Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)(=[O:25])[CH3:24].O>CN(C)C=O>[C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[C:4]3[CH:5]=[CH:6][S:2][C:3]=3[CH:10]=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OCCCCBr
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 55.5 %

Procedure:
1.0 g (3.9 mmol) of 1-Benzo[b]thiophen-4-yl-piperazine hydrochloride was suspended in 20 ml of dimethylformamide (DMF), and potassium carbonate (1.3 g, 9.4 mmol) and 4-bromobutyl acetate (0.7 ml, 4.8 mmol) were added thereto followed by stirring at 80° C. for 6 hours. The reaction mixture was cooled to room temperature, then water was added thereto and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1), then concentrated under reduced pressure to obtain 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate (0.72 g) as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].C([Li])CCC.[CH2:16]1[O:18][CH2:17]1>O1CCCC1.CCCCCC>[OH:18][CH2:17][CH2:16][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(CCO)c1OC
Reaction time: 17 h
Yield: 18.9 %

Procedure:
To 20 g (0.145 mol) of 1,2-dimethoxybenzene in 300 mL of anhydrous tetrahydrofuran stirred at room temperature under argon was added 90 mL (0.145 mol) of 1.6M butyl lithium in hexane over 30 minutes. The reaction mixture was stirred and heated at 40° for 4 hours and then cooled in an ice bath. Ethylene oxide (14 mL, 0.29 mol) was allowed to distill into the ice cooled reaction mixture over 45 minutes. The reaction mixture was stirred with ice bath cooling for 1.5 hours and then at room temperature for 17 hours. Most of the solvent was removed under reduced pressure and water was added to the residue. The product was extracted with ether and the dried extract was concentrated under reduced pressure to an oil. The remaining 1,2-dimethoxybenzene (7.5 g) was removed by distillation (bp 45°-60°/0.2 mm) and the residue was purified by HPLC using 20% ethylacetate-toluene to give 5 g (19% yield) of 1-(2-hydroxyethyl)-2,3-dimethoxybenzene. This intermediate (5 g, 0.028 mol) was dissolved in 100 mL of anhydrous methylene chloride and the solution was cooled in an ice bath. Triethylamine (7.7 mL, 0.056 mol) was added and followed by 2.6 mL (0.033 mol) of methane sulfonyl chloride added dropwise. The reaction mixture was stirred with ice bath cooling for two hours and then was washed with water, with sodium bicarbonate solution, dried and concentrated under reduced pressure to give (7.2 g) of 1-[(2-methanesulfonyloxy)ethyl]-2,3-dimethoxybenzene as an oil which was used without purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1>>[Cl-:1].[CH3:10][N+:11]1[CH:15]=[CH:14][N:13]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:12]=1
Reactant: Cn1ccnc1
Reactant: CCCCCCCCCl
Product: CCCCCCCCn1cc[n+](C)c1
Product: [Cl-]
Reaction time: 4 h

Procedure:
The procedure of Example 1 was repeated with minor changes. 654 g of 1-chlorooctane and 360 g of 1-methylimidazole were added into a 2000 ml three-neck round-bottom flask. The reaction temperature was set from 75 to 80° C. After four hours, the milk-like solution transferred into homogenous solution. After two days, 60 g of 1-chlorooctane was added into the reactor. The reaction was continued for three days. Then, the product was washed with ethyl acetate five times and toluene three times. After that, it was dried in vacuum for three days.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][CH2:8][C:9]1([CH2:26][CH2:27][CH3:28])[C:14]2[NH:15][C:16]3[C:17]([F:25])=[CH:18][CH:19]=[C:20]([C:22]([OH:24])=O)[C:21]=3[C:13]=2[CH2:12][CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>CN(C=O)C.O>[C:1]([Si:5]([CH3:29])([CH3:30])[O:6][CH2:7][CH2:8][C:9]1([CH2:26][CH2:27][CH3:28])[C:14]2[NH:15][C:16]3[C:21]([C:13]=2[CH2:12][CH2:11][O:10]1)=[C:20]([C:22]([N:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1)=[O:24])[CH:19]=[CH:18][C:17]=3[F:25])([CH3:3])([CH3:2])[CH3:4]
Reactant: C1COCCN1
Reactant: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(C(=O)O)c21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(C(=O)N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-5-carboxylic acid (6) (400 mg, 0.918 mmol), EDCI (211 mg, 1.10 mmol) and HOBt (186 mg, 1.38 mmol) in DMF ( 5 mL) was added diisopropylethylamine (0.80 mL, 4.59 mmol) at room temperature. Morpholine (0.12 mL, 1.38 mmol) was added to the mixture and the mixture was stirred overnight at room temperature. The solution was diluted with H2O (10 mL) and extracted with EtOAc (3×15 mL). The organic solution was brine washed (30 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 50% EtOAc in hexanes) to give 415 mg (90%) of title compound as a colorless oil. 1H NMR (CDCl3): 300 MHz δ 9.38 (s, 1H), 6.77 (m, 2H), 3.86–3.20 (m, 12 H), 2.67 (m, 2H), 1.97–1.15 (m, 6H), 0.81 (s, 9H), 0.76 (t, J=7.34 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([O:15]CCCCCC)=O)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[NH2:23][NH:24][C:25]([NH2:27])=[S:26].[OH-].[Na+].Cl>O>[OH:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13](=[O:15])[NH:27][C:25]([SH:26])=[N:24][N:23]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: NNC(N)=S
Reactant: CCCCCCOC(=O)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(S)nnc1-c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2.05 g of n-hexyl 3,4-dihydroxy-5-nitrophenylglyoxylate and 600.8 mg of thiosemicarbazide is stirred intensively at 90° for 30 minutes. The mixture is then cooled to 40° and treated with a solution of 870.1 mg of sodium hydroxide in 15 ml of water. The solution is subsequently heated to 90° for 30 minutes, cooled to room temperature and treated dropwise with 2 ml of conc. hydrochloric acid. The crystallized-out product is filtered under suction and then dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. There is obtained 6-(3,4-dihydroxy-5-nitrophenyl)-3 -mercapto-1,2,4-triazin-5(4H)-one of m.p. 282°-284° (from ethanol).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.C[Si](C=[N+]=[N-])(C)C.[NH2:20][C:21]1[C:26]([CH:27]=O)=[CH:25][CH:24]=[C:23]([CH2:29][O:30][CH3:31])[N:22]=1>O1CCCC1.C(O)(=O)C>[C:27]([C:26]1[C:21]([NH2:20])=[N:22][C:23]([CH2:29][O:30][CH3:31])=[CH:24][CH:25]=1)#[CH:1]
Reactant: CC(C)NC(C)C
Reactant: COCc1ccc(C=O)c(N)n1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C#Cc1ccc(COC)nc1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a mixture of diisopropylamine (0.15 mL, 1.1 mmol) and tetrahydrofuran (2 mL) was added dropwise n-butyl lithium (1.6 M n-hexane solution, 0.68 mL, 1.1 mmol) at −78° C., which was stirred for 30 minutes at that temperature. Trimethysilyl diazomethane (2 M n-hexane solution, 0.50 mL, 0.99 mmol) was added to the reaction mixture at −78° C., and stirred for 30 minutes at that temperature. A mixture of 2-amino-6-methoxymethyl-pyridine-3-carbaldehyde (150 mg, 0.90 mmol) described in Manufacturing Example 26-1-6 and tetrahydrofuran (1.5 mL) was added dropwise to the reaction mixture at −78° C., and stirred for 30 minutes at 0° C. The reaction mixture was cooled to −78° C., and a mixture of acetic acid (0.10 mL) and tetrahydrofuran (1 mL) was added dropwise to the reaction mixture. This reaction mixture was gradually warmed to 0° C., and partitioned into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:3) to obtain the title compound (73 mg, 50%).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:24]=[C:25]=[S:26])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[CH:1]1([NH:6][C:25]([NH2:24])=[S:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Product: NC(=S)NC1CCCC1

Procedure:
Cyclopentyl-thiourea was prepared following procedure D using cyclopentyl amine (2.4 g, 28 mmol), and Fmoc-isothiocyanate (5.6 g, 20 mmol). Purification (Silica gel, ethyl acetate/hexane 1:1, 100%) provided the product (1.6 g) as white a solid. LCMS m/z: 145 (M+1)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)C(=N)N(C)C.CN(C=O)C>[Cu]I.O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:20][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2oc(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of methyl 3-iodo-4-hydroxybenzoate 26 (1 g, 3.6 mmol), phenylacetylene (2 ml, 18 mmol), tetramethylguanidine (4.5 ml, 36 mmol), copper(I)iodide (34 mg, 1.8 mmol), bis(triphenylphosphine)palladium (II)chloride (130 mg, 1.8 mmol) and DMF (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, extracted, washed and dried. After evaporation of the solvent, the residue was purified by chromatography to give about 0.9 g of 2-phenyl-benzofuran-5-carboxylic acid methyl ester 27.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[O:10]1[CH2:14][CH:11]1[CH2:12][OH:13].[OH-:15].[Na+]>C(Cl)(Cl)Cl>[Cl:3][C:2]1[N:4]=[C:5]([O:13][CH2:12][CH:11]2[O:10][CH2:14]2)[N:7]=[C:8]([O:15][CH2:12][CH:11]2[O:10][CH2:14]2)[N:1]=1
Reactant: OCC1CO1
Reactant: [OH-]
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1nc(OCC2CO2)nc(OCC2CO2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mechanically stirred solution of 220.8 g (1.2 mol) cyanuric chloride in 1500 ml chloroform, cooled to 0°-10° C., was added 266.4 g (3.6 mol) 2,3-epoxy-1-propanol in one portion. Aqueous sodium hydroxide (50% solution; 192 g) was added to the mixture dropwise with stirring over about 3 hr maintaining the reaction temperature below 10° C. and preferably around 0°-5° C. The reaction mixture was allowed to warm slowly to room temperature. The chloroform layer was washed with distilled water until neutral and dried over magnesium sulfate. The reaction product was found by nuclear magnetic resonance to be 2-chloro-4,6-diglycidoxy-1,3,5-triazine. Analysis showed about 95% (by weight) chlorodiglycidoxytriazine. The reaction mixture also was found to contain small amounts of triglycidoxytriazine and dichloro monoglycidoxytriazine.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:11]=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:11]=[O:12]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1c(Cl)[nH]c2ncccc12
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=Cc1c(Cl)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
A mixture of 2-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (70 mg, 0.39 mmol) cupric acetate (140 mg, 0.77 mmol), phenylboronic acid (93 mg, 0.76 mmol), 4A molecular sieve (200 mg), triethylamine (106 μl), pyridine (61 μL) and dichloromethane (5.5 mL) is vigorously stirred at room temperature for 48 hr. The solids are removed by filtration through a pad of Hi-Flo and the filtrate is concentrated. The residue is purified by chromatography eluting with dichloromethane-2% methanol. Product containing fractions are combined and concentrated to give 2-chloro-1-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (25 mg, 25% yield) as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:21]=1[CH2:31][NH2:32].CCN(C(C)C)C(C)C>C(#N)C>[F:19][C:20]1[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:21]=1[CH2:31][NH:32][C:2]1[CH:3]=[C:4]([O:5][CH2:6][C:7]2[CH:11]=[CH:10][N:9]([CH3:12])[N:8]=2)[CH:13]=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17]
Reactant: NCc1ccc(OC(F)(F)F)cc1F
Reactant: Cn1ccc(COc2ccc([N+](=O)[O-])c(F)c2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(OC(F)(F)F)cc3F)c2)n1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 3-((3-fluoro-4-nitrophenoxy)methyl)-1-methyl-1H-pyrazole (70.0 g, 0.28 mol), (2-fluoro-4-(trifluoromethoxy)phenyl)methanamine (58.3 g, 0.28 mol), DIPEA (63.1 mL, 0.36 mol) and acetonitrile (350 mL) was stirred at 80° Celsius for 16 h. The reaction was cooled to RT, concentrated to dryness, and the resulting residue was recrystallized from ethanol (350 mL) and H2O (350 mL). The solid was collected by filtration and rinsed with a mixture of H2O/ethanol (3:1, 200 mL) followed by hexanes (2×300 mL) yielding the title compound as a yellow solid (116.3 g, 94.7%). MS (ESI): mass calcd. for C19H16F4N4O4, 440.1; m/z found, 441.0 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.68-8.52 (m, 1H), 8.20-8.14 (d, J=9.5, 1H), 7.39-7.34 (m, 1H), 7.34-7.31 (d, J=2.2, 1H), 7.06-6.97 (d, J=9.8, 2H), 6.42-6.33 (dd, J=9.5, 2.5, 1H), 6.33-6.24 (m, 2H), 5.09-5.01 (s, 2H), 4.60-4.52 (d, J=5.9, 2H), 3.93-3.85 (s, 3H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].Br[CH2:7][C:8](=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10]>O1CCOCC1>[NH:2]([C:3]1[S:4][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]=1)[NH2:1]
Reactant: NNC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: C1COCCO1
Product: CCOC(=O)c1csc(NN)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.7 %

Procedure:
To a stirred solution of thiosemicarbazide (911 mg, 10 mmol) in dioxane (10 mL) was added ethyl bromopyruvate (1258 μl, 10.00 mmol). The resulting solution was allowed to stir for 16 h at room temperature, then for 2 h at 60° C. Solvent was evaporated and the residue was purified by silica gel column chromatography with gradient of methanol (0-10%) in CH2Cl2 to afford 28 (500 mg, 27%) as an orange solid. LRMS (ESI): calc. 187.1; found 188.1 (MH)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:24]([NH2:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C(Cl)Cl>[CH2:24]([NH:36][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: OCCCSc1ccncc1
Reactant: CCCCCCCCCCCCN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNCCCSc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
In 120 ml of methylene chloride was dissolved 5.60 g (33.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.53 ml (39.7 mmol) of triethylamine. 3.07 ml (39.7 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off, 5.34 g (28.8 mmol) of dodecylamine was added to 7.12.g of the residue, and the mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 2.86 g of the desired compound (yield: 29.5%, yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[I:19]I>C(Cl)(Cl)Cl.C(#N)C.FC(F)(F)C([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[O:10][C:9]2=[O:18])[CH:5]=[CH:6][C:7]=1[I:19]
Reactant: II
Reactant: CC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: CC(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 106.8 %

Procedure:
Acetic acid (5R)-3-(3-fluoro-phenyl)-1,3-oxazolidin-2-one-5-ylmethyl ester (15.2 g, 60 mM) was dissolved in a mixture of chloroform (100 mL) and acetonitrile (100 mL) under nitrogen, and silver trifluoroacetate (16.96 g, 77 mM) added. Iodine (18.07 g, 71 mM) was added in portions over 30 minutes to the vigorously stirred solution, and stirring continued at ambient temperature for 18 hours. As reaction was not complete, a further portion of silver trifluoroacetate (2.64 g, 12 mM) was added and stirring continued for 18 hours. After filtration, the mixture was added to sodium thiosulfate solution (3%, 200 mL) and dichloromethane (200 mL), and the organic phase separated, washed with sodium thiosulfate (200 mL), saturated aqueous sodium bicarbonate (200 mL), brine (200 mL), dried (magnesium sulfate), filtered and evaporated. The crude product was suspended in isohexane (100 mL), and sufficient diethyl ether added to dissolve out the brown impurity while stirring for 1 hour. Filtration gave the desired product (24.3 g) as a cream solid.
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[C:19]1([CH3:31])[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([NH2:30])[S:28][CH:29]=2)=[CH:21][CH:20]=1.[C:32]([O:36][C:37]([NH:39][C:40]1[S:41][C:42]([C:45](O)=[O:46])=[CH:43][N:44]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C.CCOC(C)=O>[C:19]1([CH3:31])[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([NH:30][C:45]([C:42]3[S:41][C:40]([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:44][CH:43]=3)=[O:46])[S:28][CH:29]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2csc(NC(=O)c3cnc(NC(=O)OC(C)(C)C)s3)n2)cc1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
2-Chloro-1-methylpyridinium iodide (0.47 g, 1.84 mmol), DIEA (0.44 mL, 2.5 mmol) and 4-p-tolylthiazol-2-amine (0.24 g, 1.23 mmol) were added to a solution of 2-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (0.30 g, 1.23 mmol) in DMF (5 mL). The resulting solution was stirred at RT until completion of the reaction. Then the reaction mixture was diluted with AcOEt, washed with water, dried with Na2SO4 and concentrated. The crude product was purified by column (100% AcOEt), yielding tert-butyl 5-(4-p-tolylthiazol-2-ylcarbamoyl)thiazol-2-ylcarbamate (80 mg, 17%) as a solid.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:24])[C:12]([CH3:23])([S:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:24])[C:12]([CH3:13])([S:14]([C:17]2([CH3:25])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)(=[O:15])=[O:16])[CH3:23])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)no1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2(C)CCOCC2)no1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 14.9 %

Procedure:
To a solution of 202 mg (0.56 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionamide (prepared according to Method E) in anhydrous THF (10 mL) at −78° C. under nitrogen atmosphere were added 0.8 mL (1.4 mmol) of lithium diisopropylamide (1.8 M solution in THF/heptane/ethylbenzene) and the reaction was stirred at −78° C. for 0.5 h. Then 0.1 mL (1.6 mmol) of methyl iodide were added in one portion and stirring was continued for further 0.5 h at −78° C., before the reaction was warmed to room temperature. After 18 h at room temperature the reaction was quenched by the addition of saturated aqueous NH4Cl solution (25 mL). The mixture was extracted with ethyl acetate (3×25 mL). The organic extracts were combined, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue purified by mass-triggered preparative LCMS to afford 31 mg of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(4-methyl-tetrahydro-pyran-4-sulfonyl)-propionamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH2:23]([O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)OCc2ccccc2)C(=O)N1
Reaction time: 4 h

Procedure:
In 100 ml of tetrahydrofuran were dissolved 4.6 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and 2.5 ml of benzyl alcohol, and under cooling at 0°-5° C. 2.4 ml of pyridine and 3.6 g of dicyclohexylcarbodiimide were added to the solution in that order. The mixture was stirred at the same temperature as above for 4 hours and then at room temperature for 18 hours. The precipitated dicyclohexylurea were filtered off and the filtrate was concentrated under reduced pressure. The residue was poured into a mixture of 300 ml of 2 N hydrochloric acid and 300 ml of ethyl acetate. The ethyl acetate layer was separated, washed with 2 N hydrochloric acid, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-ethyl acetate (3:1). The eluate was concentrated under reduced pressure and the residue was dissolved in a small amount of ethyl ether. To this solution was added petroleum ether to give crystals. Yield 4.8 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:19])=O.C([O-])(O)=O.[Na+]>>[Cl:19][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)nc2cc(Cl)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1cc(Cl)c2ccc(Cl)cc2n1
Temperature: 25 °C

Procedure:
A mixture of 7-chloro-2-trifluoromethyl-4-quinolinol (4 g, 16.2 mmol) in phosphorus oxychloride (7.55 mL, 81 mmol) is heated at reflux temperature for 3 hours. After cooling to room temperature, ice (200 g) is added, the mixture is neutralized with NaHCO3 and extracted with EtOAc. The organic layer is washed with brine, dried (Na2SO4) and concentrated by rotary evaporator. The resulting tan residue is purified by flash chromatography on silica gel (1% ether in hexanes) to give 4,7-dichloro-2-trifluoromethylquinoline as a solid.