Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 95.9 %

Procedure:
4-amino-5-chloro-2-methoxybenzoic acid (compound of formula 9) (16.6 g, 82.28 mmol) was dissolved in dimethylformamide (166 mL) and the solution was cooled to 0° C. Then, tertiary butyl 4-(aminomethyl)piperidine-1-carboxylate (21.16 g, 98.74 mmol), triethylamine (11.56 mL, 246.84 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC, 20.51 g, 106.96 mmol), and 1-hydroxybenzotriazole (HOBT, 16.68 g, 123.42 mmol) were added thereto. The reaction mixture was warmed to room temperature, stirred for 4 hours, and extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the title compound (31.4 g, 96%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.N.CO.C(Cl)Cl>CC(O)=O>[CH:1]1([N:6]2[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[C:14]([Br:16])[C:9]=3[N:8]=[CH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2c(c1)ncn2C1CCCC1
Reactant: BrBr
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc2c(ncn2C2CCCC2)c1Br
Yield: 35 %

Procedure:
To a solution of 1-cyclopentyl-5-aminobenzimidazole (1.1 g, 5.5 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.54 g (1.9 mmol, 35%) of the product.
Reaction SMILES: [Br:1][CH:2]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]2[S:3]1=[O:29].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl.[W]>[Br:1][CH:2]1[C:7]([CH2:8][Br:30])=[C:6]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])[N:5]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1=[O:29]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1Br
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 26.2 %

Procedure:
The reference 2-bromo-3-bromomethyl compound in the above HPLC analysis was prepared as follows: To a solution of 4.6 g (9.5 mmoles) of t-butyl 2-bromo-7-phenylacetamido-3-methyl-3-cephem-4-carboxylate 1-oxide in 350 ml of methylene chloride cooled in ice and irradiated with a 150 W tungsten lamp were added in portions over a period of 105 minutes 3.05 g (17.1 mmoles) of N-bromosuccinimide. After the addition was completed, the irradiation was continued for another hour and the orange-colored solution was concentrated to dryness by evaporation at low temperature. The residue was chromatographed on silica gel (elution with methylene chloride/acetone; first 72:1, then 49:1, v/v) to obtain 1.4 g (26%) of t-butyl 2-bromo-3-bromomethyl-7-phenylacetamido-3-cephem-4-carboxylate 1-oxide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C[Si](C)(C)[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].[F-].[K+]>CN(C)C=O.[Cu](I)I>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: I[Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
Under argon in a microwave vial 2 g 1-bromo-4-iodobenzene, 3.3 g trimethyl(perfluoroethyl)silane, 493 mg potassium fluoride and 2 g copper iodide are suspended in 10 ml N,N-dimethylformamide. The mixture is heated for 12 hours at 80° C. Further 3.3 g trimethyl(perfluoroethyl)silane are added and heating is continued for 48 hours. Then the mixture is partitioned between 2 M ammonia and diethylether. The aqueous phase is twice extracted with diethylether. The combined organic phases are washed three times with water and dried with magnesium sulphate. The solvent is evaporated in vacuo (300 mbar, temperature of water bath 50° C.). The residue is chromatographed on silica gel (dichloromethane).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH:14](C(OC)=O)[C:15]([O:17]C)=O)=[O:4].CCCCCC.C(O)(=O)C>Cl>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:6]=1[CH2:14][C:15](=[O:17])[NH:11]2)([OH:2])=[O:4]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C(C(=O)OC)C(=O)OC
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=C1Cc2c(cccc2C(=O)O)N1
Reaction time: 2 h
Yield: 38.1 %

Procedure:
Dimethyl 2-methoxycarbonyl-6-nitrophenylmalonate (3.0 g) was was heated to refulux in 50 mL of 6 N hydrochloric acid overnight. The mixture was concentrated to dryness and was heated to refulux for 2 hours with 1.1 g of tin(II) chloride in 20 mL of ethanol. The mixture was filtered through Celite, concentrated and chromatographed on silica gel in ethyl acetate:hexane:acetic acid to give 0.65 g (37% yield) of 4-carboxy-2-oxindole as a white solid.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>C(O)(=O)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: Cc1[nH]cnc1CO
Reactant: NCCS
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc[nH]c1CSCCN
Yield: 184.6 %

Procedure:
(a) A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g) and cysteamine hydrochloride (23.0 g.) in acetic acid (200 ml.) was heated under reflux for 10 hours. Following cooling to 15°-20°, the solid which crystallised was collected and washed with isopropyl alcohol to give 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (45.5 g), m.p. 189°-192°.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>Cl.C(O)(C)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1[nH]cnc1CO
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc[nH]c1CSCCN
Yield: 164.7 %

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueous hydrochloric acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water afforded a residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole dihydrochloride (40.6 g.), m.p. 185°-191°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CCOCC>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: CN1CCNCC1
Solvent: CCOCC
Product: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane product (1.0 g, 3.37 mmol) in anhydrous ether (30 mL) was added N-methylpiperazine (1.0 g, 10.1 mmol). The solution was stirred at RT for 14 hours and filtered through Celite™. The filtrate was evaporated under vacuum to give a crude product that was used directly without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].Cl[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)Cl>[OH:5][CH:3]([CH3:4])[CH2:2][NH:1][C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(O)CN
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCC(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a mixture of 1-aminopropan-2-ol (2 g, 26.6 mmol) and TEA (4.03 g, 39.9 mmol) in DCM (50 mL) was added ethyl 2-chloro-2-oxoacetate (4.36 g, 31.95 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and extracted with brine. The organic layer was dried and concentrated to give a crude product which was purified by silica gel chromatography eluting with petroleum ether/ethyl acetate (2:1) to give ethyl 2-(2-hydroxypropylamino)-2-oxoacetate (2.19 g, 51% yield) as yellow syrup. LCMS retention time 0.348 min, LCMS MH+ 176.
Reaction SMILES: C[O-].[Na+].Cl.[C:5]([NH2:9])(=[NH:8])[CH2:6][CH3:7].[C:10](OC)(=[O:16])[CH2:11][C:12](OC)=[O:13]>CO>[OH:13][C:12]1[CH:11]=[C:10]([OH:16])[N:9]=[C:5]([CH2:6][CH3:7])[N:8]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CCC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1nc(O)cc(O)n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a cooled (using an ice-bath), stirred solution of 25% sodium methoxide (1200 ml, 5.55 mole) was added a slurry of 200 g (1.85 mole) of propionamidine hydrochloride in 300 ml methanol. Next, 244 g (1.85 mole) of dimethyl malonate was added and the mixture was permitted to warm to about 20° C., after which it was stirred for 16 hours. The mixture was evaporated in vacuo and water (about 2 l) was then added. This mixture was neutralized with concentrated hydrochloric acid to provide a white precipitate which was separated by filtration to provide 230 g (96%) of 4,6-dihydroxy-2-ethylpyrimidine, m.p. 312°-315° C. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH2:10][CH2:9][S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.C(N(CC)CC)C.[Cl:23][CH:24]([Cl:28])[C:25](Cl)=[O:26]>O>[C:1]1([CH:7]2[N:11]([C:25](=[O:26])[CH:24]([Cl:28])[Cl:23])[CH2:10][CH2:9][S:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: c1ccc(C2NCCS2)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(C(Cl)Cl)N1CCSC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Five grams of 2-phenyl thiazolidine was dissolved in 50 ml. of acetone, 3.1 g. of triethylamine was added and the mixture stirred in a room temperature water bath, while 4.4 g. of dichloroacetyl chloride was added dropwise. The mixture was allowed to stand for about 30 minutes and then poured into water, extracted with methylene chloride, separated, dried over magnesium sulfate, and the solvent stripped under vacuum. There was obtained a yield of 7.3 g. of an oil, the title compound, ND30 32 1.5836.
Reaction SMILES: [C:1]([O:4][CH:5]1[S:9][C@H:8]([CH2:10][O:11][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O)(=O)C.P([O-])(O)(O)=O.[K+].C(OCC)(=O)C>O1CCCC1>[C:1]([O:4][CH:5]1[S:9][C@@H:8]([CH2:10][OH:11])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OC1CC[C@H](CO)S1
Reaction time: 5 h
Yield: 71.5 %

Procedure:
To a mixture of 0.54 g of 1-O-acetyl-5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-4thioribofuranose (prepared by the procedure of J. A. Secrist et al., J. Med. Chem., 1992, 35, 533) in 8 ml of tetrahydrofuran and 0.6 g of acetic acid is added 4 mmol of 1M n-tetrabutylammonium fluoride solution. The reaction is stirred for 5 hours and then another portion of 0.10 g of acetic acid and 1 mmol of n-tetrabutylammonium fluoride is added and the reaction is stirred for 1 hour. Cold potassium dihydrogen phosphate and ethyl acetate are added to the reaction mixture, followed by an aqueous workup. Purification by chromatography gives 0.164 g of the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=CC=1.[Br:20]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:20])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Yield: 86 %

Procedure:
A solution of 100 parts of p-nitrobenzal bromide in 1,000 parts of chlorobenzene is stirred with a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in 1,000 parts of water at 50° C for 10 hours. The bottom layer is separated and evaporated to dryness to give 110 parts (86% yield) of p-nitrobenzotribromide, m.p. 66°-70° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>>[B:15]([OH:20])([OH:16])[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cn1
Yield: 71.9 %

Procedure:
5-Bromo-2-methoxypyridine (5.0 mL, 39.1 mmol) was treated with n-BuLi (1.6 M in hexanes, 26.9 mL, 43.0 mmol), triisopropyl borate (10.8 mL, 46.9 mmol) and HCl(aq) (2.7 N, 37.6 mL) as for 1 to give the title compound 3 (4.3 g, 89% yield) as a white solid: 1H NMR (CD3OD) δ 8.42 (m, 1H), 7.95 (br s, 1H), 6.76 (br s, 1H), 3.91 (s, 3H). This material was used directly in Suzuki cross coupling reactions.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O>CC#N>[Br:12][C:5]1[C:6]([C:8]([F:11])([F:9])[F:10])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)c(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 86 %

Procedure:
To a solution of 2-amino-4-trifluoromethylpyrimidine (25 g, 0.15 mol) in CH3CN (600 mL) was added in the dark a solution of N-bromosuccinimide (34.8 g, 195 mmol) in acetonitrile (200 mL) over a period of 2.5 h. The reaction mixture was stirred for 4.5 h at RT and then concentrated. The residue was dissolved in EtOAc and H2O, the organic solvents were separated, washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in hexane from 10% to 40% to provide the title compound as a beige solid (31.2 g, 85%). LC-MS: Rt 0.82 min; (LCMS method 2).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>C(O)(=O)C>[C:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1)(=[O:17])[CH3:16]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Yield: 97 %

Procedure:
18.8 g of 2-hydroxynaphthalene-6-carboxylic acid was reacted with 94 g of acetic anhydride in 94 g of acetic acid at 80° C. for 4 hours. The reaction liquid was poured to 500 g of water and the precipitate was filtrated and washed thoroughly with methanol and water and then dried to give 22.3 g of 2-acetoxynaphthalene-6-carboxylic acid.
Reaction SMILES: [CH2:1]1[CH:6]2[CH2:7][C:8]3([C:10]([OH:12])=O)[CH2:9][CH:2]1[CH2:3][CH:4]3[CH2:5]2.O=S(Cl)[Cl:15]>C1(C)C=CC=CC=1>[CH2:5]1[CH:4]2[C:8]3([C:10]([Cl:15])=[O:12])[CH2:9][CH:2]([CH2:1][CH:6]1[CH2:7]3)[CH2:3]2
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Solvent: Cc1ccccc1
Product: O=C(Cl)C12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Noradamantane carboxylic acid (4.99 g, 30.1 mmol) and SOCl2 (5 mL, 69 mmol) in toluene (5 mL) were heated to 65° C. until vigorous evolution of gas commenced. The heating bath was removed for 5-10 minutes until gas evolution had moderated. Heating the reaction again at 65° C. was resumed for 2 hours. The reaction was cooled to room temperature, the volatiles removed in vacuo and toluene added and evaporated (2×) to remove excess SOCl2. The crude acid chloride was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].[Cl:15][S:16](O)(=[O:18])=[O:17].S(Cl)(Cl)=O.C(OC(C)C)(=O)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:4][C:3]=1[S:8]([C:11]([F:12])([F:13])[F:14])(=[O:9])=[O:10]
Reactant: O=S(=O)(c1ccccc1F)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CC(=O)OC(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 22 h

Procedure:
EXAMPLE 13 (80 g) was charged to a reactor fitted with overhead stirrer, nitrogen inlet, condenser, scrubber, temperature probe and heating bath. Chlorosulfonic acid (307 g) was added slowly through an additional funnel. The mixture was then heated up to 120° C. and held for 22 hours at 120° C. The mixture was cooled down to room temperature. Thionyl chloride (118 g) was added to the reaction mixture in one portion at ambient temperature. The mixture was stirred at 25° C. for 24 hours. A sample was pulled and HPLC showed the reaction was completed with 1.1% of the sulfonic acid left. Isopropyl acetate (775 g) was cooled down to −50° C. Water (600 g) was charged to isopropyl acetate solution. The reaction mixture was transferred slowly to the isopropyl acetate/ice mixture through an additional funnel. The internal temperature increased to 0.8° C. during the addition. The cold reaction mixture was warmed up 15° C. and layers were separated. The organic layer was used in the next step (EXAMPLE 15) without isolation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)CCC(=O)c1ccc(F)cc1
Yield: 63.2 %

Procedure:
Fluorobenzene (50 mL, 530 mmol) and aluminum trichloride (156 g, 1.17 mol) were added to 500 mL of methylene chloride, and the reaction mixture was stirred. Succinic anhydride (50 g, 500 mmol) was added to the stirrring reaction mixture all at once, and the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by cautious addition of 10% HCl, and the reaction mixture was added to 500 mL of water. The aqueous mixture was extracted twice with 250 mL of methylene chloride, and the combined organic layers were dried (MgSO4), and evaporated under reduced pressure to give 62 g (316 mmol, 59.6%) of 4-(4-fluoro-phenyl)-4-oxo-butyric acid as a crude solid. MS: 197 (M+H)+.
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([OH:14])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[C:15](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(O)cc(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.7 %

Procedure:
Methyl iodide (36 ml) was added to a mixture of methyl 3,5-dihydroxybenzoate (104 g), potassium carbonate (79 g) and dimethylformamide (1200 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between water (2.5 litre) and petrol (b.p. 60°-80° C., 600 ml). The aqueous layer was washed with petrol (b.p. 60°-80° C., 600 ml) and then extracted with toluene (2×1 litre). The toluene extracts were combined, washed with water (4×800 ml), dried (MgSO4) and evaporated to give methyl 3-hydroxy-5-methoxybenzoate as an oil (33 g, 30%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
The crude 4-(4-Chloro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.10 g, 10.0 mmol) was dissolved in methylene chloride (1 mL) and treated with 4 N HCl/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour. The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated to yield 1.00 g (48%) of the title compound. 1H-NMR (CDCl3) δ: 1.90 (2H, m), 2.23 (1H, brs), 2.83 (2H, m), 3.02 (2H, m), 3.54 (4H, m), 6.58 (2H, d, j=9.3 Hz), 7.13 (2H, d, j=9.3 Hz). ESI-MS m/z: 211 (M+1), FAS method rt: 1.04 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[N:4][CH:5]=1)[CH3:17]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cncc(Br)c1

Procedure:
A solution of 5-bromonicotinic acid (5.15 g, 25.5 mmol) in ethanol (100 mL) containing 1 mL of concentrated sulfuric acid was refluxed for 18 hours. The solvent was removed under reduced pressure and the residue basified with saturated aqueous sodium bicarbonate. The solution was then extracted three times with ether. The organics were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the tittle compound (5.29 g) as an off white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[OH-].[K+]>CS(C)=O.O>[CH3:9][C:4]1[S:3][C:2]([NH:1][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:6]([C:7]#[N:8])[CH:5]=1
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-methylthiophene-3-carbonitrile (13.8 g, 100 mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dimethylsulfoxide was added potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, and the resulting suspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile as a red solid used without further purification. 1H NMR: (400 MHz, CDCl3) δ 9.69 (s, 1H), 8.27-8.25 (m, 1H), 7.56-7.52 (m, 1H), 7.23-7.20 (m, 1H), 7.0-6.96 (m, 1H), 6.80 (s, 1H), 2.49 (s, 3H).