Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=4)[N:25]=[CH:26][C:21]=3[CH2:20][C:19](=[O:38])[NH:18][C:17]=2[CH:39]=1)=[O:12])(C)(C)C.C(Cl)Cl.CO.Cl>O1CCOCC1>[NH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[CH:14]=[CH:15][C:16]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=4)[N:25]=[CH:26][C:21]=3[CH2:20][C:19](=[O:38])[NH:18][C:17]=2[CH:39]=1)=[O:12]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCN)cc2NC(=O)C3)cc1OC
Reaction time: 8 h

Procedure:
To a mixture of (2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester (I-71-a) (0.18 mmol) in 1:1 mixture of CH2Cl2:MeOH (4 mL) was added 4M HCl in dioxane (2 mL). The mixture stirred overnight and was concentrated. The mixture was purified by C-18 RP LC-MS chromatography to give I-71 (17%): HRMS Calcd. for C23H24N6O4: 449.1937, Found 449.1935.
Reaction SMILES: C([O:8][NH:9][C:10]([N:12]1[CH2:16][CH2:15][C:14](=[CH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([OH:26])=[C:20]([O:27][CH3:28])[CH:19]=2)[C:13]1=[O:29])=[O:11])C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O>[OH:8][NH:9][C:10]([N:12]1[CH2:16][CH2:15][C:14](=[CH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([OH:26])=[C:20]([O:27][CH3:28])[CH:19]=2)[C:13]1=[O:29])=[O:11]
Reactant: COc1cc(C=C2CCN(C(=O)NOCc3ccccc3)C2=O)cc(OC)c1O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Product: COc1cc(C=C2CCN(C(=O)NO)C2=O)cc(OC)c1O
Yield: 62.8 %

Procedure:
To a solution of 800 mg (2 mmol) of 1-(N-benzyloxycarbamoyl)-3-(3,5-di-methoxy-4-hydroxybenzylidene)pyrrolidin-2-one in a mixture of anisole (12 ml) and nitromethane (12 ml) was added a solution of 1.6 g (12 mmol) of aluminium chloride in anisole (4 ml) under a nitrogen atmosphere while being stirred under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 6 ml of cooled 2N hydrochloric acid and the mixture was stirred for 1 hour and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate and evaporated to give a residue, which was recrystallized from a methylene chloride/ether mixture to give 387 mg of the objective compound in 63% yield.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17].[CH2:43]([O:55][CH2:56][CH:57]([CH2:59][O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])O)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54].N1C=CC=CC=1>O1CCCC1>[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[CH:31]([C:35]([O:37][CH:57]([CH2:56][O:55][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:59][O:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])=[O:36])[CH:32]=[CH:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reactant: CCCCCCCCCCCCOCC(O)COCCCCCCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOCC(COCCCCCCCCCCCC)OC(=O)C1C=CS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 25 °C
Reaction time: 4.75 h

Procedure:
Dicyclohexylcarbodiimide (3.96 g) was added to a stirred solution of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 6.58 g] and 2-n-dodecyloxy-1-n-dodecyloxymethylethanol (8.23 g) in a mixture of dry pyridine (60 ml) and dry tetrahydrofuran (20 ml) at 3° C., and then stirred at 0° to 5° C. for 4.75 hours and further at room temperature for an hour. The resultant mixture was poured into ice water (350 ml) and extracted with ethyl acetate (500 ml). Water (50 ml) was added to the extract and adjusted to pH 2 to 3 with 20% sulfuric acid. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (100 ml×2) and an aqueous solution of sodium bicarbonate in turn, and dried over anhydrous magnesium sulfate. After evaporating the solution in vacuo, the residue was subjected to column chromatography on silica gel (266 g) with a mixture of chloroform and methanol (20:1). The eluate was evaporated in vacuo to give powder [6.24 g] of 2-n-dodecyloxy-1-n-dodecyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-2-cephem-4-carboxylate (syn isomer).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C:10]([CH:15]3[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]3)([C:13]#[N:14])[C:9]2=[O:26])[CH:5]=[CH:4][N:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C(O)(=O)C>C(O)CCC>[C:13]([C:10]1([CH:15]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]2)[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:37][C:36]3[CH:35]=[CH:34][C:33]([N:30]4[CH2:31][CH2:32][O:27][CH2:28][CH2:29]4)=[CH:39][CH:38]=3)[N:7]=2)[C:9]1=[O:26])#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC(C2(C#N)CCN(c3ccnc(Cl)n3)C2=O)C1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: CC(=O)O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1CC(C2(C#N)CCN(c3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)C2=O)C1
Yield: 25.5 %

Procedure:
A solution of tert-butyl 3-(1-(2-chloropyrimidin-4-yl)-3-cyano-2-oxopyrrolidin-3-yl)azetidine-1-carboxylate (100 mg) obtained in Step D of Example 309, 4-morpholinoaniline (61 mg) and acetic acid (50 μL) in n-butanol (4.0 mL) was stirred in a microwave reactor at 150° C. for 1 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate), and recrystallized (diisopropyl ether/ethyl acetate) to give the title compound (35 mg).
Reaction SMILES: F[C:2]1[C:10]2[S:9][C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)=[N:7][C:6]=2[C:5]([C:29](F)([F:31])F)=C[CH:3]=1.ClC1SC2C=CC([F:43])=C(F)C=2N=1>>[F:43][C:5]1[C:6]2[N:7]=[C:8]([C:11]3[C:12]([NH2:28])=[N:13][CH:14]=[C:15]([C:17]4[CH:18]=[N:19][N:20]([CH:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[CH:21]=4)[CH:16]=3)[S:9][C:10]=2[CH:2]=[CH:3][C:29]=1[F:31]
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)ccc(F)c2s1
Reactant: Fc1ccc2sc(Cl)nc2c1F
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(F)c(F)ccc2s1

Procedure:
Following the procedure for 3-(7-fluoro-4-trifluoromethylbenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, using 2-chloro-4,5-difluoro-1,3-benzothiazole and conducting the Suzuki coupling at 80° C. for 3 h, the title compound was obtained as a yellow solid. MS (ES+): m/z=413.13 [MH+]. HPLC: tR=2.46 min (ZQ3, polar—5 min).
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13])=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:44]1[CH:45]=[CH:46][C:47]2[C:48]3[N:56]([CH2:57][C:58]([CH3:61])([OH:60])[CH3:59])[C:55]([CH2:62][CH3:63])=[N:54][C:49]=3[CH:50]=[N:51][C:52]=2[CH:53]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:62]([C:55]1[N:56]([CH2:57][C:58]([OH:60])([CH3:61])[CH3:59])[C:48]2[C:47]3[CH:46]=[CH:45][C:44]([CH:2]=[CH:1][N:3]4[C:7](=[O:8])[C:6]5[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:4]4=[O:13])=[CH:53][C:52]=3[N:51]=[CH:50][C:49]=2[N:54]=1)[CH3:63]
Reactant: CCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: C=CN1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nc2cnc3cc(C=CN4C(=O)c5ccccc5C4=O)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 77.1 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (64 mg, 0.29 mmol), acetonitrile (50 mL), N-vinylphthalimide (1.19 g, 6.89 mmol), triethylamine (2.4 mL, 17 mmol), tri-o-tolylphosphine (260 mg, 0.86 mmol) and 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.00 g, 5.74 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 16 hours. The reaction was cooled to ambient temperature and silica gel (20 g) was added followed by concentration under reduced pressure. The sample absorbed on silica was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-7% gradient of methanol in dichloromethane). The recovered solid was washed with 1% aqueous sodium carbonate to provide 1.95 g of 2-{2[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethenyl}-1H-isoindole-1,3(2H)-dione as a bright yellow solid. MS (APCI) m/z 441 (M+H)+.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:20]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]>N1C=CC=CC=1>[C:21]([CH:6]([OH:7])[C@H:5]1[O:8][C@@H:1]([N:9]2[CH:20]=[C:15]([C:16]([F:18])([F:17])[F:19])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1C(F)(F)F
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)C(O)[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a stirring solution of 150 mg of trifluorothymidine in 5 mL of pyridine was added a solution of 90 mg of pivaloyl chloride in 1 mL of pyridine, with cooling. Stirring was continued at room temperature for 10 hours, then the reaction mixture was poured into 20 mL of ice water and extracted with 50 mL of ethyl acetate. The extract was washed with water and dried over sodium sulfate. The ethyl acetate was removed and the residue was purified by silica gel column chromatography using 20:1 chloroform/methanol as eluent. The title compound melted at 130°-132° C. after recrystallization from a mixture of ether and n-hexane.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:6]=12.[OH-].[NH4+:19]>C(O)C>[NH2:19][C@@H:7]1[C:6]2[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:5]=2[O:4][C:3]([CH3:17])([CH3:16])[C@H:2]1[OH:1]
Reactant: CC1(C)Oc2ccc(S(C)(=O)=O)cc2C2OC21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)Oc2ccc(S(C)(=O)=O)cc2[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3,4-dihydro-3,4-epoxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (4.0 g), ammonium hydroxide (containing ca. 28% ammonia, 40 ml), and ethanol (20 ml) was stirred at room temperature for 72 hours. The reaction mixture was concentrated, added to diisopropyl ether, and pulverized to give trans-4-amino-3,4-dihydro-3-hydroxy-6-mesyl-2,2-dimethyl-2H-1-benzopyran (4.0 g).
Reaction SMILES: [N+]([O-])=O.O=O.[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])([O-:8])=[O:7].[N+:16](C1C=CC(C)=CC=1)([O-:18])=[O:17]>C1(C)C=CC=CC=1>[N+:6]([C:9]1[CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:11][C:10]=1[CH3:15])([O-:8])=[O:7].[N+:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:16]([O-:18])=[O:17])[C:10]=1[CH3:15])([O-:8])=[O:7]
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: O=O
Agent: O=[N+][O-]
Solvent: Cc1ccccc1
Product: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
After supplying 0.2 mol of toluene and 0.002 mol of ferric chloride to an autoclave, 0.9 mol of liquid nitrogen dioxide was added to the autoclave. Next, oxygen was injected at a pressure of 120 psi. At first the reactants were reacted at room temperature. After 30 minutes, the autoclave was heated to 60° C. and then the reactants were reacted for 3 hours. After the initial 30 minutes, all of toluene was converted into o-nitrotoluene and p-nitrotoluene at a ratio of 55:45, respectively. After 3 hours, 2,4-dinitro-toluene and 2,6-dinitrotoluene (83:17) were formed at a yield of more than 98% analyzed by gas chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[C:5](/[O:16][CH2:17][CH3:18])=[CH:6]/[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2]
Reactant: CCOC(=O)/C(=C/c1cccc2[nH]ccc12)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A suspension of 15.0 g of (Z)-2-ethoxy-3-(1H-indol-4-yl)-acrylic acid ethyl ester in 250 ml of EtOH and 3.08 g of Pd/C (10%) was hydrogenated at 22° C. for 2 h, after which time hydrogen uptake ceased. The suspension was filtered, the filtrate evaporated and the residue chromatographed on silica gel (eluent: gradient of hexane and ethyl acetate) to give 12.28 g of the title compound as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:23])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[CH:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:23][C:29]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:30])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=C(O)C1CCCC1
Reactant: Cn1ncc(Br)c1-c1cc(N)ccc1OCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1ncc(Br)c1-c1cc(NC(=O)C2CCCC2)ccc1OCCN1CCOCC1
Temperature: 100 °C
Yield: 20.9 %

Procedure:
A mixture of 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-(2-morpholin-4-yl-ethoxy)-phenylamine (76 mg, 0.2 mmol), cyclopentyl carboxylic acid (27 mg, 0.24 mmol), HATU (99 mg, 0.26 mmol) and triethylamine (0.3 mL) in DMF (2 mL) was heated in microwave at 100° C. for 30 min. The crude was purified by HPLC to give title compound (20 mg, 21%) as a brown solid as TFA salt. 1H NMR (CD3CN, 400 MHz) δ 1.66-1.95 (m, 8H), 2.70-2.80 (m, 1H), 2.85-3.02 (m, 2H), 3.13-3.27 (m, 2H), 3.43 (t, 2H), 3.73 (s, 3H), 3.74-3.80 (m, 2H), 3.82-3.90 (m, 2H), 4.34-4.48 (m, 2H), 7.13 (d, J=9.09 Hz, 1H), 7.55 (d, J=2.53 Hz, 1H), 7.57 (s, 1H), 7.76 (dd, J=2.78, 9.35 Hz, 1H), 8.38 (s, 1H). Exact mass calculated for C22H2979BrN4O3 476.1, found 477.3 (M+H79Br, 100), 479.3 (M+H81Br, 98).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[OH:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(O)cc1
Product: O=C(Cc1ccc(O)cc1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(4-hydroxyphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (dd, J=7.9, 1.2 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.00 (m, 1H), 7.89-7.92 (m, 1H), 7.18 (s, 2H), 6.75 (d, 2H), 3.81-3.83 (m, 4H), 3.53 (s, 2H), 3.07-3.11 (m, 4H); MS (ESI−) M/Z 379 (M−H)−.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.[Br:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH:32]=[C:31](CO)[CH:30]=[C:29]2[O:38][C:39]1[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])=[CH:41][N:40]=1>O1CCCC1.O>[Br:25][C:26]1[CH:27]=[C:28]2[C:33]([CH:32]=[C:31]([CH2:20][Cl:24])[CH:30]=[C:29]2[O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH3:49])(=[O:46])=[O:47])=[CH:41][N:40]=2)=[CH:34][CH:35]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CO)cc3ccc(Br)cc23)nc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CCl)cc3ccc(Br)cc23)nc1
Temperature: 25 °C
Yield: 76 %

Procedure:
After a solution of triphenylphosphine (330 mg, 1.26 mmol) and carbon tetrachloride (2 mL) in anhydrous tetrahydrofuran (6 mL) was stirred at room temperature for 10 minutes under a nitrogen atmosphere, [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-methanol (265 mg, 0.63 mmol) was introduced as a solid. The resulting mixture was heated at reflux for 4 hours, cooled to room temperature, then diluted with water (10 mL), and extracted with ethyl acetate (30 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in petroleum ether) to afford 2-(7-bromo-3-chloromethyl-naphthalen-1-yloxy)-5-ethanesulfonyl-pyridine (210 mg, 76%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO.O>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 4 h

Procedure:
A mixture of compound 29c (577 mg, 1.95 mmol) and LiOH (187 mg, 7.80 mmol) in THF/MeOH/H2O (4/4/4 mL) was stirred for 4 h. A 15% citric acid solution (20 mL) was added, and the mixture was then extracted with EtOAc (3×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue, compound 29d, was dried under reduced pressure for 18 h and was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:35](O)[CH2:36][CH2:37][OH:38].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:35][CH2:36][CH2:37][OH:38]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of 5-methyl-3-(2-nitrophenylsulfonyloxy)phenol (1.1 g, 4.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.22 g, 6.0 mmol) and 1,3-propanediol (1.52 g, 20 mmol) in anhydrous tetrahydrofuran (40 mL) was added 1,1'-(azodicarbonyl)dipiperidine (1.51 g, 6.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (60 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow oil (1.05 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 7.99 (d, J=7.7 Hz, 1H), 7.84 (m, 2H), 7.70 (m, 1H), 6.65 (s, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 4.03 (t, J=6.0 Hz, 2H), 3.82 (t, J=5.9 Hz, 2H), 2.27 (s, 3H), 2.00 (t, J=6.0 Hz, 2H), 1.67 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:7]=1.[NH2:29][CH2:30][C@H:31]([OH:34])[CH2:32][OH:33]>>[OH:34][C@H:31]([CH2:32][OH:33])[CH2:30][NH:29][C:22]([C:21]1[CH:20]=[N:19][N:16]2[CH:17]=[CH:18][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@@H:8]3[C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:25]([F:27])([F:28])[F:26])=[N:14][C:15]=12)=[O:24]
Reactant: NC[C@H](O)CO
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Product: O=C(NC[C@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Yield: 73 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation M) and (S)-3-aminopropane-1,2-diol. The crude material was purified by reverse phase HPLC (0-60% acetonitrile/water) to provide the title compound (26 mg, 73% yield). MS (apci) m/z=468.1 (M+H).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8](=[CH2:28])[CH2:9][CH2:10][C:11]([O: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])=[O:12])=[O:5])C.C[N+]1([O-])CC[O:33]CC1.[O-]S([O-])=O.[Na+].[Na+]>CC(O)(C)C.O.O=[Os](=O)(=O)=O>[OH:33][CH2:28][C:8]1([CH2:9][CH2:10][C:11]([O: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])=[O:12])[O:5][C:4](=[O:3])[CH2:6][CH2:7]1
Reactant: C=C(CCC(=O)OCC)CCC(=O)OCCCCCCCCCCCCCC
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCCCCCCCCCCCOC(=O)CCC1(CO)CCC(=O)O1
Reaction time: 12 h
Yield: 62.8 %

Procedure:
A stirred solution of olefin 3.18 (0.115 g, 0.29 mmol) in t-BuOH (3 mL) and water (1 mL) at 0° C., containing N-methyl morpholine N-oxide (0.069 g, 0.59 mmol), was treated with 2.5% OsO4 solution (0.16 mL). The reaction mixture was brought to room temperature slowly and stirred for 12 h; Na2SO3 (200 mg) was added and, after stirring for a few more minutes, it was concentrated under suction. The residue was extracted with EtOAc (3×10 mL) and the combined extract was washed with water (1×10 mL) and dried (Na2SO4). The residue obtained after evaporation of the solvent was purified by flash column chromatography over silica gel using hexane:EtOAc (3:2) as eluant to give 3.2 (0.070 g ,63%) as white solid; m.p. 61° C. (EtOAc/hexane); IR (KBr) 3380 (OH) and 1728 (C=O) cm-1 ; 1H NMR (CDCl3) δ 0.85 (distorted t, 3H, CH3 (CH2)13), 1.10-1.40 (m, 22H, CH3 (CH2)11CH2CH2OCO), 1.60 (m, 2 H, CH3 (CH2)11CH2CH2OCO), 1.86-2.12 (m, 4 H, H-4, CH2CH2COOC14H29), 2.25-2.78 (multiplets, 4 H, H-3, CH2CH2COOC14H29), 2.90 (t, J=6.5 Hz, 1 H, OH), 3.50 (dd, J=12.1, 6.5 Hz, 1 H, CHHOH), 3.65 (dd, J=12.1, 6.5 Hz, 1 H, CHHOH), 4.05 (t, J=6.7 Hz, 2 H, CH3 (CH2)11CH2CH2OCO); 13C NMR (CDCl3) δ 14.09, 22.65, 25.85, 28.05, 28.33, 28.51, 29.15, 29.21, 29.32, 29.48, 29.55, 29.61, 30.97, 31.88, 65.16, 66.41, 87.54, 173.28, 177.03; FAB MS m/z (relative intensity) 385 (38, MH+), 171 (100, MH-C14H29OH). Anal. Calcd for C22H40O5 : C, 68.7; H, 10.49. Found: C, 68.63; H, 10.44.