Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.C(N(CC)CC)C.[Cl:13][CH:14]([Cl:31])[C:15]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[C:21]([C:26]([OH:28])=[O:27])=[C:22]([CH3:25])[CH2:23][S:24][C@H:19]12)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][Si:2]([O:28][C:26]([C:21]1[N:20]2[C:29](=[O:30])[CH:18]([NH:17][C:15](=[O:16])[CH:14]([Cl:31])[Cl:13])[C@H:19]2[S:24][CH2:23][C:22]=1[CH3:25])=[O:27])([CH3:5])[CH3:4]
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Reactant: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Trimethylchlorosilane(0.5 ml) and triethylamine (0.17 ml) were added to a solution of 7-dichloroacetamido-3-methyl-3-cephem-4-carboxylic acid(325 mg) in chloroform (12 ml). The reaction mixture was stirred at 10°C. overnight to afford a chloroform solution of 7-dichloroacetamido-3-methyl-3-cephem-4-carboxylic acid trimethylsilyl ester. The resulting solution was added dropwise at -50°C. to a mixture prepared from phosphorus pentachloride(220 mg), quinoline(0.15 ml) and chloroform (15 ml). The reaction mixture was stirred at -50°C. for 3 hours and diluted with dry tetrahydrofuran(20 ml). To this solution was added a methanol solution of lithium methoxide prepared from lithium(150 mg) and methanol(15 ml) a -78°C. The mixture was stirred at -78°C. for 30 minutes and treated with acetic acid(1.5 ml). The solution was poured into water and extracted with chloroform. The extracts were washed with water, dried(Na2SO4) and evaporated under reduced pressure. The residue was dissolved in a small amount of chloroform, to which was added excess hexane to precipitate the desired substance. This process was repeated three times to give 240 mg of 7β-(2'-chloro-1'-methoxyethylidenimino)-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid. NMR(CDCl3) δ ppm: 2.05(3H, singlet), 3.03 and 3.43(2H, AB-quartet, J=18 Hz), 3.40(3H, singlet), 3.75(3H, singlet), 4.18 and 4.53(2H, AB-quartet, J=12 Hz), 5.00(1H, singlet).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:18])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)(=[O:10])=[O:9].[C:19]1(=[O:25])[O:24][C:22](=[O:23])[CH2:21][CH2:20]1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:18][C:3]1[C:2]([CH3:1])=[C:6]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:19](=[O:25])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:5][N:4]=1
Reactant: Cc1noc(NS(=O)(=O)c2ccc(N)cc2)c1C
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1noc(NS(=O)(=O)c2ccc(NC(=O)CCC(=O)O)cc2)c1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of sulfisoxazole (267 mg, 1.00 mmol) in DMF (10 ml) was added succinic anhydride (1.00 g, 10.0 mmol) and 4-dimethylaminopyridine (122 mg, 1.00 mmol). The reaction mixture was stirred at 80° C. for 2 hours and then concentrated. The residue was taken up in 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The aqueous solution was acidified with dilute hydrochloric acid and organic material was extracted into ethyl acetate. The organic phase was washed with dilute hydrochloric acid, water and brine, treated with active charcoal and dried (MgSO4). The solution was filtered and concentrated to give 280 mg (76%) of white solid. The structure was verified by 1H (300 MHz) and 13C (75 MHz) NMR spectroscopy. Further characterisation was carried out using MALDI mass spectrometry (ACH matrix), giving a M+Na peak at m/z 390 and a M+K peak at m/z 406 as expected.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:30](OCC)=[O:31].[O-]CC.[Na+].Cl>C(O)C>[OH:31][CH:30]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([CH:27]([CH3:29])[CH3:28])[N:24]=[CH:25][CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)n1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Temperature: 78 °C
Yield: 83 %

Procedure:
2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.300 g, 0.7723 mmol) and ethyl formate (0.185 mL, 2.30 mmol) were dissolved in anhydrous ethanol (8 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (1.44 mL, 3.86 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 2-Isopropyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.267 g, 0.641 mmol, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:36][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:20]
Reactant: CCCCCCCCCCN
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), decylamine (0.520 g, 3.31 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-decyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.06 g, 73.8% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][C:27]1([CH3:33])[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:29]5[CH2:28][C:27]([CH3:33])([CH3:26])[O:31][C:30]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: CC1(C)CNC(=O)O1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)nn2)CC1
Yield: 16.1 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 233 and 5,5-dimethyloxazolidin-2-one (35 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (21 mg) was obtained.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[Br:22][C:23]1[CH:24]=[C:25]([CH:31]=O)[CH:26]=[N:27][C:28]=1[CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[Br:22][C:23]1[CH:24]=[C:25]([CH2:31][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)[CH:26]=[N:27][C:28]=1[CH2:29][OH:30]
Reactant: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Reactant: O=Cc1cnc(CO)c(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cnc(CO)c(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 21: 50.9 mg, 0.175 mmol) and 5-bromo-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 40: 37.9 mg, 0.175 mmol) in DCE (3 ml) was stirred under N2 at room temperature overnight. Then, sodium triacetoxyborohydride (112 mg, 0.526 mmol) was added and the mixture was stirred for 8 h at RT overnight. Saturated NaHCO3 was added and the aqueous phase was extracted twice with DCM. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Flash-Master chromatography on a 2 g silica gel cartridge using DCM/MeOH 9/1 as eluent to give 1-{2-[4-({[5-bromo-6-(hydroxymethyl)-3-pyridinyl]methyl}amino)-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one (21.5 mg, 25%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([N:13]=[C:14]([SH:15])[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1.Cl.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([N:13]=[C:14]([S:15][CH2:23][C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1
Reactant: COc1cc2c3c(c1)nc(S)n3CCC2
Reactant: ClCc1ccncc1
Agent: Cl
Solvent: CCO
Product: COc1cc2c3c(c1)nc(SCc1ccncc1)n3CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a suspension of 5,6-dihydro-8-methoxy-2-mercapto-4H-imidazo[4,5,1-ij]quinoline (2.2 g) in ethanol was added 4-picolyl chloride HCl (1.68 g) and the mixture was stirred at ambient temperature for 16 hours and at reflux for 2 hours. The solvent was removed by evaporation and the residue dissolved in water. The solution was washed with EtOAc and then basified (aqueous NaOH) and extracted with CHCl3. Following short column chromatography (SiO2 /CHCl3) the residue was crystallised from EtOAc to give the title compound (1.45 g, 43%) mp 99°-101° C. (Found: C,65.55; H,5.6; N,13.8. C17H17N3OS, requires C,65.6; H,5.5; N,13.5%).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:19]([Si:23]([CH3:33])([CH3:32])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])([CH3:22])([CH3:21])[CH3:20].[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[O:24][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:33])[CH3:32]
Reactant: Cc1ccccc1O[Si](C)(C)C(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
A catalytic amount of benzoylperoxide (0.5 g) was added to a refluxing solution of an equimolar mixture of Example 1d (30 g, 0.134 mol) and N-bromosuccinimide (24 g, 0.134 mol) in dry CCl4 (175 mL) for 1.5 h. The reaction mixture was filtered, concentrated and purified using flash chromatography (silica gel, PE60-80° C.) to obtain the title compound as an oil. Yield: 36 g, (90%); 1H NMR (CDCl3): δ 0.30 (s, 6H, 2CH3), 1.10 (s, 9H, 3CH3), 4.5 (s, 2H, CH2), 6.8-7.5 (m, 4H, Ar).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].[Br:13][CH2:14][CH:15]=[CH:16][CH2:17]Br>CC(C)=O>[Br:13][CH2:14]/[CH:15]=[CH:16]/[CH2:17][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: BrCC=CCBr
Reactant: COc1cc(C(C)=O)ccc1O
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OC/C=C/CBr
Temperature: 55 °C
Yield: 41.1 %

Procedure:
A mixture of 4-hydroxy-3-methoxyacetophenone (10 g, 59 mmol), K2 CO3 (10 g, 1.2 q) and 1,4-dibromo-2-butene (>95% trans, Aldrich, 18 g, 1.2 eq) in acetone (500 ml) was heated at 55° C. for 3 hours. At the end of the reaction, the solvent was concentrated. The crude product was extracted into dichloromethane (750 ml) and the insolubles were filtered; then the solution was concentrated again to an oil. Purification on a silica gel column (SiO2, 100 g, eluted with dichloromethane) yielded 7.25 g (40%) of white solid. Recrystallization from ether gave analytically pure
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[N:18][CH:19]=1.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>O1CCCC1>[Br:13][C:14]1[CH:15]=[C:16]([C@H:20]([C@@H:29]([C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[OH:30])[C:21]([OH:23])=[O:22])[CH:17]=[N:18][CH:19]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: O=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)[C@H](c1cncc(Br)c1)[C@H](O)c1ccc(F)cc1
Temperature: -30 °C
Reaction time: 0.08 h

Procedure:
To a solution of diisopropylamine (8.98 mL, 63 mmol) in tetrahedrofuran (22.5 mL) in 1 L flask at −78° C. was added n-butyllithium (25.2 mL, 2.5M in hexane, 63.0 mmol) dropwise. The reaction was allowed to gradually warm in the bath to −30° C., and held there for 5 minutes. It was re-cooled to −78° C. and treated with solid 2-(5-bromopyridin-3-yl)acetic acid (6.80 g, 31.5 mmol) and tetahydrofuran (78 mL). The ice bath was removed and stirring continued for 1.5 h. The reaction was again cooled to 0° C., and treated with a solution of 4-fluorobenzaldehyde (3.38 mL, 31.5 mmol) in tetrahydrofuran (22.5 mL). The reaction was allowed to gradually warm to room temperature overnight. The reaction solution, after removal of the solid by filtration, was acidified with citric acid to pH ca. 4. It was extracted with diethyl ether and concentrated. The resulting residue was dried three times with toluene and the crude product (ca. 10.1 g) was used in the next reaction without further purification. Mass spec.: 340.9 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(N(CC)CC)C.[N+:36]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N+:48]([O-:50])=[O:49])[CH:47]=1)[C:42](Cl)=[O:43])([O-:38])=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[N+:36]([C:39]1[CH:40]=[C:41]([CH:45]=[C:46]([N+:48]([O-:50])=[O:49])[CH:47]=1)[C:42]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)=[O:43])([O-:38])=[O:37]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5cc([N+](=O)[O-])cc([N+](=O)[O-])c5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.4 %

Procedure:
20.00 g (51.7 mmol) of cholesterol, 2.88 g (25.75 mmol) of 4-dimethylaminopyridine, 6.27 g (62.04 mmol) of triethylamine are dissolved in 100 mL of dichloromethane. 11.92 g (51.7 mmol) of commercial 3,5-dinitrobenzoylchloride dissolved in 50 mL of dichloromethane are added at 0° C. The solution is stirred for 2 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Crystallization from ethyl acetate:hexane mixture yielded 16.94 g (56%) of (3-β)-cholest-5-en-3-yl 3,5-dinitrobenzoate as yellowish crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:22]1[CH2:31][CH:30]([OH:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:12]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:21].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[C:37]([O:45][C:46]([F:49])([F:48])[F:47])[CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:41]([C:38]1[CH:39]=[CH:40][C:35]([O:34][CH3:33])=[CH:36][C:37]=1[O:45][C:46]([F:47])([F:48])[F:49])(=[O:43])=[O:42])[C:6](=[O:11])[C:5]2([N:22]1[CH2:31][C@H:30]([OH:32])[CH2:29][C@H:23]1[C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[C:12]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:21]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccc(CO)cc1C1(N2CC(O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3cc(CO)ccc3OC)(N3C[C@H](O)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 55.9 %

Procedure:
With 3.09 g of the compound obtained in Step 204-5 and 2.05 g of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 2.68 g of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[OH:18].CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Cc1cc(CN2CCN(C)CC2)ccc1O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CN2CCN(C)CC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.50 g, 11.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-water bath. A solution of 9A (2.0 g, 9.1 mmol) in DMF (15 mL) was added drop-wise over 15 minutes. The mixture was stirred for 15 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.0 g, 11.8 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water and some aqueous NaOH were added and the mixture was extracted three times with DCM. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 2.18 g (64%) of 9B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.22 (s, 3H), 2.28 (s, 3H), 2.30-2.63 (bm, 8H), 3.40 (s, 2H), 3.96-4.04 (m, 2H), 4.24-4.34 (m, 2H), 4.79-4.89 (m, 1H), 6.37 (d, 1H), 7.03 (d, 1H), 7.11 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40](O)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[CH2:30]([N:37]1[CH2:42][CH2:41][CH:40]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)CC2)cc1
Reaction time: 17.5 h
Yield: 35 %

Procedure:
A chilled solution of 4-nitrophenol (1.14 g, 8.12 mmol), triphenyl phosphine (3.21, 12.2 mmol) and 1-benzyl-4-hydroxypiperidine (2.6 g, 14 mmol) in THF was treated with diisopropyl azodicarboxylate (DIAD) (2.4 mL, 12 mmol), stirred at ambient temperatures, under nitrogen, for 17.5 hours, poured into excess water and extracted with ethyl acetate. The extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography with 30-40% ethyl acetate in hexane to give 1-benzyl-4-(4-nitro-phenoxy)-piperidine as a yellow semi-solid, 0.880 g (35% yield); Mass spectrum (+EI, [M+H]+) m/z 313. 1HNMR (500 MHz, DMSO-d6): δ8.11-8.15 (m, 2H), 7.24-7.30 (m, 4H), 7.18-7.22 (m, 1H), 7.10-7.14 (m, 2H), 4.53-4.59 (m, 1H), 3.45 (s, 2H), 2.60-2.64 (m, 2H), 2.20-2.26 (m, 2H), 1.91-1.95 (m, 2H), 1.58-1.67 ppm (m, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[N+:12]([C:15]1[CH:23]=[CH:22][C:18]([CH2:19][NH:20][NH2:21])=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[NH2:10][C:6]1[NH:21][N:20]([CH2:19][C:18]2[CH:17]=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=2)[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc([N+](=O)[O-])cc1
Product: Nc1cc(=O)n(Cc2ccc([N+](=O)[O-])cc2)[nH]1

Procedure:
17.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 16.7 g of 4-nitrobenzylhydrazine, analogously to the procedure described in Example 1 yield 17.3 g of the compound identified above as yellowish crystals of melting point 182°, corresponding to 74% of theory.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH:26]([NH2:29])([CH3:28])[CH3:27].O>C(O)C>[CH:26]([NH:29][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)Nc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (200 mg, 0.774 mmol) in ethanol (5 mL) was added potassium carbonate (214 mg, 1.55 mmol) and isopropylamine (137 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (227 mg, 99% yield).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH3:11][NH:12]C(O)C>C1(C)C=CC=CC=1>[CH3:11][N:12]1[CH2:6][CH2:5][O:4][C:2](=[O:3])[C:1]1=[O:8]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CNC(C)O
Solvent: Cc1ccccc1
Product: CN1CCOC(=O)C1=O

Procedure:
Following the procedure of G. Drefahl, M. Hartmann and A. Skurk, Chem. Ber. 1966, 99, diethyl oxalate (1.81 mL, 0.0133 mol) and N-methylamino-ethanol (1 g, 0.0133 mol) were dissolved in toluene(50 mL) and heated at reflux for 5 h. The reaction mixture was concentrated to dryness, triturated with ether, and the residue chromatographed (SiO2, 0-5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[N:17](COCC[Si](C)(C)C)[CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CCOC(C)=O.C(Cl)Cl>[C:1]1([C:7]2[CH:8]=[C:9]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=[CH:11][C:12]=2[NH:13][C:14]([C:16]2[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=2)=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(-c2ccccc2)cc1C1=CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(-c3ccccc3)cc2C2=CCCCC2)n1
Yield: 60 %

Procedure:
The title compound was prepared by the procedure of Example 11, step (g) using 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (3-cyclohex-1-enyl-biphenyl-4-yl)-amide (as prepared in the previous step, 16 mg, 0.032 mmol). Silica gel chromatography (2-3% EtOAc/DCM) afforded the title compound (7.1 mg, 60%) as a white solid. 1H-NMR (1:1 CDCl3/CD3OD; 400 MHz): δ 8.36 (d, 1H, J=8.6 Hz), 7.88 (s, 1H), 7.59-7.62 (m, 2H), 7.54 (dd, 1H, J=8.6, 2.3 Hz), 7.42-7.46 (m, 3H), 7.34 (m, 1H), 5.92 (m, 1H), 2.29-2.37 (m, 4H), 1.79-1.94 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H20N4O, 369.2 (M+H), found 369.1.