Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10](=[O:12])[O:9][C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].NC1C=CC=C(C)C=1C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:8][O:9][C:10](=[O:12])[C:11]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccc2[nH]c(=O)oc(=O)c12
Agent: Cc1cccc(N)c1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(N)ccc([N+](=O)[O-])c1C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
5-Methyl-6-nitro-1H-benzo[d][1,3]oxazine-2,4-dione (8 g, 36.0 mmol) prepared from 2-Amino-6-methyl-benzoic acid (Aldrich) as described by Abood, N. A., et al. (1997) Bioorganic & Med. Chem. Lett. 7: 2105-2108 and sodium carbonate (3.82, 36.0 mmol) were stirred in methanol (180 mL, 0.1 M) at 0° C. for 0.5 hours and then at ambient temperature for 3 hours. Strongly acidic ion-exchange resin (Dowex® 50 WX4-200) was added until neutral pH and the solution was filtered. The solvent was removed under reduced pressure and silica gel chromatography (60:40 hexane/ethyl acetate) afforded Intermediate 1(a) (6.59 g) in 87% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[OH:17]O>C(O)(=O)C>[CH3:13][S:12]([C:10]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[C:3]([O:2][CH3:1])[CH:11]=1)=[O:17]
Reactant: OO
Reactant: COc1cc(SC)c([N+](=O)[O-])cc1C(=O)O
Solvent: CC(=O)O
Product: COc1cc(S(C)=O)c([N+](=O)[O-])cc1C(=O)O
Reaction time: 12 h

Procedure:
A 0.50 g portion of 2-methoxy-4-methylthio-5-nitrobenzoic acid was suspended in 5 ml of acetic acid, and 0.77 ml of 30% hydrogen peroxide aqueous solution was added thereto, followed by 12 hours of stirring. After completion of the reaction, the reaction solution was poured on crushed ice, and the thus precipitated product of interest was collected by filtration, washed with water and then dried under a reduced pressure to give 0.35 g of 4-methylsulfinyl-2-methoxy-5-nitrobenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:15]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Reactant: CCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCC(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (2.3 g., 0.01 mole) and 4-dimethylaminopyridine (100 mg.) in pyridine (15 ml.) is added octanoyl chloride (1.7 ml.) over a period of 5 minutes. The reaction mixture is stirred 11/2 hours, poured into ice water and dilute hydrochloric acid, extracted into ethylacetate, washed with water, dried over magnesium sulfate and chromatographed on 35 g of silica gel (ethyl acetatehexane 1:1) to give 0.65 g of 2-sulfamoyl-6-benzothiazolyl octanoate which melts at 114° C. after recrystallization from butyl chloride.
Reaction SMILES: Cl.[O:2]1[C:31]2[C:5](=[CH:6][C:7]3[O:12][CH:11]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[O:25][CH:24]=[CH:23][C:22]5=O)[CH2:10][O:9][C:8]=3[CH:30]=2)[O:4][CH2:3]1.Cl.CC(O)C>CO.[Pd]>[O:25]1[C:26]2[C:21](=[CH:20][C:19]([O:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH:11]3[CH2:10][O:9][C:8]4[CH:30]=[C:31]5[O:2][CH2:3][O:4][C:5]5=[CH:6][C:7]=4[O:12]3)=[CH:28][CH:27]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: O=c1ccoc2ccc(OCCCNCC3COc4cc5c(cc4O3)OCO5)cc12
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: c1cc2c(cc1OCCCNCC1COc3cc4c(cc3O1)OCO4)CCCO2
Reaction time: 24 h
Yield: 56.3 %

Procedure:
6-[3-[[(6,7-Dihydro-1,3-dioxolo[4,5-g][1,4]benzodioxin-6-yl)methyl]amino]propoxy]chromen-4-one hydrochloride (0.9 g, 2.0 mmole), prepared in Example 5 above, was dissolved in 50 ml of methanol and 4N HCl/IPA (12.5 ml, 50 mmole) and 10% Palladium on Carbon (0.2 g) were added. The mixture was hydrogenated on a Parr apparatus for 24 hours and 4 psi of hydrogen was absorbed. Water (10 ml) was added to dissolved the resulting mixture and the catalyst was removed by filteration. The filtrate was concentrated, and the residue was treated with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The extract was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was chromatographed on a silica gel column using 5% methanol in dichloromethane as an eluent. The product-containing fractions (Rf=0.47 on silica gel with 5% chloroform/methanol) were combined, concentrated, dissolved in methanol and acidified with 4N HCl/IPA until the solution was 3 in pH. The resulting precipitate was collected on a Buchner funnel and recrystallized from methanol to give 0.45 g of title compound as a white solid hydrochloride, m.p. 217°-218° C.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]=[C:9]([NH:11]C(=O)OC(C)(C)C)[S:10][C:6]=2[CH:5]=[C:4]([CH3:19])[CH:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[C:7]3[N:8]=[C:9]([NH2:11])[S:10][C:6]=3[CH:5]=[C:4]([CH3:19])[CH:3]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1cc(Br)c2nc(NC(=O)OC(C)(C)C)sc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(F)c(Cl)c2)c2nc(N)sc2c1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
To a mixture of tert-butyl 4-bromo-6-methylbenzo[d]thiazol-2-ylcarbamate (0.6 g, 1.75 mmol), 3-chloro-4-fluorophenylboronic acid (0.5 g, 2.62 mmol), palladium(II) acetate (0.08 g, 0.35 mmol), triphenylphosphine (0.3 g, 1.05 mmol) was added degassed dioxane (10 mL) and degassed 1 M aqueous sodium carbonate (5.24 mL, 5.24 mmol). The mixture was heated to 100° C. for 16 hours under argon and then diluted with ethyl acetate, washed with water, brine and concentrated. The residue was redissolved in trifluoroacetic acid (2 mL) and stirred for 15 minutes. The solvent was evaporated, the residue redissolved in dichloromethane, washed with saturated sodium hydrogen carbonate, dried with sodium sulfate and concentrated. The product was purified by column chromatography on silica gel using n-heptane:ethyl acetate (v/v=9:1-4:1) as eluent to yield the title compound as white solid (0.4 g, 80%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[C@@H:14]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:15][C@@H:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1.CO.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:35]([O:34][C:32]([NH:31][C@@H:14]([CH2:15][C@@H:16]([CH:28]([CH3:30])[CH3:29])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:23]=1)[CH:13]=[O:12])=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[C@@H](Cc1ccc(C(C)(C)C)cc1)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
At -75° C., 4.2 ml of 1.2M diisobutylaluminium hydride solution in toluene are slowly added dropwise to a solution of 1 g of 2(S)-tert-butoxycarbonylamino-4(S)-isopropyl-5-(p-tert-butyl-phenyl)-pentanoic acid methyl ester in 20 ml of toluene. The reaction mixture is then stirred for a further 30 minutes at -70° C., 10 ml of methanol are added, the mixture is poured onto a mixture of ice and 10 ml of 1N hydrochloric acid, and extraction is carried out with ethyl acetate. The title compound is obtained: Rf (dichloromethane)=0.35.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[N:14][CH:15]=[CH:16][C:6]=2[O:5]1.[C:17]([OH:22])(=[O:21])[C:18]([OH:20])=[O:19].[CH3:23][NH:24][CH3:25]>C(O)(C)C.O>[OH2:5].[C:17]([OH:22])(=[O:21])[C:18]([OH:20])=[O:19].[CH3:23][N:24]([CH3:25])[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[N:14][CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: CN1CC(CCCl)Oc2ccncc2C1=O
Reactant: CNC
Agent: O=C(O)C(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN(C)CCC1CN(C)C(=O)c2cnccc2O1
Reaction time: 72 h

Procedure:
A solution of 5 g (0.02 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,4-f][1,4]oxazepin-5(4H)-one, in 25 ml of dimethylamine was placed in a sealed vessel and stirred for 72 hr. The vessel was opened and the excess dimethylamine allowed to evaporate. The residue was dissolved in chloroform and the solvent was stripped off in vacuo to remove excess dimethylamine. The residue was partitioned between dilute sodium hydroxide and ethyl acetate. The ethyl acetate solution was concentrated and the residue was treated with 3 g (0.033 mole) of oxalic acid in 50 ml of isopropyl alcohol and enough water to dissolve the salt while boiling. The resulting crystals were recrystallized from the same solvent. Yield of product was 5.3 g (60%), m.p. 179°-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O[C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:12]1[CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]1)[N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: Brc1ccc2[nH]ncc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](n2ncc3cc(Br)ccc32)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A solution of 5-bromoindazole (15 g), tert-butyl trans-4-hydroxycyclohexylcarbamate (50 g) and triphenylphosphine (50 g) in THF was stirred at 0° C. for 15 minutes. To the reaction solution was added dropwise diisopropylazodicarboxylate (38.5 g) under nitrogen atmosphere at 0° C., and the mixture was stirred at 50° C. for 1 day. Then, the solvent was removed out, ethyl acetate (300 mL) and petroleum ether (90 mL) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:80-1:15 as the eluting solvent) to give Compound Q11 (8.00 g).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].Cl[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1
Reactant: Nc1ccc(Br)c(F)c1
Reactant: COC(=O)Cl
Product: COC(=O)Nc1ccc(Br)c(F)c1

Procedure:
The title compound, m.p. 121–122° C., was prepared in accordance with the general method of example 81a) from 4-bromo-3-fluoroaniline and methyl chloroformate.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:40][C:41]1([C:44]([OH:46])=[O:45])[CH2:43][CH2:42]1>[Br-].C([N+](C)(C)C)CCCCCCCCCCC.ClC(Cl)C>[F:29][C:2]([F:28])([F:1])[CH:3]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([Cl:26])=[C:21]([Cl:27])[CH:20]=1)/[CH:4]=[CH:5]/[C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:40][C:41]2([C:44]([OH:46])=[O:45])[CH2:43][CH2:42]2)=[O:12])=[C:8]([C:15]([F:17])([F:18])[F:16])[CH:7]=1
Reactant: O=C(O)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: NC1(C(=O)O)CC1
Agent: CCCCCCCCCCCC[N+](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=C(NC1(C(=O)O)CC1)c1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Yield: 77.1 %

Procedure:
A 250 mL round bottomed (rb) flask equipped with a magnetic stir bar, temperature probe and reflux condenser was charged with (E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (5.3 g, 11.10 mmol) and dichloroethane (DCE) (40 mL). Thionyl chloride (1.620 mL, 22.19 mmol) was added neat in one portion and the resulting reaction mixture was heated at reflux for 2.5 h. After which time the reaction mixture was allowed to cool and then concentrated to give the crude acid chloride which was used without further purification. The acid chloride intermediate was taken up in anhydrous THF (56 mL) and was added to a 250 mL flask equipped with a magnetic stir bar, a temperature probe and a reflux condenser. While stirring, dodecyltrimethylammonium bromide (0.03 g, 0.111 mmol), sodium carbonate (0.932 g, 11.10 mmol) and 1-aminocyclopropanecarboxylic acid (1.6 g, 12.0 mmol) were added in this order and stirred at reflux overnight. The reaction was allowed to cool and the white solid residue was filtered via vacuum filtration. The filtrate was concentrated to afford the title compound as a light brown solid (4.8 g, 77%). This material was used without further purification.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:15])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[OH:15][CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:6]1[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC1Cc2ccccc2C1=O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCC1Cc2ccccc2C1O

Procedure:
A solution of 1-oxoindane-2-acetic acid ethyl ester acid (5 g), described in Example 475, in dry THF (20 ml) is added to a stirred slurry of lithium aluminum hydride (3.6 g) in 120 ml of the same solvent. The reaction mixture is heated at reflux for 36 hr., allowed to cool, and decomposed with 30% aqueous solution of sodium potassium tartrate (14.4 ml). After filtration, the precipitate is washed with THF. The filtrate and washing are dried. Removal of solvent gives an oil which crystallizes from benzene to give the title compound m.p. 80°-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:17]
Reactant: Cc1ccc(Br)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(Br)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 7630.9 %

Procedure:
To a solution of 2-bromo-5-methylpyridine (4 g, 2.3 mmol) in dichloromethane (500 mL) was added m-CPBA (52 g, 304 mmol) at 0° C. The reaction mixture was stirred at room temperature for 20 hours and the then the pH was adjusted to about 9 with a saturated solution of K2CO3. The organic layers were separated and concentrated to give a residue which was purified by flash silica chromatography eluted with petroleum ether/ethyl acetate (1:1) to give 2-bromo-5-methylpyridine 1-oxide (33 g; 75%). 1H NMR (CDCL3): δ ppm 8.25 (s, 1H), 8.75 (d, 1H, J=8.4 Hz), 6.95-6.94 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=[O:2].[C:12]1([CH2:18][CH2:19]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6])=[O:2]
Reactant: OCCc1ccccc1
Reactant: O=Cc1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=Cc1ccccc1C(=O)OCCc1ccccc1
Reaction time: 0.25 h
Yield: 11 %

Procedure:
A solution of 12.72 g (84.8 mmol) 2-formylbenzoic acid, 8.27 g (67.8 mmol) DMAP and 20.69 g (169.6 mmol) 2-phenylethanol in 130 ml dichloromethane was cooled in an ice bath before adding a solution of 19.25 g (93.3 mmol) DCC in 40 ml dichloromethane for 10 min. The reaction medium was maintained under stirring at 0° for 15 min, then at 20° for 48 h. The precipitate formed during the reaction was filtered and the filtrate washed with HCl (10%, 2×) and with a saturated Na2CO3 solution (2×) and with water (2×). The organic phase was dried over Na2SO4, concentrated and chromatographed (SiO2, 8:2 heptane/ether) to give 2.38 g (11%) 2-phenylethyl 2-formylbenzoate in the pure state in the form of a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]([CH2:30][CH2:31][O:32][CH3:33])[CH2:26][C:27]([OH:29])=O)[CH:21]=[CH:22][C:23]=1[Cl:24].[Li].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>CN(C=O)C.CCOCC.C(OCC)(=O)C.O.CC#N.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]([CH3:16])[C:27](=[O:29])[CH2:26][N:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH2:30][CH2:31][O:32][CH3:33])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: COCCN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CNC(CN1CCCC1)c1ccc(Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COCCN(CC(=O)N(C)C(CN1CCCC1)c1ccc(Br)cc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine (6.0 g of 50% purity, 10.5 mmol) was dissolved in 30 mL of anhydrous DMF and treated with N-(3,4-dichlorophenyl)-N-[2-(methyloxy)ethyl]glycine, lithium salt (3.0 g, 10.5 mmol), triethyl amine (2.9 mL, 21.0 mmol), and (1H-1,2,3-benzotriazol-1-yloxy) [tris(dimethylamino)]phosphonium hexafluorophosphate (BOP Reagent, 5.6 g, 12.6 mmol). The reaction mixture was stirred for 2 hours at room temperature, after which time HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that the reaction was complete. The reaction mixture was treated with 50 mL of 50% saturated aqueous sodium bicarbonate solution and stirred for 30 minutes. The mixture was poured into 100 mL of water and 300 mL of a 1:1 ether/ethyl acetate mixture. The layers were separated and the organic phase was washed with 50% saturated aqueous sodium bicarbonate solution (2×300 mL), 1M HCl (1×300 mL), 50% saturated aqueous sodium bicarbonate solution (1×300 mL), saturated NaCl (1×200 mL), dried over magnesium sulphate, filtered, and concentrated to an orange foam. The compound was adsorbed onto approximately 30 g of silica gel and purified by column chromatography (300 g silica gel 40 um, 20 minute isocratic flush with ethyl acetate followed by gradient elution from 0% MeOH/100% CH2Cl2 to 30% MeOH/70% CH2Cl2 over 90 minutes) to give N1-[1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethyl]-N2-(3,4-dichlorophenyl)-N1-methyl-N2-[2-(methyloxy)ethyl]glycinamide (3.85 g, 7.1 mmol, 67%) as a yellow glass. MS (ES) m/e 542, 544 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([S:38][CH3:39])[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=[O:42].C(OO)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([S:38]([CH3:39])=[O:42])[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CSc1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCNC(=O)OC(C)(C)C)c1
Agent: CC(C)(C)OO
Product: CS(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c(OCCNC(=O)OC(C)(C)C)c1
Reaction time: 8 h
Yield: 212.8 %

Procedure:
To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)-benzoylamino]-N-(5-chloropyridin-2-yl)-5-chlorobenzamide (893 mg, 1.51 mmol), camphorsulfonic acid (92 mg, 0.40 mmol) and CHCl3 (8.5 mL) was added tert-butyl hydroperoxide (0.30 mL, 3.02 mmol). After stirring overnight, the mixture was chromatographed (10% EtOAc/CH2Cl2 to 10% MeOH/CH2Cl2) to give the desired product as a white solid (517 mg, 56%).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCCCCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCCCCCC(=O)O

Procedure:
From the obtained ethyl 8-methylnonanoate, 19.20 g was dissolved in ethanol (72.0 ml) and 2M NaOH aqueous solution (72.0 ml) was slowly added at 0° C. (ice bath). The mixture was heated with stirring using an oil bath at 60° C. for 1 hour, the reaction vessel was returned to room temperature and ethanol was evaporated under reduced pressure. 2M NaOH (30 ml) and water (30 ml) were added to the solution, and the solution was washed with tert-butyl methyl ether (100 ml). The aqueous layer was washed with tert-butyl methyl ether (100 ml) once again. The aqueous layer was carefully acidified with 2M HCl aqueous solution (150 ml), and the mixture was extracted twice with heptane (150 ml). The combined heptane layer was washed with water (100 ml) and then saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 8-methylnonanoic acid (15.9 g, crude yield 96.6%) as a crude product of a pale-yellow oil. As a result of the GCMS analysis, it contained structurally unidentified impurities A (0.01%), B (0.03%), C (0.04%), and D (0.07%), and the purity of 8-methylnonanoic acid was 99.6%.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([F:16])[C:13](Cl)=[N:12][C:11]=1[Cl:18])[CH3:7].O>C1COCC1>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[C:14]([F:16])[C:13]([S:3][CH2:1][CH3:2])=[N:12][C:11]=1[Cl:18])[CH3:7]
Reactant: CCOC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(F)c(SCC)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Ethanethiol (15.08 mL, 204 mmol) was added slowly to a stirred suspension of NaH (60% in Mineral oil, 8.15 g, 204 mmol) in THF and stirred for 30 min at room temperature to yield a white thick suspension. This suspension was diluted by cold THF, cooled to 0° C. and transferred to an already cooled solution of 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester (65) (48.5 g, 204 mmol) in THF at −20° C. under argon by maintaining the temperature below −10° C. The solution was stirred at −20° C. for 15 min and allowed to come at room temperature slowly. The solution was poured into water and extracted by ethyl acetate. The organic layer was dried over MgSO4 and concentrated under reduced pressure to yield 53 g (98%) of 2-chloro-6-ethylsulfanyl-5-fluoro-nicotinic acid ethyl ester (66) as brown liquid. 1H-NMR (DMSO-d6): δ 1.33 (m, 6H), 3.19 (q, J=7.2 Hz, 2H), 4.33 (q, J=7.2 Hz, 2H), 8.10 (d, J=9.6 Hz, 1H); EIMS m/z 264 (M+1).