Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:13][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-nitrobenzyl alcohol (6 g, 39 mmoles) is put into solution in dichloromethane (100 ml) and carbon tetrabromide (14.9 g, 45 mmoles) is added. Triphenylphosphine (11.8 g, 45 mmoles) is added in portions to the medium at 0° C. Then the mixture is agitated for 2 hours at ambient temperature. The solvent is evaporated off and the product obtained is purified on silica gel in an ethyl acetate/heptane mixture (1/2). It is obtained in the form of white needle-shaped crystals (7.9 g; 85%). Melting point: 97-98° C.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:16]([Cl:22])=[C:17](F)[CH:18]=[CH:19][CH:20]=1>>[Br:14][C:15]1[C:16]([Cl:22])=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: Fc1cccc(Br)c1Cl
Product: Cc1cc2c(o1)CN(C)CCC2Oc1cccc(Br)c1Cl

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][N:20]1[C:24](=[O:25])[C:23]([CH3:29])([CH2:26][CH2:27][CH3:28])[N:22]([CH3:30])[S:21]1(=[O:32])=[O:31]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:19][N:20]1[C:24](=[O:25])[C:23]([CH3:29])([CH2:26][CH2:27][CH3:28])[N:22]([CH3:30])[S:21]1(=[O:31])=[O:32])=[O:5]
Reactant: CCCC1(C)C(=O)N(CCl)S(=O)(=O)N1C
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCC1(C)C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.2 %

Procedure:
To a stirred solution of 2,6-dichlorobenzoic acid (206 mg, 1.08 mmol) and 112 mg (0.812 mmol) of potassium carbonate in 20 ml of DMF under nitrogen was added 2-chloromethyl-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (250 mg, 0. 981 mmol) and the mixture was allowed to react at room temperature for 12 hours. After adding an additional 2,6-dichlorobenzoic acid (0.038 g) and 0.055 g of potassium carbonate, the mixture was stirred at room temperature for additional 12 hours. The mixture was diluted with ice/water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by flash chromatography (silica gel; 10% ethyl acetate in hexane) to afford 266 mg (66%) of 2- (2,6-dichlorophenylcarbonyloxymethyl)-4-methyl-4-propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar-2,6-Cl2 -phenyl; R1 =propyl; R2 =CH3 ; R3 =CH3) as a solid, m.p. 93°-95° C.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][NH2:25])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.49 g, 2.9 mmol) and sodium methoxide (0.16 g, 2.9 mmol) were added. The mixture was stirred at room temperature for 10 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with dichloromethane (50 ml×3). The dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was crystallized from dichloromethane-diethyl ether to give the title compound (0.48 g, 2.1 mmol, yield: 79%) as colorless needles.
Reaction SMILES: N1CCCCC1.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=O)[S:11][CH:12]=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18]>C(Cl)Cl.C(OC(C)C)(C)C>[Br:7][C:8]1[CH:9]=[C:10](/[CH:13]=[CH:16]/[C:17]([OH:19])=[O:18])[S:11][CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)cs1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1cc(Br)cs1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
Piperidine (1.036 mL, 10.47 mmol) was added to a mixture of 4-bromothiophene-2-carbaldehyde (20 g, 105 mmol) and malonic acid (13.07 g, 126 mmol) at 80° C. under nitrogen atmosphere. The reaction mixture was stirred for 2 h at 100° C. The reaction mixture was cooled to room temperature and extracted with EA/water. The organic phase was washed with 2N NaOH. The aqueous phase was acidified and a precipitate was formed. The solid was stirred in a mixture of DCM and diisopropyl ether (1:1). The solid was sucked off and dried under reduced pressure to give a bright beige solid (12.3 g, 50.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[C:25]1([CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCOCC>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)([CH2:34][CH2:33][CH2:32][CH2:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: BrCCCCc1ccccc1
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CCOC(=O)C(CCCCc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Yield: 73.4 %

Procedure:
To a solution of 2.62 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 40 ml of dry 1,2-dimethoxyethane was added 0.46 g of a 50% sodium hydride (suspension in oil) while ice-cooling, and then 2.05 g of 4-phenylbutyl bromide was added dropwise to the mixture. The mixture was heated under reflux for 19 hours. After cooling, an aqueous ether was added to the reaction mixture and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 2.77 g of 2-(1-naphthylmethyl)-2-(4-phenylbutyl)malonic acid diethyl ester as a colorless oil.
Reaction SMILES: C([S@@]([NH:7][C@H:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=O)(C)(C)C.C(N(CC)CC)C>CO>[F:25][C:20]1[CH:19]=[C:18]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[CH2:10][CH2:9]2)[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: COC(=O)C(C)(C)CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(F)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)NC1=O
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of methyl (5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)-2,2-dimethylpentanoate from Step E (300. mg, 0.800 mmol) in MeOH (16 mL) was cooled to 0° C. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 30 seconds, after which time the reaction vessel was sealed and allowed to sit in the ice bath for 15 minutes. Dry nitrogen was then bubbled through the solution for 30 minutes, prior to removal of solvent in vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. After dissolving in a third volume of MeOH (16 mL), triethylamine (323 mg, 3.2 mmol) was introduced and the mixture was heated to 65° C. for 16 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between diethyl ether (50 mL) and 1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=240 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C@@H:21]([NH2:23])[CH3:22])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C@@H:21]([NH:23][C:10]([C@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])[CH3:22])=[CH:19][CH:18]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C)c1ccc(Cl)cc1

Procedure:
Boc-D-Proline (4.3 g, 20 mmol) was dissolved in DMF (100 ml). Then (S)-4-Chloro-α-methybenzylamine (3 ml, 22 mmol) and HBTU (7.58 g, 20 mmol), DIEA (6.96 ml, 40 mmol) were added while stirring. The reaction mixture was stirred overnight. The reaction mixture was diluted with EtOAc (100 ml), washed with 1N HCl (2×50 ml), sat. aq. NaHCO3 (2×50 ml) and brine, dried over Na2SO4, and concentrated in vacuo. The crude desired product as a white solid (6 g, 85.7%) directly used for next step.
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:19][CH2:18]1>>[ClH:16].[CH:1]1([CH2:5][CH2:6][NH:7][C:8]([C:10]2[N:11]=[N:12][C:13]([N:17]3[CH2:18][CH2:19][CH:20]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[CH2:21][CH2:22]3)=[CH:14][CH:15]=2)=[O:9])[CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Reactant: O=C(NCCC1CCC1)c1ccc(Cl)nn1
Product: Cl
Product: O=C(NCCC1CCC1)c1ccc(N2CCC(Nc3ccccc3C(F)(F)F)CC2)nn1
Yield: 60 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (2-cyclobutylethyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide to react with piperidin-4-yl-(2-trifluoromethylphenyl)amine, the title compound was obtained as a white powder in 60% yield. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (t, J=5.4 Hz, 1H), 7.91 (d, J=9.6 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.42-7.36 (m, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 4.42 (d, J=13.5 Hz, 2H), 3.81 (s, br., 1H), 3.30-3.13 (m, 4H), 2.29-2.16 (m, 1H), 1.99-1.97 (m, 4H), 1.84-1.55 (m, 8H). 13C NMR (75 MHz, DMSO-d6) δ 162.4, 144.8, 144.6, 134.0, 128.3, 127.2, 126.9, 116.8, 116.1, 113.5, 112.6, 49.3, 44.9, 37.4, 36.6, 33.7, 31.1, 28.2, 18.6. MS (ES+) m/z 448.3 (M+1-HCl).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:28][C:29]([CH3:37])([CH2:33][N:34]([CH3:36])[CH3:35])[C:30](Cl)=[O:31]>CC(C)=O>[CH3:28][C:29]([CH3:37])([CH2:33][N:34]([CH3:36])[CH3:35])[C:30]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[S:15][C:14]([S:16](=[O:17])(=[O:18])[NH2:19])=[CH:13][CH:12]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1)=[O:31]
Reactant: CN(C)CC(C)(C)C(=O)Cl
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)c2ccc(O)cc2)s1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)CC(C)(C)C(=O)Oc1ccc(S(=O)(=O)c2ccc(S(N)(=O)=O)s2)cc1
Reaction time: 72 h

Procedure:
A solution of 5-[(4-hydroxyphenyl)sulfonyl]thiophene-2-sulfonamide (3.19 g. 0.01 mole) in acetone (60 ml) at -10° was treated with triethylamine (1.11 g, 0.011 mole). Then 2,2-dimethyl-3-dimethylaminopropionyl chloride hydrochloride (2.20 g, 0.011 mole) was added portionwise, during 15 minutes at -10°. The cooling bath was removed and stirring was continued. After 72 hours at room temperature, the reaction mixture was heated on a steam bath for 4 hours. The reaction mixture was cooled and treated with triethylamine (1.11 g, 0.011 mole) and heated on a steam bath for 1 hour.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH2:4].[C:5]([C:8]1[CH:16]=[C:15]([CH3:17])[C:14]([CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=O)[CH3:6]>O>[OH2:3].[CH3:6][C:5]1[C:8]2[C:9](=[CH:13][C:14]([CH3:18])=[C:15]([CH3:17])[CH:16]=2)[C:10](=[O:11])[O:12][C:2]=1[C:1]([OH:4])=[O:3]
Reactant: CC(=O)c1cc(C)c(C)cc1C(=O)O
Reactant: CCO
Solvent: O
Product: Cc1cc2c(C)c(C(=O)O)oc(=O)c2cc1C

Procedure:
4,6,7-Trimethylisocoumarin-3-carboxylic acid monohydrate, mp. (EtOH-H2O) 241°, (Found: C, 62.27; H, 5.74 C13H12O4. H2O requires C, 62.39; H, 5.64) was prepared from 2-acetyl-4,5-dimethylbenzoic acid by an analogous procedure to that described in Example 2.
Reaction SMILES: [C:1]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:28])=O)[CH2:22][CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:30][O:31][NH:32][CH3:33].C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl>[CH3:33][N:32]([O:31][CH3:30])[C:26]([CH:23]1[CH2:22][CH2:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:25][CH2:24]1)=[O:28]
Reactant: CNOC
Reactant: O=C(O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-tritylpiperidine-4-carboxylic acid (7.0 g), O,N-dimethylhydroxylamine hydrochloride (2.0 g) and triethylamine (2.9 ml) in dichloromethane (70 ml) was added WSC (3.97 g), and the mixture was stirred at room temperature for 1 hour and concentrated. To the residue was added ethyl acetate, and the mixture was washed with water, dried (MgSO4) and concentrated. The resulting crystals (6.3 g) were washed with isopropylether.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](O)=[O:19])[C:11]=2[N:10]=1.[CH3:23][C:24]1([CH3:38])[O:28][C@H:27]([CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH2:26][O:25]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:23][C:24]1([CH3:38])[O:28][C@H:27]([CH2:29][O:30][C:31]2[CH:32]=[C:33]([NH:34][C:18]([C:17]3[C:11]4[N:10]=[C:9]([C:4]5[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=5[C:2]([F:1])([F:21])[F:22])[NH:13][C:12]=4[CH:14]=[CH:15][CH:16]=3)=[O:19])[CH:35]=[CH:36][CH:37]=2)[CH2:26][O:25]1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Reactant: CC1(C)OC[C@@H](COc2cccc(N)c2)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1(C)OC[C@@H](COc2cccc(NC(=O)c3cccc4[nH]c(-c5ccccc5C(F)(F)F)nc34)c2)O1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-(2-(Trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (3; 75 mg, 0.24 mmol) was taken up in NMP (2 mL) along with (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)aniline (133; 64.3 mg, 0.288 mmol) and HATU (186 mg, 0.49 mmol). DIEA (81 μL, 0.49 mmol) was added and the resulting reaction mixture was stirred at room temperature for 12 h. The temperature was then raised to 60° C. and the reaction mixture was allowed to stir for an additional 1 h. The reaction mixture was diluted with water and filtered. The collected solids were further purified by silica gel chromatography to afford the desired product 134, as a yellow solid (51.5 mg, 42%).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9](O)=[O:10].[OH:14][OH:15].[O-:16]S([O-])(=O)=O.[Mg+2]>S(=O)(=O)(O)O>[C:1]([O:13][OH:16])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:14][OH:15])=[O:10]
Reactant: O=S(=O)([O-])[O-]
Reactant: OO
Reactant: O=C(O)CCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Agent: [Mg+2]
Product: O=C(CCCCCCCC(=O)OO)OO

Procedure:
As described in example 4 50 grams (0.27 moles) of azelaic acid were treated with 72.3 grams (1.06 moles) of 50% aqueous hydrogen peroxide in 70 ml of concentrated sulfuric acid. After the addition of 170 grams of an aqueous solution of MgSO4 the reaction mixture was cooled and treated with an aqueous solution of Mg(OH)2 until a pH-value of 3 was obtained. The solids were separated by filtration and after drying there were obtained 99.5 grams of diperoxyazelaic acid, desensitized with MgSO4. The content of peroxy-acid is 39.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[OH:29])[CH:5]=1.Br[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[O:29][CH2:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:5]=1
Reactant: BrCC1CCCC1
Reactant: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3O)nc3cc(F)c(F)cc32)c1
Product: COC(=O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 3-[2-(4-chloro-2-hydroxy-phenyl)-5,6-difluoro-benzoimidazol-1-ylmethyl]-benzoic acid methyl ester and bromomethyl-cyclopentane (CAS Reg. No. 3814-30-0). Brown sticky solid (72%). MS (Turbo Spray): m/z=511.2 (M+H).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11]1)=[O:7])(C)(C)C.[CH:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35](C(O)=O)=[C:34]([O:42][CH3:43])[CH:33]=1>>[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35]([C:6]([NH:8][CH2:9][C@H:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][S:27]([C:24]3[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:11]2)=[O:7])=[C:34]([O:42][CH3:43])[CH:33]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(CCCCCN)C1
Product: COc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CCN(CCCCCNS(=O)(=O)c2ccccc2)C1

Procedure:
5-((3R)-3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)pentylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 1 using 4-benzenesulfonyl chloride (0.49 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.70 g) to give 4-amino-N-((3R)-1-(5-benzenesulfonylaminopentyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH3:1][NH2:2].CO.[CH2:5]([O:7][CH:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:24])[C:19](OCC)=[O:20])[CH3:9])[CH3:6].C1COCC1>O>[CH2:5]([O:7][CH:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[O:24])[C:19]([NH:2][CH3:1])=[O:20])[CH3:9])[CH3:6]
Reactant: CCOC(=O)C(=O)c1ccccc1COC(C)OCC
Reactant: CN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(C)OCc1ccccc1C(=O)C(=O)NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A 40% methylamine-methanol solution (1.63 g, 0.021 mol) was added to a mixed solution of ethyl 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-oxoacetate (1.96 g, 0.007 mol) and THF (7 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane (80 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (1.35 g, Yield: 72.7%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Mg]Cl.[Cl-].[NH4+]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:20])([CH3:21])[C:16]([F:17])([F:18])[F:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)(c1ccc(OCc2ccccc2)cc1)C(F)(F)F

Procedure:
A solution of 30.0 g (0.107 mol) of 4-(trifluoroacetyl)phenyl benzyl ether in 50 ml of diethyl ether was added dropwise at 0° C. to a solution of 12.0 g (0.161 mol) of methylmagnesium chloride in 150 ml of diethyl ether. After 2 hours at reflux, the mixture was poured into saturated ammonium chloride solution. 31.3 g (99% of theory) were obtained of colorless product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]1C(=O)[CH:19]3[CH2:22][CH2:23][CH:16]1[CH2:17][CH2:18]3)[CH:7]=[N:6]2.[CH3:24][O-:25].[Na+].[CH3:27][OH:28]>CO>[CH3:24][O:25][C:27]([C@H:19]1[CH2:18][CH2:17][C@H:16]([NH:15][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH2:23][CH2:22]1)=[O:28]
Reactant: CO
Reactant: C[O-]
Reactant: COc1cc2ncc(N3C(=O)C4CCC3CC4)nc2cc1OC
Agent: [Na+]
Product: COc1cc2ncc(N[C@H]3CC[C@H](C(=O)OC)CC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(6,7-dimethoxy-quinoxalin-2-yl)-2-aza-bicyclo[2.2.2]octan-3-one (100 mg, 0.32 mmole) in 10 mL of methanol is added a freshly prepared NaOMe/methanol solution (54 mg, 1 mmole) and the mixture is stirred at ROOM TEMPERATURE for 0.5 hour before concentrated. Methylene chloride is used to extract and then dried with magnesium sulfate. The residue after filtration and concentration is chromatographed on silica gel (40% ethyl acetate) to give 85 mg (77%) of cis/trans-4-(6,7-dimethoxy-quinoxalin-2-ylamino)-cyclohexanecarboxylic acid methyl ester as a light yellow solid (m.p. 68-80° C.).
Reaction SMILES: [FH:1].N1C=CC=CC=1.O1[C:10]2([CH2:19][CH2:18][CH2:17][CH2:16][C:13]3([O:15][CH2:14]3)[O:12][CH2:11]2)C1.[C:20]([O-:23])([O-])=O.[Na+].[Na+]>ClCCl>[F:1][C:18]1([CH2:20][OH:23])[CH2:17][CH2:16][C:13]2([O:12][CH2:11][CH2:14][O:15]2)[CH2:10][CH2:19]1
Reactant: C1CCC2(CO2)OCC2(C1)CO2
Reactant: O=C([O-])[O-]
Reactant: F
Agent: *CC*
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: OCC1(F)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of pyridine hydrofluoride (4 g) in dichloromethane (10 mL) was added dropwise to a solution of EXAMPLE 443A (1.7 g) in dichloromethane (20 mL) in a polyethylene bottle at 0° C. The mixture was stirred at room temperature overnight. The mixture was carefully poured over a mixture of ice-water and Na2CO3 and extracted with ethyl acetate (2×300 mL). After washing with water and brine, the organic layer was dried over Na2SO4, and filtered. Concentration of the filtrate gave the crude product.