Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:4]([C:10]1[C:11]([I:34])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])=[O:27])[C:13]([I:25])=[C:14]([C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[O:18])[C:15]=1[I:16])CC(O)CO)=[O:3].CC(N(C1C(I)=C(C(NCC(O)CO)=O)C(I)=C(C(NCC(O)CO)=O)C=1I)CC(O)CN(C(C)=O)C1C(I)=C(C(NCC(O)CO)=O)C(I)=C(C(NCC(O)CO)=O)C=1I)=O.NC1C(I)=C(C(NCC(O)CO)=O)C(I)=C(C=1I)C(NCC(O)CO)=O>>[C:2]([NH:4][C:10]1[C:15]([I:16])=[C:14]([C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[O:18])[C:13]([I:25])=[C:12]([C:11]=1[I:34])[C:26]([NH:28][CH2:29][CH:30]([OH:33])[CH2:31][OH:32])=[O:27])(=[O:3])[CH3:1]
Reactant: CC(=O)N(CC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: CC(=O)N(CC(O)CN(C(C)=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Product: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I

Procedure:
In the acetylation step of the industrial scale synthesis of Iohexol and Iodixanol, 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Compound B) is acetylated to produce 5-acetylamino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Compound A) using acetic anhydride as the acetylating reagent. We have now found that Compound A can be prepared from Compound B in an optimized process wherein the generation of certain impurities is significantly reduced.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.[CH2:27]([S:31](Cl)(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[C:1]([OH:4])(=[O:3])[CH3:2].[CH2:13]([O:12][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:5][S:31]([CH2:27][CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1OCc1ccccc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCS(=O)(=O)Nc1ccccc1OCc1ccccc1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
5.0 g (0.00194 mol) of 3-amino-4-benzyloxybenzene acetate are mixed under a nitrogen atmosphere in 15 ml of methylene chloride, and 3.3 ml of triethylamine (0.0236 mol) and 3.3 ml (0.0245 mol) of 1-butansulfonyl chloride are added thereto. The mixture is stirred at ambient temperature overnight and afterwards at 30° C. for 4 hours. Washing with water is carried out, the two phases are separated, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated under reduced pressure. Purification is carried out by chromatography on a column of silica gel, elution being carried out with a cyclohexane/ethyl acetate=9:1 mixture. The title compound is obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].CCN(C(C)C)C(C)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CSCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CSCCCOS(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(methylthio)propan-1-ol in dichloromethane (0.2 M) was added sequentially at −78° C. Hunig's base (1.3 eq.) and methanesulfonyl chloride (1.3 eq.). The resulting reaction mixture was stirred at −78° C. for 1 h and then warmed slowly to RT. The reaction was quenched with sat. aq. NH4Cl and then extracted with ether. The combined organic extracts were washed with water and brine, dried over MgSO4, and filtered. Concentrated of the filtrate in vacuo afforded the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([CH:27]([CH3:29])[CH3:28])[CH2:11][C@H:12]1[C:17]([O:18][CH2:19][CH3:20])=N[C@H](C(C)C)C(OCC)=[N:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])(O)=[O:32].[Na+]>CC#N>[NH2:13][C@@H:12]([CH2:11][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:27]([CH3:29])[CH3:28])[C:17]([O:18][CH2:19][CH3:20])=[O:32]
Reactant: O=C([O-])O
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1C[C@H](COCc1ccccc1)C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)[C@@H](N)C[C@H](COCc1ccccc1)C(C)C
Reaction time: 1.5 h

Procedure:
To a solution of (2S,5R)-2-((S)-2-(benzyloxymethyl)-3-methylbutyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (17.5 g, 46.8 mmol) in CH3CN (187 mL) was added 1 N aq HCl (187 mL, 187.2 mol) at rt and stirring was continued for 1.5 h. The mixture was poured into ice-cold, satd aq NaHCO3 and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried and evaporated to afford (2S,4S)-ethyl 2-amino-4-(benzyloxymethyl)-5-methylhexanoate as a pale yellow oil (13.5 g) which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.C1COCC1.[CH3:18][NH2:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[N:19][CH3:18]
Reactant: CN
Reactant: O=Cc1ccc([N+](=O)[O-])c(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN=Cc1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 25 °C
Reaction time: 18.5 h

Procedure:
3-Chloro-4-nitrobenzaldehyde (251 mg 1.35 mmole) was dissolved in dichloromethane (2 mL) and methylamine, 2M in THF (0.88 mL, 1.76 mmole) was added along with 3A Sieves (400 mg). The reaction was stirred at room temperature for 18.5 hours. The sieves were filtered and washed with more dichloromethane. The filtrate was evaporated, however only partial conversion to the imine was observed. The residue was redissolved in dichloromethane (2 mL) and methylamine. 2M in THF (1.0 mL, 2.0 mmole) was added along with powdered 3A Sieves (400 mg). The reaction was stirred at room temperature for a further 16.5 hours. The sieves were filtered and washed and the filtrate evaporated to give the title compound as an oil which quickly crystallised (199 mg). 1H-NMR (CDCl3, 500 MHz): δ 3.60 (d, J=1.89 Hz, 3H), 7.73 (dd, J=1.89, 8.51 Hz, 1H), 7.93 (m, 2H), 8.30 (q, J=1.58 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]2[C:28]3[CH:29]=[CH:30][C:31](Br)=[CH:32][C:27]=3[CH2:26][O:25][CH2:24][C:23]=2[CH:34]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[CH:40]=[CH:41][O:42]CC)CCC.O.C1C(=O)N([Br:61])C(=O)C1>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:20]=[CH:21][C:22]2[C:28]3[CH:29]=[CH:30][C:31]([C:41](=[O:42])[CH2:40][Br:61])=[CH:32][C:27]=3[CH2:26][O:25][CH2:24][C:23]=2[CH:34]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)COCc1cc(Br)ccc1-2
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)c1ccc2c(c1)COCc1cc(C(=O)CBr)ccc1-2
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 90.3 %

Procedure:
To the solution of pyrrolidine-1,2-dicarboxylic acid 2-[2-(9-bromo-5,7-dihydro-dibenzo[c,e]oxepin-3-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (160 mg, 0.30) and tributyl(ethoxyvinyl)stannane (112 μl, 0.33 mmol) in dioxane (2 ml) was added PdCl2(PPh3)2 (8 mg). The mixture was heated at 80° C. for 16 hours and was cooled to 0° C. Water (0.7 ml) was added, followed by slow addition of NBS (59, 0.33 mmol) over 5 minutes period. The mixture was stirred at 0° C. for additional 40 minutes, and the solvent was removed under reduced pressure. The mixture was diluted with EtOAc, and was washed with water and brine and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexane/EtOAc) gave pyrrolidine-1,2-dicarboxylic acid 2-{2-[9-(2-bromo-acetyl)-5,7-dihydro-dibenzo[c,e]oxepin-3-yl]-2-oxo-ethyl}ester 1-tert-butyl ester (156 mg). m/z: 593.9 (M+Na)+.
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(#N)C.[OH-].[K+].[CH2:27]([N:29]([CH3:33])[C:30](Cl)=[O:31])[CH3:28]>C(O)CO>[I-:1].[CH2:27]([N:29]([CH3:33])[C:30]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:31])[CH3:28]
Reactant: CCN(C)C(=O)Cl
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CC#N
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Mix 7.9 g (0.02 mol) of (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 180 ml of acetonitrile, 1.7 g (0.03 mol) of potassium hydroxide, 3.6 (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of macrogol 400 at room temperature, heat it to 60° C. and react it for 12 hours. After it is cooled to room temperature, filter it and reduce the pressure to recover the solvent and receive 10.2 g of red-brown liquid to be directly used in the next reaction.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH2:20]([S:22][CH2:23][CH:24]([OH:27])[C:25]#[CH:26])[CH3:21]>>[CH2:20]([S:22][CH2:23][CH:24]([C:25]1[N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]2[C:2]([CH:26]=1)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)[OH:27])[CH3:21]
Reactant: C#CC(O)CSCC
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I
Product: CCSCC(O)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as described in General Procedures Example C, starting from N-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (1.89 g, 4.6 mmol) and 1-ethylsulfanyl-but-3-yn-2-ol (0.6 g, 4.6 mmol), reacted to yield the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([O:13][CH2:14][P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[CH2:1]([O:8][CH2:9][C@@H:10]([O:13][CH2:14][P:15]([O:21][CH:22]([CH3:24])[CH3:23])([O:17][CH:18]([CH3:19])[CH3:20])=[O:16])[CH3:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OP(=O)(CO[C@@H](CI)COCc1ccccc1)OC(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)OP(=O)(CO[C@@H](C)COCc1ccccc1)OC(C)C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A solution of (R)-1-(benzyloxy)-2-[(diisopropylphosphono)methoxy]-3-iodopropane (12.0 g, 25.5 mmol) in 15 mL of methanol was treated with triethylamine (3.10 g, 30.6 mmol) and 10% palladium on carbon (2.0 g), and the mixture was placed under 40 psi hydrogen atmosphere in a Parr shaker apparatus. After 2 hours, the reaction mixture was filtered through a 1" pad of Celite, and the collected solid was washed with methanol. The filtrate was concentrated and treated with ethyl acetate (200 mL). The precipitate was removed by filtration, the filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (10:1, 75% ethyl acetate/hexane) to afford 8.24 g (94%) of the title compound as a clear, colorless oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.Cl>C(O)(C)C.C(O)C>[C:1]1([C:7]2[O:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11]=2[C:12](=[O:14])[CH2:13][CH2:19][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCNC1
Reactant: CC(=O)c1c(-c2ccccc2)oc2ccccc12
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: O=C(CCN1CCCC1)c1c(-c2ccccc2)oc2ccccc12

Procedure:
To a solution of 23.6 grams of 2-phenyl-3-acetylbenzofuran in 70 milliliters of isopropanol was added 4.2 grams of paraformaldehyde, 10 grams of pyrrolidine and 30 milliliters of a saturated solution of hydrogen chloride in ethanol and the mixture was heated under reflux at its boiling point for 10 hours.
Reaction SMILES: O[C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]1=[O:13].CCN(C(C)C)C(C)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[Cl:38][C:39]1[CH:40]=[C:41]([C@H:46]2[CH2:50][CH2:49][NH:48][CH2:47]2)[CH:42]=[C:43]([Cl:45])[CH:44]=1>C(Cl)Cl.O>[Cl:38][C:39]1[CH:40]=[C:41]([C@H:46]2[CH2:50][CH2:49][N:48]([C@H:2]3[CH2:6][CH2:5][N:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:3]3=[O:13])[CH2:47]2)[CH:42]=[C:43]([Cl:45])[CH:44]=1
Reactant: Clc1cc(Cl)cc([C@H]2CCNC2)c1
Reactant: O=C1[C@H](O)CCN1c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1[C@@H](N2CC[C@H](c3cc(Cl)cc(Cl)c3)C2)CCN1c1ccccc1
Reaction time: 0.33 h

Procedure:
Synthesized according to General Procedure 10. To a solution of (R)-3-hydroxy-1-phenylpyrrolidin-2-one (822 mg, 4.64 mmol) and DIEA (1.50 g, 2.02 mL, 11.59 mmol) in DCM (10 mL) at −20° C. was added triflic anhydride (1.57 g, 936 μL, 5.56 mmol) and the reaction mixture was stirred at this temperature for 20 min. A solution of (R)-3-(3,5-dichlorophenyl)pyrrolidine (835 mg, 3.86 mmol) in DCM (6 mL) was added and the reaction mixture was stirred at −20° C. for 1 hour. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organic extracts were washed with water (2×), brine, dried (Na2SO4) and evaporated to dryness. Purification by silica gel chromatography (30-60% EtOAc in hexane) gave (3R,3′S)-3-(3,5-dichlorophenyl)-1′-phenyl-1,3′-bipyrrolidin-2′-one as an oil that solidified upon standing (0.9 g, 62%). 1H-NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.0 Hz, 2H), 7.42-7.36 (m, 5H), 7.15 (t, J=7.3 Hz, 1H), 3.77 (m, 2H), 3.52 (t, J=8.7 Hz, 1H), 3.05-2.98 (m, 4H), 2.88 (m, 1H), 2.31-2.23 (m, 2H), 2.06 (m, 1H) and 1.77-1.74 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA), m/z: M+1 obs=375.5; tR=1.35 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:34])([F:33])[CH:26]([F:32])[O:27][C:28]([F:31])([F:30])[F:29])[CH:6]=1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16]([CH2:17][C:18]([F:21])([F:20])[F:19])=[O:43])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:34])([F:33])[CH:26]([F:32])[O:27][C:28]([F:31])([F:29])[F:30])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(F)(F)C(F)OC(F)(F)F)nn1-c1cc(S(=O)CC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
0.5 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 0.22 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:1) to obtain 0.46 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[O:16][CH3:17])(O)=[O:2].Cl.CN.O[N:22]1[C:26]2C=CC=CC=2N=N1.O>CN(C)C=O>[CH3:17][O:16][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:4]=1[C:1](=[O:2])[NH:22][CH3:26])[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution of methyl 4-carboxy-3-methoxycinnamate (400 mg) in N,N-dimethylformamide were added methylamine hydrochloride (126 mg), I-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (390 mg) and 1-hydroxybenzotriazole (320 mg) at ambient temperature, and the mixture was stirred for 18 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform: methanol=40:1, v/v) to give methyl 3-methoxy-4-(methylcarbamoyl)cinnamate (319 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].[CH3:24][C:25]([CH3:27])=O>>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[O:12][CH2:27][CH:25]=[CH2:24])[C:5]([O:7][CH3:8])=[O:6])[CH:21]=[CH2:22]
Reactant: COC(=O)c1cc(O)c(O)c(Br)c1
Reactant: CC(C)=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1cc(C(=O)OC)cc(Br)c1OCC=C
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Methyl 3,4-dihydroxy-5-bromobenzoate (49 g, see Chem. Abs., 89:2327 g) and K2CO3 (92 g) were placed in a flask in acetone (500 ml). Allyl bromide (49 ml) was slowly added to the mixture, which was stirred at room temperature for 5 days. After filtration, solvent was evaporated, the residue taken up in ethyl acetate, washed with water, and dried (MgSO4). Evaporation of the solvent gave methyl 3,4-diallyloxy-5-bromobenzoate (65 g): NMR (DMSO-d6) 3.86 (s, 3H); 4.67 (m, 4H); 5.20-5.53 (m, 4H); 5.95-6.19 (m, 2H); 7.54 (d, 1H); 7.73 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[N:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:13]=1[CH3:14])=[O:7].[CH3:31][I:32]>C(OCC)(=O)C>[I-:32].[CH3:30][N+:2]([CH3:31])([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)=[N:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:13]=1[CH3:14])=[O:7]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)NCCN(C)C
Reactant: CI
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(=O)NCC[N+](C)(C)C
Product: [I-]

Procedure:
A solution of N-(2-dimethylaminoethyl)-6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxamide (1 g) and methyl iodide (10.46 ml) in ethyl acetate (2 ml) was stirred for 5 days at room temperature. The reaction mixture was evaporated and the residue was recrystallized from ethyl alcohol to afford N-(2-trimethylammonioethyl)-6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxamide iodide (0.95 g).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:33][CH2:34][O:35][CH3:36])=[C:29]([CH:32]=1)[CH:30]=[O:31]>C1COCC1>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([O:33][CH2:34][O:35][CH3:36])=[C:29]([CH:32]=1)[CH:30]([C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:31]
Reactant: COCOc1ccc(Br)cc1C=O
Reactant: Brc1ncccc1C1OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(Br)cc1C(O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a solution of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (m.p. 35°-40° C.; 3.60 g) synthesized by a known method in THF (60 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (10.8 ml). The mixture was stirred for 15 minutes at the same temperature, to which was then added a solution of 5-bromo-2-methoxymethoxybenzaldehyde (3.83 g) in THF (10 ml). The mixture was stirred for 15 minutes at the same temperature, then stirred for further 20 minutes while warming up to room temperature. The reaction mixture was poured into a saturated aqueous saline solution, which was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 2-(5-bromo-α-hydroxy-2-methoxymethoxybenzyl)-3-(1,3-dioxolan-2-yl)pyridine (4.50 g) (Compound D-2). The physical properties and spectrum data are shown in Table 13 and Table 14.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[C:11]1[C:16]([CH:17]=[CH:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=[C:13]([C:22]([F:25])([F:24])[F:23])N=1.[CH2:26]1COCC1>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:11]2[CH:26]=[C:13]([C:22]([F:25])([F:24])[F:23])[CH:14]=[CH:15][C:16]=2[CH:17]=[CH:18][C:19]([OH:21])=[O:20])[CH:3]=1
Reactant: Oc1cccnc1
Reactant: C1CCOC1
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Product: O=C(O)C=Cc1ccc(C(F)(F)F)cc1Oc1cccnc1

Procedure:
3-Hydroxypyridine (69.1 mg) and sodiumhydride (65 mg, 1.6 mmol) were added in THF. 3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (156 mg, 0.620 mmol) was added the reaction mixture. The reaction mixture was purified to yield the title compound (15 mg) after purification by column chromatography (Hex/EtOAc=1/4).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:26][CH:23]1[CH2:24][CH2:25][N:20]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: OC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccccc1[N+](=O)[O-]
Yield: 59.7 %

Procedure:
1.55 g (0.00837 mol) of 2-nitro-benzoyl chloride were dissolved in 70 ml of toluene and treated with 2.0 g (0.0104 mol) of 1-benzyl-4-hydroxypiperidine and 2.6 ml (0.0184 mol) of triethylamine. After boiling under reflux for 18 hrs. the suspension was filtered, the filtrate was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2->1:1) as the eluent. 1.7 g (60%) of 1-benzyl-piperidin-4-yl 2-nitro-benzoate were obtained as yellow crystals; m.p. 98°-99°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[CH:9][CH:10]=2)[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[CH3:25][O:24][C:22]([C:4]1[N:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:6]2[C:11]([C:12](=[O:13])[C:3]=1[CH2:2][NH:1][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][CH:35]=[C:27]([Cl:26])[CH:28]=1)=[CH:10][CH:9]=[C:8]([O:14][CH3:15])[CH:7]=2)=[O:23]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)c2cccc(Cl)c2)c(=O)c2ccc(OC)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 3-(aminomethyl)-7-methoxy-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylate (intermediate K) (30 mg, 0.089 mmol), 3-chlorobenzoyl chloride (35 mg, 0.200 mmol), and triethylamine (40 mg, 0.305 mmol) in methylene chloride (4 mL) was stirred at 0° C. for 1 hr. After this time, the reaction mixture was concentrated, and the crude material was triturated with diethyl ether. The product 3-[(3-chloro-benzoylamino)-methyl]-7-methoxy-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester was obtained without further purification. MS calcd. for C26H21ClN2O5 [(M+H)+] 477.1, obsd. 476.9.