Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C(=O)C)[C:3]1[S:4][CH:5]=[C:6]([CH3:16])[C:7]=1[C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>C(O)C.O>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([CH3:16])[C:7]=1[C:8](=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)N(C)c1scc(C)c1C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1scc(C)c1C(=O)c1ccccc1
Temperature: 95 °C

Procedure:
To a solution of 400 mg of N-methyl-2-acetylamino-3-benzoyl-4-methylthiophene in 8 ml of ethanol, is added 0.11 g of potassium hydroxide in 2.9 ml of water. The mixture is heated at 95°C for 30 minutes, evaporated under reduced pressure to a residue. Water is added to the residue and the resulting mixture is extracted with dichloromethane. The dichloromethane extracts are washed with water, dried over sodium sulfate and then evaporated under reduced pressure to give crystals, which are recrystallized from ethanol-ether to give 2-methylamino-3-benzoyl-4-methylthiophene as crystals having a melting point of 144° - 145°C.
Reaction SMILES: C[C:2]1[C:3](C)=[C:4]([C:13]#[C:14]CO)[C:5]2[C:10]([C:11]=1[F:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[F:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:13]#[CH:14])=[CH:3][CH:2]=1
Reactant: Cc1c(C)c(C#CCO)c2ccccc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#Cc1ccc(F)c2ccccc12
Temperature: 120 °C
Yield: 67.5 %

Procedure:
Dimethylhydroxymethyl-4-fluoro-1-naphthylacetylene (1.88 g, 8.23 mmol) and NaOH (396 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98% article, 9.90 mmol) were placed in a 30 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 20 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 946 mg of the desired compound as a yellow solid (yield: 67.5%).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)([CH3:22])[CH3:21])=[CH:16][CH:15]=1>ClCCl>[N:27]1([CH2:26][CH2:25][CH2:24][NH:23][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:15][CH:16]=2)([CH3:22])[CH3:21])[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzenesulphonyl chloride (0.25 g) in dichloromethane (3 ml) was added dropwise to a solution of N-{1-[4-(2-aminoethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propylamine (0.4 g) in dichloromethane (7 ml) with stirring at 0° C. The mixture was treated in a similar manner to Example 55 to give N-[2-(4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl)ethyl]benzenesulphonamide as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:35]([N:37]([CH2:38][CH3:39])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34])[CH3:36]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCCOc1cc2nccc(Oc3ccc(C)cc3C(=O)c3ccccc3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), diethylamine (29 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (27 mg, yield 41%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]([Cl:16])=[O:13])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cccc(Cl)c2s1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc2cccc(Cl)c2s1

Procedure:
16.6 g of the 7-chloro-2-benzo[b]thiophenecarboxylic acid prepared in A above was added to thionyl chloride (48 ml) and toluene (10 ml) and refluxed for 4 hours. Excess thionyl chloride was then removed and the resultant residue was treated with toluene (20 ml). The toluene was then removed under reduced pressure to produce 17.8 g of 7-chloro-2-benzo[b]thiophenecarboxylic acid chloride as a reddish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH2:32])[O:28][N:27]=1)[CH3:25]>>[CH:24]([C:26]1[CH:30]=[C:29]([CH2:31][NH:32][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:21])[O:28][N:27]=1)([CH3:25])[CH3:23]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: CC(C)c1cc(CN)on1
Product: CC(C)c1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)nn2)on1

Procedure:
The title compound was synthesized in analogy to Example 41, using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 3-(1-methylethyl)-5-isoxazolemethanamine (CAN. 543713-30-0) as starting materials, LC-MS (UV peak area/ESI) 100.0%, 455.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1.[CH3:15][Sn:16](C)([CH3:39])[C:17]1C=CC2C3C=CC(CO[Si](C(C)(C)C)(C)C)=CC=3OC=2C=1>>[CH3:15][Sn:16]([CH3:39])([CH3:17])[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[S:7][C:6]=2[CH:14]=1
Reactant: Brc1ccc2c(c1)sc1ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc2c(c1)oc1cc([Sn](C)(C)C)ccc12
Product: C[Sn](C)(C)c1ccc2c(c1)sc1ccccc12
Yield: 82 %

Procedure:
Using the procedure described in Example 316, but substituting 3-bromodibenzothiophene for the bromodibenzofuran 10 of Example 316, provided the title compound in 82% yield.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/C.[CH:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])OCC.[N+]([O-])([O-])=O.[NH4+]>CCO.CCOC(C)=O>[CH2:14]([O:13][CH:6]([O:10][CH2:11][CH3:12])[CH:1]=[CH:2][CH3:3])[CH3:15]
Reactant: C/C=C/C=O
Reactant: CCOC(OCC)OCC
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC=CC(OCC)OCC
Reaction time: 22 h
Yield: 88.7 %

Procedure:
Crotonaldehyde (23.64 mL, 285.35 mmol), triethyl orthoformate (57.02 mL, 342.42 mmol) and ammonium nitrate (2.28 g, 28.54 mmol) were combined in 60 mL EtOH. After 22 h at ambient temperature, the reaction was diluted with EtOAc (60 mL) and washed with saturated sodium bicarbonate solution (40 mL). The aqueous layer was back extracted with EtOAc (20 mL). The combined organics were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 36.5 g (89%) of 1,1-diethoxybut-2-ene. 1H NMR (CDCl3, 400 MHz) 5.84 (m, 1H); 5.54 (m, 1H); 4.82 (d, J=5.7 Hz, 1H); 3.64 (m, 2H); 3.49 (m, 2H); 1.73 (m, 3H); 1.21 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[F-].[K+].[F:12][C:13]([F:17])([F:16])[CH2:14]I.O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][C:13]([F:17])([F:16])[F:12])=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: FC(F)(F)CI
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Fc1cc(Cl)ccc1OCC(F)(F)F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 4-Chloro-2-fluoro-phenol (521, 5.0 g, 0.034 mol) in methanol (50.0 mL) was added potassium fluoride (2.2 g, 0.038 mol). The solvent was removed. The resulting salt was added to N,N-dimethylformaldehyde (25 mL), followed by adding 1,1,1-trifluoro-2-iodo-ethane (8.60 g, 40.9 mmol). The reaction was stirred at 50° C. overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give colorless oil (522, 2.0 g, 26%).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:13][CH2:14][CH3:15])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1cc(C(=O)OC)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCc1cc(C(=O)OC)ccc1CO
Temperature: 25 °C
Yield: 66.2 %

Procedure:
To a solution of 0.609 g (2.96 mmol) of the product of Step C dissolved in 10 mL of methanol was added 0.056 g (1.48 mmol) of sodium borohydride in small portions as the reaction mixture was stirred at room temperature under a nitrogen atmosphere. After stirring for 30 minutes the excess sodium borohydride was quenched by addition of 10% aqueous NaHSO4. The methanol was removed in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was then purified on a silica gel flash chromatography column eluted with 20% EtOAc-hexane; evaporation of the purified fractions and drying in vacuo afforded 0.408 g (66%) of the title compound.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:16]=[CH:17][C:18]=1[CH3:19])[N:10]=2
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc(N)cn1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To a solution of potassium thiocyanate (62.9 g, 647 mmol) in acetic acid (500 ml) was added benzyl {3-[(5-aminopyridin-2-yl)oxy]-4-methylphenyl}carbamate (56.5 g, 162 mmol), and a solution of bromine (27.1 g, 170 mmol) in acetic acid (100 mL) was added dropwise. The reaction mixture was stirred at room temperature for 18 hr, and the insoluble material was filtered off through a celite pad. The filtrate was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (300 mL). The obtained aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with saturated brine (100 mL), and purified by silica gel (ethyl acetate). The obtained solution was concentrated under reduced pressure, and the crystals precipitated during concentration were collected by filtration to give the title compound (48.4 g, 74%) as a pale-brown solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:5])=[O:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[S:15])=[CH:9][CH:8]=1>C(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[S:15])[NH:1][CH2:2][C:3]([NH2:5])=[O:4])=[CH:9][CH:8]=1
Reactant: NCC(N)=O
Reactant: Fc1ccc(N=C=S)cc1
Solvent: ClC(Cl)Cl
Product: NC(=O)CNC(=S)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
Glycinamide (5.0 g) and 4-fluorophenyl-isothiocyanate (9.18 g) were stirred in chloroform (200 mL). The mixture was heated at reflux for 5 minutes then stirred at ambient temperature for 20 minutes. The precipitated solid was collected by filtration, washed with chloroform and air dried to give 2-[3-(4-fluorophenyl)-thioureido]acetamide (10.7 g) as a light pink solid, m.p. 168°-170° C (dec.). Mass spectrum (EI, M.+) m/z 277. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.97 (broad s, 1H), 7.82 (broad s, 1H), 7.45-7.52 (m, 3H), 7.10-7.17 (m, 3H), and 4.06 ppm (s, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[Cl:33][CH2:34][CH2:35][NH2:36].CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[Cl:33][CH2:34][CH2:35][NH:36][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NCCCl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCCCl)[nH]2)c1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (150 mg, 0.34 mmol) synthesized in Example (18a), 2-chloroethylamine hydrochloride (78 mg, 0.68 mmol) and 4-dimethylaminopyridine (41 mg, 0.34 mmol) were dissolved in dichloromethane (15 mL), WSCI.HCl (71 mg, 0.37 mmol) was added at room temperature, and stirring was carried out for 2 hours under nitrogen atmosphere. The reaction solution was diluted with dichloromethane (150 mL), washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-60%) to afford the desired product (105 mg, yield 62%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[C:13]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][CH3:23])[C:13]([CH3:22])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)C1(C)CN(C(=O)OCc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CN(C(=O)OCc2ccccc2)CC1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of ethyl 1-benzyloxycarbonyl-4-hydroxy-3-methylpyrrolidine-3-carboxylate (0.55 g, 1.8 mmol) in N,N-dimethylformamide (10 mL), methyl iodide (0.22 mL, 3.6 mmol) and sodium hydride (55% in oil, 117 mg, 2.7 mmol) were added in an ice bath, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×3). The extract was washed with water (20 mL×3) and saturated aqueous solution of sodium chloride (20 mL) in this order, and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 2:1) to obtain 0.38 g (66%) of the title compound as a pale yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[Cl:19][S:20](O)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:14])([F:15])[F:13]
Reactant: C[C@@](O)(C(=O)Nc1cccc(Cl)c1Cl)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Temperature: 85 °C
Yield: 45.2 %

Procedure:
(R)-N-{2,3-Dichlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 74) (5.0 g, 16.6 mmol) was added in portions to cooled (0° C.) chlorosulphonic acid (5.3 ml, 81 mmol) over 15 mins and then the mixture was heated to 85° C. for 4.5 hours. The reaction mixture was cooled in an ice bath and then poured slowly onto a stirred ice-water mixture (60 ml). The mixture was extracted with DCM (2×75 ml), the DCM washed with brine, dried and evaporated. The residue was chromatographed on silica with 20% EtOAc in hexane as eluent to give the title compound as a solid (3.0 g, 7.5 mmol). NMR (CDCl3): 1.8 (s, 3H), 3.4 (s, 1H), 8.15 (d, 1H), 8.65 (d, 1H) and 9.55 (brs, 1H); m/z 400.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.[C:13]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])(=[O:17])[C:14]([CH3:16])=O>>[CH2:19]([O:18][C:13](=[O:17])[C@H:14]([CH3:16])[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2)[CH:20]([CH3:22])[CH3:21]
Reactant: Cc1ccc2cc(N)ccc2n1
Reactant: CC(=O)C(=O)OCC(C)C
Product: Cc1ccc2cc(N[C@@H](C)C(=O)OCC(C)C)ccc2n1

Procedure:
Following General Procedure AA above and using 6-amino-2-methylquinoline (Lancaster) and iso-butyl pyruvate (prepared by following General Procedure AO above), the title compound was prepared. The reaction was monitored by silica gel tlc (Rf=0.44 in 50% EtOAc/hexanes). Purification was by flash chromatography (silica gel using 50% EtOAc/hexanes as the eluant).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[NH2:13][CH2:14][C:15]1[CH:47]=[CH:46][CH:45]=[CH:44][C:16]=1[CH2:17][N:18]1[C:22]([CH3:33])([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:21](=[O:34])[N:20]([CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[CH:39]2)[C:19]1=[O:43]>ClCCl>[N:38]1([CH2:37][CH2:36][CH2:35][N:20]2[C:21](=[O:34])[C:22]([CH3:33])([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[N:18]([CH2:17][C:16]3[CH:44]=[CH:45][CH:46]=[CH:47][C:15]=3[CH2:14][NH:13][S:2]([CH3:1])(=[O:4])=[O:3])[C:19]2=[O:43])[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc3ccccc23)C(=O)N(CCCn2ccnc2)C(=O)N1Cc1ccccc1CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2cccc3ccccc23)C(=O)N(CCCn2ccnc2)C(=O)N1Cc1ccccc1CNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
0.02 ml (0.24 mmol) of methansulfonyl chloride was added to 10 ml dichloromethane solution of 0.06 ml (0.4 mmol) of triethylamine and 0.10 g (0.2 mmol) of 1-(2-aminomethyl-benzyl)-3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione prepared in Example 35-1) at 0° C. After stirring for 1 hour at room temperature, it was washed with saturated potassium carbonate solution and saturated sodium chloride solution sequentially. After removal of dichloromethane, chromatography using a solvent mixture of methanol-dichloromethane (7:93) as the eluent was carried out to obtain 0.1 g (0.18 mmol, Yield: 87%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]([Sn](CCCC)CCCC)[CH2:13][CH2:14]C.O>CN(C=O)C>[CH2:14]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH:13]=[CH2:12]
Reactant: CCCC[Sn](CCCC)CCCC
Reactant: COC(=O)c1cccc(Br)c1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1cccc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-bromobenzoate (10.0 g, 46.5 mmol) in DMF (50 mL) was added ally tributyltin (23.1 g, 69.8 mmol) followed by tetrakis(triphenylphoshine) palladium(0) (1.08 g, 0.93 mmol). After stirring 80° C. overnight the reaction mixture was poured into H2O (500 mL), extracted with ethyl acetate (three times), dried over MgSO4 and concentrated under vacuum to afford the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Oc1ccc(C=c2[nH]c(=O)c(=CCc3ccccc3)[nH]c2=O)nc1)c1ccccc1
Temperature: 150 °C
Yield: 10.3 %

Procedure:
A reaction mixture containing compound B (0.05 g, 0.16 mmole; obtained from Example 14), benzoyl chloride (15 ml, 0.16 mmole) and 50 mL of chloroform was heated to 150° C. for 2 hr. Chloroform was removed in vacuo to produce a residue. The residue was chromatographied using silica gel column with a developing solvent (CH2Cl2) to give 0.007 g (10%) of Compound 15.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[K+].CO>O>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCC(F)(F)F
Yield: 98 %

Procedure:
To 160 g of ethyl 4,4,4-trifluorobutyrate, a mixed solution of 123 g of potassium hydroxide, 900 ml of methanol and 80 ml of water was added under ice cooling and the mixture was further reacted at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was then partitioned between water and diethyl ether. The ether layer was extracted once with water and the water layer was combined with the aqueous layer which had already been partitioned. After adjusting the pH to about 1 by the addition of an aqueous 10% ice-cooled hydrochloric acid solution, the mixture was extracted three times with diethyl ether. The layers were combined and the Combined ether layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 131 g of 4,4,4-trifluorobutyric acid (yield: 98%).