Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15](=O)[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:80])=CC=1>O1CCOCC1.CCOC(C)=O>[CH3:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15](=[S:80])[NH:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:21]2=[N:22][CH:23]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@@H]4CN(C(=O)OC(C)(C)C)CC[C@@H]4C)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)[C@@H]4CN(C(=O)OC(C)(C)C)CC[C@@H]4C)cnc32)cc1
Temperature: 80 °C
Yield: 90 %

Procedure:
A round bottom flask was charged with cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)piperidine-1-carboxylate (5.62 g, 10.6 mmol, prepared using O from 4-methylnicotonic acid, M, H from Example #5, Step C, HATU and DIEA) and Lawesson's reagent (3.0 g, 7.4 mmol) in 1,4-dioxane (100 mL). The reaction was heated at about 80° C. for about 1 h, cooled to ambient temperature, and concd under reduced pressure. The crude product was dissolved in EtOAc (200 mL) and washed with saturated aqueous NaHCO3 (3×100 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (5.2 g, 90%): LC/MS (Table 1, Method b) Rt=2.65 min; MS m/z: 544 (M+H)+. A round bottom flask was charged with cis-tert-butyl 4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (2.6 g, 4.8 mmol) and mercury (II) trifluoroacetate (2.1 g, 4.8 mmol) in 1,4-dioxane (72 mL) and stirred at ambient temperature for about 1 h. The reaction mixture was filtered through a pad of Celite®. The Celite® pad was rinsed with DCM (30 mL) and EtOAc (30 mL). The filtrate was concd under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with saturated aqueous sodium thiosulfate (10 mL), and saturated aqueous NaHCO3 (25 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford cis-tert-butyl-4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (2.2 g, 90%): LC/MS (Table 1, Method b) Rt=2.57 min; MS m/z: 510 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11]([CH2:12][C@@H:13]([OH:23])[CH2:14][CH2:15]2)=[CH:10][CH2:9]3)[CH2:6][CH:5]=1.[NH2:25][C:26]([NH2:28])=[S:27]>C(O)C>[NH2:28][C:26]1[S:27][CH:2]=[C:3]([C:4]2[C@:21]3([CH2:20][CH2:19][C@H:18]4[C@@H:8]([CH2:9][CH:10]=[C:11]5[C@:16]4([CH3:17])[CH2:15][CH2:14][C@H:13]([OH:23])[CH2:12]5)[C@@H:7]3[CH2:6][CH:5]=2)[CH3:22])[N:25]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(C(=O)CBr)=CC[C@@H]12
Reactant: NC(N)=S
Solvent: CCO
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3csc(N)n3)=CC[C@@H]12
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Dissolve 16-dehydropregnenolone (5.00 g, 15.90 mmol) and 5,5-dibromobarbituric acid (4.55 g, 15.90 mmol) in tetrahydrofuran (60 mL). Add concentrated aqueous hydrogen bromide (100 μL of a 48% solution) to the stirring solution and heat the reaction at reflux for 1 hour. Cool slightly and then concentrate under vacuum to produce a brown oily foam. Dissolve the residue in methylene chloride (350 mL), rinse with 50% saturated sodium bicarbonate (2×200 mL), brine (125 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide 21-bromo-3β-hydroxypregna-5,16-dien-20-one (6.53 g) as an orange-brown solid, slightly contaminated with starting material. Scheme II, step B; Suspend 21-bromo-3β-hydroxypregna-5,16-dien-20-one (16 mmol) in ethanol (260 mL) and add thiourea (1.33 g, 17.5 mmol). Heat the reaction at reflux for 1 hour and distill off approximately half of the solvent. Allow the reaction to cool to room temperature. Collect the solid by filtration and dry under high vacuum to provide the title compound (3.62 g) as a bright yellow solid. Concentrate the filtrate to approximately 20 mL to provide a second crop, dry under high vacuum and combine with the first crop to provide a total of 4.25 g. Recrystallize this from ethanol to provide the title compound (2.77 g) as a white crystalline solid , mp 258-260° C. (dec); 1H NMR (DMSO-d6) δ 8.85 (broad singlet, 2H), 6.81 (s, 1H), 6.28 (dd, 1H, J=1.9, 3.3 Hz), 5.29 (broad doublet, 1H, J=4.7 hz), 3.43 (q, 2H, J=7.0 Hz), 3.32-3.18 (m, 1H), 1.05 (t, 3H, J=7.0 Hz), 0.99 (s, 3H), 0.94 (s, 3H); 13C NMR (DMSO-d6) δ 169.4, 142.5, 141.6, 135.6, 131.0, 120.1, 102.0, 69.9, 56.4, 55.9, 49.7, 46.1, 42.2, 36.8, 36.2, 34.4, 31.3, 31.2, 30.8, 29.7, 20.4, 19.0, 18.5, 15.8; MS (CI,CH4) m/z (rel. intensity) 371 (MH+, 76), 370 (33), 369 (34), 353 (100), 83 (26), 81 (27).
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:11][NH2:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:13]=O>O.C1(C)C=CC=CC=1>[CH2:4]([O:11][N:12]=[CH2:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NOCc1ccccc1
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A NaOH (1.25 g, 31.32 mmol) solution in water (6 mL) was added to the mixture of O-benzyl-hydroxylamine hydrochloride (5.00 g, 31.32 mmol) and formaldehyde (˜37 wt. % in H2O) (2.3 mL, 31.32 mmol) in toluene (40 mL). The reaction mixture was stirred at room temperature for 1 h. After this time, the organic phase was separated and the water phase was extracted with dichloromethane (3×30 mL). The combined organic phases were dried over Na2SO4, and concentrated in vacuo to yield formaldehyde O-benzyl-oxime (LI, 4.15 g, 98%). 400 MHz 1H NMR (CDCl3, ppm) 7.40-7.29 (5H, m), 7.09 (1H, d, J=8.2 Hz), 6.47 (1H, d, J=8.2 Hz), 5.14 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[H][H]>[Ni].CO>[C:28]([O:27][C:25]([NH:24][CH:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:32])=[CH:11][CH:10]=2)=[CH:14][CH:15]=1)[C:21]([OH:23])=[O:22])=[O:26])([CH3:30])([CH3:31])[CH3:29]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc2)cc1
Yield: 54.9 %

Procedure:
Raney nickel 2800 (15.4 g) was added to a degassed solution of the unsaturated ester 3 (14.7 g) in MeOH (100 mL) and the resulting suspension was treated with hydrogen at atmospheric pressure for 18 h. The suspension was filtered over a Celite® bed and concentrated. Flash chromatography (30-50% ethyl acetate in hexane containing 1% acetic acid) of the resulting residue gave the desired saturated ester 4 (8.1 g, 55%). 1H NMR (400 MHz, DMSO-d6): 12.7 (br, 1H), 7.22 (overlapped d, J=8.4 Hz, 4H), 7.08 (d, J=8.0 Hz, 1H), 6.88 (overlapped d, J=8.0 Hz, 4H), 4.07 (br, 1H), 3.00 (m, 1H), 2.82 (t, J=7.6 Hz, 2H), 2.79 (m, 1H), 2.62 (t, J=8.0 Hz, 2H), 1.33 (s, 9H).
Reaction SMILES: N[CH:2]1[C:18](=[O:19])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[CH:6][CH:7]([CH3:9])[S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:23].Cl>C(N(CC)CC)C>[O:23]=[C:2]1[C:18](=[O:19])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[CH:6][CH:7]([CH3:9])[S:8][C@H:3]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(=O)[C@H]2S1

Procedure:
2,2,2-Trichloroethyl 7-amino-2-methyl-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 2,2,2-trichloroethyl 7-oxo-2-methyl-3-cephem-4-carboxylate. Mp. 98° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH3:17][O:18][C:19]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:20]=1[CH:21]=[CH:22][C:23](O)=O>>[CH3:17][O:18][C:19]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:20]=1/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: COc1cccc(C=CC(=O)O)c1OC
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3OC)nc2n(CCC)c1=O
Yield: 35.7 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.0 g (8.85 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.2 g (10.6 mmol) of 2, 3-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from chloroform/cyclohexane to give 1.26 g (yield 36%) of Compound 28 as yellow crystals.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Oc1nc(Cl)nc2c1CCCC2
Reactant: c1ccc2c(c1)CCNC2
Product: Oc1nc(N2CCc3ccccc3C2)nc2c1CCCC2
Yield: 26.3 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 2-chloro-4-hydroxy-5,6,7,8-tetrahydroquinazoline (2.0 g, 10.8 mmol) prepared in Step 1 of Example 82 and 1,2,3,4-tetrahydroisoquinoline (2.8 g, 22.4 mmol) were used as starting materials, 0.8 g of the titled compound was prepared. (Yield: 26.3%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH2:28][CH3:29])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1.ClC1C=CC(CN=C=O)=CC=1Cl>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH2:5][NH:6][C:25](=[O:26])[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[CH:17]=[CH:16][N:15]=[CH:14]2)[CH2:28][CH3:29]
Reactant: CCC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Agent: O=C(O)Cc1cccc2cnccc12
Agent: O=C=NCc1ccc(Cl)c(Cl)c1
Product: CCC(C(=O)NCc1ccc(C(F)(F)F)c(F)c1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 3-fluoro-4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)butanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 0.91 (t, J 7.5, 3H), 1.81 (m, 1H), 2.17 (m, 1H), 4.35 (m, 2H), 7.17 (m, 2H), 7.69 (t, J 7.8, 1H), 7.86 (t, J 7.8, 1H), 8.04 (d, J 7.1, 1H), 8.23 (d, J 8.1, 1H), 8.65 (d, J 6.8, 1H), 8.83 (t, J 6.8, 1H), 9.60 (s, 1H); Anal. Calcd for C21H18F4N2O+1 HCl: C, 54.77; H, 3.80; N, 5.55. Found: C, 54.62; H, 3.57; N, 5.50.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]O.P(Br)(Br)[Br:13].O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][Br:13]
Reactant: COc1ccc(CO)cc1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CBr)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of 3-chloro-4-methoxybenzyl alcohol (164 g) in dichloromethane (800 ml) was added phosphorus tribromide (45.1 ml) under ice-cooing and the mixture was stirred at ambient temperature for an hour followed by adding water to the mixture. The separated aqueous layer was extracted with dichloromethane. The combined organic layers were washed with an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was triturated with n-hexane to obtain 3-chloro-4-methoxybenzyl bromide (200 g) as a white powder.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]2OCC[O:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[S:21]([O-:24])([OH:23])=[O:22].[Na+]>O>[S:21](=[O:22])([OH:24])[OH:23].[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2cccc(C3OCCO3)c2)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=Cc1cccc(Oc2ccccc2)c1
Product: O=S(O)O
Yield: 89.5 %

Procedure:
To a solution of 24.2 g. of 2-(3-phenoxyphenyl)-1,3-dioxolane in 120 ml. of methanol a solution of 41.6 g. of sodium hydrogensulfite in 120 ml. of water is added, and the reaction mixture is boiled until no traces of starting compound can be detected by thin layer chromatography. The reaction mixture is cooled, the precipitated crystals are filtered off, washed with a 50% aqueous methanol solution and dried at 60° to 80° C. 27 g. (89.5%) of 3-phenoxybenzaldehyde bisulfite are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: CN(C)CCCl
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (1.5 g, 7.80 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (2.25 g, 15.60 mmol) and potassium carbonate (6.47 g, 46.80 mmol) in 25 mL DMF was stirred at room temperature for 3 days. After this time, the mixture was poured into 20 mL H2O then extracted with 3×150 mL EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow viscous oil (1.5 g, 73.2%). 1H-NMR (CDCl3) δ: 8.14 (dd, J=2.4, 9.0 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 4.09 (t, J=7.5 Hz, 2H), 3.03-2.98 (m, 2H), 2.73-2.68 (m, 2H), 2.51 (t, J=7.5 Hz, 2H), 2.31 (s, 6H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:20][CH2:21][O:22]C(/N=N/C(OCC)=O)=O.[C:32]([N:39]1[CH2:43][C@@H:42](O)[C@@H:41]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([O:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[S:62]1C=CC=C1CC(O)=O>C1COCC1>[C:32]([N:39]1[CH2:43][C@H:42]([S:62][C:21](=[O:22])[CH3:20])[C@@H:41]([NH:45][S:46]([C:49]2[CH:54]=[CH:53][C:52]([O:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)=[CH:51][CH:50]=2)(=[O:47])=[O:48])[CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: O=C(O)Cc1cccs1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@@H](NS(=O)(=O)c2ccc(Oc3ccccc3)cc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
To a stirred solution of PPh3 (525 mg, 2.0 mmol) in THF (3 mL) at 0° C. was added DEAD (315 μL, 2.0 mmol) dropwise. After 10 min, a solution of (3S,4R)—N-Boc-3-(4-phenoxybenzenesulfonamido)-4-hydroxypyrrolidine (435 mg, 1.0 mmol) and thiolacetic acid (228 μL, 2.29 mmol) in THF (3 mL) was added. The resulting reaction mixture was stirred at room temperature for 6 hr, then it was concentrated under reduced pressure. The residue was purified be flash chromatography (15% ethyl acetate in hexane) to give (3S,4S)—N-Boc-3-(4-phenoxybenzenesulfonamido)-4-acetylthiopyrrolidine (400 mg, 81%): 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=9, 2H), 7.42 (m, 2H), 7.23 (t, J=8, 1H), 7.06 (m, 4H), 5.21 & 5.00 (br s, 1H, NH), 3.75 (m, 4H), 3.16 (m, 2H), 2.31 & 2.25 (br s, 3H), 1.44 (s, 9H); [α]20D=+22.8° (c=0.62, CHCl3).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]2.I[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]I.C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]21[CH2:12][CH2:13][CH:14]([N:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:15][CH2:16]2
Reactant: ICCCCCI
Reactant: NC1CCC2(CCc3ccccc3C2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)CCC1(CCC(N3CCCCC3)CC1)C2

Procedure:
The amine prepared from 1.5 g. of 3',4'-dihydrospiro[ cyclohexane-1,2'(1'H)-naphthalen]-4-ylamine hydrochloride [I(c)] (prepared as in Example 10C), 1.9 g. of 1,5-diiodopentane and 1.6 g. of potassium carbonate in 18 ml. of ethanol is stirred at reflux temperature for about 18 hours. The mixture after cooling is diluted with water, the solid collected on a filter and recrystallized from methanol to give 1-[3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-yl]piperidine [I(c)].
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:16]O>C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:3]([C:8]([O:10][CH3:16])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C(O)c1ncccc1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ncccc1Br

Procedure:
To a solution of 3-bromopyridine-2-carboxylic acid (CAS number 30683-23-9; 2.0 g, 9.90 mmol) in methanol (15 ml) was added concentrated H2SO4 (3 ml) and the reaction mixture was refluxed for 2 hours. The reaction was diluted with a saturated solution of sodium bicarbonate and extracted with ethyl acetate (3×75 ml). The organics were washed with water (50 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: C(Cl)Cl.[CH2:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].C(OC(=O)C)(=[O:14])C>[Cr].CC#N>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])[CH3:5]
Reactant: CCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Cr]
Solvent: CC#N
Solvent: ClCCl
Product: CC(=O)c1ccccc1
Temperature: 0 °C
Yield: 96.1 %

Procedure:
To a freshly prepared CH2Cl2 solution of chromyl diacetate (O2Cr(OAc)2, 1 mL, 1 M) was added dropwise a CH3CN solution of H5IO6 (0.33 M, 3 mL) at −40° C. for 10 minutes to give a deep orange solution which is stable at −40° C. for several hours. In a different flask, a CH2Cl2 (0.4 mL) solution of ethyl benzene (212 mg, 2 mmol) and acetic anhydride (0.38 mL, 4 mmol, 2 eq) was cooled to −40° C. The earlier prepared chromium oxidant solution (0.4 mL, 0.25 M. 5 mol %) was added in one portion to the solution of starting material, followed; by the addition of a CH3CN solution of H5IO6 (0.33 M, 18.2 mL, 3 eq) at −40° C. over a period of 30 minutes. The resulting orange colored reaction mixture was gradually warmed up to 0° C. for a period of 1.5 h, quenched by addition of saturated aqueous Na2SO4, extracted with EtOAc, washed with water, brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography to give acetophenone (231 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[CH:9])[CH:5]=[CH:6][CH:7]=1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=1.CCOC(C)=O.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)[CH:3]=1
Reactant: FC(F)Oc1ccc(I)cc1
Reactant: C#Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccc(C#Cc2cccc(Br)c2)cc1
Reaction time: 4 h

Procedure:
To a solution of 3-bromophenylacetylene (9.1 g, 50.26 mmol), TEA (22.4 g, 221 mmol, 30.8 mL), bis(triphenylphosphine)dichloropalladium(II) (1.41 g, 2.01 mmol), and CuI (230 mg, 1.2 mmol) in DMF (60 mL) was added 4-iodo(difluoromethoxy)benzene (10.85 g, 40.21 mmol) at room temperature. The reaction mixture had gotten warm after the addition was completed. The mixture was stirred for 4 h then the mixture was portioned between EtOAc and water. The aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated over 40 g Celite. Flash chromatography (SiO2, Hexanes) gave 12 g, 92%, of the title compound as a yellow oil that had crystallized into a solid after being undisturbed for 3d. 1H NMR 500 MHz (DMSO-d6) δ 7.34 (dt, 2H, J=8.92 Hz, 4.70 Hz); 7.42 (t, 1H, 72.99 Hz); 7.54 (t, 1H, J=7.88 Hz); 7.85-7.88 (m, 1H); 7.94-7.97 (m, 1H); 8.00 (dt, 1H, J=8.93 Hz, 4.87 Hz); 8.04 (t, 1H, J=1.80 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of (2-chlorophenyl)acetic acid (15 g, 88 mmol) in cone. H2SO4 (100 mL) was cooled to −20° C. and treated (drop wise) with cone. HNO3 (9.4 g, 97 mmol). The resulting mixture was stirred at −20° C. for an additional 30 min. The reaction mixture was poured into the ice-water, and the mixture was extracted with EtOAc (3×200 mL), the combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to give (2-chloro-5-nitrophenyl)acetic acid (15 g, 79% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1 H), 8.35 (m, 1 H), 7.96 (m, 1 H), 4.12 (s, 2 H).