Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[NH:13][C:12]([CH2:20][CH3:21])([CH3:19])[CH:11]1[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:25][CH:24]=[CH2:23])[C:12]([CH2:20][CH3:21])([CH3:19])[CH:11]1[CH3:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1
Reactant: C=CCBr
Solvent: CN(C)C=O
Product: C=CCN1C(C)(CC)CC(OC(=O)c2ccccc2)C(C)C1(C)CC
Yield: 23.6 %

Procedure:
To a solution of 6.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidyl benzoate (Compound 10 - prepared using the same procedure as is described in Preparation 2) in 20 ml of dimethylformamide were added 6.0 g of allyl bromide, and the mixture was heated at 110° - 115° C for 9 hours. The mixture was then concentrated by evaporation under reduced pressure and 50 ml of benzene were added. The resulting mixture was then washed, in turn, with an aqueous solution of sodium carbonate and with water and was then dried over anhydrous sodium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 1.6 g of Compound 36 as a colourless, viscous liquid (bp 163° C/0.004 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:8]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[O:11][N:10]=2)=[CH:17][CH:16]=1
Reactant: Oc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc(-c2noc(-c3sccc3Cl)n2)cc1

Procedure:
The title compound was prepared from 4-[5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-phenol and methyl bromoacetate by a procedure similar to that of Example 37 as a white solid, (30.3 mg, 52.0%). 1H NMR (DMSO-d6): 8.18 (d, J=5.1 Hz, 1H), 8.00 (d, J=8.7 Hz, 2H), 7.42 (d, J=5.1 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 4.90 (s, 2H), 1.2 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:42])=[C:4]([C:8]([I:41])=[C:9]([C:12](=[O:40])[NH:13][CH2:14][CH:15]([O:36][C:37](=[O:39])[CH3:38])[CH:16]([O:32][C:33](=[O:35])[CH3:34])[CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:10]=1[I:11])[C:5](O)=[O:6].S(Cl)([Cl:45])=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[NH2:1][C:2]1[C:3]([I:42])=[C:4]([C:8]([I:41])=[C:9]([C:12](=[O:40])[NH:13][CH2:14][CH:15]([O:36][C:37](=[O:39])[CH3:38])[CH:16]([O:32][C:33](=[O:35])[CH3:34])[CH:17]([O:28][C:29](=[O:31])[CH3:30])[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][O:20][C:21](=[O:23])[CH3:22])[C:10]=1[I:11])[C:5]([Cl:45])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(CNC(=O)c1c(I)c(N)c(I)c(C(=O)Cl)c1I)OC(C)=O
Reaction time: 1.5 h

Procedure:
15.5 g (16.4 mmol) of 3-amino-5-(2,3,4,5,6-pentaacetoxyhexylcarbamoyl)-2,4,6-triiodobenzoic acid [Example 18a)] is suspended in 80 ml of ethyl acetate and refluxed with 1.9 ml (24.6 mmol) of thionyl chloride for 5 hours. The reaction mixture is added to 30 g of sodium bicarbonate in 300 ml of water and stirred vigorously for 1.5 hours. Then, the phases are separated and the organic phase is dried on sodium sulfate, filtered, and the solution is concentrated by evaporation. The oily reaction product is foamed up in a high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.[C:13]([O-])(O)=O.[Na+]>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[OH:11]
Reactant: O=C(O)c1ccc(Cl)cc1O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cl)cc1O

Procedure:
To a mixture of 4-chlorosalicylic acid (16 g, 92.6 mmol) in MeOH (210 mL) was added conc. HCl solution (5 mL). The resultant solution was refluxed for 23 h. After cooled, solid NaHCO3 was added to neutralize the mixture and then was concentrated. The slurry was suspended in EtOAc and filtered through a silica gel plug, washing with EtOAc. The filtrate was washed with ¼saturated NaHCO3 solution (2×), brine, dried over Na2SO4, filtered and concentrated to provide the title compound (17.2 g). MS ESI(−) m/e: 185.0 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Br.Br[CH2:20][CH2:21][NH2:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3([C:10]([F:13])([F:11])[F:12])[NH:22][CH2:21][CH2:20][O:14]3)=[N:6][C:5]=2[CH:15]=1
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reactant: NCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: FC(F)(F)C1(c2nc3cc(Cl)c(Cl)cc3[nH]2)NCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (594 mg), 2-bromoethylamine-hydrobromide (860 mg) and potassium carbonate (871 mg) were dissolved in DMF (5 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (2×20 mL). The extracts were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2; 40% ethyl acetate/hexanes) to yield the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[C:7](Cl)=[O:8].C(N(CC)CC)C.[NH2:21][C:22]1[CH:43]=[CH:42][C:25]([C:26]([N:28]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[CH2:32][N:31]3[CH:39]=[CH:40][CH:41]=[C:30]3[CH2:29]2)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl>[CH:41]1[CH:40]=[CH:39][N:31]2[CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[N:28]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:7]([C:6]4[S:5][C:4]5[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=5[C:2]=4[Cl:1])=[O:8])=[CH:43][CH:42]=3)=[O:27])[CH2:29][C:30]=12
Reactant: O=C(Cl)c1sc2ccccc2c1Cl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1sc2ccccc2c1Cl
Reaction time: 0.25 h
Yield: 0.1 %

Procedure:
To a stirred solution of 0,440 g of 3-chlorobenzo[b]thiophen-2-carbonyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0,485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 18 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.49 g of solid, m.p. 220°-222° C.
Reaction SMILES: [H-].[K+].[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]23[C:20]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:21]=4[O:22][CH:16]2[CH:15]2[CH2:29][CH2:30][C:12]3([CH:13]([CH2:31][OH:32])[CH2:14]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:33]I.Cl>O1CCCC1.CCCCCC>[CH2:3]([N:10]1[CH2:19][CH2:18][C:17]23[C:20]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:21]=4[O:22][CH:16]2[CH:15]2[CH2:29][CH2:30][C:12]3([CH:13]([CH2:31][O:32][CH3:33])[CH2:14]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: COc1cccc2c1OC1C3CCC4(CN(Cc5ccccc5)CCC214)C(CO)C3
Agent: Cl
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCC1CC2CCC13CN(Cc1ccccc1)CCC31c3cccc(OC)c3OC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.1 %

Procedure:
To a suspension of 12.0 g of 35% potassium hydride in oil, prewashed with hexane, in 100 mL of tetrahydrofuran was added a solution of 9.91 g of 3-benzyl-5-hydroxymethyl-9-methoxy-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethanobenzofuro[3,2-e]isoquinoline (E. Ciganek and B. K. Wong, coassigned pending application, U.S. Ser. No. 774,025) in 50 mL of tetrahydrofuran and the mixture was heated under reflux for 4 hours. Methyl iodide (5.2 g dissolved in 10 mL of tetrahydrofuran) was added to the cooled mixture which was then stirred at room temperature for 18 hours. Addition of 5% hydrochloride acid followed by aqueous ammonium hydroxide solution and extraction with methylene chloride gave 10.47 g of 3-benzyl-9-methoxy-5-methoxymethyl-1,2,3,4,5,6,7,7a-octahydro4a,7-ethanobenzofuro[3,2-e]isoquinoline. NMR spectrum (δ in CDCl3): 7.5-7.2 (m, 7H); 6.8 (m, 2H); 4.4 (s, 1H); 3.9 (s, 3H), 3.7 (d, J=12 Hz, 1H); 3.5 (d, J=12 H, 1H) and 3.2 (s, 3H), among others.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4]=1[C:16](O)=[O:17])[CH3:2].S(Cl)(Cl)=O>>[CH2:1]([C:3]1[O:7][C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:5][C:4]=1[CH2:16][OH:17])[CH3:2]
Reactant: CCc1oc(C=Cc2ccccc2)nc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCc1oc(C=Cc2ccccc2)nc1CO

Procedure:
A mixture of 5-ethyl-2-styryl-4-oxazolecarboxylic acid (5.57 g) and thionyl chloride (17 ml) was refluxed with stirring for an hour and the thionyl chloride was completely distilled off. The residue was dissolved in dimethoxyethane (20 ml) and the solution was added dropwise to a mixture of sodium borohydride (1.74 g) and dimethoxyethane (50 ml) under cooling with ice-sodium chloride and stirring. The whole mixture was stirred for 15 minutes, adjusted to pH 2 with 2N hydrochloric acid and refluxed for 30 minutes. The reaction mixture was concentrated, neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was treated with hexane to give 5-ethyl-4-hydroxymethyl-2-styryloxazole as crystals; yield 4.37 g (83.4%). Recrystallization from ethyl ether gave colorless prisms melting at 90°-91° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.[OH-].[K+].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[CH2:17]([N:4]1[C:5]2[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1n[nH]c2cccc([N+](=O)[O-])c12
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1nn(Cc2ccccc2)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
To a solution of 3-methyl-4-nitro-1H-indazole (0.100 g, 0.564 mmol) in acetone (0.4M, 1.4 mL) cooled to 0° C. was added potassium hydroxide (0.0475 g, 0.847 mmol). After 15 minutes at 0° C., (bromomethyl)benzene (0.0737 ml, 0.621 mmol) was added. The mixture was allowed to stir at ambient temperature overnight and then concentrated. The residue was purified on silica gel (10-50% EtOAc in hexanes) to provide 1-benzyl-3-methyl-4-nitro-1H-indazole (0.052 g, 34% yield) as a yellow gum.
Reaction SMILES: CN(C)C=O.[C:6]([NH:9][C:10]1[N:19]=[C:18]([OH:20])[C:17]2[C:12](=[N:13][CH:14]=[C:15]([CH:21]=O)[N:16]=2)[N:11]=1)(=[O:8])[CH3:7].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.B.CNC>C(O)(=O)C>[C:6]([NH:9][C:10]1[NH:19][C:18](=[O:20])[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:16]=2)[CH2:21][NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=2)[N:11]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)Nc1nc(O)c2nc(C=O)cnc2n1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: B
Agent: CNC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(NCc2cnc3nc(NC(C)=O)[nH]c(=O)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.07 g (10 m ole) of the dimethylformamide solvate of 2-acetamido-4-hydroxypteridine-6-aldehyde, 3.30 g (20 mmole) of ethyl p-aminobenzoate and 50 ml of glacial acetic acid is stirred at ambient temperature for 30 minutes. To the resulting suspension is added dropwise 1.00 g of dimethylamine borane in 15 ml of acetic acid. The mixture is stirred for an additional 20 minutes, heated to 60° C for 10 minutes and cooled to 25° C. The precipitate is collected by filtration, washed with acetic acid and ether and then dried. The crude product is crystallized from 50 ml of dimethylformamide, with dilution by 20 ml ether, to yield ethyl N2 -acetylpteroate.
Reaction SMILES: [S:1]([O-:17])([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:3])=[O:2].[Na+].Cl>>[S:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])([OH:17])(=[O:2])=[O:3]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCCCCCCCCCCCOS(=O)(=O)O

Procedure:
When sodium lauryl sulfate is used as the surfactant (4), the acid of step (B) is preferably a dilute mineral acid, such as hydrochloric acid. The dilute hydrochloric acid reacts with the sodium lauryl sulfate to give hydrogen lauryl sulfate, which is an active polymerization catalyst for the polydiorganosiloxane oligomer.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.Cl[C:20](Cl)(Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[CH2:9]([NH:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:17][CH:18]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: ClC(Cl)(Cl)c1ccccc1
Reactant: CCCCCCCCNC(=O)c1ccc(N)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)c1ccc(N=C(Nc2ccc(C(=O)NCCCCCCCC)cc2)c2ccccc2)cc1

Procedure:
N,N'-Bis(4-n-octylcarbamylphenyl)benzamidine (4) was prepared from 4-amino-N-n-octylbenzamide and α,α,α-trichlorotoluene; pale-yellow oil: 1H-NMR (CDCl3) 7.7-6.9 (m, 14H), 6.2 (br t, 2H, J=6 Hz), 3.3 (br q, 4H, J=6 Hz), 1.7-0.7 (m, 30H); IR (CHCl3) 3430, 1640, 1590; MS (m/e) 582 (M+), 335 (base).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14])=[O:8])(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([OH:15])=[O:14])=[O:8]
Reactant: CCOC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(NC(=O)C(CS)Cc2ccccc2)c1
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Ethyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)-amino]benzoate (6.37 g) is dissolved in methanol (100 ml), and thereto is added 1 N aqueous sodium hydroxide solution (49.5 ml) under ice cooling, and the mixture is stirred for 2 hours under nitrogen. After stirring further at room temperature overnight, the reaction mixture is acidified with saturated aqueous citric acid solution, and methanol is distilled off under reduced pressure. To the residue is added water (50 ml), and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and the precipitates are separated by filtration to give the title compound (4 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([C:17]([N:19]([CH:33]([CH3:35])[CH3:34])[C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)=[O:18])[C:14]([CH3:16])=[CH:15][C:10]=2[O:9][C:8]([CH3:37])([CH3:36])[C:7]1=[O:38].[H-].[Na+].CN(C)C=O.Br[CH:47]1[CH2:49][CH2:48]1>O>[CH:47]1([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:11]3[CH:12]=[C:13]([C:17]([N:19]([CH:33]([CH3:34])[CH3:35])[C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:21]4)=[O:18])[C:14]([CH3:16])=[CH:15][C:10]=3[O:9][C:8]([CH3:36])([CH3:37])[C:7]2=[O:38])[CH2:49][CH2:48]1
Reactant: BrC1CC1
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCCCO)C(=O)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCCCOC1CC1)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3R)-3-[{[4-(4-hydroxybutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added sodium hydride (60 mg) and N,N-dimethylformamide (3 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added bromocyclopropane (0.30 ml), and the mixture was stirred at 150° C. for 6 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (30 mg) as a colorless liquid.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=4)=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[C:14]([N:16]2[CH2:19][CH:18]([C:20]([O:22]C)=[O:21])[CH2:17]2)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O>C1COCC1.O>[C:1]([C:5]1[S:9][C:8]([C:10]([NH:12][C@@H:13]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=4)=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[C:14]([N:16]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[CH2:17]2)=[O:15])=[O:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)OC)C4)cc3)nc2)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)s4)C(=O)N4CC(C(=O)O)C4)cc3)nc2)cc1
Reaction time: 24 h
Yield: 69.8 %

Procedure:
To a stirred solution of (S)-methyl 1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylate (341 mg, 0.489 mmol) in THF (10 mL) was added sulfuric acid (3 mL of a 5 M aqueous solution, 15 mmol). After 24 h, the mixture was diluted with water (100 mL) and extracted with EA (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4 and solvents evaporated. Column chromatography (AcOH/EA/DCM/iso-hexanes) gave 233 mg (70%) of (S)-1-(2-(5-(tert-butyl)thiophene-2-carboxamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoyl)azetidine-3-carboxylic acid Compound 635 as a white solid. LCMS-ESI (m/z) calculated for C39H46N4O5S: 682.3; no m/z observed, tR=10.17 min (Method 10). The chiral purity was >98% e.e. (Chiral Method). 1H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 9.17 (d, J=1.8 Hz, 2H), 8.77 (app dd, J=8.3, 2.7 Hz, 1H), 8.32 (dd, J=8.2, 4.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.70 (d, J=3.9 Hz, 1H), 7.47-7.52 (m, 2H), 7.11-7.07 (m, 2H), 6.93 (app dd, J=3.9, 1.4 Hz, 1H), 4.70-4.63 (m, 1H), 4.43 (t, J=9.0 Hz, 0.5H), 4.30 (dd, J=8.7, 6.0 Hz, 0.5H), 4.21 (t, J=8.9 Hz, 0.5H), 4.15 (dd, J=8.5, 6.3 Hz, 0.5H), 4.08-3.99 (m, 3H), 3.47-3.40 (m, 1H), 3.93-3.87 (m, 1H), 3.15-3.01 (m, 2H), 1.77-1.70 (m, 2H), 1.49-1.16 (m, 17H), 0.88 (t, J=6.8 Hz, 3H).
Reaction SMILES: O.O.[Na].[Na].[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1)(O)=[O:6].[NH3:25]>S(Cl)(Cl)=O>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH:18]=[CH:17]3)=[CH:10][CH:9]=1)(=[O:6])[NH2:25]
Reactant: O=C(O)c1ccc(-c2ccc3[nH]c(=O)ccc3c2)cc1
Reactant: N
Agent: [Na]
Solvent: O=S(Cl)Cl
Solvent: O
Product: NC(=O)c1ccc(-c2ccc3[nH]c(=O)ccc3c2)cc1

Procedure:
A suspension of 6-[4-carboxyphenyl]-2-(1H)-quinolone disodium salt dihydrate (0.5 g) (see Example 13B) in thionyl chloride (10 cm3) was heated under reflux for 10 minutes. The cooled solution was evaporated in vacuo to afford a yellow solid which was treated without purification with aqueous ammonia solution (5 cm3, S.G. 0.88) with stirring. The solid material was filtered off and warmed with chloroform:methanol, 4:1, to remove soluble impurities and the remaining solid was filtered to afford the title compound, m.p. >320°, (0.3 g).
Reaction SMILES: O.O.O.[Br:4]([O-])(=O)=O.[Na+].[Cl:9][C:10]1[C:18]2[O:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][C:14]=2[CH:13]=[C:12]([C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)=[O:25])[C:11]=1[Cl:32]>O.C(O)(=O)C>[Cl:9][C:10]1[C:18]2[O:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:15][C:14]=2[CH:13]=[C:12]([C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[Br:4])=[O:25])[C:11]=1[Cl:32]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CCOC(=O)C1Oc2cc(C(=O)c3ccnn3C)c(Cl)c(Cl)c2O1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1Oc2cc(C(=O)c3c(Br)cnn3C)c(Cl)c(Cl)c2O1
Reaction time: 15 h
Yield: 41.2 %

Procedure:
A solution of 1.53 g of sodium bromate trihydrate in 5 ml of water is added to a solution of 2.0 g of ethyl 4,5-dichloro-6-(1-methyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate in 20 ml of acetic acid at room temperature. The mixture is stirred at the same temperature for 15 hours. The reaction mixture is concentrated under reduced pressure to remove acetic acid. The residue is neutralized by addition of an aqueous saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane-ethyl acetate) to give 1.0 g of ethyl 4,5-dichloro-6-(1-methyl-4-bromo-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylate as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[C:31]([C:40](O)=[O:41])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[C:37]2[C:32](=[CH:33][C:34]([O:38][CH3:39])=[CH:35][CH:36]=2)[C:31]([C:40]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:41])=[CH:30][CH:29]=1
Reactant: COc1ccc2c(OC)ccc(C(=O)O)c2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc2c(OC)ccc(C(=O)N3CCC(N4N=C(c5ccc(OC)c(OC)c5)C(C)(C)C4=O)CC3)c2c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 4,7-dimethoxynaphthalene-1-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from diethyl ether to yield the title compound.