Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=[C:2]([CH2:7][CH:8]([N+:22]([O-:24])=[O:23])[CH:9]([C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])[CH2:10][CH:11]=C)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.CS(C)=O>ClCCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[N+:22]([C@@H:8]1[CH2:7][C:2]([C:3]([O:5][CH3:6])=[O:4])=[CH:11][CH2:10][C@H:9]1[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[CH:15][C:14]=1[F:21])([O-:24])=[O:23]
Reactant: C=CCC(c1cc(F)c(F)cc1F)C(CC(=C)C(=O)OC)[N+](=O)[O-]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: CS(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=CC[C@@H](c2cc(F)c(F)cc2F)[C@H]([N+](=O)[O-])C1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A stream of dinitrogen gas was bubbled through a mechanically-stirred solution of methyl 2-methylene-4-nitro-5-(2,4,5-trifluorophenyl)oct-7-enoate (98 g, 285.7 mmol, 1:1 mixture of erythro and threo isomers) in DCE (1.43 L) at 70° C. A solution of Grubbs' 2nd generation catalyst (9.7 g, 11.4 mmol) in DCE (61 mL) was added via syringe pump over about twelve hours. The reaction was then cooled to 55° C., and triethylamine (3.98 mL, 28.6 mmol) was added. After eight hours, the heating bath was removed, and DMSO (64 mL, 912 mmol) was added to the reaction. After stirring for twelve hours, the reaction was concentrated under reduced pressure, and the crude residue was purified by MPLC on SiO2 gel (15% EtOAc in Hx) to give the title compound as a dark waxy solid (63 g, 72%). 1H NMR (300 MHz, CDCl3) δ ppm 7.06-6.90 (m, 3H), 5.03 (ddd, J=5.8, 10.5 and 10.5 Hz, 1H), 3.79 (s, 3H), 3.64 (ddd, J=6.1, 10.5, and 10.5 Hz, 1H), 3.20-3.12 (m, 1H), 3.01-2.89 (m, 1H), 2.80-2.70 (m, 1H), 2.63-2.51 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13]S(C(C)(C)C)=O)[C:9]([F:12])([F:11])[F:10])[CH:5]=[N:6][CH:7]=1.Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:13])[C:9]([F:10])([F:11])[F:12])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)S(=O)NC(c1cncc(Br)c1)C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(c1cncc(Br)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To N-(1-(5-bromopyridin-3-yl)-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide (1.5 g, 4.18 mmol) in MeOH (8.35 ml) was added HCl 4N in dioxane (2.088 ml, 8.35 mmol) dropwise, and the mixture stirred at room temperature for 16 h. Concentrated, and then the mixture was quenched with saturated NaHCO3 and extracted with EtOAc two times, dried over magnesium sulfate, filtered, concentrated. The title compound was isolated as a light yellow oil used as is for next step. LC-MS (M+1) 257.0, t=1.05 min
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[Cl:30]N1C(=O)CCC1=O.[OH-].[Na+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]([C@H:14]2[CH2:18][N:17]([C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[CH3:20])[C:16](=[O:29])[CH2:15]2)[CH3:13])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[Cl:30])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4nccc34)CC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Br)cn4ncc(Cl)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-4-((R)-1-(6-bromopyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.01 (111 mg, 0.242 mmol) in acetonitrile (2.4 mL) was added N-chlorosuccinimide (38.8 mg, 0.290 mmol). The solution was stirred at room temperature for 3 h. The reaction was poured into 1N NaOH and extracted with dichloromethane. The combined organic layers were washed with brine, dried, filtered and concentrated under reduced pressure to afford (R)-4-((R)-1-(6-bromo-3-chloropyrazolo[1,5-a]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 6.36, which was used without further purification.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[N-:10]=[N+:11]=[N-:12].[Na+]>CS(C)=O.O>[N:10]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(N=[N+]=[N-])cc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A solution of 4-fluorobenzonitrile (10.0 g, 82.57 mmol, 1.00 equiv) and NaN3 (6.0 g, 92.29 mmol, 1.12 equiv) in DMSO (100 mL) was stirred at 100° C. for 2 h. The reaction was cooled to room temperature and then diluted with 700 mL of water. The precipitate was collected by filtration and air-dried to give 5.8 g (49%) of 4-azidobenzonitrile as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ: 7.88 (d, J=13.5 Hz, 2H), 7.31 (d, J=13.5 Hz, 2H) ppm.
Reaction SMILES: [Cl-].[NH4+].O.[Br:4][C:5]1[CH:6]=[C:7]([N+:17]([O-])=O)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14]>[Fe].C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[NH2:17]
Reactant: CC(C)(C)COc1ccc([N+](=O)[O-])cc1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)COc1ccc(N)cc1Br
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
Furthermore, ammonium chloride (10 g) and iron powder (75 g) were added to a mixed solvent of water (286 ml) and ethanol (753 ml), and the mixture was heated to 65° C. 3-Bromo-4-neopentyloxynitrobenzene (80 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added sodium hydroxide and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g), melting point: 45° C.
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5]([S@:8](/[N:10]=[CH:11]/[C:12]1[CH:13]=[N:14][N:15]([CH3:21])[C:16]=1[C:17]([F:20])([F:19])[F:18])=[O:9])([CH3:7])[CH3:6].[Cl-].[NH4+].[CH2:24](Cl)Cl.CO.[NH4+].[OH-].II>ClCCl.O.CO>[CH3:21][N:15]1[C:16]([C:17]([F:18])([F:20])[F:19])=[C:12]([C@@H:11]([NH:10][S@@:8]([C:5]([CH3:4])([CH3:6])[CH3:7])=[O:9])[CH3:24])[CH:13]=[N:14]1
Reactant: Cn1ncc(/C=N/[S@](=O)C(C)(C)C)c1C(F)(F)F
Reactant: ClCCl
Agent: C[Mg]Cl
Agent: II
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: C[C@H](N[S@](=O)C(C)(C)C)c1cnn(C)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl magnesium chloride (3M in diethyl ether, 3.56 ml, 0.0107 moles) was added dropwise to a stirred solution of (R,E)-2-methyl-N-((1-methyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (1.0 g, 0.035 moles) in dichloromethane (30 ml) at −70° C. under nitrogen. The mixture was allowed to warm to RT to give a cloudy solution and the solution was stirred overnight at RT under nitrogen. Ammonium chloride solution (saturated) was added slowly dropwise to quench the reaction. The mixture was diluted with water and extracted with ethyl acetate (3×20 ml). The organic layer was separated and back-washed with brine (2×30 ml). The organic layer was separated, dried (Na2SO4), filtered and evaporated to give an oil. Yield 1.1 g. 1H NMR (300 MHz CDCl3) ratio 4.5:1 of diastereoisomers. The diastereoisomers were separated by silica gel chromatography using IPA/Heptane 20:80. The top diastereoisomer (100% de) was isolated. Yield 660 mg, 62%. 1H NMR (400 MHz CD30D) δ 7.48 (s, 1H) 4.79, 4.78, 4.76, 4.75, 4.73 (quin, 1H) 3.23, 3.21 (d, 1H) 1.58, 1.57 (d, 3H) 1.21 (s, 9H). MS (ESI) m/z 298 (M+H)+. GC-MS Cl+298 (M+H)+. TLC CH2Cl2:MeOH:NH4OH 95:5:0.5 0.3 UV−ve I2+ve. [α]D=−13.94° (c 1.65, CH3OH).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[C:12]1([CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:15]1[CH:16]=[CH:17][C:12]([CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[CH:13][CH:14]=1)=[O:6]
Reactant: CCCCC(CC)COC(=O)Cc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(CC)COC(=O)Cc1ccc(C(=O)CCCCl)cc1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
Mix chlorobutyryl chloride (16.9 g) and AlCl3 (29.3 g) at room temperature. Add 2-phenylacetic acid, 2-ethylhexyl ester (27.6 g), keeping the temperature below 10° C. Beat at 35° C. for 24 hours, quench in ice water (200 g). Separate the organic phase, dry (MgSO4) and evaporate the solvent in in vacuo. Dilute the residue with ethanol (150 mL), add hydrogen chloride (5 g) and heat to 75° C. After 2.5 hours, add another 5 g of hydrogen chloride and stir at 75° C. for 24 hours. Evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [I-].C(OC([NH:9][C@@H:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O:29]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:28])=[C:14]([CH2:17][N+:18]3[N:19]([CH3:26])[C:20]([NH:23][CH:24]=[O:25])=[CH:21][CH:22]=3)[CH2:15][S:16][C@H:11]12)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl.C(OCC)(=O)C>[NH2:9][C@@H:10]1[C:43](=[O:44])[N:12]2[C:13]([C:27]([O-:29])=[O:28])=[C:14]([CH2:17][N+:18]3[N:19]([CH3:26])[C:20]([NH:23][CH:24]=[O:25])=[CH:21][CH:22]=3)[CH2:15][S:16][C@H:11]12
Reactant: Cn1c(NC=O)cc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Agent: [I-]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: Cn1c(NC=O)cc[n+]1CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 168.1 %

Procedure:
To a solution of benzhydryl 7β-tert-butoxycarbonylamino-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (20.9 g) and anisole (20 ml) in methylene chloride (40 ml) was added dropwise trifluoroacetic acid (40 ml) under ice-cooling. After being stirred for 1.5 hours at ambient temperature, the mixture was poured into a mixture of diisopropyl ether (300 ml) and ethyl acetate (300 ml). The resultant precipitate was collected by filtration to give bis(trifluoroacetic acid) salts of 7β-amino-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (16.20 g).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:30](=[O:32])[CH3:31])[CH2:14][CH2:13]1
Reactant: Clc1ccc(Oc2ccccc2NC2CCNCC2)c(Cl)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To an ice cooled solution of [2-(2,4-dichlorophenoxy)phenyl]piperidin-4-ylamine (AMR01040, 132 mg, 0.39 mmol) in dry DCM (5 mL) were added triethylamine (0.137 mL, 0.98 mmol) and acetyl chloride (0.031 mL, 0.43 mmol). The reaction mixture was stirred at room temperature until completion by TLC (1 h), and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane to EtOAc gradient as eluent gave 1-{4-[2-(2,4-dichlorophenoxy)phenylamino]piperidin-1-yl}ethanone (95.3 mg, 64%) as a white solid after, mp 145-146° C. Rf: 0.22 (EtOAc) LC/MS (APCI) tr=1.44 min, m/z 381.29 (63), 379.34 (M++H, 100) HPLC tr=3.10 min (99.31%) 1H NMR (270 MHz, CDCl3) δ 1.36 (2H, m, CH2), 2.06 (2H, m, CH2), 2.08 (3H, s, CH3), 2.89 (1H, m), 3.20 (1H, m), 3.53 (1H, m), 3.74 (1H, m), 4.05 (1H, m), 4.37 (1H, m), 6.63 (1H, m, ArH), 6.74 (1H, dd, J=7.9, 1.5 Hz, ArH), 6.75 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.80 (1H, d, J=8.9 Hz, ArH), 7.03 (1H, m, ArH), 7.12 (1H, dd, J=8.9, 2.5 Hz, ArH) and 7.43 (1H, d, J=2.5 Hz, ArH). Anal. Calcd. for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 59.90; H, 5.47; N, 7.13%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2Cl)[N:3]=1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[S:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[N:3]=[C:4]2[C:9]([C:8]([NH:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[S:21][C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:24][CH:23]=3)=[CH:7][CH:6]=[N:5]2)=[CH:10][CH:11]=1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Clc1ccc2c(Cl)ccnc2n1
Product: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Yield: 46 %

Procedure:
The product from Example 13d (200 mg, 1.0 mmol) and the product from Example 18b (215 mg, 1.0 mmol) were reacted following the procedure from Example 1g giving a crude solid that was purified by HPLC with TFA to give the title compound 200 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[C:12]([O:21][CH3:22])(=[O:20])[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH2:14].[H-].[Na+].O>CN(C)C=O.C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:14][CH:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:12]([O:21][CH3:22])=[O:20])=[C:4]([Cl:11])[N:3]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)CC(Cn1cnc2c(Cl)nc(N)nc21)C(=O)OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.5 %

Procedure:
A mixture of 2-amino-6-chloropurine (4.07 g, 0.024 mol), dimethyl itaconate (5.00 g, 0.032 mol), and sodium hydride (55% in oil, 0.2 g) in 50 ml of dry dimethylformamide was stirred at room temperature for 3 days. About 50 ml of water was added and the mixture was washed with n-hexane (2×50 ml) and then extracted with 2×50 ml of dichloromethane. The combined CH2Cl2 extracts were washed with 2×20 ml of water, dried with magnesium sulfate, and evaporated in vacuum. Treatment with ether and drying afforded a white crystalline product. Chromatography (silica gel, chloroform+methanol 15+1) yielded 5.54 g (71%) or recrystallization (MeOH--H2O) yielded 5.15 g (66.1%) of dimethyl 2-(2-amino-6-chloropurin-9-ylmethyl)succinate.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[OH:22][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:39])[CH:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30]2)=[CH:25][CH:24]=1>>[CH3:20][O:19][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][O:22][C:23]2[CH:32]=[C:31]3[C:26]([C:27](=[O:39])[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30]3)=[CH:25][CH:24]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:21]
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc3c(=O)cc(-c4ccccc4)oc3c2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and 7-hydroxyflavone in a manner analogous to that described for Example 24, Step B. MS(ES) for C30H26O6[M+H]+:483.2.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[CH:4][CH2:3]1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)C1=CCC(F)(F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the above ester (0.58 g, 2.29 mmol) in 6 mL of methanol and 0.5 mL of THF was added 2.5 mL of 1 molar sodium hydroxide solution. The solution was stirred for 4 hours at ambient temperature, and then the pH was adjusted to 6 by the addition of 2 M HCl. The reaction mixture was men concentrated under vacuum, and the residue was azeotroped with toluene to provide 4,4-difluorocyclohex-1-ene-1-carboxylic acid an oily solid.
Reaction SMILES: C1(C([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][C:11]=2[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=O)C=CC=CC=1.O1CCCC1>CO.[OH-].[Na+]>[C:26]1([C:24]([C:11]2[CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=[CH:15][C:10]=2[NH2:9])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccc2)cc1C(=O)c1ccccc1
Yield: 107.1 %

Procedure:
A solution of phenyl-N-[2-(phenylcarbonyl)-4-(phenylmethoxy)phenyl]carboxamide (3.24 g, 8.0 mmol) in methanol (20 mL) and 10 N sodium hydroxide (NaOH) (6 mL) was heated to reflux temperature when tetrahydrofuran (THF) (15 mL) was added. The solution was then heated to reflux overnight when the methanol and THF was removed under vacuo. The solution was then added to water (100 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuo to an oil to isolate the title compound (2.60 g, >100% yield, analytical).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH:15]([CH:16]=[CH2:17])[CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>ClCCl>[CH:12]([CH:13]1[CH:15]([CH:16]=[CH2:17])[CH:14]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:11]
Reactant: C=CC1C(CO)C1C(=O)OCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: C=CC1C(C=O)C1C(=O)OCC
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of oxalyl chloride (0.30 mL, 3.5 mmol) in anhydrous dichloromethane (30 mL) at −78° C. under nitrogen atmosphere, dimethylsulfoxide (0.51 mL, 7.2 mmol) was added and stirred for 30 minutes. To this mixture, a solution of ethyl (1SR,2SR,3RS)-2-hydroxymethyl-3-vinylcyclopropane carboxylate (490 mg, 2.9 mmol) in anhydrous dichloromethane (20 mL) was added and reaction stirred at the same temperature for 45 minutes. Then, triethylamine (2.0 mL, 14.4 mmol) was added and mixture was allowed to react at room temperature. After 30 minutes, the reaction was quenched with water (30 mL), the layers were separated and the aqueous one was extracted with dichloromethane (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The resulting residue was purified by column chromatography using ethyl acetate and hexane 1:4 as eluent to afford 460 mg (95% yield) of ethyl (1SR,2SR,3RS)-2-formyl-3-vinylcyclopropane carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)[OH:9])[O:5][C:6]=1[CH3:7]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)=[O:9])[O:5][C:6]=1[CH3:7]
Reactant: Cc1ccnc(C(O)c2cc(C)c(C)o2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(C(=O)c2cc(C)c(C)o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(4-methyl-pyridin-2-yl)-methanol (900 mg) was dissolved in chloroform (20 ml) to prepare a solution. Manganese dioxide (3.6 g) was added to the solution, and the mixture was stirred at room temperature overnight. Further, manganese dioxide (1.8 g) was then added to the reaction solution, and the mixture was stirred at room temperature for 5 hr. The reaction solution was filtered through Celite, and the solvent was removed from the filtrate by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give (4,5-dimethylfuran-2-yl)-(4-methyl-pyridin-2-yl)-methanone (690 mg, yield 77%).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]2[C:19]([F:20])=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=2[F:23])[O:11][CH2:12][CH3:13])=[C:5]([OH:27])[CH:4]=1)#[N:2].I[CH2:29][C:30]([NH2:32])=[O:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:30]([CH2:29][O:27][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:26]=[CH:25][C:6]=1[CH2:7][NH:8][C:9](=[O:24])[CH:10]([C:14]1[C:15]([F:23])=[CH:16][C:17]([O:21][CH3:22])=[CH:18][C:19]=1[F:20])[O:11][CH2:12][CH3:13])(=[O:31])[NH2:32]
Reactant: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1c(F)cc(OC)cc1F
Reactant: NC(=O)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C#N)cc1OCC(N)=O)c1c(F)cc(OC)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide was alkylated with iodoacetamide/cesium carbonate in DMF to give (RS)-N-(2-carbamoylmethoxy-4-cyano-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide as a colorless solid. MS 434.3 ([M+H]+)
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]1)=[O:13]>C(#N)C>[CH3:10][O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([NH:20][CH2:2][CH2:3][S:4][C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: BrCCSc1cccs1
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](NCCSc2cccs2)CC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2-(2-Bromo-ethylsulfanyl)-thiophene (275 mg, 1.21 mmol, 1.0 eq) is added at room temperature to a stirred solution of trans-4-amino-cyclohexanecarboxylic acid methyl ester (200 mg, 1.21 mmol, 1.0 eq) in acetonitrile (6 mL). After 15 hours stirring at 100° C., the reaction mixture is evaporated to afford trans-4-[2-(thiophen-2-ylsulfanyl)-ethylamino]-cyclohexanecarboxylic acid methyl ester as an off-white oil (261 mg, 68% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:44])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:7]=1.[C:45](Cl)(=[O:49])[CH2:46][CH2:47][CH3:48]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])[CH:3]=[CH:4][C:5]=2[Cl:44])[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: CCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)CCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of 100 mg (0.154 mmole) of 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 60), 18.8 mg (0.154 mmole) of 4-(dimethylamino)pyridine (DMAP), 80 μL (82 mg, 0.77 mmole) of butyryl chloride, and 1 mL of pyridine was stirred at room temperature overnight. Work-up of the reaction as in Example 57 provided a 65% yield of the title compound as a white solid, mp >130° C., homogeneous by TLC (9:1 MeOH-CH2Cl2), mass spectrum (FAB) m/e 758 (M+K)+.