Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:42](=[O:48])[O:43][C:44](Cl)(Cl)Cl)Cl.[Cl:50][C:51]1[CH:61]=[CH:60][C:54]([O:55][CH2:56][CH2:57]CO)=[CH:53][CH:52]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:48])[O:43][CH2:44][CH2:57][CH2:56][O:55][C:54]1[CH:60]=[CH:61][C:51]([Cl:50])=[CH:52][CH:53]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: OCCCOc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4ccc(Cl)cc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Yield: 47.1 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (121 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(4-chlorophenoxy)-1-propanol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (58 mg, yield 44%).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:11])=[C:3](/[CH2:9][CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:22](=[O:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]([NH:1]/[C:2](/[CH3:11])=[C:3](/[CH2:9][CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:29])[CH3:28]
Reactant: CCOC(=O)/C(CC)=C(/C)N
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)N/C(C)=C(/CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A 100-mL round bottom flask was charged with ethyl (Z)-3-amino-2-ethyl-but-2-enoate (880 mg, 5.6 mmol, 1 eq.), diisopropylethylamine (750 mg, 5.8 mmol, 1.04 eq.) and THF (10 ml). To the mixture was added ethyl 3-chloro-3-oxo-propanoate (840 mg, 5.6 mmol, 1 eq.) dropwise by a syringe at 0° C. After the addition was complete, the resulting mixture was stirred at room temperature overnight and then added to aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (3×15 ml). The combined organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude product ethyl (Z)-3-[(3-ethoxy-3-oxo-propanoyl)amino]-2-ethyl-but-2-enoate as yellow oil (1.3 g, 86% yield).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12](=[O:13])[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: O=C(CBr)c1cccs1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Br)cnc1=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-bromopyrimidin-2-one hydrobromide (780 mg) and 2-bromoacetylthiophene (633 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 11/2 hours. A solution formed within 10 minutes but a suspension subsequently resulted. This was chilled in ice, and the collected solid was crystallised from acetone to give the title pyrimidinone: yield 293 mg; m.p. 173°-175° C. dec; λmaxEtOH 259.5 nm (ε 9470), 287 nm (ε 6830), 332 nm (ε 2780).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[N:7][OH:8])[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N+](=[CH2:28])=[N-].N(CNC(N)=O)=O.[OH-].[K+]>C(O)(=O)C.O.C(COC)OC>[OH:1][CH:2]1[CH2:6][C:5](=[N:7][OH:8])[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:28])=[O:16])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=NO
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COCCOC
Solvent: O
Product: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=NO

Procedure:
A cold solution of 1 part of 3-hydroxy-5-hydroxyimino-2-styrylcyclopent-1-eneheptanoic acid in 42.3 parts of dimethoxyethane is treated with a cold ethereal solution of diazomethane, prepared from 1.2 parts of N-nitrosomethylurea, 1.4 parts of potassium hydroxide and 2.5 parts of water. That mixture is allowed to react for 2 minutes, after which time, the cold excess diazomethane is decomposed by the careful addition of glacial acetic acid. The ethereal solution is washed with dilute aqueous sodium bicarbonate, then with water and dried over anhydrous sodium sulfate. The ether is removed and the crystalline residue is recrystallized from ethyl acetate-hexane to yield colorless crystals of methyl 3-hydroxy-5-hydroxyimino-2-styrylcyclopent-1-eneheptanoate. That compound melts at about 109°-110° and displays, in chloroform, absorption peaks in the infrared spectrum at about 3590 and 1735 reciprocal centimeters. It is further characterized by the following structural formula ##SPC19##
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:16][O:15][C:14]2[C:5](=[CH:6][C:7]3[C:8]([C:21]([F:24])([F:23])[F:22])=[CH:9][C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11][C:12]=3[CH:13]=2)[N:4]1[CH2:25][C:26]([F:29])([F:28])[F:27].[H-].[Na+].I[CH2:33][CH3:34]>C1COCC1>[CH2:33]([O:1][CH2:2][CH:3]1[CH2:16][O:15][C:14]2[C:5](=[CH:6][C:7]3[C:8]([C:21]([F:22])([F:23])[F:24])=[CH:9][C:10]([O:17][CH:18]([CH3:20])[CH3:19])=[N:11][C:12]=3[CH:13]=2)[N:4]1[CH2:25][C:26]([F:28])([F:29])[F:27])[CH3:34]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2cc3c(cc2n1)OCC(CO)N3CC(F)(F)F
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC1COc2cc3nc(OC(C)C)cc(C(F)(F)F)c3cc2N1CC(F)(F)F
Yield: 90.3 %

Procedure:
This compound was prepared according to General Method 16 (EXAMPLE 30) from (±)-2,3-dihydro-2-(hydroxymethyl)-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline (EXAMPLE 28) (10 mg, 0.024 mmol), NaH (4.7 mg, 0.12 mmol) and iodoethane (17 mg, 0.12 mmol) in 1.0 mL THF to afford 9.8 mg (89%) of (±)-2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline, a yellow oil, after flash chromatography (5:1 hexanes:EtOAc). Data for (±)-2-(ethoxymethyl)-2,3-dihydro-7-isopropoxy-1-(2,2,2-trifluoroethyl)-9-(trifluoromethyl)-1H-[1,4]oxazino[3,2-g]quinoline: Rf 0.60 (5:1 hexanes: EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.14 (broad s, 1H), 7.00 (s, 1H), 5.48 (hept, 1H, J=6.2), 4.45 (dd, 1H, J=10.9, 1.5), 4.16 (dd, J=10.9, 2.5), 4.00-4.20 (m, 2H), 3.70 (broad t, 1H, J=6.8), 3.54-3.63 (m, 2H), 3.50 (q, 2H, J=6.9), 1.38 (d, 6H, J=6.2), 1.20 (t, 3H, J=7.0).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][C:28]([O-])([CH3:30])[CH3:29].[K+].ClCC(CCl)=C>CN(C=O)C>[CH:1]1([C:7]2[C:15]3[CH:14]=[CH:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:10]=3[N:9]3[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:30][C:28](=[CH2:27])[CH2:29]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3O)[nH]c2c1
Reactant: CC(C)(C)[O-]
Agent: C=C(CCl)CCl
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A solution of methyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1H-indole-6-carboxylate (prepared as described in International patent application publication WO2006/046030, Example 9)(0.12 M) in DMF was treated with KOtBu (2.1 eq.) in one portion; the resulting mixture was stirred for 30 min at RT then treated dropwise with 3-chloro-2-(chloromethyl)prop-1-ene (1.1 eq.). The resulting solution was stirred at RT overnight before being quenched by addition of HCl (1N) and extracted into EtOAc. The combined organic layers were washed with sat. aq. NaHCO3 and brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 85:15) affording the product as a yellow oil (97%). (ES+) m/z 402 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C@H:11]([NH:13][C@@H:14]2[C@@H:19]([OH:20])[C@H:18]([CH2:21][C:22]3[CH:27]=[C:26]([O:28][C@H:29]([CH2:34][O:35][CH3:36])[C:30]([F:33])([F:32])[F:31])[C:25]([N+:37]([O-:39])=[O:38])=[C:24]([F:40])[CH:23]=3)[CH2:17][S:16][CH2:15]2)[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:41]O>C1COCC1.CC(O)=O.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([C@H:11]([NH:13][C@@H:14]2[C@@H:19]([OH:20])[C@H:18]([CH2:21][C:22]3[CH:27]=[C:26]([O:28][C@H:29]([CH2:34][O:35][CH3:36])[C:30]([F:32])([F:31])[F:33])[C:25]([N+:37]([O-:39])=[O:38])=[C:24]([F:40])[CH:23]=3)[CH2:17][S:16](=[O:41])[CH2:15]2)[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: COC[C@@H](Oc1cc(C[C@@H]2CSC[C@H](N[C@H](C)c3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC[C@@H](Oc1cc(C[C@@H]2CS(=O)C[C@H](N[C@H](C)c3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (3R,4S,5S)-3-[(R)-1-(3-tert-butyl-phenyl)-ethylamino]-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-tetrahydro-thiopyran-4-ol (0.249 g, 0.423 mmol) in THF (2 mL) and AcOH (1 mL) was treated with 0.22 mL 30% H2O2 and stirred for 18 h at 25° C. The mixture was diluted with EtOAc and washed with aq. Na2S2O3, and brine. The organic layer was dried over Na2SO4 and evaporated to give (3R,4S,5S)-3-[(R)-1-(3-tert-butyl-phenyl)-ethylamino]-5-[3-fluoro-4-nitro-5-((R)-2,2,2-trifluoro-1-methoxymethyl-ethoxy)-benzyl]-1-oxo-hexahydro-1lambda*4*-thiopyran-4-ol as a mixture of sulfoxide diastereomers (HPLC RtH1=2.30, 2.39 min; ESIMS [M+H]+=605), pure enough for further transformation. This product was dissolved in THF-MeOH 4:1 (5 mL) and stirred in the presence of 10% Pd—C (0.1 g) under an atmosphere of hydrogen at 45° C. for 1.5 h. The mixture was filtered over Celite, evaporated and dissolved in 5 mL 3N HCl in MeOH. After 3 d the reaction mixture was concentrated and taken up in 10% aq. Na2CO3 solution and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The title compound was obtained after purification by column chromatography on silica gel (EtOAc/5% MeOH) 70-0% hexane as a colorless foam: HPLC RtH1=2.535 min; ESIMS [M+H]+=575; [α]D=−9.8° (c=0.4, CH2Cl2); 1H NMR (600 MHz, DMSO-d6): δ 7.37 (s, 1H), 7.23-7.20 (m, 2H), 7.13 (m, 1H), 6.69 (s, 1H), 6.61 (d, 1H), 5.10 (m, 1H), 4.82 (s, OH), 4.59-4.55 (NH2), 3.80 (m, 1H), 3.70 (m, 2H), 3.30 (s, 3H), 3.23 (d, 1H), 3.02 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.62 (m, 1H), 2.39 (m, 1H), 2.25-2.18 (m, 3H), 1.25 (s, 9H), 1.20 (d, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][N:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[CH:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c([N+](=O)[O-])cn1)c1ccc(F)cc1
Temperature: 180 °C
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-nitropyridin-4-amine (Method 90, 0.15 g, 0.54 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.093 g, 0.67 mmol), and DIEA (0.12 ml, 0.67 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 180° C. for 32 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:1) to give the title compound as a yellow solid (0.168 g, 82%). 1H NMR (400 MHz) 12.37 (s, 1H), 9.59 (b, 1H), 8.83 (s, 1H), 8.20 (b, 1H), 7.37 (m, 2H), 7.13 (m, 2H), 6.69 (b, 1H), 5.88 (b, 1H), 5.29 (m, 1H), 1.91 (m, 1H), 1.43 (d, J=6.4 Hz, 3H), 0.97 (m, 2H), 0.71 (m 2H). MS: Calcd.: 382; Found: [M+H]+ 383.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[O:15]=[C:11]([CH3:10])[CH2:12][C:13]([NH:2][C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:9])=[O:14]
Reactant: CCOC(=O)[C@H](C)N
Reactant: C=C1CC(=O)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H](C)NC(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
20.00 g (0.13 mol) of ethyl (2S)-2-aminopropanoate hydrochloride were added to a solution of 10.95 g (0.13 mol) of diketene in 500 ml toluene at 0° C. Then, 21.90 g (0.26 mol) NaHCO3 was added and the reaction mixture was stirred overnight at room temperature. Since no more starting material was detected by thin-layer chromatography, the reaction mixture was filtered, evaporated and the residue purified by column chromatography. This gave 19.36 g (0.096 mol, 74% yield) of a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12]C=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:19][CH2:20]O.O.[NH3:23]>[Fe].CC(O)=O>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:23]=[CH:12][C:13]([NH:16][C:20]3[CH:19]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:14][CH:15]=2)[CH2:8][CH2:9]1)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: CCO
Reactant: N
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)N1CCN(c2ccc(Nc3ccccc3)cn2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-isopropyl-4-(4-nitro-phenyl)-piperazine (Step 33.2) (1.58 g, 6.32 mmol), iron (1.4 g, 25.3 mmol, 4 equiv), EtOH (20 mL), H2O (5 mL) and AcOH (2.5 mL) was stirred for 2 h at 90° C. The reaction mixture was allowed to cool to rt, basified by addition of aqueous NH3, filtered through a pad of celite. The filtrate was concentrated (to remove EtOH), extracted with EtOAc and DCM, saturated with NaCl and extracted with DCM. The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH/NH3aq, 91:8:1) afforded 1.1 g of the title compound as a purple solid: ESI-MS: 221.1 [M+H]+; TLC: Rf=0.20 (DCM/MeOH/NH3aq, 91:8:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[NH4+].[OH-:28]>C(O)(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:28])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CSc1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1ccc(-c2nc(-c3ccc(F)cc3)c(-c3ccncc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-fluorophenyl)-2-(4-methylthiophenyl)-5-(4-pyridyl)-1H-imidazole (0.80 g, 2.2 mmol) [See Ex. 17 above] in glacial acetic acid (15 mL) was added a solution of K2S2O8 (0.72 g, 2.6 mmol) in H2O (20 mL). Additional glacial acetic acid (15 mL) was added to ensure homogeneity, and the resulting solution was stirred at rt for 18 h. The mixture was then poured in to H2O, and the pH was adjusted to neutral by the addition of conc. NH4OH. The solid which formed was collected by filtration to afford the title com-pound (0.65 g, 78%) as a tan solid, which was recrystallized from MeOH: mp 250°-252° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([O:7][CH:8]1[CH2:13][CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10][CH2:9]1)=[O:6])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([NH:4][C:5](=[O:6])[O:7][CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)NC(=O)OC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)NC(=O)OC1CCNCC1

Procedure:
Benzyl 4-(isopropylcarbamoyloxy)piperidine-1-carboxylate (113 mg) is dissolved in ethanol (3 mL), treated with palladium on carbon (10%, 38 mg) and the mixture is hydrogenated at room temperature for 8 hours under 3 bar hydrogen pressure. Then the catalyst is filtered off and washed with ethanol. The combined mother liquours are concentrated to give the title compound, which is used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:43]=[CH:42][C:7]([C:8]([O:10][C@@H:11]2[C@H:15]([O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C@@H:14]([CH2:28][O:29][C:30](=[O:40])[C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[O:13][C@H:12]2Br)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC=CC=1.CC(C)=[O:52]>ClCCl.O.C(=O)([O-])[O-].[Ag+2]>[N+:1]([C:4]1[CH:43]=[CH:42][C:7]([C:8]([O:10][C@@H:11]2[C@H:15]([O:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C@@H:14]([CH2:28][O:29][C:30](=[O:40])[C:31]3[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=3)[O:13][CH:12]2[OH:52])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OC[C@H]1O[C@@H](Br)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: O
Product: O=C(OC[C@H]1OC(O)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
3 g of 2,3,5-tri-O-(p-nitrobenzoyl)-β-D-ribofuranosyl bromide prepared by the procedure described in Example 2 were dissolved in a mixture of 25 ml of acetone and 25 ml of dichloromethane. This solution was cooled to 5° C. and treated with a suspension of silver carbonate (1.25 g) in water (5 ml) with vigorous stirring. Stirring was continued for 90 minutes while the mixture was maintained at 5° C. The mixture was filtered and the filtrate evaporated under reduced pressure to yield a syrup. This syrup was redissolved in 50 ml of dichloromethane, dried over anhydrous MgSO4 and evaporated to yield a syrup which solidified on slow coevaporation with benzene. This yielded 1.76 g (65% yield) of 2,3,5-tri-O-(p-nitrobenzoyl)-D-ribofuranose. Recrystallization of this product from nitromethane yielded colorless needles which had a melting point of 177° to 178° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][NH:21][N:20]=2)[C:14]=1[F:30])(=[O:11])=[O:10].[H-].[Na+].Cl.[C:34]([O:37][CH2:38][CH3:39])(=O)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:22][N:21]([CH:38]3[CH2:39][CH2:34][O:37]3)[N:20]=2)[C:14]=1[F:30])(=[O:10])=[O:11]
Reactant: O=S(=O)(Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1F)c1cc(F)ccc1F
Reactant: CCOC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cccc(-c2nn(C3CCO3)cc2-c2ccncc2)c1F)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 2,5-Difluoro-N-[2-fluoro-3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-benzenesulfonamide (200 mg, 0,465 mmol)(prepared as described in Example 15) in anhydrous DMF (4 mL) was added to sodium hydride (60% in mineral oil)(46 mg, 1.162 mmol, 2.5 eq) previously washed with n-hexane under argon atmosphere and cooled to 0° C. After stirring at 0° C. for 40 minutes, freshly prepared 3-oxetanol trifluoromethanesulfonyl ester (144 mg, 0.689 mmol, 1.5 eq) dissolved in dry DMF (1 mL) was added and the mixture was stirred at 0° C. for 1 h. A further addition of sodium hydride (40 mg) and 3-oxetanol trifluoro-methanesulfonyl ester (40 mg) was then made and the reaction mixture was then allowed to warm to room temperature during a night. The reaction mixture was then diluted with water and ethyl acetate. The aqueous phase was brought to pH 4-5 with HCl 2 N and extracted with ethyl acetate. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (ethyl acetate/n-hexane 7:3) affording 24 mg of the title product as a white solid. HPLC (254 nm): Rt: 6.99 min; 1H NMR (DMSO-d6) Shift: 10.68 (br. s., 1H), 8.52 (s, 1H), 8.36-8.40 (m, 2H), 7.51-7.59 (m, 1H), 7.31-7.49 (m, 4H), 721-7.29 (m, 1H), 7.02-7.08 (m, 2H), 5.64 (quip, J=6.9 Hz, 1H), 4.90-5.00 (m, 4H); HRMS (ESI) calcd for C23H18F3N4O3S [M+H]+ 487.1046. found 487.1043.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9]O)=[CH:7][CH:8]=1.C(Br)(Br)(Br)[Br:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][Br:12])=[CH:7][CH:8]=1
Reactant: COc1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
3.0 g (0.0217 mol) of p-methoxybenzyl alcohol were dissolved in 50 ml of ether and treated with 14.4 g (0.0433 mol) of carbon tetrabromide. 11.4 g (0.0433 mol) of triphenyl-phosphine were added while cooling with ice. The mixture was stirred at room temperature for 3 hrs. After removal of the solvent the residue was filtered over a short silica gel column with ether/hexane (1:1) as the eluent. The filtrate was subjected to a bulb-tube distillation. 2.05 g (47%) of 4-methoxybenzyl bromide were obtained as a colorless oil; b.p. 120°-140°(22 Torr). MS: me/e (% basic peak)=202, 200 (C8H9BrO+, 3), 121 (C8 H9O+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]=[C:11]=[O:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.ClCCl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)=[O:12]
Reactant: O=C=Nc1c(F)cc(Cl)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2c(F)cc(Cl)cc2Br)CC1

Procedure:
1-Bromo-5-chloro-3-fluoro-2-isocyanatobenzene (D6) (4.4 mmol, 1.1 g) and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 4.4 mmol, 0.88 g) were mixed together. Dichloromethane (5 ml) was added to the mixture at room temperature for 1 hour. THF (5 ul) was added at room temperature for one hour. Solvent was subsequently evaporated and the crude obtained was purified by chromatography to afford the title compound, 0.6 g, 30%.