Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C([N:20]1[CH2:24][CH2:23][C@H:22]([F:25])[CH2:21]1)(OC(C)(C)C)=O>C(#N)C>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:7][CH:8]=1.[F:25][C@H:22]1[CH2:23][CH2:24][NH:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: F[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Methylbenzenesulfonic acid monohydrate (752 mg, 3.95 mmol) was added to a stirred solution of Step 2 intermediate (280 mg, 1.48 mmol) in dry acetonitrile (20 ml) and the mixture was stirred at room temperature for 24 h under nitrogen atmosphere. The solvent was evaporated under reduced pressure and the oily residue obtained was triturated with dry diethyl ether (10 ml) to give 563 mg of the product as a white crystalline solid, which was used as such for the next step; IR (neat) 3443, 3019, 2783, 1626, 1434, 1215, 1034 cm−1
Reaction SMILES: [CH:1]([C:3]1[NH:8][C:7]([CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23])=O.S(O)(O)(=O)=O.[NH2:31]O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C.C(OCC)(=O)C>[C:1]([C:3]1[NH:8][C:7]([CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[CH:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:4]=1[C:22]([O:24][CH3:25])=[O:23])#[N:31]
Reactant: NO
Reactant: COC(=O)C1=C(C=O)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C1=C(C#N)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a solution of 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 6-formyl-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (3.00 g) in acetic acid (15 ml) were added hydroxylamine sulfate (2:1) (0.49 g) and sodium acetate (0.57 g), followed by stirring at ambient temperature for an hour. To the resulting mixture was added acetic anhydride (15 ml), followed by stirring at ambient temperature for 2 hours and under reflux for additional 2 hours. The reaction mixture was evaporated under reduced pressure and the residue obtained was dissolved in ethyl acetate. This solution was successively washed with water, an aqueous sodium bicarbonate and an aqueous sodium chloride, followed by drying over anhydrous magnesium sulfate. After removal of the solvent, the residual oily product (3.6 g) was subjected to column chromatography using silica gel (90 g). Elution was carried out with a mixture of ethyl acetate and toluene (1:10 to 1:4 by volume) and the fractions containing the desired compound were collected and evaporated to give 3-nitrooxy-2,2-bis(nitrooxymethyl)propyl ester of 6-cyano-5-methoxycarbonyl-2-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CC([S@](N)=O)(C)C.C(Cl)Cl>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Ti+4]
Agent: CC(C)(C)[S@](N)=O
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)/N=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 139 %

Procedure:
To a solution of 4-chlorobenzaldehyde (2.88 g, 20.5 mmol), (S)-(−)-2-methyl-2-propanesulfinamide (1.40 g, 11.6 mmol), and (R)-(+)-2-methyl-2-propanesulfinamide (1.40 g, 11.6 mmol) in anhydrous tetrahydrofuran (30.0 mL) under nitrogen atmosphere was added titanium tetraisopropoxide (6.00 mL, 20.3 mmol) dropwise. The clear solution was stirred at room temperature for 3 hours. Methylene chloride (200 mL) and water (2.0 mL) were added and the mixture was stirred at room temperature for 1 hour. The suspension was filtered through Celite and washed with DCM. The filtrate was concentrated in vacuo and purified by column chromatography (gradient elution: 0-20% EtOAc/hexane) to afford N-[(E)-(4-chlorophenyl)methylene]-2-methylpropane-2-sulfinamide (3.93 g, yield 78.7%). LCMS: (FA) ES+ 244; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.78-7.80 (d, 2H, J=8.53 Hz), 7.44-7.47 (d, 2H, J=8.53 Hz), 1.26 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:15](=[O:18])[N:4]3[CH:5]=[CH:6][C:7]([C:8]4[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=4)=[C:2]([Cl:1])[C:3]3=[N:17]2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(-c2ccn3c(=O)[nH]nc3c2Cl)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(-c2ccn3c(=O)n(Cc4ccc(C(F)(F)F)cc4)nc3c2Cl)cc1
Temperature: 25 °C
Yield: 62.6 %

Procedure:
To a stirred solution of 8-chloro-7-p-tolyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.39 mmol) in acetone (10 mL) at room temperature under argon was added 1-(bromomethyl)-4-(trifluoromethyl)benzene (111 mg, 0.46 mmol), followed by K2CO3 (107 mg, 0.77 mmol). The resulting suspension was heated at reflux overnight. Analysis by HPLC/MS indicated that starting material had been consumed. After cooling the reaction mixture to room temperature, most of the solvent was removed under reduced pressure. Water (15 mL) and EtOAc (15 mL) were added. The layers were separated. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with ethyl acetate-hexanes) to obtain 102 mg of the title compound as a white solid. HPLC/MS: retention time=4.03 min, [M+H]+=418. 1H NMR (CDCl3): δ 7.77 (d, J=7.0 Hz, 1H), 7.61-7.45 (m, 4H), 7.38 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 6.58 (d, J=7.0 Hz, 1H), 5.31 (s, 2H), 2.46 (s, 3H). N-alkylation, rather than O-alkylation, was demonstrated by the presence of a 13C NMR resonance at 49.6 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:24])[C:12]1[C:13]([CH3:23])=[C:14]([CH:19]=[C:20]([Cl:22])[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)cc(NCCNC(=O)OC(C)(C)C)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)CCNC(=O)OC(C)(C)C)c1C
Temperature: 80 °C
Yield: 62.4 %

Procedure:
To a stirred solution of methyl 3-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-chloro-2-methylbenzoate (0.5 g, 1.46 mmol) in acetonitrile (10 mL), cesium carbonate (0.95 g, 2.92 mmol) and methyl iodide (1 g, 7.3 mmol) were added and the resulting reaction mixture heated at 80° C. for 12 h. On completion, the reaction mixture was cooled to room temperature and filtered, the residue washed with ethyl acetate and the filtrate concentrated before purification by column chromatography to afford desired product (0.325 g, 62%).
Reaction SMILES: [Na].[Na].[OH:3][C:4]1[C:5](=[O:12])[CH:6]=[C:7]([CH2:10][OH:11])[NH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22]Cl.O>CS(C)=O.C(Cl)(Cl)Cl>[O:12]1[C:5]2[CH:6]=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][C:4]=2[O:3][CH2:22][CH2:21][CH2:20]1
Reactant: O=c1cc(CO)[nH]cc1O
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: OCc1cc2c(cn1)OCCCO2
Temperature: 95 °C
Reaction time: 0.75 h

Procedure:
To a solution of 0.11 kg of 5-hydroxy-2-(hydroxymethyl)-1,4-dihydropyridin-4-one disodium salt in 600 mL of dimethyl sulfoxide, 0.25 kg of potassium carbonate and 81 mL of 1-bromo-3-chloropropane were added, and the mixture was stirred at 80 to 90° C. for 3 hours 20 minutes, at 90 to 100° C. for 45 minutes, and further at 80 to 95° C. for 5 hours. The reaction mixture was cooled to room temperature, water and chloroform were then added thereto, and the insoluble substance was filtered off. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol=10:1 to obtain 31 g of (3,4-dihydro-2H-(1,4)dioxepino(2,3-c)pyridin-8-yl)methanol as a brown oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH2:12].Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Nc1ccc(C(F)(F)F)cc1F
Reactant: CCOC(=O)CBr
Product: CCOC(=O)CNc1ccc(C(F)(F)F)cc1F

Procedure:
Prepared analogously to Example 165a starting from 2-fluoro-4-trifluoromethyl-phenylamine and ethyl bromoacetate. The crude product was purified by column chromatography (silica gel, gradient dichloromethane/MeOH 20:0→19:1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](=[O:35])[C:20]1[CH:25]=[CH:24][C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[F-].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:17][O:18][C:19]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1)=[O:35]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN(C(C)(C)C)S(=O)(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: COC(=O)c1ccc(-c2ccc(S(=O)(=O)N(C)C(C)(C)C)cc2)cc1
Yield: 64.6 %

Procedure:
Procedure S′: 4′-(tert-Butyl-methyl-sulfamoyl)-biphenyl-4-carboxylic acid methyl ester is prepared in a manner substantially analogous to Procedure O′ using 4-bromo-N-tert-butyl-N-methyl-benzenesulfonamide (459 mg, 1.5 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (CAS 17136-80-0) (490 mg, 1.87 mmol), tricyclohexylphosphine (65 mg, 0.23 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), and CsF (906 mg, 6 mmol) to give the intermediate 4′-(tert-Butyl-methyl-sulfamoyl)-biphenyl-4-carboxylic acid methyl ester (350 mg, 65% yield). MS (ES+) 384.1 (M+Na)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH2:32][CH2:33][N:34]([CH3:36])[CH3:35])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N(C)CCN(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N(C)CCN(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-(2-dimethylamino-ethyl)-4,N-dimethyl-benzenesulfonamide (Intermediate 154), the title compound was obtained as a yellow sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>C(O)C>[CH2:10]([N:9]([C:20]([NH:19][CH2:17][CH3:18])=[O:21])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)NNCc1ccccc1
Solvent: CCO
Product: CCNC(=O)N(Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
To a solution of N′-benzylhydrazinecarboxylic acid tert-butyl ester (2.5 g, 11.8 mmol) in 99% ethanol (40 ml) was added ethyl isocyanate (1.1 g, 15.2 mmol) and the mixture was stirred for 2 h. Then the mixture was concentrated in vacuo and chromatographed on silica (20 g) with petrol etherlethyl acetate 3:2 to give 3.0 g of 2-benzyl-1-tert-butoxycarbonyl-4-ethylsemicarbazide.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[CH:11]1([C:20](O)=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1>C(OCC)C.O1CCCC1>[CH:11]1([CH2:20][OH:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)C1CCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.4 %

Procedure:
To a suspension of LiAlH4 (4.7 g) in diethyl ether (200 ml) was added dropwise a solution of AlCl3 in diethyl ether (200 ml). A solution of 1-indanecarboxylic acid (10 g) (prepared according to the method of Hansen et al. Helv. Chim. Acta 1982, 33, 325-343) in dry tetrahydrofuran (200 ml) was added drop-wise at 10-15° C. The mixture was finally stirred at room temperature for 1.5 hours. Excess AlH3 was destroyed by addition of concentrated aqueous NaOH solution (25 ml) at 0° C. Precipitated inorganic salts were filtered off and the solvents evaporated in vacuo leaving 6.8 g of the title compound 1a as a viscous oil which was used without further purification.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+:14]>C(#N)C>[C:1]1(/[CH:7]=[CH:8]/[S:9]([NH2:14])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: NS(=O)(=O)/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 38 %

Procedure:
3.3 g (1 mol equiv.) Trans-2-phenyl-ethenesulfonyl chloride was dissolved in 33 mL acetonitrile and cooled to 0° C. Dropwise, 7.7 mL (3 eq) ammoniumhydroxide was added and the reaction mixture was stirred at room temperature for 10 min. Volatiles were removed under reduced pressure, and the solid residue was washed with water and dried in vacuo to afford 1.13 g (38%) trans-2-phenyl-ethenesulfonic acid amide. 1H NMR (400 MHz, DMSO-d6) δ 7.11 (br.s., 2H), 7.23 (d, J=16.0 Hz, 1H), 7.31 (d, J=16.0 Hz, 1H), 7.41-7.45 (m, 3H), 7.64-7.71 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:23]2[S:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])[CH:19]=[CH:20][C:21]=1[CH3:22]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:29]([C:24]3[N:25]=[C:26]([CH3:28])[S:27][C:23]=3[C:18]3[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([CH3:15])[CH:17]=3)=[O:30])[CH2:10]2)=[N:6][CH:7]=1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(C)c(C)c2)s1
Product: Cc1nc(C(=O)N2CCC[C@@H](Nc3ncc(Br)cn3)C2)c(-c2ccc(C)c(C)c2)s1

Procedure:
prepared by reaction of (R)-(5-bromo-pyrimidin-2-yl)-piperidin-3-yl-amine with 5-(3,4-dimethyl-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@H:39]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[C:66]([OH:72])([C:68]([F:71])([F:70])[F:69])=[O:67]>ClCCl>[F:69][C:68]([F:71])([F:70])[C:66]([OH:72])=[O:67].[CH3:6][NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:25]([O:59][CH3:60])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:57][CH3:58])[C@@H:35]([CH3:56])[C:36]([NH:38][C@@H:39]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26 mg (29 μmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzyloxy)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 1.8 ml of dichloromethane, and 370 μl of TFA were added. The reaction mixture was stirred at RT for 30 min and then concentrated. The residue was taken up in water and lyophilized. 26.4 mg (quant.) of the title compound were obtained.
Reaction SMILES: C1(C[O:8][C:9](=[O:49])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:26]=[C:25]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:24]=[C:25]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH:26]=[C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:28]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:49])=[O:8]
Reactant: CCCCCCCCCCc1cc(CCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cc(CCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 5 h
Yield: 81.3 %

Procedure:
A mixture of 1.65 g of N-(3,5-didecylphenyl)-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 100 ml of THF was shaken under an initial hydrogen pressure of 53 psi for 5 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from methanol-water to give 0.98 g (81% yield, mp 78°-81°) of N-(carboxymethyl)-N-(3,5-didecylphenyl)glycine.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[Cl-].[OH:16][C@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[NH3+:23].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([NH:23][C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[OH:16])=[O:14])[CH:3]=1
Reactant: [NH3+][C@@H]1CCCC[C@@H]1O
Reactant: O=C(O)c1cc(Br)c2ccccc2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCC[C@@H]1O)c1cc(Br)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the 4-bromoquinoline-2-carboxylic acid (A3) (0.10 g, 0.40 mmol) in 2.0 mL, CH2Cl2 was added (cis)-2-hydroxycyclohexanaminium chloride (0.12 g, 0.80 mmol), BOP reagent (0.35 g, 0.80 mmol), and triethylamine (0.16 mL, 1.2 mmol). The reaction mixture was stirred at room temperature for 16 h, diluted with CH2Cl2, washed with water, dried over sodium sulfate, filtered, and concentrated. The resultant residue subjected to silica gel chromatography eluting with 0-60% ethyl acetate in hexanes to afford 4-bromo-N-[(cis)-2-hydroxycyclohexyl]quinoline-2-carboxamide (I1) that gave a mass ion (ES+) of 349.2 (79Br) for M+H+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:4]([CH2:16][CH3:17])[N:3]=1.[N+:18]([O-])([OH:20])=[O:19].S(=O)(=O)(O)O>N>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[C:13]([N+:18]([O-:20])=[O:19])[CH:14]=2)=[C:4]([CH2:16][CH3:17])[N:3]=1
Reactant: CCc1nc(N)nc(N)c1-c1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: CCc1nc(N)nc(N)c1-c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 60 h
Yield: 93.8 %

Procedure:
2,4,-Diamino-5-(4-chlorophenyl)-6-ethylpyrimidine (103.8 g, 0.417 mol) ("Pyrimethamine" obtained from Sigma Chemical Co. Ltd.) was added in portions to a stirred mixture of concentrated nitric acid (210 ml) and concentrated sulphuric acid (210 ml). The mixture was heated at 50° C. for 1 h and then set aside at room temperature for 2.5 days. The reaction mixture was poured onto concentrated ammonia ("0.88" 5 dm3)/ice to effect a neutralisation. The resulting precipitate was collected by filtration and washed with water and sucked to dryness to give nitropyrimethamine as a yellow solid (115 g, 93.8% yield).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([NH2:17])[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([NH2:17])=[CH:11][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
Benzoyl chloride (10.7 ml, 92.5 mmol) was added to a stirred solution of 1,4-phenylenediamine (10.0 g, 92.5 mmol) and triethylamine (14.2 ml, 102 mmol) in dichloromethane (250 ml) at 0° C. The reaction was allowed to warm to ambient temperature over 3 hours, the solid was filtered off and water (100 ml) was added to the filtrate, causing precipitation of a second solid. Collection of this solid by suction filtration and drying in vacuo yielded N-benzoyl 4-aminoaniline (5.55 g, 28% yield) as a white solid:
Reaction SMILES: Br.[N:2]1([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31].O>CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11]3)[CH2:3][CH2:4]1)=[O:31]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=C1Cc2cc(N3CCNCC3)ccc2N1
Agent: Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CC(=O)N4)CC2)cc1OC
Yield: 58.6 %

Procedure:
5-(1-Piperazinyl)oxindol.hydrobromide (2.0 g) was suspended in 30 ml of N,N-dimethylformamide (DMF), and 2.3 ml of triethylamine was added thereto subsequently. The mixture was cooled to 0° to 5° C. To the mixture was added dropwise 5 ml of DMF solution containing 1.5 g of 3,4-dimethoxybenzoyl chloride at the same temperature as above with stirring. After completion of addition, the mixture was stirred at room temperature for one hour. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate and chloroform was removed by distillation. The residue was purified by silica-gel column chromatography (eluent: chloroform:methanol=100:1) and recrystallized from methanol to give 1.5 g of 5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]oxindol.