Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=2[CH2:20][N:21]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH3:23])[CH:9]=[C:10]([Cl:12])[CH:11]=1)C.[CH3:30][S-:31].[Na+].[F-].Cl>CN(C=O)C.O.CCOC(C)=O>[Cl:12][C:10]1[CH:11]=[C:6]([CH2:5][C:4]([OH:3])=[O:29])[CH:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([S:31][CH3:30])=[CH:15][C:14]=2[CH2:20][N:21]([C:24]([CH:26]2[CH2:28][CH2:27]2)=[O:25])[CH2:22][CH3:23])[CH:9]=1
Reactant: C[S-]
Reactant: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(F)cc2CN(CC)C(=O)C2CC2)c1
Agent: Cl
Agent: [F-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(Cc1cc(SC)ccc1-c1cc(Cl)cc(CC(=O)O)c1)C(=O)C1CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
{5-Chloro-2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-fluoro-biphenyl-3-yl}-acetic acid ethyl ester (0.118 g, 0.28 mmol) and sodium thiomethoxide (0.043 g, 0.62 mmol) were combined in DMF (2 mL) and stirred at 100° C. overnight. Analytical LCMS indicated that the fluoride hadn't been displaced, but the ethyl ester had hydrolyzed. Additional sodium thiomethoxide (0.040 g, 0.57 mmol) was added, and the reaction was stirred overnight at 100° C. Analytical LCMS indicated that the reaction was complete, so the mixture was acidified with 1N aqueous HCl (4 mL) and worked-up with EtOAc and H2O. The combined organic layers were dried, filtered, and concentrated, and the residue was purified by preparative HPLC to give the title compound. M+H is 418.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]2[C:3]=1[CH2:4][N:5]([CH3:15])[C:6]2=[O:14].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.[CH:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([CH3:31])[CH3:30]>CS(C)=O.O>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]3[C:3]=2[CH2:4][N:5]([CH3:15])[C:6]3=[O:14])[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: CN1Cc2c(F)ccc([N+](=O)[O-])c2C1=O
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a suspension of 4-fluoro-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one (5.0 g, 24 mmol) and potassium carbonate (3.32 g, 24 mmol), triethylamine (6.7 mL, 28.8 mmol) in dimethylsulfoxide (50 mL), 1-isopropyl piperazine (4.1 mL, 28.8 mmol) is added and the mixture is stirred at 60° C. for 4 hours. The mixture is poured into iced water, and the resulting brown solids are collected by filtration and dried in vacuo at 50° C. to afford 4-(4-Isopropyl-piperazin-1-yl)-2-methyl-7-nitro-2,3-dihydro-isoindol-1-one as brown solids in 91% yield. Rf=0.14 (AcOEt). 1H-NMR (400 MHz, CDCl3, δ, ppm): 1.09 (s, 3H), 1.11 (s, 3H), 2.70 (t, 4H), 2.80-2.74 (m, 1H), 3.19 (s, 3H), 3.21 (t, 4H), 4.37 (s, 2H), 7.01 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[Br:7][C:8]1[CH:9]=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1.CN(C)C(Cl)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:7][C:8]1[C:9]([C:5]#[N:6])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: [O-][n+]1cccc(Br)c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1ncccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trimethylsilylcyanide (10 g, 0.1 mol, 1.25 eq) were added to a solution of 3-brom-pyridine-N-oxide (80 mmol, 1 eq) in 80 mL of CH2Cl2. After that a solution of dimethylcarbamoylchloride (10.8 g, 0.1 mol, 1.25 eq). dissolved in 20 mL of dry CH2Cl2 was added drop-wise to the stirred solution. The mixture was stirred overnight at r.t. An aqueous solution of K2CO3 (80 mL, 10%) was added and the mixture was stirred for additional 10 min. The organic layer was separated and the aqueous layer was again extracted two times by means of 30 mL of CH2Cl2. The organic phases were combined and dried by means of Na2SO4. The product was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCC(O)c1ccc(O)c(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCC=Cc1ccc(O)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Hydroxy-5-(1-hydroxyoctadecyl)benzoic acid (100 mg) was dissolved in 20 ml of benzene and a trace of p-toluenesulfonic acid monohydrate added. The solution was refluxed for 10 minutes, then 10 ml of solvent was distilled. Reflux was continued for about 18 hours. Upon cooling to room temperature, the solution was extracted with 1% sodium bicarbonate solution and the solvent removed under a stream of nitrogen gas to give crystals. The material was recrystallized from methanol to give the title compound, m.p. ca. 95° C. ##STR11##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)=[CH:14][CH:13]=1.Cl>>[C:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: CC(=O)c1cccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccc(Cl)cc2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 1-(3-hydroxyphenyl)ethanone and N-(3-{1-[6-(4-chlorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.41 (s, 1H), 7.72–6.84 (m, 12H), 5.18–5.10 (m, 1H), 3.62–3.50 (m, br, 2H), 3.00–2.92 (m, 2H), 2.90–2.58 (m, 4H), 2.54 (s, 3H), 2.50–2.12 (m, 2H), 2.02–1.70 (m, br, 6H), 1.64–1.50 (m, br, 1H), 1.50–1.14 (m, br, 3H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 575.3 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)(=[O:3])[CH3:2].C(OO)(=[O:14])C>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N+:6]=1[O-:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(Br)n1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(Br)[n+]1[O-]
Reaction time: 19 h
Yield: 83 %

Procedure:
More specifically, the mercapto pyridine-1-oxide derivatives of the instant invention are prepared from known starting materials. 2-amino-6-bromopyridine which may be prepared by hydrogen bromide induced cyclization of 3-hydroxyglutaronitriles, a method described in U.S. Pat. No. 3,096,337, or by any other known process, is dissolved in an excess amount of acetic anhydride and heated at 70° C for 45 minutes and the excess acetic anhydride is hydrolyzed by the addition of 300 ml. water, to give a substantially quantitative yield (95%) of 2-acetamido-6-bromopyridine which has a melting point of 159.2°-160.0° C. The 2-acetamido-6-bromopyridine is oxidized by heating a solution thereof in glacial acetic acid with an excess of peracetic acid at 70° C for 2 hours and at 55° C for 19 hours. The reaction mixture is diluted with 1600 ml. water and concentrated in vacuum, unreacted material removed by filtration, and the solvent evaporated from the filtrate, giving an 83% yield of impure 2-acetamido-6-bromopyridine- 1-oxide which is purified and recrystallized from 2-propanol to yield fine white needles having a melting point of 180.0°-180.5° C. The mercapto derivative of 2-acetamido-6-bromopyridine-1-oxide may be prepared by reaction with an excess of sodium hydrosulfide (1M NaSH) in an aqueous-ethanol medium while stirring for 5 hours at 60° C and overnight at room temperature, adding concentrated hydrochloric acid dropwise to the cold yellow solution and collecting the light yellow solid by filtration, purifying by recrystallization from 2-propanol and obtaining pale yellow crystals having a melting point of 172.8°-173.5° C. A 79% yield of 2-acetamido-6-mercaptopyridine-1-oxide is obtained with the aforedefined process.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[OH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22](=[O:24])[CH3:23])[CH:17]=[CH:18][CH:19]=1.Cl>C(O)C.O.C(Cl)Cl>[OH:6][C:4]1[CH:3]([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([OH:13])[CH:15]=2)[CH2:21][C:22](=[O:24])[CH:23]=1
Reactant: CC(=O)C=Cc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1C(O)=CC(=O)CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 4.72 g (0.205 mol) of freshly cut sodium metal dissolved in absolute ethanol was added 16.8 g (0.105 mol) of diethyl malonate in 25 mL of absolute ethanol. To this solution was added 16.2 g (0.10 mol) of 1-(3-hydroxyphenyl)but-1-en-3-one, prepared as described by Marrion et al. in J. Biochem. vol. 45, 533, (1949), and 100 mL of absolute ethanol. The solution was stirred at ambient temperature for 17 hours, diluted with 500 mL of water and acidified with 19 mL of concentrated HCl. The mixture was diluted with 400 mL of methylene chloride and the organic layer separated, washed with 150 mL of water and dried over Na2SO4. The solvent was removed in vacuo leaving 26.5 g (96 percent of theoretical) of the above named product as a light yellow oil; 1H NMR (CDCl3 +D6 --DMSO) δ 0.8- 1.3 (m, 3H, --CH2CH3), 2.3-4.3 (m, 6H, ring protons and --CH2CH3), 5.5 (s, 1H, --CH=), 6.5-7.2 (m, 4H, ArH), 6.8 (b, 1H, ArOH), 18.0 (b, 1H, OH).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Si](Cl)(C(C)(C)C)(C)[CH3:14].N1C=CN=C1.[Li]CCCC.CI>>[CH3:14][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [Li]CCCC
Agent: c1c[nH]cn1
Solvent: CI
Product: Cc1ccc2cc(O)ccc2c1

Procedure:
React 6-bromo-2-naphthol with t-butyl dimethylsilyl chloride and imidazole, followed by adding n-BuLi and CH3I. Deprotect the hydroxyl group by reacting with n-Bu4F to produce the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3=[N:14][CH:15]=[N:16][C:17](=O)[CH:12]3[CH:11]=[N:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=[CH:11][C:12]=12
Reactant: COc1ccc(N2N=CC3C(=O)N=CN=C32)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-n2ncc3c(Cl)ncnc32)cc1
Temperature: 100 °C

Procedure:
A mixture of compound 44B (2 g, 8.26 mmol) and phosphoryl trichloride (11.51 mL, 124 mmol) was heated at 100° C. for 2 h and cooled. The reaction mixture was slowly poured onto ice. The precipitate was collected, washed with water and dried to provide the desired product. MS (APCI): m/z 261 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:33])[C@H:21]([CH3:32])[NH:22]C(=O)CC1C=CC=CC=1.[F:34][C:35]1[CH:36]=[C:37]([CH2:42][C:43]([OH:45])=O)[CH:38]=[C:39]([F:41])[CH:40]=1>>[F:41][C:39]1[CH:38]=[C:37]([CH2:42][C:43]([N:19]([C@@H:3]2[C:2](=[O:1])[NH:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C@@H:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:20](=[O:33])[C@H:21]([CH2:32][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:7]=2)[NH2:22])=[O:45])[CH:36]=[C:35]([F:34])[CH:40]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)N(C(=O)Cc1cc(F)cc(F)c1)[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that N-[(2,3-cis)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-L-phenylalaninamide (105a) was used as the amine component and 3,5-difluorophenylacetic acid was used as the acid component to afford the title compound as a 1:1 mixture with the 2S,3S diastereomer (58 mg), white solid, m.p. 115-120° C. 1H NMR (300 MHz, d6-DMSO) δ 4.45 (m, 1H), 4.75 (m, 1H), 5.10 (m, 1H), 6.70 (m, 2H), 6.95-7.90 (m, 16H), 8.25 (two d, 1H, J=8 Hz), 10.5 (m, 1H). MS APCI, m/z=572 (M+1). LC/MS: 2.68 min.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][C:16]([N:18]([C:20]2[C:21]([Cl:48])=[C:22]([C:44]([Cl:47])=[CH:45][CH:46]=2)[CH2:23][O:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[C:32]([CH3:35])[CH:31]=[C:30]3[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)[CH3:19])=[O:17])=[O:13])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN.Cl.[CH2:53]([N:55]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[Cl:48][C:21]1[C:20]([N:18]([CH3:19])[C:16](=[O:17])[CH2:15][NH:14][C:12](=[O:13])/[CH:11]=[CH:10]/[C:7]2[CH:8]=[N:9][C:4]([C:1](=[O:2])[NH:55][CH3:53])=[CH:5][CH:6]=2)=[CH:46][CH:45]=[C:44]([Cl:47])[C:22]=1[CH2:23][O:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[C:32]([CH3:35])[CH:31]=[C:30]2[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(C(=O)O)nc4)c3Cl)c2n1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cn1
Reaction time: 24 h
Yield: 19.6 %

Procedure:
To a solution of 8-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (25 mg) and methylamine hydrochloride (3 mg) in N,N-dimethylformamide (2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7 mg) and 1-hydroxybenzotriazole (7 mg) at ambient temperature, and the mixture was allowed to stand for 1 day at ambient temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(methylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]-benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (5 mg) as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].CO.I([Cl:28])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>ClCCCl>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Cl:28])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: ClCCCl
Solvent: CO
Product: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12

Procedure:
A solution of 5-acetyl-8-benzyloxycarbostyril (1.75 g, 6 mMol) in 1,2-dichloroethane (60 ml)/methanol (40 ml) and benzyltrimethylammonium dichloroiodate (4.2 g, 12 mMol) was heated at 60° C. under an argon atmosphere for 2 hours.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(C)(C)C([O-])=O.[K+].O>CS(C)=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:11])=[CH:16][CH:15]=1
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: COc1ccc(N)cc1
Agent: CC(C)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Nc2c(C)cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42 %

Procedure:
To a solution of 50 g of 2-fluoro-3-nitrotoluene in 1.1 L of DMSO are added at room temperature 59.5 g of para-anisidine (1.5 equivalents). After 5 minutes of stirring at room temperature, 57.9 g of potassium tert-butanoate (1.6 equivalents) are added to the reaction medium and the whole is heated to 110° C. for 1 hour. The reaction medium is directly hydrolyzed by adding 1 L of ice and water and then the aqueous phase is extracted several times with ethyl acetate. The organic phases are collected, dried on sodium sulphate, filtered and then dry concentrated. The raw product is chromatographed on silica gel (ether/cyclohexane:0/100, 5/95 and then 20/80) in order to provide 34.95 g of the expected compound as a dark red solid.
Reaction SMILES: [CH:1]([O-:6])([O-])[O:2][CH2:3][CH3:4].[F:7][CH:8]([F:27])[O:9][C:10]1[C:11]([F:26])=[C:12]([CH:21]=[C:22]([F:25])[C:23]=1[F:24])[C:13]([CH2:15][C:16](OCC)=O)=[O:14].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>C(OC(=O)C)(=O)C>[CH:28]1([NH:31][CH:16]=[C:15]([C:13](=[O:14])[C:12]2[CH:21]=[C:22]([F:25])[C:23]([F:24])=[C:10]([O:9][CH:8]([F:7])[F:27])[C:11]=2[F:26])[C:1]([O:2][CH2:3][CH3:4])=[O:6])[CH2:30][CH2:29]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(OC(F)F)c1F
Reactant: NC1CC1
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(OC(F)F)c1F

Procedure:
20 ml of acetic anhydride and 6 ml of ethyl orthoformate were added to the whole of the ethyl 3-difluoromethoxy-2,4,5-trifluorobenzoylacetate [(XV), R1 =--OCHF2, R3' =H, R17 =C2H5, X=X'=F] prepared as described in step (b) above, and, after the mixture had been heated under reflux for 2 hours, the excess acetic anhydride and ethyl orthoformate were removed by evaporation under reduced pressure. The residue was dissolved in 200 ml of methylene chloride, and 1.25 g (0.022 moles) of cyclopropylamine was added dropwise, whilst stirring and ice-cooling; the stirring was continued, whilst ice-cooling, for an additional 1 hour. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using a 9:1 by volume mixture of toluene and ethyl acetate as the eluent, to give 3.29 g of ethyl 3-cyclopropylamino-2-(3-difluoromethoxy-2,4,5trifluorobenzoyl)acrylate as an amber colored liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:29]=[CH:30][C:31]([F:37])=[C:32](B(O)O)[CH:33]=1)#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:30]2[CH:29]=[C:28]([C:26]#[N:27])[CH:33]=[CH:32][C:31]=2[F:37])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(F)c(B(O)O)c1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1cc(-c2cc(C#N)ccc2F)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), (5-cyano-2-fluorophenyl)boronic acid (198 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (57.8 mg), the title compound was obtained as a pale-yellow oil (yield 28.9 mg, 6%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:5])[OH:4].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C[C:16]1[CH:21]=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH2:8]([O:4][CH:3]([O:5][CH2:20][CH2:21][CH2:16][CH2:17][CH2:18][CH3:19])[C:2]([Cl:7])([Cl:6])[Cl:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CCCCCCO
Solvent: c1ccccc1
Product: CCCCCCOC(OCCCCCC)C(Cl)(Cl)Cl

Procedure:
A mixture of 5 g of chloral hydrate, 11 g of hexanol, 0.1 g of 4-methyl-benzene-sulphonic acid and 50 ml of benzene is kept at reflux temperature and the formed water is separated by means of a Dean-Stark apparatus. After a reaction time of 9 hours the benzene is washed with a sodium hydrogen carbonate solution and water, dried on magnesium sulfate, then distilled in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[OH-:11].[Na+].[CH3:13]O>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:11][CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)cccc1Cl
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: COc1cccc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.2 %

Procedure:
2-Chloro-6-fluorobenzaldehyde (51.5 g., 0.030 mole) was taken into 500 ml. of methanol. Sodium hydroxide (14.4 g., 0.35 mole) was added and the stirred reaction mixture heated to reflux for 3 hours. The mixture was cooled to room temperature, and the volume reduced to 200 ml. by distillation in vacuo. Water (400 ml.) and methylene chloride (200 ml.) were added and the two phase system equilibrated. The organic phase was separated and the aqueous phase extracted with two additional 100 ml. portions of methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the methylene chloride removed by distillation at atmospheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml. The product layer, initially present as an oil, began to crystallize at 45° C. The mixture was cooled to room temperature, granulated for 16 hours, and filtered to yield 2-chloro-6-methoxybenzaldehyde [35.6 g., 64.2%; Rf 0.2 (CHCl3 )].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][OH:42])=[O:38])([CH3:35])([CH3:34])[CH3:33].O[C:44]1[CH:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:55][CH3:56])[O:46][N:45]=1>O1CCCC1>[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][O:42][C:44]1[CH:48]=[C:47]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:55][CH3:56])[O:46][N:45]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: COc1ccccc1-c1cc(O)no1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(OCCNC(=O)OC(C)(C)C)no1
Temperature: 25 °C
Yield: 85.8 %

Procedure:
Triphenylphosphine (0.45 g) was dissolved in tetrahydrofuran (5 ml), and diethyl azodicarboxylate (0.27 ml) was added dropwise to the solution under ice-cooling with stirring, and the resulting mixture was stirred at the same temperature for 30 minutes. Then, 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) and 3-hydroxy-5-(2-methoxyphenyl)isoxazole (0.22 g) were added to the reaction mixture, followed by stirring of the resulting mixture under ice-cooling for 10 minutes and at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1) to obtain the title compound (0.33 g, 86%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH3:13].[Mn]([O-])(=O)(=O)=[O:15].[K+].[OH2:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:20]
Reactant: O
Reactant: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: COc1cc(C(=O)O)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of 1-chloro-4-methoxy-2-methyl-5-nitrobenzene (1 mmol) and potassium permanganate (4 mmol) in water (100 mL) was heated at reflux temperature for 48 hours. The mixture was allowed to cool to room temperature and the pH was adjusted 2. The solution was extracted with EtOAc (2×100 mL), then the combined organic extracts was dried (Na2SO4) and concentrated under reduced pressure to give the title compound (78%) as a solid.