Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[OH:17][CH2:18][CH2:19][NH:20][C:21]([C:23]1[CH:31]=[CH:30][C:26]2[N:27]=[CH:28][NH:29][C:25]=2[CH:24]=1)=[O:22]>>[C:11]1([C@@H:9]([NH:8][C:6]2[N:7]=[C:2]([N:27]3[C:26]4[CH:30]=[CH:31][C:23]([C:21]([NH:20][CH2:19][CH2:18][OH:17])=[O:22])=[CH:24][C:25]=4[N:29]=[CH:28]3)[CH:3]=[N:4][CH:5]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(NCCO)c1ccc2nc[nH]c2c1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Product: C[C@H](Nc1cncc(-n2cnc3cc(C(=O)NCCO)ccc32)n1)c1ccccc1

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (91 mg, 0.39 mmol) and benzimidazole 5-carboxylic acid (2-hydroxyethyl)amide (88 mg, 0.43 mmol) furnished the product which was purified by column chromatography (22 mg, 14%).
Reaction SMILES: [C:1]([C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C1C=CC=CC=1.[NH2:32][CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=1>O1CCCC1.O>[C:1]([C:9]1[C:10]([N+:19]([O-:21])=[O:20])=[C:11]([CH2:15][C:16]([NH:32][CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([O:44][CH3:45])[CH:37]=2)=[O:18])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccccc2)c1[N+](=O)[O-]
Reactant: COc1ccc(CCCN)cc1OC
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: COc1ccc(CCCNC(=O)Cc2cccc(C(=O)c3ccccc3)c2[N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
A mixture of 0.028 mole of 3-benzoyl-2-nitrobenzeneacetic acid, 50 mL of thionyl chloride and 50 mL of benzene is heated at reflux. The dark solution is concentrated under vacuum. The residue is diluted with benzene and concentrated under vacuum (twice). A portion of the acid chloride (0.01 3 mole) in tetrahydrofuran is added to a solution of 3-amino (3,4-dimethoxyphenyl)propane (0.015 mole). The mixture is stirred at room temperature and then added to 200 mL of cold water. The resulting mixture is extracted with diethyl ether. The combined extracts are washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified using standard procedures to give the product.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:12]2[S:11]C(N)=[N:9][C:8]=2[C:7]([CH3:14])=[CH:6][CH:5]=1>C(O)CO>[NH2:9][C:8]1[C:7]([CH3:14])=[CH:6][CH:5]=[C:4]([Cl:3])[C:12]=1[SH:11]
Reactant: Cc1ccc(Cl)c2sc(N)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Cc1ccc(Cl)c(S)c1N
Temperature: 150 °C
Reaction time: 24 h
Yield: 54.3 %

Procedure:
To a solution of NaOH (10N, 8.0 mL) was added 7-chloro-4-methyl-benzothiazol-2-ylamine (530 mg, 2.67 mmol) and ethylene glycol (10 mL) then the reaction mixture was stirred at 150° C. for 1 day. After being cooled down, the reaction mixture was filtered. The filtrate was extracted with DCM. The aqueous phase was acidified with HCl 1N and extracted with DCM. Then, the combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated to yield 2-amino-6-chloro-3-methyl-benzenethiol (252 mg, 1.45 mmol, 54%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:20]3[CH2:19][CH2:18][N:17]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:16][CH2:15][C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCCNC3)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2,3,4,5-Tetrahydro-1H-benzo[c]azepin-7-yloxymethyl)-benzoic acid methyl ester (D4) (2.83 g, 9.1 mmol) and cyclopentanone (1.6 ml, 18.2 mmol) were dissolved in dichloromethane (30 ml) and acetic acid (0.5 ml). Sodium triacetoxy borohydride (3.85 g, 18.2 mmol) was added and the solution was stirred at room temperature for 4 hours. The reaction mixture was washed with a saturated solution of sodium carbonate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E88); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)=O>C1(C)C=CC=CC=1.C(O)(=O)C.[Fe]>[NH:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=[C:4]1[C:3]1[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:2]=1[Cl:1]
Reactant: O=C(Nc1ccccc1[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Nc1ccc(Cl)c(-c2nc3ccccc3[nH]2)c1
Temperature: 125 °C
Yield: 49.7 %

Procedure:
Iron powder (15.42 g, 280 mmol) was added to a solution of amide 1 (15.00 g, 46.7 mmol) in toluene (125 ml) and acetic acid (60 ml). The mixture was heated at 125° C. for about 1 h (completion of the reaction was monitored by LCMS) and the resulting crude mixture was filtered through a cotton wool plug (to remove iron particles). The crude solution was evaporated to dryness, diluted with EtOAc, washed with saturated NaHCO3 then brine, dried over MgSO4, filtered, and concentrated at reduced pressure. The resulting brown solid was re-dissolved in CH2Cl2 and few drops of hexane were added to form a solid which was isolated by filtration to give 2 (5.66 g, 42%) as a beige solid: 1H NMR (CD3OD) δ 7.64 (broad s, 2H), 7.30-7.26 (m, 3H), 7.13 (app d, 1H), 6.84 (dd, 1H); MS (ES, positive mode): 244 [M++1].
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][CH2:17][S:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C@H:24]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:23][CH2:22]3)=[C:12]([CH2:36][CH2:37][CH3:38])[CH:11]=1.C(O)C.[Li+].[OH-].Cl>C1COCC1.O>[S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:35]=[CH:34][C:13]([O:14][CH2:15][CH2:16][CH2:17][S:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C@H:24]([CH2:28][C:29]([OH:31])=[O:30])[CH2:23][CH2:22]3)=[C:12]([CH2:36][CH2:37][CH3:38])[CH:11]=1
Reactant: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1OCCCSc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1OCCCSc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.2 %

Procedure:
To a solution of ethyl [(1S)-5-({3-[4-(6,7-dihydro-5H-pyrano[2,3-d][1,3]thiazol-2-yl)-2-propylphenoxy]propyl}sulfanyl)-2,3-dihydro-1H-inden-1-yl]acetate (50 mg, 0.09 mmol) (Example 509) in a mixture of THF (2 mL), ethanol (1 mL), and water (2 mL) was added LiOH (8.7 mg, 0.36 mmol). The reaction mixture was stirred vigorously at rt for 18 h, and then it was acidified to pH ˜2 using HCl (1M aqueous solution). The aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4:1 hexanes/EtOAc) to give the title compound (18 mg, 38%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.64 (d, 1H), 7.62 (dd, 1H), 7.22 (s, 1H), 7.15 (d, 1H), 7.08 (d, 1H), 6.75 (d, 1H), 4.31 (t, 2H), 4.15-4.05 (m, 2H), 3.58-3.50 (m, 1H), 3.12 (t, 2H), 2.93-2.80 (m, 2H), 2.78 (t, 2H), 2.78-2.73 (m, 1H), 2.60 (t, 2H), 2.49 (dd, 1H), 2.45-2.36 (m, 1H), 2.17-2.06 (m, 4H), 1.81-1.73 (m, 1H), 1.68-1.58 (m, 2H), 0.95 (t, 3H); LC-MS: RT=4.54 min, (M+H)+ 524.2.
Reaction SMILES: [O:1]=[C:2]1[N:9]2[CH:4]([CH2:5][CH2:6]OC2(C)C)[CH:3]1[CH:12]([CH3:14])C.[Si:15](N1C(C=C)CC1=O)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O=C1N2C(CCOC2(C)C)C1.C(I)C>>[CH2:12]([CH:3]1[CH:4]([CH:5]=[CH2:6])[N:9]([Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:2]1=[O:1])[CH3:14]
Reactant: CC(C)C1C(=O)N2C1CCOC2(C)C
Reactant: C=CC1CC(=O)N1[Si](C)(C)C(C)(C)C
Agent: CC1(C)OCCC2CC(=O)N21
Solvent: CCI
Product: C=CC1C(CC)C(=O)N1[Si](C)(C)C(C)(C)C

Procedure:
Following the procedure for the preparation of 8-oxo-2,2-dimethyl-7α-isopropyl-3-oxa-1-azabicyclo[4.2.0]octane (Example 4a, above), except that an equivalent amount of 1-(t-butyl-dimethylsilyl)-4-vinyl-2-azetidinone is substituted for the 8-oxo-2,2-dimethyl-3-oxa-1-azabicyclo [4.2.0]octane of Example 4a and using ethyl iodide instead of isopropyl iodide, the title compound is obtained.
Reaction SMILES: COC1(C2C=C(C=CC=2)CO)CCOCC1.[H-].[Na+].ClC1OC([C:31]2[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=2)=C(C2C=CC=CC=2)N=1>CC(N(C)C)=O>[C:34]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(Cl)nc2-c2ccccc2)cc1
Agent: COC1(c2cccc(CO)c2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-[tetrahydro-(4-methoxy)pyran-4-yl]benzyl alcohol (prepared as described in U.S. Pat. No. 5,424,320) (0.07 g, 0.3 mmol) in 2 mL of anhydrous DMA was added to a suspension of sodium hydride (7.2 mg, 0.3 mmol) in 2 m of anhydrous DMA at 5° C., and the reaction mixture was stirred for 20 minutes at 5° C. A solution of 4-[(2-chloro)-4-phenyloxazol-5-yl]benzenesulfonamide in 2 mL of anhydrous DMA was then added. The reaction mixture was stirred for 2 h at 5° C. and for 5 h at room temperature. The reaction mixture was quenched with water (50 mL). The aqueous solution was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 40% ethyl acetate in hexane, to give 0.1 g (64%) of 4-[2-[3-(3,4,5,6-tetrahydro-4-methoxypyran-4-yl)phenyl]methoxy]-4-phenyloxazol-5-yl]-benzenesulfonamide as a white solid: 1H NMR (CDCl3/300 MHz) δ 1.95-2.06 (m, 4H), 2.98 (s, 3H), 3.81-3.88 (m, 4H), 4.81 (s, 2H), 5.53 (s, 2H), 7.39-7.46 (m, 6H), 7.55-7.67 (m, 5H), 7.84 ( d, 2H, J=8.70 Hz). HRMS calcd for C28H28N2O6S 521.1746. Found 521.1701.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:22]4[N:23]=[C:24]([NH:26][C:27]([CH:29]5[CH2:31][CH2:30]5)=[O:28])[N:25]=[C:21]4[CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=[O:33].[K+].[K+].OO>CS(C)=O>[CH:29]1([C:27]([NH:26][C:24]2[N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([C:14]4[CH:13]=[CH:12][C:11]([O:10][CH2:9][C:6]5[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:33])=[N:8][CH:7]=5)=[CH:16][CH:15]=4)[N:22]3[N:23]=2)=[O:28])[CH2:30][CH2:31]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of cyclopropanecarboxylic acid {5-[4-(6-cyano-pyridin-3-ylmethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-amide (30 mg, 0.073 mmol, 1 equiv) and K2CO3 (10 mg, 0.073 mmol, 1 equiv) in DMSO (0.2 mL) at 10° C., 30% H2O2 (17 μL, 0.146 mmol, 2 equiv) was added dropwise. After stirring at room temperature the mixture for 4 h, it was diluted with DMSO and filtered. The filtrate was submitted for preparative HPLC purification: UPLC system (Xbridge™ Prep C18, 5 μm, 19×100 mm column); 8 min LC; flow: 20 mL/min; gradient: from 30% to 70% acetonitrile in water 0.1% TFA; isolating the final pure product.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=3)[NH:7][C:6]=2[CH2:5][CH2:4]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:16]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]2[CH2:5][CH2:4][CH:3]([N:2]([CH3:1])[CH3:19])[CH2:15][C:14]3=2)=[O:18])[CH2:22][CH2:21]1
Reactant: NC1CC1
Reactant: CN(C)C1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(C(=O)NC4CC4)cc3c2C1
Yield: 41 %

Procedure:
Beginning with 7.4 mg (0.029 mMol) 3-dimethylamino-1,2,3,4-tetrahydro-9H-carbazole-6-carboxylic acid and cyclopropylamine, 3.5 mg (41%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[C:28]1([CH3:35])[C:33](O)=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])[O:11][C:12]=2[CH2:13][CH2:14][CH2:15][O:16][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:35])=[CH:6][CH:7]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCO)o1
Reactant: Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CS(=O)(=O)Cl
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Yield: 91.2 %

Procedure:
To a solution of 4-(4-chlorophenyl)-5-(3-hydroxypropyl)-2-(2-methylimidazol-1-yl)oxazole (509 g), triethylamine (254.6 mL) in toluene (4072 mL) was added dropwise methanesulfonyl chloride (136.4 mL) at not higher than 10° C. Ten minutes later, o-cresol (248.0 mL) and tetrabutylammonium bromide (25.8 g) were added to the obtained mixture and a solution of NaOH (255 g) in water (1018 mL) was further added. The mixture was heated under reflux for 1 h. After cooling, the toluene layer was separated and washed with 1N aqueous NaOH solution (4072 mL×3) and then with 5% aqueous NaCl solution. The solvent was evaporated and the obtained crystals were recrystallized from ethanol-water (9:1) to give the title compound (595.6 g, yield: 91.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[N:18]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CO.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)C.COCCOC>[F:16][C:17]1[N:18]=[C:19]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]3[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]3)[CH:3]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Reactant: N[C@H]1CC[C@H](Nc2cc(Br)ccn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CS(C)=O
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)ccn2)CC1
Temperature: 85 °C

Procedure:
A mixture of trans-N1-(4-bromopyridin-2-yl)cyclohexane-1,4-diamine (102 mg, 0.377 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (80 mg, 0.359 mmol), PdCl2(dppf).CH2Cl2 adduct (29.3 mg, 0.036 mmol), DME (2 ml), Ethanol (0.2 ml), and 2M sodium carbonate (0.717 ml, 1.435 mmol) reaction mixture was stirred at about 85° C. until completion, as indicated by LCMS. The crude mixture was cooled to room temperature, diluted with 5 ml of ethyl acetate and 2 ml of methanol, filtered and concentrated to yield a crude solid. The solid was dissolved in DMSO, refiltered, purified by prep LC, and lyophilized to yield 64 mg of the title compound as its TFA salt. LCMS (m/z): 287.2 (MH+), retention time=0.43 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([C:24](OC)=[O:25])[N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH2:24][OH:25])[N:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1
Reactant: COC(=O)c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(COc2cc(CO)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of methyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazole-5-carboxylate (12.10 g) in tetrahydrofuran (300 ml) was added aluminum lithium hydride (890 mg) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate 10 hydrate (7.57 g) was added to the reaction mixture and stirred at room temperature for 1 hr. The precipitate was filtered off and the filtrate was concentrated. The obtained colorless crystals were collected by filtration to give [3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxy]-1-phenyl-1H-pyrazol-5-yl]methanol (11.19 g, yield 98%), which was then recrystallized from ethyl acetate-hexane. melting point: 106–107° C.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:10]=[N:9][N:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:7]=1.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>>[F:1][C:2]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:3]=1[O:4][CH2:5][C:6]1[CH:10]=[N:9][N:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:15][CH2:16]2)[N:7]=1
Reactant: CS(=O)(=O)c1ccc(OCc2cnn(C3CCNCC3)n2)c(F)c1
Reactant: CC(C)OC(=O)Cl
Product: CC(C)OC(=O)N1CCC(n2ncc(COc3ccc(S(C)(=O)=O)cc3F)n2)CC1

Procedure:
The title compound was synthesized using 4-[4-(2-Fluoro-4-methanesulfonyl-phenoxymethyl)-[1,2,3]triazol-2-yl]-piperidine (Intermediate 7) and isopropyl chloroformate in a manner similar to that described in Example 35. 1H NMR (CDCl3): δ 7.66 (3H, m), 7.27 (1H, m), 5.30 (2H, s), 4.94 (1H, m), 4.63 (1H, m), 4.20 (2H, m), 3.04 (3H, s), 2.19 (2H, m), 2.17 (2H, m), 1.25 (6H, d).
Reaction SMILES: C([O:3][C:4]([C:6]([CH3:33])([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=1)[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[O:5])C.[OH-].[Na+].O1CCCC1>CO.C(OCC)(=O)C>[C:4]([C:6]([CH3:33])([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=1)[CH2:7][CH2:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([OH:5])=[O:3]
Reactant: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCC(C)(CCP(=O)(OCC)OCC)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 82.6 %

Procedure:
To a solution of (±)-diethyl 3-ethoxycarbonyl-3-methyl-5-(4-(octyl)phenyl)pentylphosphonate (0.211 g, 0.437 mmol) in methanol (2 ml) was added 1N aqueous sodium hydroxide (1.3 ml, 1.3 mol). Tetrahydrofuran was added as necessary to keep the substrate in solution. The reaction was heated to 50° C. for 16 h then warmed to 70° and stirred at this temperature for 20 h. The reaction was diluted with ethyl acetate (30 ml) and washed with 2N aq HCl (20 ml), saturated aqueous sodium chloride (20 ml), dried over magnesium sulfate and concentrated to give a colorless oil (0.164 g): MS m/e 455.2 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][C:3]=1[F:28].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.CC(C)([O-])C.[K+].B(O)O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:30]4[O:29][CH:33]=[CH:32][CH:31]=4)=[C:3]([F:28])[CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: OB(O)c1ccco1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: OBO
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccco2)c(F)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-3-fluorobenzenesulfonamide (E105) (150 mg, 0.32 mmol) and 2-furanylboronic acid (71 mg, 0.64 mmol) in DME (3 ml) was added potassium tert-butoxide (320 mg, 2.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The reaction was checked by LC-MS and as starting material was still present (20%) more boronic acid (71 mg, 0.64 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) were added. The mixture was stirred in the microwave (set at high absorbance) at 100° C. for another 30 minutes. The resulting mixture was then purified using an SCX cartridge and mass directed autoprep HPLC to afford the title compound (E307). MS (ES+) m/e 460 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:12]1[C:20]2[O:19][C:18]([F:22])([F:21])[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[CH:5]=1.Cl[CH2:24][CH2:25][N:26]=[C:27]=[S:28]>C(OCC)C>[S:28]1[CH2:24][CH2:25][N:26]=[C:27]1[N:26]1[CH2:25][CH2:24][S:28][C:27]1=[N:1][CH:2]([C:12]1[C:20]2[O:19][C:18]([F:22])([F:21])[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[CH:5]=1
Reactant: S=C=NCCCl
Reactant: Cc1cc(C)cc(CC(N)c2cccc3c2OC(F)(F)O3)c1
Solvent: CCOCC
Product: Cc1cc(C)cc(CC(N=C2SCCN2C2=NCCS2)c2cccc3c2OC(F)(F)O3)c1
Reaction time: 5 h
Yield: 32 %

Procedure:
A solution of 1-amino-1-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-(3,5-dimethylphenyl)-ethane (0.39 g) in diethyl ether was treated at 0° C. with 2-chloroethyl isothiocyanate (0.16 g) and stirring was continued for 5 h at this temperature. The mixture was quenched with an aqueous sodium hydroxide solution (1 M, 4 ml) and water (15 ml) and stirred for 15 minutes. The organic phase was washed with water, the aqueous phase was extracted with diethyl ether, the combined organic phases were dried over sodium sulphate and the solvent was removed in vacuo. The remainder was purified by column chromatography to yield 0.1 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[CH3:14][O:15][C:16]1(OC)[CH2:20][CH2:19][CH:18](OC)O1>>[CH3:14][O:15][C:16]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]3)[CH:18]=[CH:19][CH:20]=1
Reactant: COC1CCC(OC)(OC)O1
Reactant: Nc1ccc2[nH]c(=O)c(=O)[nH]c2c1
Product: COc1cccn1-c1ccc2[nH]c(=O)c(=O)[nH]c2c1

Procedure:
28 mmol of 6-amino-2,3(1H,4H)-quinoxalinedione were reacted with 28 mmol of 2,2,5-trimethoxytetrahydrofuran by the method of Example 5d.