Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])=O)N)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:40](CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:40][N:6]=2)[CH:7]=1
Reactant: C[C@H]1COCCN1C(=O)N(N)c1ccc(F)cn1
Reactant: CCN(CC)CC
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nnc2ccc(F)cn12
Temperature: 55 °C
Yield: 28.8 %

Procedure:
To an ice cold solution of Intermediate 139a (574 mg, 2.26 mmol) in THF (23.0 mL) was added sequentially triphenylphosphine (1.18 g, 4.52 mmol), triethylamine (1.26 mL, 9.04 mmol) and hexachloroethane (1.07 g, 4.52 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo and then re-submitted to the above reaction conditions overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (154 mg, 29%). 1H NMR (300 MHz, CDCl3): 0.94 (3H, d, J=6.3 Hz), 3.13 (1H, dt, J=12.2, 3.1 Hz), 3.32 (1H, ddd, J=12.4, 9.5, 3.2 Hz), 3.49 (1H, dd, J=11.1, 8.6 Hz), 3.56-3.68 (1H, m), 3.84 (1H, ddd, J=12.1, 9.4, 2.7 Hz), 3.92-4.01 (2H, m), 7.16 (1H, ddd, J=9.9, 7.5, 2.3 Hz), 7.68 (1H, ddd, J=10.0, 4.8, 0.8 Hz), 7.85 (1H, m).
Reaction SMILES: S1C=C[N:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:17]([OH:19])=[O:18])[CH:7]=1.[CH:20]1C=CC2C(=CC=CC=2O)C=1>>[C:2]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH:9]=[C:8]([C:17]([O:19][CH3:20])=[O:18])[CH:7]=1)#[N:3]
Reactant: O=C(O)c1cc(-c2nccs2)c2ccc(O)cc2c1
Reactant: Oc1cccc2ccccc12
Product: COC(=O)c1cc(C#N)c2ccc(O)cc2c1

Procedure:
Following the procedure described in Naphthol 5, Step 8, but substituting 1-cyano-3-carboxy-6-naphthol from Step 4 for 1-(2-thiazolyl)-3-carboxy-6-naphthol, the title product was obtained as an orange solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[C:33](Cl)=[O:34].CCN(C(C)C)C(C)C>CC#N>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:33]([C:24]4[CH:25]=[CH:26][C:27]5[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=5)[N:23]=4)=[O:34])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc5ccccc5n4)cc3C2=O)C(=O)N1
Yield: 840.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and quinoline-2-carbonyl chloride (0.57 g, 3.00 mmol) in MeCN (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 (100 mL). The organic layer was washed with water (100 mL), brine (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O for 18 h. The product was isolated by filtration and dried in vacuo to give quinoline-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (11.15 g, 76% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.08 min (96.58%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.93-2.16 (m, 1H, CHH), 2.53-2.70 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.74 (d, J=6.4 Hz, 2H, CH2), 5.15 (dd, J=5.3, 12.8 Hz, 1H, CH), 7.66-7.82 (m, 1H, Ar), 7.82-7.99 (m, 4H, Ar), 8.03-8.25 (m, 3H, Ar), 8.59 (d, J=8.1 Hz, 1H, Ar), 9.75 (t, J=6.4 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.92, 42.55, 48.99, 118.74, 122.24, 123.55, 128.15, 128.89, 129.15, 129.84, 130.60, 131.59, 133.67, 137.94, 146.05, 147.44, 149.89, 164.48, 169.82, 172.73; LCMS: MH=448; Anal Calcd for C24H18N4O5: C, 65.15; H, 4.10; N, 12.68. Found: C, 65.05; H, 4.05; N, 12.58.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[C:9](C)=[CH:8][NH:7][N:6]=1.N1C=CC=N1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:9]=[CH:8][NH:7][N:6]=1
Reactant: COCCc1n[nH]cc1C
Agent: c1cn[nH]c1
Product: COCCc1cc[nH]n1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 305.4, except 1H-pyrazole was used instead of 4-methyl-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])=[CH:5][C:3]=1[NH2:4].[CH:14](O)=O>>[Cl:9][C:7]1[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])=[CH:5][C:3]2[N:4]=[CH:14][NH:1][C:2]=2[CH:8]=1
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Reactant: O=CO
Product: NS(=O)(=O)c1cc2nc[nH]c2cc1Cl
Temperature: 100 °C

Procedure:
In a round bottomed flask equipped with a condenser 24.0 g of 2-amino-4-chloro-5-sulfamyl-aniline and 7.0 g of formic acid is refluxed at 100° C. for two hours. Concentrate under vacuum. Dissolve in hot methanol, stir, cool and filter off the solid wt.=11.0 gm. m.p. 243.8° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH:20]=O>C1(C)C=CC=CC=1>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19]/[CH:20]=[N:3]/[NH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)NN
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)N/N=C/CN1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of ethyl carbazate (435 mg, 4.18 mmol) in toluene (6 ml) was slowly added dropwise to a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde (719 mg, 3.80 mmol) in toluene (12 ml), and the mixture was stirred at 75° C. for 3 hours. Crystals were collected by filtration and washed with diethyl ether to give 612 mg (58.5% (2 steps)) of the desired product as a solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:12]=[C:11]([F:21])[CH:10]=1)C1C=CC=CC=1.[OH-].[Na+]>C1(SC)C=CC=CC=1.C(C(O)=O)(F)(F)F>[F:21][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: Fc1cc(OCc2ccccc2)cc(-c2ccncc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: Oc1cc(F)cc(-c2ccncc2)c1
Temperature: 80 °C

Procedure:
A mixture of O-benzyl-3-fluoro-5-(4-pyridyl)phenol (120 mg) in thioanisole (1 mL) and CF3CO2H (0.6 mL) was heated at 80° C. for 1 h. The mixture was cooled to r.t., made basic with 10N NaOH and extracted with Et2O. The organics were washed with NaHCO3, brine, dried (MgSO4) and concentrated. The residue was triturated with hexane to provide the title compound as a solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].B(Cl)([C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.N(CCO)CCO>C1COCC1>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccccc1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: OCCNCCO
Solvent: C1CCOC1
Product: OC(CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloroacetophenone (6.25 g., 40.4 mmol) was treated with (+) DIP-chloride (18 g., 56.1 mmol) in anhydrous THF (40 mL) at dry-ice bath temperature and left overnight. The temperature was raised to room temperature and THF was removed in vacuo. The residue was dissolved in ether (210 mL). The diethanolamine (9 g., 8 5.6 mmol) was added and the mixture stirred at room temperature for 5 hrs. The separated solid was filtered and the filtered cake was washed with ether (150 mL). The combined filtrates were evaporated to dryness to give 15.53 g. of crude product. This was purified by silica gel column chromatography using 1% ether and petroleum ether 4.32 g (68%) of the desired product as an oil.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.[Br:25]C1C=C(N2CCNCC2)C2OCCOC=2C=1>>[Br:25][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Brc1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(O)cc3c2OCCO3)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Br)cc3c2OCCO3)CC1

Procedure:
The intermediate 1 -(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(t-butyloxycarbonyl)piperazine was prepared similar to the method described for 1-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)-4-(t-butyloxycarbonyl)piperazine (Intermediate 12a) using 1-(7-bromo-2,3-dihydro-1,4-benzodioxin-5-yl)piperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[CH:12][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:9]2[N:18]=[C:17]([OH:19])[C:16]3[C:11](=[CH:12][C:13]([C:20]([F:22])([F:21])[F:23])=[CH:14][CH:15]=3)[N:10]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: Oc1nc(C(O)c2ccc(F)cc2)nc2cc(C(F)(F)F)ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)c1nc(O)c2ccc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 129.8 %

Procedure:
To 2-((4-fluorophenyl)(hydroxy)methyl)-7-(trifluoromethyl)quinazolin-4-ol (2000 mg, 5.89 mmol) was added Dess-Martin periodinane (3000 mg, 7.07 mmol) in acetonitrile (25 mL) and the mixture was stirred at rt for 2 h. To the crude mixture was added aq sodium bicarbonate solution and the mixture was stirred for 0.5 h. The resulting brown precipitate was collected, washed with diethyl ether and dried under high vacuum to afford (4-fluorophenyl)(4-hydroxy-7-(trifluoromethyl)quinazolin-2-yl)methanone (2.57 g, quantitative yield) LC-MS (ESI) m/z 336 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:16]([NH:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[N:22]=3)[C:15](=[O:32])[N:6]2[C:7]=1[C:8]([O:10]C(C)(C)C)=[O:9].[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[CH:16]([NH:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:23][CH2:24][NH:25][C:26](=[O:31])[C:27]([F:28])([F:30])[F:29])[N:22]=3)[C:15](=[O:32])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(Nc3nc(CCNC(=O)C(F)(F)F)c[nH]3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(Nc3nc(CCNC(=O)C(F)(F)F)c[nH]3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of t-butyl 3-methyl-7-[4-(2-trifluoroacetylaminoethyl)imidazol-2-yl]aminoceph-3-em-4-carboxylate (0.34 g.) in TFA (5 ml.) was stirred for 2 hours at ambient temperature and then evaporated to dryness. The residue was purified by precipitation from a THF solution with ether to give 3-methyl-7-[4-(2-trifluoroacetylaminoethyl)imidazol-2-yl]aminoceph-3-em-4-carboxylic acid trifluoroacetate as a cream solid (0.2 g.), m.p. 165° (decomp.), having the following n.m.r. spectrum in CH3OD: 2.14 (s, 3H); 2.82 (t, 2H); 3.5 (m, 4H); 5.14 (d, 1H); 5.38 (d, 1H); 6.7 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([N:18]2[CH2:23][CH2:22][N:21]([CH2:2][CH2:3][CH2:4][N:5]3[CH2:9][CH2:8][CH2:7][C:6]3=[O:10])[CH2:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCCN1CCCCl
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=C1CCCN1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 150 °C

Procedure:
A mixture of 1-chloro-3-[2-oxopyrrolidin-1-yl]propane (1 g, 6.2 mmcl), 1-(3-chlorophenyl)piperazine (1.22 g, 6.2 inmol) anhydrous Na2CO3 (0.33 g, 3.1 mmol) and Nal (0.093 g, 0.6 mmcl) in dry xylene (15 ml) was stirred at 150° C. for 14 hirs. The solvent was removed at reduced pressure and residue was poured on water (30 ml). The separated residue was extracted with dichloromethane (2×25 ml), dried over Na2SO4 and concentrated to give 1-[4-(3-chlorophenyl)piperazin-1-yl]-3-[2-oxopyrrolidin-1-yl]propane as an oil which was purified by flash column chromatography over silica gel using chloroform as fluent, yield 0.72 g (36%).
Reaction SMILES: C1O[C:5]([OH:9])([CH2:7][OH:8])[CH2:4][O:3][C:2]1([OH:12])[CH2:10]O.[C:13](OC(=O)C)(=[O:15])[CH3:14].CO>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:13]([O:8][CH2:7][C:5]([CH2:4][O:3][C:2](=[O:12])[CH3:10])=[O:9])(=[O:15])[CH3:14]
Reactant: OCC1(O)COC(O)(CO)CO1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: CC(=O)OCC(=O)COC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon, 90 g of 1,3-dihydroxyacetone dimer and 250 mg of 4-(N,N-dimethylamino)pyridine were dissolved in 250 ml of pyridine. To the resulting solution, 225 ml of acetic anhydride was added dropwise at room temperature over 1 hour. After the resulting liquid was stirred at room temperature for 30 minutes, thereto was added 50 ml of methanol and the resulting liquid was further stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue was subjected to a recrystallization from ether-petroleum ether to give 190 g of the desired compound.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11](O)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(NC2CCCCC2)CCCCC1.S(Cl)([Cl:34])=O>ClCCl>[CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:11]([Cl:34])=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1C1(C)CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Product: COc1ccc(C(=O)Cl)cc1C1(C)CCCCC1
Reaction time: 1 h
Yield: 99.3 %

Procedure:
In a round bottom flask, there are introduced 4.96 g (20 mmoles) of 3-(1-methylcyclohexyl)-4-methoxy benzoic acid, 75 ml of dichloromethane, and 4 ml (20 mmoles) of dicyclohexylamine. The reaction mixture is stirred for 1 hour. To the resulting solution, there are added 1.45 ml (20 mmoles) of thionyl chloride (SOCl2) and the mixture is stirred for 2 hours at ambient temperature. The reaction mixture is then evaporated to dryness and taken up in 200 ml of ether. The dicyclohexyl-ammonium chloride is filtered off and the solvent is evaporated, yielding 5.30 g (100% yield) of crude 3-(1-methylcyclohexyl)-4-methoxy benzoyl chloride which is used, as is, for the following synthesis:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:20]([N:21]([CH2:24][CH3:25])[CH2:22][CH2:23][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:19]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C

Procedure:
To a solution of 4-nitro-phenol 1 (36.0 mmol) in toluene (40 mL) is added cesium carbonate (53.8 mmol) and (2-chloro-ethyl)-diethyl-amine hydrochloride (28.7 mmol). The reaction mixture is heated at 100° C. for 2 h then cooled to rt. The solid is filtered under vacuum and washed with warm toluene. The filtrate is concentrated to afford diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine 2 and used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.10-8.08 (m, 2H), 6.86-6.84 (m, 2H), 4.05 (t, J=4.0 Hz, 2H), 2.81 (t, J=4.0 Hz), 2.55 (q, J=8.0 Hz, 4H), 0.98 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)+: 239.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][C:27]=2[CH3:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccncc1B(O)O
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccncc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 51.9 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (4-methylpyridin-3-yl)boronic acid (206 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (87 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 80° C. for 6 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→0:1) to give the title compound as a colorless oil (yield 230 mg, 52%).
Reaction SMILES: N1CCCCC1.C([N:14]1[CH2:18][CH2:17][C:16]2([CH2:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19]2)[CH2:15]1)C1C=CC=CC=1.ClC(OCC)=O.[OH-].[K+]>ClCCl.[OH-].[NH4+].CO.C(O)C.O.C1(C)C=CC=CC=1>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][C:16]3([CH2:17][CH2:18][NH:14][CH2:15]3)[CH2:22][C:21]=2[CH:23]=1
Reactant: Clc1ccc2c(c1)CC1(CCN(Cc3ccccc3)C1)O2
Agent: CCOC(=O)Cl
Agent: [K+]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: Clc1ccc2c(c1)CC1(CCNC1)O2
Yield: 61.9 %

Procedure:
The experimental procedure is the same as described above for the corresponding piperidine derivative using 1′-benzyl-5-chloro-3H-spiro[1-benzofuran-2,3′-pyrrolidine] (555 mg, 1.85 mmol), ethyl chloroformate (261 mg, 2.4 mmol), toluene (5 mL), potassium hydroxide (KOH) (3.0 g), water (3 mL) and ethanol (6 mL) to give the titled compound (240 mg) after silica gel flash chromatography (0-2% methanol in dichloromethane, 0.2% ammonium hydroxide, NH4OH).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([CH2:10][C:11]#[N:12])=[N:8][CH:9]=1.Cl.Br[CH2:16][CH2:17]Cl>O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)C>[Br:3][C:4]1[CH:5]=[C:6]([Cl:13])[C:7]([C:10]2([C:11]#[N:12])[CH2:17][CH2:16]2)=[N:8][CH:9]=1
Reactant: N#CCc1ncc(Br)cc1Cl
Reactant: ClCCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: N#CC1(c2ncc(Br)cc2Cl)CC1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 81.8 %

Procedure:
1.38 g of sodium hydroxide was dissolved in 40 ml of water and 0.93 g of benzyltriethylammonium chloride was added at ambient temperature. A solution of 1.00 g of (5-bromo-3-chloro-pyridin-2-yl)-acetonitrile (step 1) in 1.31 g of 1-bromo-2-chloroethane was then added dropwise. Then the reaction mixture was stirred at 60° C. for 2.5 hours. Subsequently, the reaction mixture was cooled to 0° C. and 36% aqueous hydrochloric acid was added in order to obtain pH=1 (about 10 ml). The reaction mixture was extracted with two 50 ml portions of ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. 1.16 g of crude material was obtained as a pale brown sticky solid. The crude material was stirred in diethyl ether and the orange suspension was filtered. The filtrate was concentrated to give 910 mg of 1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropanecarbonitrile as an orange oil. 1H-NMR (CDCl3): 8.96 ppm (s, 1H), 7.92 ppm (s, 1H), 1.75 ppm (m, 2H), 1.60 ppm (m, 2H).
Reaction SMILES: O.O.O=[Al]O[Si](O[Si](O[Al]=O)=O)=O.[P:14](=[O:18])([OH:17])([OH:16])[OH:15].[N+:19]([O-:22])([O-:21])=[O:20].[Ce+3:23].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[C:32]([O-:37])(=[O:36])[C:33]([O-:35])=[O:34].[V+5:38].[C:39]([O-:44])(=[O:43])[C:40]([O-:42])=[O:41].[C:45]([O-:50])(=[O:49])[C:46]([O-:48])=[O:47].[C:51]([O-:56])(=[O:55])[C:52]([O-:54])=[O:53].[C:57]([O-:62])(=[O:61])[C:58]([O-:60])=[O:59].[V+5]>O>[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[N+:19]([O-:22])([O-:21])=[O:20].[Ce+3:23].[N+:19]([O-:22])([O-:21])=[O:20].[N+:19]([O-:22])([O-:21])=[O:20].[C:32]([O-:37])(=[O:36])[C:33]([O-:35])=[O:34].[V+5:38].[C:39]([O-:44])(=[O:43])[C:40]([O-:42])=[O:41].[C:45]([O-:50])(=[O:49])[C:46]([O-:48])=[O:47].[C:51]([O-:56])(=[O:55])[C:52]([O-:54])=[O:53].[C:57]([O-:62])(=[O:61])[C:58]([O-:60])=[O:59].[V+5:38]
Reactant: O=P(O)(O)O
Agent: [V+5]
Agent: O=C([O-])C(=O)[O-]
Agent: O=[Al]O[Si](=O)O[Si](=O)O[Al]=O
Solvent: O
Product: O=P([O-])([O-])[O-]
Reaction time: 0.5 h

Procedure:
A clay/phosphate/cerium nitrate, vanadium oxalate slurry was prepared by adding 1340 grams of Theile RC-32® kaolin clay slurry to 1795 milliliters of water in a high speed mixer. To this mixture, 192 grams of phosphoric acid was added. Thereafter, 431 grams of cerium nitrate solution and 232 grams of vanadium oxalate solution were added to the slurry. The slurry was then spray dried and then resulting particles were calcined at 650° C. for 30 minutes in a muffle furnace. The calcined particles were then mixed with magnesium oxide in a 50/50 weight percent ratio and analyzed by TGA tests. These tests indicated that the resulting material produced an SOx absorption of 0.27% per minute.
Reaction SMILES: C(OC1C=[C:11]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29]C(F)=CC=2)N=NC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:39][C:40]1[N:41]=[N:42][C:43](Cl)=[CH:44][C:45]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(CNC)CC1>>[CH2:47]([O:46][C:45]1[CH:44]=[C:43]([N:23]([CH2:24][CH:25]2[CH2:30][CH2:29]2)[CH3:11])[N:42]=[N:41][C:40]=1[O:39][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: Fc1ccc(CNc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: CNCC1CC1
Product: CN(CC1CC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 17 %

Procedure:
Prepared as described for 5,6-bis(benzyloxy)-N-[(4-fluorophenyl)methyl]pyridazin-3-amine (Intermediate 45) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and 1-cyclopropyl-N-methylmethanamine in 17% yield.