Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1([Cl:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:8][CH2:7][CH:3]2[C:4]([CH3:6])([CH3:5])[C:2]2([Cl:9])[Cl:1])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)C(CO)C1(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2C(C)(C)C2(Cl)Cl)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 95.9 %

Procedure:
A solution of 33.8 g of 2,2-dichloro-3,3-dimethylcyclopropane methanol in 200 ml of pyridine was cooled to 0° C., and 38.2 g of p-toluenesulfonyl chloride was added portionwise. The reaction mixture was left to stand for 12 hours in a refrigerator (0° C.), and then poured into 1 liter of ice water. The crystals precipitated were collected by filtration, washed with water, dried in the air, and washed with hexane to give 62 g of 2,2-dichloro-3,3-dimethylcyclopropylmethyl p-toluenesulfonate, the desired compound shown above. The melting point of the product was 96.5° to 97.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:11]1([CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:16][C@H:15]([C:17]([OH:19])=[O:18])[CH2:14][CH:11]2[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: N[C@@H](CC1CC1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N[C@@H](CC2CC2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (1.33 g) in dimethyl sulfoxide (20 mL) were added 3-cyclopropyl-L-alanine (1.00 g) and cesium carbonate (3.28 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 2.05 g, 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3]Cl.C(N(C(C)C)C(C)C)C.[CH2:14]=[C:15]([CH2:18][CH3:19])[CH2:16][OH:17]>C1COCC1>[CH3:1][O:2][CH2:3][O:17][CH2:16][C:15]([CH2:18][CH3:19])=[CH2:14]
Reactant: COCCl
Reactant: C=C(CC)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=C(CC)COCOC
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.4 %

Procedure:
Chloromethyl methyl ether (103.4 ml, 1363 mmol) and N-ethyldiisopropylamine (247.2 ml, 1419 mmol) were added to a solution of 2-methylene-1-butanol (65.1 g, 757 mmol) prepared in Reference Example 205 in THF (750 ml) while cooling in an ice-bath, and the mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether, and the mixture was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford 2-methoxymethoxymethyl-1-butene (98 g, quantitative) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]1[C:33](=[O:34])[N:15]2[C:16]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]12)=[O:11])=O>C(O)C.O>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([C:9](=[N:35][O:36][CH3:37])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:4]=1
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: NC(N)=S
Solvent: CCO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 27.4 %

Procedure:
Thiourea (0.14 g.) was added to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.8 g.) in ethanol (20 ml.) and water (5 ml.), and stirred at room temperature for 3.5 hours. The resultant solution was concentrated under reduced pressure, and to the residue were added water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product (0.6 g.) The product was purified by column chromatography on silica gel (eluent: benzene and ethyl acetate (8:2) to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.21 g.), mp 165° to 170° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCC)[NH:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][CH:35]1[NH:39][CH2:38][CH:37]([NH:40][CH3:41])[CH2:36]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]([CH:37]5[CH2:36][CH:35]([CH2:34][O:33][CH3:32])[NH:39][CH2:38]5)[CH3:41])=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CNC1CNC(COC)C1
Reactant: CCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: COCC1CC(N(C)C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CN1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(5-methoxymethyl-pyrrolidin-3-yl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazolidin-4-one and (5-Methoxymethyl-pyrrolidin-3-yl)-methyl-amine following General Procedure C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH:26](C)[CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: CC(Br)CCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(3-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][OH:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:20][S:21]([O:16][CH2:15][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:6](=[C:5]([C:17](=[O:18])[NH2:19])[CH:4]=[CH:3][C:2]=3[Br:1])[NH:7][C:8]=2[CH:9]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(CO)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
Step 1 A suspension of 4-bromo-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-2, 300 mg, 0.940 mmol) and TEA (0.262 mL, 1.880 mmol) in THF (9.4 mL) was treated dropwise with methanesulfonyl chloride (0.077 mL, 0.987 mmol) and the mixture was stirred at rt for 1 hr. It was treated with NaHCO3 (aq) and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated to provide crude (5-bromo-8-carbamoyl-9H-carbazol-2-yl)methyl methanesulfonate as a light yellow solid (390 mg, 89%). This material was suspended in DMF (8.3 mL) and treated with sodium azide (271 mg, 4.17 mmol). After being stirred overnight at rt, the mixture was diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated to provide crude 7-(azidomethyl)-4-bromo-9H-carbazole-1-carboxamide as a light yellow solid (350 mg, 97%). 1H NMR (400 MHz, DMSO-d6) δ 11.80 (1H, s), 8.62 (1H, d, J=8.4 Hz), 8.22 (1H, br. s.), 7.88 (1H, d, J=8.1 Hz), 7.83 (1H, s), 7.58 (1H, br. s.), 7.46 (1H, d, J=8.4 Hz), 7.28 (1H, dd, J=8.1, 1.5 Hz), 4.63 (2H, s).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)C.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH:37]1[CH:36]=[C:35]([C:22]2[CH:21]=[CH:20][C:19]([C:13]3([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:26])=[CH:12][CH:11]=4)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:24][CH:23]=2)[CH:39]=[N:38]1
Reactant: CCOC(=O)COc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)COc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 80 °C
Yield: 5 %

Procedure:
{4-[4-(4-bromo-phenyl)-piperidin-4-yl]-phenoxy}-acetic acid ethyl ester was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine) palladium (0) as the catalyst and heating at 80° C. for 30 minutes, to yield a mixture of the title compounds. On work up the basic aqueous extract was neutralised with hydrochloric acid and extracted with ethyl acetate (×2), then these organic extracts were combined and washed with brine, dried (MgSO4), filtered and concentrated to give a crude product that was recrystallised from water to afford (4-{4-[4-(1H-pyrazol-4-yl)-phenyl]-piperidin-4-yl}-phenoxy)-acetic acid (12 mg, 5%); LCMS (PS-A3) Rt 5.33 min [M+H]+ 378. 1H NMR (DMSO-d6) δ 2.22-2.26 (4H, m), 2.67-2.71 (4H, m), 4.65 (2H, s) 6.67 (2H, d), 7.11 (2H, d), 7.24 (2H, d), 7.46 (2H, d), 7.96 (2H, br.s).
Reaction SMILES: [CH2:1]([O:3][C:4]1(OC)[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[C:6]([C:7](O)=O)[CH:5]1[OH:16])[CH3:2].C(N(CC)CC)C.[C:26](Cl)(=O)[O:27]CC>C1COCC1>[CH2:1]([O:3][C:4]1[C:12]([O:27][CH3:26])=[C:11]([O:13][CH2:14][CH3:15])[CH:10]=[C:6]([CH3:7])[C:5]=1[OH:16])[CH3:2]
Reactant: CCOC1=CC(OC)(OCC)C(O)C(C(=O)O)=C1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOc1cc(C)c(O)c(OCC)c1OC

Procedure:
53 g of 3,5-diethoxy-2-hydroxy-3-methoxybenzoic acid prepared in Referential Example 5 and 45.5 g of triethylamine were dissolved in 400 ml of THF, and 48.4 g of ethyl chlorocarbonate in 100 ml of THF was dropwise added thereto with ice cooling while stirring. After the completion of the dropwise addition, the formed crystals were separated by filtration and washed with 100 ml of THF. The mother liquor was combined with the wash liquid, and a 10% aqueous solution of 30.3 g of sodium borohydride was added to the resultant solution and cooled by ice while stirring. After the completion of the dropwise addition, the mixture was stirred at room temperature for one hr, neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (eluent: n-hexane :ethyl acetate=95.5) to prepare 40 g of the product compound as a colorless oleaginous substance.
Reaction SMILES: C([O:8][C:9]1[C:14]([F:15])=[C:13]([F:16])[C:12]([N+:17]([O-:19])=[O:18])=[C:11]([O:20][CH2:21][CH:22]=[CH2:23])[C:10]=1[F:24])C1C=CC=CC=1>FC(F)(F)C(O)=O>[CH2:21]([O:20][C:11]1[C:10]([F:24])=[C:9]([OH:8])[C:14]([F:15])=[C:13]([F:16])[C:12]=1[N+:17]([O-:19])=[O:18])[CH:22]=[CH2:23]
Reactant: C=CCOc1c(F)c(OCc2ccccc2)c(F)c(F)c1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1c(F)c(O)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
33.9 g of the 1-benzyloxy-3-(prop-2-enyloxy)-4-nitro-2,5,6-trifluorobenzene prepared as described in Example 5 (0.1 mol) are dissolved in 120 ml of trifluoroacetic acid in a three-neck flask fitted with reflux condenser and stirrer, and the mixture is then refluxed for 4 hours. The reaction solution is then allowed to cool to room temperature, and the crude product is extracted by shaking with 200 ml of ethyl acetate and 300 ml of water. The organic phase is washed three times with water, dried over sodium sulfate and evaporated to half in a rotary evaporator. The precipitated reaction product is then recrystallized from a mixture of n-hexane and methylene chloride (volume ratio 1:1) and then dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:30])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([P:22]([O:27]CC)(=[O:26])[O:23]CC)=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[Br-].[Na+].C[Si](C)(C)Cl>C(#N)C>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6](/[C:14](/[CH3:30])=[CH:15]/[C:16]3[CH:21]=[CH:20][C:19]([P:22]([OH:26])(=[O:23])[OH:27])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOP(=O)(OCC)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Product: C/C(=C\c1ccc(P(=O)(O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
2 g (4.5 millimoles) of diethyl (E)-4-[2(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1propenyl]-benzenephosphonate, 1.86 g (18 millimoles) of sodium bromide and 3 g (27 millimoles) of trimethylchlorosilane in 10 ml of acetonitrile were stirred for 3 hours at 40° C. The mixture was then allowed to cool and was filtered, and the filtrate was evaporated down. The oil which remained was stirred for 30 minutes with water at room temperature and then extracted with ether, and the organic phase was washed with water, dried over sodium sulfate and evaporated down. Recrystallization of the residue from ethyl acetate gave 1.1 g of the title compound of melting point 208°-209° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]Cl)=[C:9]([F:15])[CH:8]=1)[CH:4]=[CH2:5].[N:16]1([CH2:21][CH2:22][OH:23])[CH:20]=[CH:19][N:18]=[N:17]1.O>CN(C=O)C>[CH2:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:23][CH2:22][CH2:21][N:16]2[CH:20]=[CH:19][N:18]=[N:17]2)=[C:9]([F:15])[CH:8]=1)[CH:4]=[CH2:5]
Reactant: OCCn1ccnn1
Reactant: C=CCOc1ccc(CCl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(COCCn2ccnn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
816 mg (32.3 mmol) 95% Sodium hydride were given at −50° C. to a solution of 4.32 g (21.5 mmol) 1-allyloxy-3-fluoro-4-chloromethyl-benzene and 2.51 g (22.2 mmol) 2-(1H-[1,2,3]-triazol-1-yl)-ethanol in 30 ml DMF. The mixture was allowed to warm slowly to r.t., stirred overnight and 10 ml water added. The mixture was extracted twice with ethyl acetate, and the combined organic phases dried over Na2SO4. Solvents were removed in vacuum to yield 6.18 g 1-[2-(4-allyloxy-2-fluoro-benzyloxy)-ethyl]-1H-[1,2,3]triazole yellow oil that was used without further purification.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17]([CH2:21][C:22](Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18]>N1C=CC=CC=1>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:21][C:22]([NH:16][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:23]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: CC(C)(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 56.8 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (1.1 g, 5.0 mmol) and t-butylacetyl chloride (0.77 mL, 5.5 mmol) in pyridine (10 mL) provided 3,3-dimethyl-N-[6,7,8,9,10,11-hexahydro-benzo[b]-cycloocta[d]furan-2-yl]butyramide (0.89 g). Mp 157-158° C.;MS (El) m/z 314.2 ([M+H]+); Anal. Calcd. for C20H27NO2: C, 76.64; H, 8.68; N, 4.47; Found: C, 76.71; H, 8.81; N, 4.45.
Reaction SMILES: C(O/[CH:4]=[C:5](\[C:11](=O)[C:12]([F:15])([F:14])[F:13])/[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(N(C(C)C)CC)(C)C.F.[F:27][C:28]1[CH:29]=[CH:30][C:31]([NH:34][NH2:35])=[N:32][CH:33]=1>C(O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([N:34]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=[N:35]2)=[N:32][CH:33]=1
Reactant: NNc1ccc(F)cn1
Reactant: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Agent: F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(-c2ccc(F)cn2)c1C(F)(F)F
Temperature: 80 °C
Yield: 29.7 %

Procedure:
To (E)-ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (0.441 g, 1.835 mmol) in ethanol (2 mL) was added diisopropylethylamine (0.427 mL, 2.447 mmol) followed by 5-fluoro-2-hydrazinylpyridine, hydrofluoride (0.3 g, 2.039 mmol) dissolved in 1 mL of ethanol (slightly exothermic). The reaction mixture was heated at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure, dissolved in dichloromethane (2 mL) and subjected to column chromatography using an ISCO setup (40 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield ethyl 1-(5-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.165 g, 27%) as a white solid. LC/MS M+1=304.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)(C(C)(C)C)(C)C.O>C(O)(=O)C>[OH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)C1
Solvent: CC(=O)O
Solvent: O
Product: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CC[C@@H](O)C2)c(F)c1

Procedure:
3-(4-((3R)-3-t-Butyldimethylsilyloxy-1-pyrrolidinyl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (1.8 g, 3.77 mmol) was stirred in a mixture of acetic acid, water, and tetrahydroftiran (3:1:1, 40 ml) at 90° for four hours. Solvent was evaporated, and the residue purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% MeOH in dichloromethane. Relevant fractions were combined and evaporated to givc the desired product (420 mg) as a foam. MS (ESP): 364 (MH+) for C17H18FN3O5.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][CH2:13]O>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-bromophenyl)acetic acid 1103 (10.0 g, 46.5 mmol) in 100 mL EtOH was added conc. H2SO4 (10 drops) and the mixture heated to relux temperature for 3 hours. The mixture was allowed to cool to room temperature and the volatiles were removed under reduced pressure. The residue was taken up in EtOAc (100 mL) and washed with water (2×50 mL), saturated NaHCO3 (1×25 mL), brine (2×25 mL) and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure to give ethyl 2-(3-bromophenyl)acetate 1097 (11.1 grams) as a liquid). 1H NMR 300 MHz CDCl3: δ 7.41 (m, 2H), 7.20 (m, 2H), 4.14 (q, 2H, J=9.5 Hz), 3.57 (s, 2H), 1.25 (t, 3H, J=9.5 Hz).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([OH:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:23][C:24]1[C:29](F)=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34].O>CN(C)C=O>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]([O:22][C:29]2[C:28]([F:31])=[C:27]([F:32])[C:26]([F:33])=[C:25]([F:34])[C:24]=2[F:23])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1c(F)c(F)c(OC2(c3ccccc3)CCN(Cc3ccccc3)CC2)c(F)c1F
Reaction time: 20 h
Yield: 14.53 %

Procedure:
To a stirred suspension of sodium hydride (60% in oil, 4.0 g) in 75 ml of dimethylformamide was added a solution of 22.69 g of 1-benzyl-4-hydroxy-4-phenyl piperidine in 100 ml of dimethylformamide. The mixture was heated with a heat gun to initiate evolution of gas. When evolution had ceased, the mixture was cooled to ice bath temperature and 18.61 g of hexafluorobenzene was added, dropwise, and the reaction was allowed to proceed for 20 hours. The reaction mixture was then poured into 500 ml of iced water and the aqueous suspension extracted with ethyl acetate. The organic layer was washed with water, followed by a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After filtering, evaporation of the solvent afforded a residue which was purified by means of high pressure liquid chromatography (silica gel; elution with 10% ethyl acetate/dichloromethane) to yield 5.36 g, (14.53%) of 1-benzyl-4-(2,3,4,5,6,-pentafluorophenoxy)-4-phenyl piperidine, m.p. 80°-83° C.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)=[O:10])[CH2:4][CH3:5].Cl.[C:19]1([CH2:25][S:26]([Cl:29])(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[ClH:29].[CH2:4]([N:3]([CH2:2][CH3:1])[CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:28])=[O:27])=[CH:13][CH:12]=1)=[O:10])[CH3:5]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)CCNC(=O)c1ccc(NS(=O)(=O)Cc2ccccc2)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of 7.1 g (0.026 moles) of procainamide hydrochloride in 100 ml acetone and 5 ml triethylamino at -50° C., is added slowly 5.0 g (0.026 moles) of α-toluenesulfonyl chloride. Stir at -50° C. for 1 hour, then warm to room temperature and stir for 16 hours. Remove the solvent in vacuo. Slurry the residue in 200 ml ether, and wash 2×100 ml portions of methylene chloride. The combined methylene chloride extracted are vacuum stripped to dryness. The residue is dissolved in 100 ml ethanol and brought to pH 3 with concentrated hydrochloric acid. The solvent is removed in vacuo, and the residue triturated with methylene-chloride to provide the title compound.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([C:15]1[C:20]([OH:21])=[C:19]([Cl:22])[CH:18]=[CH:17][C:16]=1[N:23]1[C:27](=[O:28])[C:26]2[CH2:29][CH2:30][CH2:31][CH2:32][C:25]=2[C:24]1=[O:33])[CH:13]=[CH2:14]>ClCCCl>[Cl:22][C:19]1[C:20]2[O:21][CH:13]([CH2:14][OH:9])[CH2:12][C:15]=2[C:16]([N:23]2[C:27](=[O:28])[C:26]3[CH2:29][CH2:30][CH2:31][CH2:32][C:25]=3[C:24]2=[O:33])=[CH:17][CH:18]=1
Reactant: C=CCc1c(N2C(=O)C3=C(CCCC3)C2=O)ccc(Cl)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Cl)c2c1CC(CO)O2
Temperature: 70 °C

Procedure:
A solution of 1.50 g of 80% m-chloroperbenzoic acid (MCPBA) in 20 mL of 1,2-dichloroethane was added dropwise to a solution of 2.0 g of 3D in 25 mL of 1,2-dichloroethane at room temperature. The resulting mixture was heated at 70° C. for four hours, cooled and extracted with saturated aqueous sodium sulfite solution, until no reaction to starch/iodide paper occurred. The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution, water, brine, dried (Na2SO4) and stripped of solvent. The residue was flash chromatographed over silica gel, with a 2:3 v:v mixture of ethyl acetate and hexane as eluent, to obtain the title compound, as yellow crystals, m.p.: 193°-195° C.