s, 2H), 3.40 (broad, 8H), 3.09 (broad, 4H), 2.32 (s, 6H); LCMS M+1 (calc. 467, found 467).
Reaction SMILES: [C:1]([CH2:14][C:15]([CH2:18][C:19]([CH2:22][CH2:23]I)([F:21])[F:20])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].CNC=[O:28].O>CCOCC>[C:1]([CH2:14][C:15]([CH2:18][C:19]([CH2:22][CH2:23][OH:28])([F:21])[F:20])([F:17])[F:16])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(CCI)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CNC=O
Solvent: O
Solvent: CCOCC
Product: OCCC(F)(F)CC(F)(F)CC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
Ethylene (56 g) was introduced to an autoclave charged with C4F9(CH2CF2)2I (714 g) and d-(+)-limonene (3.2 g), and the reactor heated at 240° C. for 12 hours. The product was isolated by vacuum distillation to provide C4F9(CH2CF2)2CH2CH2I. A mixture of C4F9(CH2CF2)2CH2CH2I (10 g, 0.02 mol) and N-methylformamide (8.9 mL, 0.15 mol) was heated to 150° C. for 26 hours. The mixture was cooled to 100° C., followed by the addition of water to separate the crude ester. Ethyl alcohol (3 mL) and p-toluene sulfonic acid (0.09 g) were added and the mixture stirred at 70° C. for 0.25 hours. Ethyl formate and ethyl alcohol were removed by distillation to give a crude product. The crude product was dissolved in ether, washed with 10 wt % aqueous sodium sulfite, water and brine, in turn, and dried over magnesium sulfate. Distillation provided the product C4F9(CH2CF2)2CH2CH2OH (6.5 g, 83% yield): bp 94-95° C. at 2 mm Hg (266 Pa).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.C(O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC1=CC(=O)NC1
Reactant: OCc1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1C=C(OCc2ccccc2)CN1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
5.7 g (50 mmol) of 4-methoxy-3-pyrrolin-2-one and 10.8 g (100 mmol) of benzyl alcohol were mixed with 0.4 g (4 mmol) of methanesulfonic acid and stirred for 24 hours at 80° C. and 20 mbars. Then the reaction solution was mixed with 50 ml of ice water and 100 ml of methylene chloride, and neutralized with 4 ml of saturated NaHCO3 solution. The aqueous phase was extracted twice with 50 ml of methylene chloride each. After drying of the organic phase over Na2SO4 and distilling off of the solvent, the residue was mixed with 150 ml of ice water, heated to 100° C. and azeotropically distilled off with 100 ml of water-benzyl alcohol. The crystals precipitated during cooling were recrystallized hot from 50 ml of toluene. 6.7 g of white, crystalline product with a melting point of 147° to 148° C. was obtained:
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:10]([O:12][CH2:13]C)=[O:11])=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:13][O:12][C:10]([C:4]1[C:3]([CH2:2][O:16][CH3:15])=[CH:8][CH:7]=[C:6]([Cl:9])[CH:5]=1)=[O:11]
Reactant: C[O-]
Reactant: CCOC(=O)c1cc(Cl)ccc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(Cl)cc1C(=O)OC

Procedure:
Ethyl α-Bromo-4-chloro-o-toluate (26.4 g.) is added to a solution (10°) of sodium methoxide (5.4 g.) in 110 ml. of methanol. When the addition is complete, the mixture is refluxed for two hours, then cooled and concentrated in vacuo. The oily residue is partioned between ether-water. The ether layer is separated and dried. Removal of the drying agent and concentration of the filtrate in vacuo leaves 17.3 g. of a white solid. A sample of the product recrystallized from methanol had mp 44°-45°.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:30])[C:13]([CH2:28][OH:29])([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:33](I)[CH3:34]>O1CCCC1>[C:1]12([NH:11][C:12](=[O:30])[C:13]([CH2:28][O:29][CH2:33][CH3:34])([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCI
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(CO)(Cc1ccncc1)Cc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
To a well-stirred suspension of N-adamantan-1-yl-2-hydroxymethyl-3-pyridin4-yl-2-pyridin-4-ylmethyl-propionamide (40 mg, 0.1 mmol) in anhydrous tetrahydrofuran (0.50 ml), sodium hydride (7.8 mg of 60% mineral oil dispersion; 0.2 mmol of sodium hydride) was added. After stirring at ambient temperature for 15 minutes, ethyl iodide (15.8 μl, 0.20 mmol) was added. After stirring for 2 hours at ambient temperature, the reaction was quenched by the addition of dilute aqueous sodium bicarbonate/methylene chloride (10 ml of each). The mixture was then extracted with three 10 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil (54 mg). Flash chromatography (silica gel, 40 micron mesh; elution with methanol/ethyl acetate=1:9 in volume) afforded the title compound (free base) (19 mg) as an amorphous solid.