Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][CH:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:16]3[C:20]=2[N:19]=[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=32)=[CH:8][CH:9]=1)=[O:4].[OH-].[K+].Cl>CO.O>[CH2:25]([CH:15]1[C:16]2=[C:17]3[CH2:24][CH2:23][CH2:22][CH2:21][C:18]3=[N:19][C:20]2=[C:12](/[CH:11]=[CH:10]/[C:7]2[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=2)[CH:13]=[CH:14]1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCC1C=CC(/C=C/c2ccc(C(=O)OC)o2)=C2N=C3CCCCC3=C21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCC1C=CC(/C=C/c2ccc(C(=O)O)o2)=C2N=C3CCCCC3=C21
Yield: 63.6 %

Procedure:
A solution of 6.5 g of (E)-5-[2-(1,2,3,4-tetrahydro-9-octyl-9H-dibenzo [b,d]pyrrol-6-yl)ethenyl]-2-furancarboxylic acid methyl ester from Example 33 in 72 ml of methanol was treated with a solution of 4.9 g of 87% potassium hydroxide in 18 ml of water. The mixture was refluxed for 45 minutes, cooled, diluted with water, acidified with 2N HCl and then extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 6.0 g of crude acid. Crystallization from ethyl acetate and hexane afforded 4.0 g (63.7%) of (E)-5-[2-(1,2,3,4-tetrahydro-9-octyl-9H-dibenzo[b,d]pyrrol-6-yl)ethenyl]-2-furancarboxylic acid as yellow crystals, mp 142°-144° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[CH2:20])[C:14]1=[O:21].C12BC(CCC1)CCC2.[O:31]1CCCC1>>[OH:31][CH2:20][CH2:19][C:15]1[C:14](=[O:21])[N:13]([C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[CH2:3][O:2][CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2COC)c1=O
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Product: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
23 g (80 mmol) of the compound from Example 29A are dissolved in 80 ml of anhydrous tetrahydrofuran and cooled to 5° C. Over a period of 15 min, 21 g (176 mmol) of 9-borabicyclo[3.3.1]nonane (0.5M solution in tetrahydrofuran) are added. Cooling is removed, and the mixture is stirred at room temperature for another 2 h. The mixture is then again cooled to 5° C., and 400 ml of 1N aqueous sodium hydroxide solution are added. After the addition has ended, 81 ml of 30% strength hydrogen peroxide solution are added a little at a time at this temperature. After dilution with 500 ml of ethyl acetate, the mixture is washed with 32 ml of 40% strength sodium bisulphite solution to destroy the peroxides. The organic phase is separated off, and the aqueous phase is extracted four times with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and, after filtration, concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 20 g (77% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([OH:19])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:17]([C@@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])=[O:19]
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: CN
Product: CNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Preparation 39 from (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid [see Preparation 38] and methylamine to afford N2-methyl-(2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxamide as an oil.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Mg+2].[O-]S(C(F)(F)F)(=O)=O.[C:18]1([CH:24]2[C:27]3([CH2:29][O:28]3)[O:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1>C1COCC1>[OH:28][CH2:29][C:27]1([N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)[CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][O:26]1
Reactant: c1nc[nH]n1
Reactant: c1ccc(C2COC23CO3)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: C1CCOC1
Product: OCC1(n2cncn2)OCC1c1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of magnesium triflate (0.40 g, 1.23 mmol) in dry THF (5 mL) was added to a stirred solution under N2 of 3-phenyl-1,5-dioxaspiro[3.2]hexane (0.20 g, 1.23 mmol) in dry THF (2 mL). The temperature was then lowered to 0° C., and a solution of 1H-1,2,4-triazole (0.22 g, 1.48 mmol) in dry THF (10 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 2.5 hours, warmed to room temperature and stirred for an additional 3 hours. Then, the mixture was concentrated to provide a yellow oil, which was purified by flash chromatography on silica gel (CH2Cl2/methanol 99.5:0.5 to 99:1). 2-Hydroxymethyl-3-phenyl-2-(1,2,4-triazol-1-yl)oxetane was isolated as an oil which was a 2:1 mixture of diastereomers (0.13 g, 45%): IR (film) 3403, 2903, 1499, 1279, 702 cm−1; Major diastereomer: 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.11 (s, 1H), 7.40 (m, 5H), 5.11 (m, 1H), 5.06 (m, 1H), 4.74 (dd, J=16.3, 8.4 Hz, 1H), 3.94 (d, J=12.8 Hz, 1H), 3.83 (d, J=12.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 133.3, 129.0, 127.9, 127.7, 127.4, 127.4, 98.5, 68.9, 63.7, 48.7. Minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.67 (s, 1H), 7.12 (m, 5H), 5.11 (m, 1H), 5.06 (m, 1H), 4.74 (dd, J=16.3, 8.4 Hz, 1H), 4.75 (d, J=12.8 Hz, 1H), 4.31 (d, J=12.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 133.3, 129.0, 127.9, 127.7, 127.4, 127.4, 98.5, 70.6, 67.2, 45.8; MS (EI) m/z 167, 149 (100), 71; HRMS (FAB) calculated for C12H14N3O2 (M++H) m/z 232.1086. Found: 232.1101.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17]CC)[CH:11]=2)[C:4]=1[Cl:20].Br>>[F:22][C:2]([F:1])([F:21])[C:3]1[N:7]([CH3:8])[N:6]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[CH:11]=2)[C:4]=1[Cl:20]
Reactant: CCOc1cc(Oc2nn(C)c(C(F)(F)F)c2Cl)ccc1Cl
Agent: Br
Product: Cn1nc(Oc2ccc(Cl)c(O)c2)c(Cl)c1C(F)(F)F
Reaction time: 20 h
Yield: 45.9 %

Procedure:
2 g (0.006 mol) of 5-trifluoromethyl-4-chloro-3-(3'-ethoxy-4-chlorophenoxy)-1-methylpyrazole was combined with 2 ml of HBr and 0.16 g of methyl tricapryl ammonium chloride and refluxed with stirring for 20 hours after removing aqueous forerun. The mixture was poured into water and extracted with ether. The ether layer was washed with water and brine, stirred with MgSO4, filtered and evaporated to a solid which was purified by chromatography to give 0.9 g of a white solid m.p. 106°-108° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([F:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:23]1[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:29][C:26]1[CH:25]=[N:24][C:23]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([CH:10]3[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]3)=[CH:15][C:16]=2[F:21])=[N:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(F)c2)C1
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(Cl)cn3)c(F)c2)C1
Temperature: 120 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
(RS)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (60 mg), 2,5-dichloropyrimidine (30.2 mg, CAS 22536-67-0) and cesium carbonate (99 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.03 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.29 mg) were then added. The reaction mixture was then capped and stirred at 120° C. for 2 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 80% EtOAc in hexanes) to afford tert-butyl (RS)-2-(4-(5-chloropyrimidin-2-ylamino)-3-fluorophenyl)morpholine-4-carboxylate (26 mg, 31%) as a colourless amorphous solid. MS (ISP): 411.3 ([{37Cl}M+H]+), 409.2 ([{35Cl}M+H]+), 355.3 ([{37Cl}M+H—C4H8]+), 353.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].C(=O)(O)[O-].[Na+].[CH2:31](I)[CH3:32]>CC(N(C)C)=O>[CH2:31]([O:2][C:1]([CH:4]([NH:13][CH:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:3])[CH3:32]
Reactant: CCI
Reactant: O=C(O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(CCc1ccccc1)NC1CCc2ccccc2NC1=O

Procedure:
A solution of 3-(1-carboxy-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (6.0 g), sodium bicarbonate (4.0 g), and ethyl iodide (11.6 g) in dimethylacetamide (200 ml) was stirred at room temperature under nitrogen for 72 hours. The reaction mixture was filtered and evaporated under high vacuum. Water (250 ml) was added, and the resulting solution extracted with dichloromethane (2×400 ml). The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure to give 3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as a mixture of isomers. NMR(CDCl3) δ9.22(s, 1H), 4.10(2 superimposed quartets, 2H), 1.13(2 superimposed triplets, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH:15]=[O:16])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[C:20]([F:23])([F:22])[F:21].[F-].[Cs+].C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH:11]=[C:12]([CH:15]([OH:16])[C:20]([F:23])([F:22])[F:21])[O:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(=O)c(OCc2ccccc2)co1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1cc(C(O)C(F)(F)F)occ1OCc1ccccc1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
The entire experiment was performed under an inert atmosphere by bubbling argon gas into the ice-salt cooled reaction mixture. To a cloudy solution of 5-benzyloxy-4-oxo-4H-pyran-2-carbaldehyde (5.00 g, 21.7 mmol) in dry tetrahydrofuran (185 mL) previously purged with argon for 35 min was added trimethyl(trifluoromethyl)silane (10.8 g, 76.0 mmol) dropwise, followed by caesium fluoride (0.34 g, 2.2 mmol). The color of the reaction mixture turned to yellow and almost clear within a min. TLC was used to monitor the reaction (eluant: 50:50, ethyl acetate:hexanes, v:v). The reaction was completed within 10 min. The reaction mixture was quenched with a 6.0N hydrochloric acid solution (20 mL) under cooling, followed by addition of a brine solution (50 mL). The mixture was stirred for 10 min, and then transferred to a separatory funnel. The organic THF fraction was collected, and then concentrated in vacuo to about 10 mL using the rotary evaporator. The residual solution was diluted with dichloromethane (80 mL). The mixture was transferred to a separatory funnel, and the separated dichloromethane layer was collected, dried over Na2SO4 and filtered. Upon concentration under reduced pressure, a first crop of the titled compound was obtained as a solid product (3.72 g, 57% yield, HPLC Method 1 (Example 24), RT=16.8 min, HPLC purity (peak percent area): 96% at λ=280 nm). 1H NMR (DMSO-d6+D2O) 6 ppm: 8.20 (s, 1H), 7.36 (br m, 5H), 6.57 (s, 1H), 5.11 (q, J=7 Hz, 1H), 4.92 (s, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[O:35]1[CH2:37][CH2:36]1>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][N:1]([CH2:37][CH2:36][OH:35])[CH:5]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: C1CO1
Product: OCCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 71 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and oxirane, 152 was obtained as a light yellow solid (102 mg, 71%) over two steps. 1H NMR (500 MHz, CDCl3) δ (ppm) 8.941-8.942 (d, J=0.5 Hz, 1H), 8.57 (s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 7.86 (s, 1H), 7.57-7.60 (t, J=16 Hz, 1H), 7.22-7.26 (t, J=20.5 Hz, 1H), 6.36-6.37 (d, J=8 Hz, 1H), 4.30-4.32 (t, J=9.5 Hz, 2H), 4.05-4.07 (t, J=9.5 Hz, 2H), 3.77-3.82 (m, 4H), 3.11-3.13 (t, J=10.5 Hz, 2H), 2.88-2.91 (t, J=11.5 Hz, 2H), 2.26 (s, 2H), 1.97-2.01 (m, 2H); MS (ESI) m/z: 405 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][O:6][CH2:7][C:8]([C:20](=[O:24])[NH:21][CH2:22][CH3:23])([C:15](=[O:19])[NH:16][CH2:17][CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:17]([NH:16][C:15]([C:8]([C:20](=[O:24])[NH:21][CH2:22][CH3:23])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:7][O:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])=[O:19])[CH3:18]
Reactant: CCNC(=O)C(COCCC(=O)OC)(C(=O)NCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)C(COCCC(=O)O)(C(=O)NCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
3-(2,2′-Bisethylcarbamoyl-2-phenylethoxy)propionic acid methyl ester (125 mg) was dissolved in THF (0.5 mL) and MeOH (0.5 mL), and 1N sodium hydroxide (0.5 mL) was added thereto. The solution was stirred at room temperature for 1 hour and then concentrated. The residue was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and concentrated to give 3-(2,2′-bisethylcarbamoyl-2-phenylethoxy)propionic acid (115 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[Ca+2].[Br-:15].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>C(Cl)Cl.CO>[Br:15][C:7]1[C:6]([CH3:9])=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[CH:8]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N)c(F)cc1Br
Yield: 81.7 %

Procedure:
To a slurry of 2-fluoro-5-metylaniline (6.75 g, 54 mmol) and CaCO3 (10 g, 100 mmol) in CH2Cl2 (1 L) and MeOH (400 mL) was added a solution of Benzyltrimethylammonium tribromide (22.3 g, 57 mmol) in CH2Cl2 (180 mL) and MeOH (70 mL). The solution was added dropwise and the mixture was stirred over night. The solution was a light orange/tan color. The mixture was filtered and the solvent was removed under reduced pressure. The resulting slurry was diluted with H2O (100 mL) and extracted with Et2O (3×200 mL). The mixture was purified by flash column chromatography (Hex:Et2O 2:1 to Et2O) to provide (9 g, 69.5% yield) the product as a white solid. 1H-NMR (DMSO-d6) δ 7.23 (d, J=10.8 Hz, 1H), 6.74 (d, J=10.8 Hz, 1H), 5.27 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:7])[CH:4]([CH3:6])[CH3:5].[C:8]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:18][C:17]3([O:36][C:21]4=[CH:22][N:23]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:32]([CH3:35])(=[O:34])=[O:33])[CH2:30][CH:31]=5)[CH:25]=[C:20]4[CH2:19]3)[CH2:16]2)[CH2:12][CH2:11]1)#N>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH:4]([C:3]1[N:7]=[C:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:18][C:17]4([O:36][C:21]5=[CH:22][N:23]=[C:24]([C:26]6[CH2:31][CH2:30][N:29]([S:32]([CH3:35])(=[O:33])=[O:34])[CH2:28][CH:27]=6)[CH:25]=[C:20]5[CH2:19]4)[CH2:16]3)[CH2:14][CH2:15]2)[O:1][N:2]=1)([CH3:6])[CH3:5]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(C#N)CC3)C2)CC1
Reactant: CC(C)C(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC3(CC2)CC2(Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O2)C3)n1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Zinc chloride (0.7 mol/L in tetrahydrofuran, 0.42 mL) is added to a solution of N-hydroxy-isobutyramidine (30 mg) and 1″-cyano-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (100 mg) in tetrahydrofuran (4 mL) and ethyl acetate (4 mL) at room temperature. The solution is heated to 60° C. and stirred at this temperature for 2 h.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>>[CH:16]1([NH:21][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NC2CCCC2)c1Cl
Yield: 59 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.6 g, 5.5 mmol), cyclopentylamine (0.54 mL, 5.5 mmol) and triethylamine (1.1 mL, 7.8 mmol) were reacted to form the desired product (1.1 g, 59%). LC-MS m/z 339(M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH:9]=[CH:13][N:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccc(Cl)cc1

Procedure:
A mixture of 10.0 g. of p-chloroacetophenone and 25 ml. of dimethylformamide dimethylacetal is refluxed for 3 hours. Evaporation gives a thick oil which crystallized with the addition of hexane, to give the product, m.p. 78.5°-80.5° C. Recrystallization from methylene chloride and hexane provides the product of the Example as crystals, m.p. 83°-84° C.
Reaction SMILES: [C:1]1([N:7]2[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)/[C:9](=[CH:17]\[C:18](=O)[CH3:19])/[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:22]1([CH2:28][CH2:29][CH2:30][O:31][NH2:32])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1C=CC=CC=1>[C:1]1([N:7]2[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)/[C:9](=[CH:17]\[C:18](=[N:32][O:31][CH2:30][CH2:29][CH2:28][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH3:19])/[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NOCCCN1CCCCC1
Reactant: CC(=O)/C=C1/C(=O)N(c2ccccc2)C1c1ccccc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: c1ccccc1
Product: CC(/C=C1/C(=O)N(c2ccccc2)C1c1ccccc1)=NOCCCN1CCCCC1
Yield: 36.1 %

Procedure:
A mixture of 1.11 g of (E)-1-phenyl-3-(2-oxopropylidene]-4-phenyl-2-azetidinone, 0.63 g of O-[3-(1piperidyl)propyl]-hydroxylamine, 46.5 mg of 10-camphorsulfonic acid and 40 ml of benzene was heated at reflux for 8 hours, and the solvent was evaporated under reduced pressure. The residue was chromatographed on alumina [eluent; hexane-acetone (7:3)] to give the fractions containing the end compound, and the solvent was evaporated. The residue was recrystallized from hexane to give 0.6 g of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][S:14]([O-:16])=[O:15].[Na+].O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][S:14]([CH3:13])(=[O:16])=[O:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)[O-]
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 18 h

Procedure:
To a solution of 4-methanesulfonylbenzyl chloride (2 g, 10 mmol) in DMF (20 mL) at 21° C. was added sodium methanesulfinate (1.5 g, 15 mmol). After 18 h, the mixture is poured into cold water (100 mL), stirred for 30 min then filtered off to afford the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([OH:6])=[O:5].[C:8]([C:12]([O:14][CH2:15][C:16]([NH2:18])=[S:17])=[O:13])([CH3:11])([CH3:10])[CH3:9].ClCCl>C(O)C>[CH3:10][C:8]([CH3:11])([CH3:9])[C:12]([O:14][CH2:15][C:16]1[S:17][CH:2]=[C:3]([C:4]([OH:6])=[O:5])[N:18]=1)=[O:13]
Reactant: CC(C)(C)C(=O)OCC(N)=S
Reactant: O=C(O)C(=O)CBr
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)C(=O)OCc1nc(C(=O)O)cs1
Reaction time: 15 h

Procedure:
To a solution of bromopyruvic acid (0.37 g, 2.22 mmol) and 2-(tert-butylcarbonyloxy)thioacetamide (0.41 g, 2.22 mmol) in ethanol (20 ml) was added 4 A molecular sieves (2 g). After stirring for 15 h, 20 mL of dichloromethane was added. The mixture was stirred 5 min and filtered to give the product as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:32])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[CH2:10][N:9]1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[H-].[Na+].[CH3:35]I>C1COCC1>[F:32][CH:2]([F:1])[CH2:3][N:4]([CH3:35])[CH2:5][CH2:6][CH2:7][C:8]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[CH2:10][N:9]1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]
Reactant: CI
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCCNCC(F)F)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C)CC(F)F
Reaction time: 1 h

Procedure:
To 35 mg (0.08 mmol) of amine 19-4 in THF was added 22 mg (0.55 mmol) of NaH (60% dispersion in oil) and 24 μL (0.39 mmol) of MeI. After stirring for 1 h, the reaction was quenched with water and partitioned with EtOAc, washed with brine, dried over MgSO4, concentrated by rotary evaporation, and the residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 19-5 a colorless gum. Data for 19-5: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.2 (s, 1H), 5.8 (m, 1H), 4.9 (m, 1H), 4.7 (m, 1H), 3.0 (m, 1H), 2.8-2.7 (m, 8H), 2.55 (m, 2H), 2.35 (s, 3H), 2.1 (m, 1H), 1.5 (m, 2H) ppm. HRMS (MS) calc'd M+H for C25H29F4N3O: 464.2320. Found: 464.2320.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=[O:7].C(#N)C.[OH-].[Na+:17]>O>[C:1]([O-:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[Na+:17].[Na+:17]
Reactant: COC(=O)CCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
17.4 Grams (0.1 mole) of dimethyl adipate are dissolved in 100 mls. of acetonitrile and heated to 70° C. 8.2 Grams (0.2 mole) of sodium hydroxide dissolved in 6.0 g. of water are added to the reaction mixture. The reaction mixture is stirred at reflux temperature for 18 hours. The resulting solution is filtered hot and the solids are air dried to yield disodium adipate as the reaction product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)C(=Cc1ccc([N+](=O)[O-])cc1)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CC(C(=O)O)c2cccc(C(F)(F)F)c2)cc1
Yield: 99.2 %

Procedure:
3-(4-Nitro-phenyl)-2-(3-trifluoromethyl-phenyl)-acrylic acid (9.9 g, 29 mmol) was hydrogenated in methanol using palladium/charcoal (10%) as the catalyst in 13 hours. The catalyst was filtered off and the filtrate was evaporated to give 8.9 g of the desired product (98% yield). MS m/z: 310.2 (M+H)+.