Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])=[CH:26][CH:25]=3)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[OH:44]OS([O-])=O.[K+].O>O1CCCC1.O>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][S:33]([CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:39])([F:40])[F:41])=[O:44])=[CH:26][CH:25]=3)[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: O=S([O-])OO
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCOc1ccc(OCCSCCCC(F)(F)C(F)(F)F)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCOc1ccc(OCCS(=O)CCCC(F)(F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-{4-[2-(4,4,5,5,5-pentafluoropentylthio)ethoxy]phenoxy}propyl}thiochroman (11) prepared in Step 8 (110 mg, 0.17 mmol) was dissolved in tetrahydrofuran (5 ml), which was then cooled down to 0° C. Oxone® (monopersulfate compound; DuPont product) (63 mg, 0.1 mmol) and water (3 drops) were added thereto, and the resulting mixture was stirred for 1 hour. Water (2 drops was further added, and the mixture was stirred for 1 hour. Water was added to the reaction solution and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and subjected to silica gel column chromatography to give (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-{3-{4-[2-(4,4,5,5,5-pentafluoropentylsulfinyl)ethoxy]phenoxy}propyl}thiochroman (12) (64.5 mg, yield 57%) as a colorless foamy substance.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:15]([CH:16]=[N:17]O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1>CN(C)C=O>[Cl:5][C:6]1[C:15]([C:16]#[N:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1
Reactant: COc1ccc2nc(Cl)c(C=NO)cc2c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc2nc(Cl)c(C#N)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
Thionyl chloride (7.9 ml) was added dropwise over a 12 min period to a stirred solution of 16.3 g 2-chloro-6-methoxy-3-quinolinecarboxaldehyde oxime in 160 ml dimethylformamide at 0° C. The reaction mixture was stirred for 15 min longer at 0° C. and then at room temperature overnight. The mixture was then quenched in ice-water, and the yellow solid product was collected, washed with water and dried in vacuo at 75° C. to give 14.8 g 2-chloro-6-methoxy-3-quinolinecarbonitrile, m.p. 201°-202° C.
Reaction SMILES: C([O-])=O.[NH4+].[OH:5][CH:6]([CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>[Pd].C(O)C>[OH:5][CH:6]([CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:7][NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCC(O)CN2CCCCC2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)NCC(O)CN2CCCCC2)cc1
Yield: 84.8 %

Procedure:
Ammonium formate (1.1 g, 17.46 mmol) followed by a slurry of 10% palladium on carbon catalyst (0.7 g) in ethanol was added in portions to a suspension of 4-[N-(2-Hydroxy-3-piperidinopropyl)sulphamoyl]nitrobenzene (Method 117; 1.2 g, 3.5 mmol) in ethanol (100 ml). The mixture was heated at reflux under nitrogen for 2 hours. The mixture was cooled and the catalyst was removed by filtration through diatomaceous earth. The filter pad was washed with ethanol and the combined filtrates were evaporated. The residue was triturated with diethyl ether, collected by filtration and dried, to give the title compound (0.93 g, 85%) as a pale green solid. NMR: 1.3-1.5 (m, 6H), 2.10-2.32 (m, 6H), 2.60 (m, 1H), 2.75 (m, 1H), 3.52 (m, 1H), 4.50 (brs, 1H), 5.85 (s, 2H), 6.59 (d, 2H), 6.98 (brs, 1H), 7.39 (d, 2H); m/z: 314.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])(=[O:28])=[O:27])=[CH:22][CH:21]=1)=O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:18][C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][C:31]([OH:34])([CH3:32])[CH3:33])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:3]=1
Reactant: CC(C)(O)CNS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(Cl)cc1Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)CNS(=O)(=O)c1ccc(C=CC(=O)c2ccc(Cl)cc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a mixture of 1-(4-chloro-2-phenylaminophenyl)ethanone (0.401 g) and 4-formyl-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide (0.420 g) in MeOH (10 mL) was added NaOH (1.35 mL, 2 N, aq), and the mixture stirred overnight at RT. The product was concentrated under reduced pressure, washed with EtOAc, H2O and brine, then dried over Na2SO4. The partially-purified product was chromatographed on anhydrous silica (DCM for 0-10 min, then MeOH/DCM for 11-30 min) to provide 4-[3-(4-chloro-2-phenylaminophenyl)-3-oxo-propenyl]-N-(2-hydroxy-2-methylpropyl)-benzene sulfonamide (0.540 g).
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:23]=[CH:22][N:21]([Si](C(C)C)(C(C)C)C(C)C)[CH:20]=4)[CH:18]=[C:13]3[C:12]([C:34]3[CH:38]=[CH:37][O:36][CH:35]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>CCO>[O:36]1[CH:37]=[CH:38][C:34]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([C:19]4[CH:23]=[CH:22][NH:21][CH:20]=4)[CH:18]=3)[NH:10][CH:11]=2)=[CH:35]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2cnc3c(c2)c(-c2ccoc2)cn3S(=O)(=O)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc(-c2cnc3[nH]cc(-c4ccoc4)c3c2)c[nH]1
Temperature: 110 °C
Yield: 5946 %

Procedure:
A mixture of 31 (15.3 mg, 0.28 μmol), EtOH (1.0 mL) and 10% aq. NaOH (0.5 mL) were heated at 110° C. for 40 min then cooled and poured onto saturated aqueous NaHCO3 (5 mL) and extracted with ethyl acetate (4×10 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by PTLC using 5% MeOH in CH2Cl2 to give the pure product as a solid (4.15 mg, 59%); 1H NMR (400 MHz, CDCl3) δ 6.60 (d, J=1.6 Hz, 1H), 6.72 (s, 1H), 6.92 (dd, J=4.7, 2.5 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.41 (d, J=2.3 Hz, 1H), 7.54 (s, 1H), 7.82 (s, 1H), 8.15 (d, J=1.7 Hz, 1H), 8.37 (bs, NH), 8.57 (d, J=1.8 Hz, 1H), 8.96 (bs, NH).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[S:20]([CH2:23][CH2:24][NH2:25])(=[O:22])=[O:21])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]>>[CH:10]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[S:20]([CH2:23][CH2:24][NH:25][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])(=[O:21])=[O:22])[CH2:15][CH2:14]1)([CH3:12])[CH3:11]
Reactant: CC(C)N1CCC(N(Cc2nccs2)S(=O)(=O)CCN)CC1
Reactant: O=C(O)c1ccc(Cl)s1
Product: CC(C)N1CCC(N(Cc2nccs2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1

Procedure:
5-Chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-sulfamoyl]-ethyl}-amide was prepared by an analogous procedure as described in example 5 iii) starting from 61 mg (1 equiv.) 5-chloro-thiophene-2-carboxylic acid and 129 mg (0.37 mmol) 2-amino-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 5-chloro-thiophene-2-carboxylic acid {2-[(1-isopropyl-piperidin-4-yl)-thiazol-2-ylmethyl-sulfamoyl]-ethyl}-amide. The title compound was obtained as its formate in form of a light brown amorphous material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH2:7])=[O:6].[C:14](=O)([O-])[O-].[Cs+].[Cs+].S(OC)(OC)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH:7][CH3:14])=[O:6]
Reactant: NC(=O)c1cc(F)cc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CNC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.3 %

Procedure:
To a solution of 3-fluoro-5-nitrobenzamide (1.0 g, 5.43 mmoL) in DMF (17 mL) was added cesium carbonate (2.6 g, 8.14 mmoL) and dimethyl sulphate (547 mg, 4.34 mmol) and the reaction mixture was stirred at RT for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-fluoro-N-methyl-5-nitrobenzamide (0.800 g, 80%) as a solid. Observed mass (M−1): 196.9.
Reaction SMILES: C[C:2]1[C:3]([CH:13]2[CH2:16][N:15]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:14]2)=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]2[C:27]([CH:28]3[CH2:38][CH:29]3[CH2:30][O:31]2)=[CH:26][CH:25]=1>N1C=CC=CC=1.C(Cl)Cl>[F:8][C:7]1[CH:6]=[CH:5][C:4]([S:9]([NH:23][C:24]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:32]3[C:27]([CH:28]4[CH2:38][CH:29]4[CH2:30][O:31]3)=[CH:26][CH:25]=2)(=[O:10])=[O:11])=[C:3]([CH:13]2[CH2:14][N:15]([C:17](=[O:22])[C:18]([F:20])([F:19])[F:21])[CH2:16]2)[CH:2]=1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: Cc1c(F)ccc(S(=O)(=O)Cl)c1C1CN(C(=O)C(F)(F)F)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CN(C(=O)C(F)(F)F)C2)ccc2c1OCC1CC21
Reaction time: 18 h
Yield: 104.2 %

Procedure:
A solution of methyl 4-fluoro-2-[1-(2,2,2-trifluoroacetyl)azetidin-3-yl]benzenesulfonyl chloride (Intermediate 89, 0.192 g) and methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 42, 0.122 g) in pyridine (1 mL) and DCM (3 mL) was left to stand at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-30% to give methyl (1aRS,7bSR)-5-{4-fluoro-2-[1-(2,2,2-trifluoro-acetyl)azetidin-3-yl]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.294 g) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1>CN(C=O)C>[NH2:11][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:19][C:20]1[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=1
Reactant: CCOP(=O)(Cc1ccc(CBr)cc1)OCC
Reactant: Nc1nc(Cl)nc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(Cn2cnc3c(N)nc(Cl)nc32)cc1)OCC
Temperature: 60 °C
Yield: 18 %

Procedure:
To a solution of commercially available 2-chloro-9H-purin-6-amine (1 equiv.) in DMF (0.50 M) was added potassium carbonate (1.2 equiv.) and diethyl 4-(bromomethyl)benzylphosphonate (1 equiv.) (described in ref. 88, Ex 25 Step 1). The reaction mixture was then heated to 60° C. for 5 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system (ISCO) using a gradient of 0-5% MeOH/DCM to provide the title compound (18%) as a solid.
Reaction SMILES: [C:1]1([C:7]2([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]=[C:26]=[O:27]>C1C=CC=CC=1>[CH3:24][NH:25][C:26]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([O:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)[CH2:12][CH2:11]1)=[O:27]
Reactant: CN=C=O
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1
Reaction time: 4 h
Yield: 54.5 %

Procedure:
To a solution of 3.89 g of 4-phenyl-4-(4-trifluoromethylphenoxy)piperidine in 25 ml of benzene was added a solution of 0.68 g of methyl isocyanate in 25 ml of benzene. The reaction mixture was stirred for four hours at room temperaure. Evaporation of the volatiles afforded a solid which was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane). Recrystallization from 30% hexane/isopropyl ether yielded 2.46 g (54.19%) 1-(N-methylamino)carbonyl-4-phenyl-4-(4-trifluoromethylphenoxy)piperidine, m.p. 118°-120° C.
Reaction SMILES: [I-].[K+].FC(F)(F)[C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15](CCl)=[N:16][N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:9]=2[CH:27]=1.C1(N)CC1>O1CCCC1>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:10]1[C:9]2[CH:27]=[CH:5][CH:6]=[CH:7][C:8]=2[N:14]2[CH:15]=[N:16][N:17]=[C:13]2[CH2:12][N:11]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Agent: NC1CC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccccc1C1=NCc2nncn2-c2ccccc21

Procedure:
In the manner given in Example 1, potassium iodide and 8-(trifluoromethyl)-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in tetrahydrofuran is treated with cyclopropylamine to give 8-trifluoromethyl-1-(cyclopropylamino)methyl]-6(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26]Br>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH2:25][CH2:26][N:15]1[CH2:16][C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:20])[CH:12]=2)[C:14]1=[O:19]
Reactant: Clc1cccc(CCBr)c1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3cccc(Cl)c3)C2=O)cn1
Yield: 27 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 3-chlorophenethyl bromide. Yield: 27%. MS M+H calculated 414.13; found 414.2. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.20 μM.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@@H:22]3[C@@H:27]([OH:28])[CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>O1CCOCC1.C(OCC)(=O)C.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>[N:35]1[CH:36]=[CH:37][N:38]=[CH:39][C:34]=1[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@@H:22]3[C@@H:27]([OH:28])[CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2c(n1)CCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(-c3cnccn3)nc2)c2c(n1)CCCC2
Temperature: 25 °C

Procedure:
To a solution of 1,5-anhydro-3-[({4-[(6-chloropyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-2,3-dideoxy-L-threo-pentitol (Example 1, 0.038 g, 0.095 mmol) in 1 mL of dioxane under an atmosphere of nitrogen was added 2-(tributylstannyl)-pyrazine (0.060 mL g, 0.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.0095 mmol). The mixture was irradiated in a microwave reactor at 130° C. for 1.5 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-6% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 446.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.52 (s, 1H), 8.74-8.70 (m, 2H), 8.64 (s, 1H), 8.34-8.30 (m, 2H), 7.77-7.66 (m, 1H), 7.63 (s, 1H), 4.16 (s, 2H), 3.82-3.72 (m, 3H), 3.69-3.53 (m, 1H), 3.04-2.99 (m, 1H), 2.92 (br s, 2H), 2.75 (br s, 2H), 1.96-1.66 (m, 4H), 1.65-1.55 (m, 2H), 1.13-1.09 (m, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.CC1C=CC(S(O[CH2:23][C@@H:24]([C@@H:39]2[C@:56]3([CH3:57])[C@H:42]([C@H:43]4[C@H:53]([CH2:54][CH2:55]3)[C@:51]3([CH3:52])[C:46]([CH2:47][C@@H:48]([O:65][CH:66]5[CH2:71][CH2:70][CH2:69][CH2:68][O:67]5)[CH2:49][C@@H:50]3[O:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][O:60]3)=[CH:45][CH2:44]4)[CH2:41][CH2:40]2)[CH2:25][CH2:26][C:27]([F:38])([F:37])[C:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH3:29])(=O)=O)=CC=1>CCOCC>[O:60]1[CH2:61][CH2:62][CH2:63][CH2:64][CH:59]1[O:58][C@@H:50]1[C@@:51]2([CH3:52])[C:46](=[CH:45][CH2:44][C@@H:43]3[C@@H:53]2[CH2:54][CH2:55][C@@:56]2([CH3:57])[C@H:42]3[CH2:41][CH2:40][C@@H:39]2[C@H:24]([CH3:23])[CH2:25][CH2:26][C:27]([F:37])([F:38])[C:28]([O:31][CH:32]([O:34][CH2:35][CH3:36])[CH3:33])([CH3:30])[CH3:29])[CH2:47][C@@H:48]([O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][O:67]2)[CH2:49]1
Reactant: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)OC(C)(C)C(F)(F)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 0.410 g (0.0108 mol) of lithium aluminum hydride, 50 mL of tetrahydrofuran and 2.98 g (0.0033 mol) of [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate) was heated at reflux (60°) for 1 hr and cooled to 0° C. The mixture was diluted with 120 mL of ether and quenched with the dropwise addition of 0.82 mL of water and 0.65 mL of 10% aqueous sodium hydroxide solution. The mixture was then stirred for 1 hr and filtered. The solids were triturated with ether and filtered. The combined filtrates were evaporated to dryness and chromatographed on 0.06-0.20 mm silica gel to yield [1α,3β]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24,24-difluorocholest-5-ene, [α]D16 +2° (c 1, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][N:7]([CH3:11])[N:6]=1)=[O:4].C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][N:7]([CH3:11])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(C)cc1N
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C)cc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 91.1 %

Procedure:
A solution of 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (160 mg, 1.03 mmol) in N,N-dimethylformamide (1.0 mL) at 25° C. was treated with triethylamine (0.35 mL, 2.6 mmol) and triphenylmethylchloride (316 mg, 1.13 mmol). Additional N,N-dimethylformamide (2.0 mL) was added to the reaction to aid stirring. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and then was washed with a IN aqueous hydrochloric acid solution (1×10 mL), a saturated aqueous sodium bicarbonate solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-methyl-4-(trityl-amino)-1H-pyrazole-3-carboxylic acid methyl ester (373 mg, 91.1%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) δ7.25 (m, 16H), 3.74 (s, 3H), 3.53 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:46])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:36](=[O:45])[NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[CH2:25][N:26]2[CH2:30][CH2:29][CH:28]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:27]2)=[CH:20][CH:19]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:46])/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH:24]([C:36](=[O:45])[NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[CH2:25][N:26]2[CH2:30][CH2:29][CH:28]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH2:27]2)=[CH:22][CH:23]=1
Reactant: CCN(CC)C1CCN(CC(C(=O)Nc2ccc(Cl)cc2)c2ccc(/C=C/C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C1CCN(CC(C(=O)Nc2ccc(Cl)cc2)c2ccc(/C=C/C(=O)Nc3ccccc3N)cc2)C1
Reaction time: 4 h

Procedure:
To a solution of (E)-[2-(3-{4-[1-(4-chloro-phenylcarbamoyl)-2-(3-diethylamino-pyrrolidin-1-yl)-ethyl]-phenyl}-acryloylamino)-phenyl]-carbamic acid tert-butyl ester (528 mg, 0.8 mmol) in CH2Cl2 (10 mL) was added CF3COOH (612 uL, 8 mmol). The mixture was stirred for about 4 h, and then NaHCO3 was added to the reaction system. After filtration of solids, the crude mixture was purified by preparative HPLC to obtain a light yellow solid. MS: calc'd 560 (MH+), exp 560 (MH+). 1H NMR (d4-MeOD, 400 MHz), 7.66 (d, 1H, J=15.6 Hz), 7.60-7.57 (m, 4H), 7.49 (d, 2H, J=8.0 Hz), 7.29 (d, 2H, J=8.8 Hz), 7.22 (d, 1H, J=7.6 Hz), 7.06 (t, 1H, J=7.6 Hz), 6.89 (d, 1H, J=8.8 Hz), 6.84 (d, 1H, J=15.6 Hz), 6.76 (t, 1H, J=7.6 Hz), 3.94 (m, 1H), 3.48-3.35 (m, 2H), 2.82-2.53 (broad m, 9H), 2.01-1.95 (m, 1H), 1.74-1.71 (m, 1H), 1.00 (q, 6H, J=7.0 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3](=[O:5])[CH3:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1.C(OCC)(=O)C>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:1][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)COC1CCCCO1
Yield: 80.8 %

Procedure:
A solution of 1-hydroxy-propan-2-one (95%, 78 g, 1.0 mol), 3,4-dihydro-2H-pyrane (95%, 88.5 g, 1.0 mol) and pyridinium p-toluenesulfonate (25.1 g, 0.1 mol) in THF (1.2 l) is stirred at room temperature for 16 hours. The mixture is diluted with ethyl acetate and repeatedly washed with brine. The organic phase is dried, filtered evaporated to afford 1-(tetrahydropyran-2-yloxy)-propan-2-one (127.8 g, 80.8%) as a liquid.