Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][O:27][NH2:28])=[CH:24][CH:23]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:28][O:27][CH2:26][C:25]2[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:17][CH3:18])[CH:3]=1
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOCc1ccc(Cl)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 0.1 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (1.75 g, 5.54 mmol), O-(4-chlorobenzyl)hydroxylamine hydrochloride (1.13 g, 5.82 mmol) and anhydrous NaOAc (477 mg, 5.82 mmol) in EtOH (80 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-{4-chloro-2-[1-(4-chlorobenzyloxyimino)propyl]phenyl}trifluoromethanesulfonamide 11 (1.74 mg, 69%), as a white solid. M.p. 54-55° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.55, br s, 1H, 7.63, d, J=8.8 Hz, 1H, 7.47, d, J=2.2 Hz, 1H, 7.39-7.29, m, 5H; 5.17, s, 2H, 2.84, q, J=7.6 Hz, 2H, 1.18, t, J=7.6 Hz, 3H.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>C(O)C>[NH:1]([CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: O=C(CNc1ccccc1)c1ccccc1
Temperature: 22 °C
Reaction time: 1.5 h
Yield: 54 %

Procedure:
To a solution of 102.44 grams (1.1 mol) of aniline in 500 mL of absolute ethanol stirring at 22° C. was added 99.52 grams (0.5 mol) of 2-bromoacetophenone while maintaining a reaction temperature of 22° C. The reaction was stirred for 1.5 hours at 22° C. during which time a light yellow precipitate formed. The crude product mixture was diluted with 200 mL of ethanol and the precipitated product was collected on a Buchner funnel and washed with 3×200 mL of ethanol, 1×200 mL water, and again 1×200 mL ethanol. The crude product was dried to afford 56.9 grams (0.27 mol, 54% yield) of 2-anilinoacetophenone, m. p.=98°-101° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]([OH:17])[CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:17][C@H:7]([C@H:5]1[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[O:6]1)[CH2:8][NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)[C@H]1COC(C)(C)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H](OS(C)(=O)=O)[C@H]1COC(C)(C)O1

Procedure:
Alcohol 24 was dissolved in dichloromethane and cooled to 0°. Triethylamine and methanesulfonyl chloride were added and the solution stirred until the reaction was completed. The solution was extracted and the solvent removed to obtain the mesylate (25) which was purified using silica gel column chromatography. Solvent removal afforded a liquid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([OH:28])=[CH:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][O:19][CH3:20])[CH:15]=2)[N:10]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]=1)=[O:7].[OH-].[Li+]>O1CCOCC1>[C:24]([O:23][C:21]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][CH:12]=2)[C:8]([C:6](=[O:7])[CH:5]=[C:4]([OH:28])[C:3]([OH:29])=[O:2])=[CH:9]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COCOc1ccc2c(c1)c(C(=O)C=C(O)C(=O)OC)cn2C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCOc1ccc2c(c1)c(C(=O)C=C(O)C(=O)O)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84 %

Procedure:
To a solution of 0.345 g (0.85 mmol) of the ester derivative obtained in above (1) in dioxane (7 ml) was added 1.7 ml of 1 N lithium hydroxide. The mixture was stirred for 1.5 hours at room temperature. The Solvent was removed under reduced pressure at room temperature and the residue was dissolved in water. The aqueous layer was washed twice with ethyl acetate and neutralized with 1 N hydrochloric acid (1.7 ml) and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried. The solvent was removed and the obtained crystal was washed with ethyl acetate to give 0.28 g of the titled compound.
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[CH:8]=[CH:7][N:6]=1>C1COCC1.C(OCC)(=O)C>[Cl:4][C:5]1[N:10]=[C:9]([S:2][CH3:1])[CH:8]=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: Clc1ccnc(Cl)n1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccnc(Cl)n1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
Sodium thiomethoxide (5.18 g, 73.8 mmol) was added slowly portion-wise via powder addition funnel to a stirring solution of 2,4-dichloropyrimidine (10 g, 67.1 mmol) in THF (150 mL) at room temperature. After stirring overnight, the reaction was taken up in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give 2-chloro-4-(methylsulfanyl)pyrimidine (10.127 g, 47.3 mmol, 70.4%) as a white solid.
Reaction SMILES: Br[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1.C([Mg]Cl)(C)C.[CH3:13][C:14]([CH3:24])([CH3:23])/[CH:15]=[N:16]/[S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18]>C1COCC1.C1(C)C=CC=CC=1>[CH3:13][C:14]([CH3:24])([CH3:23])[CH:15]([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1
Reactant: CC(C)(C)/C=N/S(=O)C(C)(C)C
Reactant: Cc1nnc(Br)o1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nnc(C(NS(=O)C(C)(C)C)C(C)(C)C)o1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-oxadiazole (CAN 864750-58-3, 0.473 g, 2.91 mmol) in dry THF (8 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex (2.23 ml, 2.91 mmol). (During the addition the temperature was kept below −12° C.). The reaction was then stirred at −15° C. for 30 minutes followed by slow addition of a solution of (NE)-N-(2,2-dimethylpropylidene)-2-methyl-propane-2-sulfinamide (CAN 917104-90-6, 500 mg, 2.64 mmol) in dry toluene (8 ml). The reaction was allowed to warm up to room temperature overnight. The reaction was quenched by addition of water. The reaction medium was diluted with ethylacetate and the organic phase was extracted with a saturated aqueous solution of ammonium chloride. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (462 mg, 64%). MS (ESI, m/z): 274.5 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH2:9].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]2[C:26](=[C:27]([Cl:29])[CH:28]=1)[CH2:25][N:24]([CH3:30])[CH2:23][CH:22]2[C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>C(Cl)Cl>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:10])[CH2:6][CH2:7][CH2:8][NH:9][S:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([CH:22]2[C:21]3[C:26](=[C:27]([Cl:29])[CH:28]=[C:19]([Cl:18])[CH:20]=3)[CH2:25][N:24]([CH3:30])[CH2:23]2)[CH:32]=1)(=[O:39])=[O:38]
Reactant: CN(CCCN)CCCN
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CCCN)CCCNS(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of N1-(3-aminopropyl)-N1-methylpropane-1,3-diamine (560 mg, 3.85 mmol) dissolved in DCM (20 mL), was added triethylamine (300 mg, 2.96 mmol) and 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.77 mmol). The resulting solution was stirred for 3 h at room temperature. After removing the solvent, the resulting residue was diluted with EtOAc (50 mL), washed with water (2×10 mL) and dried over anhydrous sodium sulfate. The crude product was purified by Flash-Prep-HPLC with H2O:MeOH (1:4) to afford 300 mg (74%) of N-(3-((3-aminopropyl)(methyl)amino)propyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow oil.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[C:25](Cl)(=[O:27])[CH3:26]>C(=S)=S>[C:25]([C:10]1[CH:9]=[C:8]2[C:13]([CH2:14][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[N:6]([C:15](=[O:20])[C:16]([F:17])([F:18])[F:19])[CH2:7]2)=[CH:12][CH:11]=1)(=[O:27])[CH3:26]
Reactant: CC(C)CC1Cc2ccccc2CN1C(=O)C(F)(F)F
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C(CC(C)C)C2
Temperature: 45 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixed liquid of 193 mg of 3-isobutyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline, 533 mg of aluminum chloride, and 5 mL of carbon disulfide was added 157 mg of acetyl chloride at 44° C., followed by stirring at 45° C. for 1 hour. The reaction liquid was concentrated under reduced pressure, and 2N hydrochloric acid and ice were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and then with brine, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation to obtain 202 mg (yield 91%) of a title compound as a yellow oily substance.
Reaction SMILES: Br[CH2:2][C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[NH:14]C(=O)C1C=CC=CC=1)=[O:6].[CH3:27][NH:28][CH3:29].[OH-].[K+]>C(Cl)Cl.O>[NH2:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[C:5]([C:4]1[CH:23]=[CH:24][CH:25]=[CH:26][C:3]=1[CH2:2][N:28]([CH3:29])[CH3:27])=[O:6]
Reactant: CNC
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)c1ccccc1CBr)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1ccccc1C(=O)c1cc(Cl)ccc1N
Reaction time: 16 h

Procedure:
To a solution of N-[4-chloro-2-(2-methyl-benzoyl)-phenyl]-benzamide (5.1 g, 14.6 mmol) and N-bromosuccinimide (2.85 g, 16 mmol) in CCl4 (150 mL) was added 2,2′-azobisisobutrylnitrile (0.2 g, 1.5 mmol). The solution was refluxed for 4 h. The solution was then cooled to room temperature, diluted with CH2Cl2 (150 mL) and washed with H2O (3×50 mL). The organic portion was dried over Na2SO4 and evaporated to dryness in vacuo to provide N-[2-(2-bromomethyl-benzoyl)-4-chloro-phenyl]-benzamide (4.6 g, 74%). A solution of the benzamide (2.3 g, 5.4 mmol) in CH2Cl2 (50 mL) was saturated with dimethylamine, stirred for 16 h and evaporated to dryness in vacuo. The resulting residue was dissolved in MeOH (50 mL) and KOH (0.9 g, 16 mmol) in H2O (5 mL) was added. The solution was refluxed for 24 h. The solution was concentrated in vacuo and then diluted with EtOAc (150 mL) and H2O (50 mL). The organic portion was washed with H2O (3×50 mL), dried over Na2SO4 and purified by column chromatography (silica gel, 18:80.2 MeOH:CH2Cl2:NHOH) to provide lq (0.9 g, 53% yield) MS m/z=289 (M+H).
Reaction SMILES: [CH2:1]1[CH2:36][O:35][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:4][CH2:5][C:6]23[CH2:13][CH:12]([O:14][C:15](=[O:28])[C:16]4C=CC(C5C=CC=CC=5)=CC=4)[CH2:11][CH:10]2CC(=O)O3)[O:2]1.C(=O)([O-])[O-:38].[K+].[K+].C(O)(=O)C>CO>[CH2:36]1[CH2:1][O:2][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([CH2:4][CH2:5][C@H:6]2[C@H:10]([OH:38])[CH2:11][C@H:12]3[C@@H:13]2[CH2:16][C:15](=[O:28])[O:14]3)[O:35]1
Reactant: O=C([O-])[O-]
Reactant: CCCCCC1(CCC23CC(OC(=O)c4ccc(-c5ccccc5)cc4)CC2CC(=O)O3)OCCO1
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCCC1(CC[C@@H]2[C@H]3CC(=O)O[C@H]3C[C@H]2O)OCCO1

Procedure:
To a solution of (1S,5R,6R,7R)-6-(3,3-ethylenedioxyoctyl-7-(4-phenylbenzoyloxy)-2-oxabicyclo[3.3.0]octan-3-one (5a) (8.20 g) in methanol (200 ml) was added potassium carbonate (1.15 g) and the resultant mixture was stirred overnight, and acetic acid (1 ml) was added thereto. The crude product obtained by treating in the conventional manner was subjected to silica gel column chromatography to give the title compound (6a).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:20]=[CH:19][C:10]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[CH:9][C:8]=1[O:21][CH3:22].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.Cl>C1COCC1.CCCCCC>[Si:12]([O:11][C:10]1[CH:19]=[CH:20][C:7]([B:23]([OH:28])[OH:24])=[C:8]([O:21][CH3:22])[CH:9]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(O[Si](C)(C)C(C)(C)C)ccc1B(O)O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, n-butyl lithium (a hexane solution) was added at −75° C. to a THF solution of (4-bromo-3-methoxyphenoxy)(tert-butyl)dimethylsilane, followed by stirring at −75° C. for 1 hour. Triisopropyl borate was added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was treated with hydrochloric acid to obtain (4-{[tert-butyl(dimethyl)silyl]oxy}-2-methoxyphenyl)boronic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=2[C:18](O)=[S:19])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[C:28]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:16]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=2[C:18]([NH:26][C:27]2[C:28]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)=[O:34])=[N:29][CH:30]=[CH:31][CH:32]=2)=[S:19])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: Cc1ccc(C(O)=S)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1
Product: Cc1ccc(C(=S)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(O[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c1

Procedure:
Using a procedure analogous to Example 1-G, 2-(cis-4-t-butoxycarbonylaminocyclohexyloxy)-4-methylthiobenzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a white solid (2.68 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31]>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:24]=[CH:23][CH2:22][N:11]([CH2:12][C:13]#[CH:14])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: Clc1ccccc1/C=C/CBr
Reactant: C#CCNS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#CCN(CC=Cc1ccccc1Cl)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To an oven-dried, 100 mL, three-necked round-bottomed flask equipped with a stir bar, two septa and a nitrogen gas inlet adaptor, was added 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (1.0 g, 4.8 mmol) and K2CO3 (2.69 g, 19.2 mmol). The flask was evaporated and refilled with nitrogen three times, then MeCN (60 mL) was added. (E)-1-(3-bromoprop-1-en-1-yl)-2-chlorobenzene (1.66 g, 7.2 mmol) was added dropwise via syringe, turning the solution dark yellow. The mixture was heated at reflux and stirred overnight. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 1:9). At the end of the reaction the solvent was removed in vacuo. The reaction residue was taken up in saturated NaHCO3 solution (70 mL) and extracted with ether (3×50 mL). The combined organic layers were washed with brine (70 mL), dried over Na2SO4, gravity filtered and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 1:9, to provide 1.35 g of the title compound as a light yellow solid in a 78% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[NH:5][C@@H:6]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14](=[O:25])[NH:15][C:16]1[N:17]=[C:18]2[N:22]([CH:23]=1)[CH:21]=[C:20](Br)[S:19]2)=[O:8])[CH3:2].[CH3:33][O:34][C:35](=[O:68])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:58]=[CH:57][C:56](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:54]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]>>[CH3:33][O:34][C:35](=[O:68])[NH:36][C@H:37]([C:41]([N:43]1[CH2:47][CH2:46][CH2:45][C@H:44]1[C:48]1[NH:49][C:50]([C:53]2[CH:54]=[CH:55][C:56]([C:20]3[S:19][C:18]4=[N:17][C:16]([NH:15][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@H:6]([NH:5][C:4]([O:3][CH2:1][CH3:2])=[O:32])[C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[O:25])=[CH:23][N:22]4[CH:21]=3)=[CH:57][CH:58]=2)=[CH:51][N:52]=1)=[O:42])[CH:38]([CH3:40])[CH3:39]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CCOC(=O)N[C@H](C(=O)N1CCC[C@@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Product: CCOC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]4)cc3)sc2n1)c1ccccc1
Yield: 11 %

Procedure:
Compound A55 was synthesized from compounds 44 (0.125 mmol) and 8 (0.187 mmol), following the procedure as described for compound A1, to give compound A55 as a lyophilized white solid in 11% yield. MS (ESI, EI+) m/z=810.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:10]2[CH:9]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[CH:13]=[CH:12][C:11]=2[O:14][C:15]([F:18])([F:17])[F:16])=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)OC(C)(C)C)ccc2OC(F)(F)F)cc1
Yield: 72.8 %

Procedure:
A mixture of (3-bromo-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (250 mg), 4-ethoxycarbonyl-phenyl boronic acid (136 mg), cesium carbonate (228 mg) and tetrakis(triphenylphosphine)palladium0 (catalytic quantity), in 1:2 aqueous DME (15 ml) was heated to reflux for 18 h. The mixture was then cooled and partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue purified on silica gel. Elution with 5-40% ethyl acetate:petrol gave a pale yellow solid (217 mg)
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[P:15]([O:22]CC)([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]>>[O:14]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12](=[O:13])[N:4]1[CH2:3][CH2:2][P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCN1C(=O)c2ccccc2C1=O)OCC
Temperature: 130 °C
Reaction time: 18 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(2-bromoethyl)isoindoline-1,3-dione (8 g, 31.50 mmol, 1.00 equiv) and triethyl phosphite (6.2 g, 37.35 mmol, 1.19 equiv). The resulting solution was stirred for 18 h at 130° C. The resulting mixture was concentrated under vacuum. The crude product was re-crystallized from ether:n-hexane (1:2). This resulted in 5 g (48%) of diethyl 2-(1,3-dioxoisoindolin-2-yl)ethylphosphonate as a white solid.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[Cl:15][C:16]1[CH:21]=[C:20]([C:11]2[CH:12]=[CH:13][CH:2]=[C:3]([CH:10]=2)[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CON(C)C(=O)c1cc(Br)ccc1N
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+]
Solvent: O
Solvent: COCCOC
Product: CON(C)C(=O)c1cccc(-c2cccc(Cl)c2)c1
Temperature: 85 °C
Yield: 60.4 %

Procedure:
A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78 g, 30 mmol), 3-chlorophenyl boronic acid (5.63 g, 36 mmol), tetrakis(triphenylphosphine)palladium (0) (1.73 g, 1.5 mmol), and sodium carbonate (7.63 g, 72 mmol) in a mixture of DME and water (150 mL/30 mL) was degassed to remove the oxygen and was then heated at 85° C. under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and treated with brine (30 mL) and ethyl acetate (100 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine and dried with MgSO4. After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to give 5-(3-chlorophenyl)-N-methoxy-N-methylbenzamide as a brown oil (5 g, 57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THF was added in a dropwise fashion a solution of methyllithium in ether (1.4M, 28.6 mL, 40 mL) at −78° C. under nitrogen. After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous ammonium chloride solution (50 mL) at −78° C. Ethyl acetate (100 mL) was added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed (brine) and dried (MgSO4). After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/2:1) to afford 1-(4-amino-3 ′-chloro-biphenyl-3-yl)-ethanone as yellow solid (2 g, 47%): mp 89-90° C.; 1H-NMR (CDCl3) δ 7.89 (d, 1H, J=2.0 Hz), 7.51 (m, 2H), 7.25-7.40 (i, 3H), 6.73 (d, 1H, J=8.6 Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m/z 268([M+Na]+, 60%); Anal. Calc. For C14H12ClNO: C, 68.44, H, 4.92, N, 5.70. Found: C, 68.40, H, 4.89, N, 5.61.