Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([F:26])=[C:20]([Cl:19])[CH:21]=2)=[O:29])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 3-chloro-4-fluoro phenyl isocyanate (0.045 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 52 as a colorless solid (0.067 g, 54%). LCMS m/z (%)=485 M+H+ (81Br 37Cl, 30), 483 M+H+ (81Br 35Cl, 100), 481 M+H+ (79Br 35Cl, 72), 1H NMR (400 MHz, CDCl3) δ: 7.7 (s, 1H), 7.4 (d, J=1.8 Hz, 1H), 7.3 (d, J=1.8 Hz, 1H), 7.25 (s, 1H), 7.1-6.8 (m, 3H), 4.2 (m, 1H), 3.8 (s, 3H), 1.5 (d, J=6.61 Hz, 3H), 1.3 (d, J=6.61 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[O:13][C:14](C)(C)[CH3:15].CSCC(OCC)=O>[Ni].C(N(CC)CC)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:14](=[O:13])[CH2:15]2
Reactant: CC(C)(C)OCl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Ni]
Agent: CCOC(=O)CSC
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(C(F)(F)F)ccc2N1

Procedure:
In analogous fashion, 4-trifluoromethylaniline was reacted with t-butyl hypochlorite, ethyl 2-(methylthio)acetate and triethylamine followed by reduction of the 3-thiomethyl-5-trifluoromethyl-2-oxindole thus obtained with Raney nickel, to give 5-trifluoromethyl-2-oxindole, mp 189.5°-190.5° C.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1cccs1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1cccs1
Temperature: 25 °C
Reaction time: 15.67 h
Yield: 49.7 %

Procedure:
Ethyl difluoroacetate (1.84 g,14.8 mmol) was placed in a 100 mL round bottom flask and dissolved in ether (5 mL). To the stirred solution was added 25 weight % sodium methoxide (3.39 g, 15.7 mmol) followed by 2acetylthiophene (1.72 g,13.6 mmol). The reaction was stirred at room temperature overnight (15.67 hours), then treated with 3N HCl (8 ML). The organic layer was collected and washed with brine, dried over MgSO4, concentrated in vacuo, and recrystallized from methylene chloride/isooctane to give a brown solid (1.38 g, mp 78°-80° C., 50%). 1H NMR (CDCl3) 300 MHz 14.90 (br s, 1H), 7.80 (d, J=4.0 Hz, 1H), 7.71 (d, J=3.8 Hz, 1H), 7.19 (m, 1H), 6.41 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -126.98 (d); M+ 204.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH2:33][C:34]([O:36]CC)=[O:35])[N:29]=5)[C:25]=4[S:39][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[OH-].[K+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH2:33][C:34]([OH:36])=[O:35])[N:29]=5)[C:25]=4[S:39][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCOC(=O)Cn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 158.9 %

Procedure:
To THF/MeOH/H2O (150 mL, 10/1/1) cooled to 0° C. was added ethyl [6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]acetate (1673 mg, 2.7 mmol), followed by a solution of potassium hydroxide (1.2 g, 21.6 mmol) in THF/MeOH/H2O (20 mL, 10/1/1). The contents were stirred with warming to rt over 1 h, after which time the solvent was removed under reduced pressure. The crude residue was diluted with water (200 mL) which was vigorously stirred for 0.5 h, neutralized with aq. 1N HCl (12.0 mL) to pH=2-3. The contents were filtered to a light yellow solid, which was washed with water, and then hexanes. The collected product was dried in vacuo, to afford the final product (2.3 g, 99%) as a light yellow solid. 1H-NMR (DMSO-d6) δ 13.1 (br s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.77 (d, 1H), 7.52 (dd, 1H), 7.45 (dd, 1H), 7.14-7.33 (m, 4H), 5.24 (s, 2H), 4.92 (s, 2H), 3.39 (t, 2H), 2.95 (t, 2H); LCMS RT=3.32 min; [M+H]+=536.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)#[CH:25].CO>C(N(CC)CC)C.C1C=CC=CC=1.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[S:22][C:13]=12
Reactant: C#Cc1ccc(OC)cc1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C#Cc2cc3ncc(C#N)c(Nc4cc(OC)c(Cl)cc4Cl)c3s2)cc1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (134 mg, 0.28 mmol), 1-ethynyl-4-methoxybenzene (50 μL, 0.39 mmol), 3 mg of tetrakis(triphenylphosphine)palladium(0) and 5 mg of copper(I) iodide in 2 mL of triethylamine and 7 mL of benzene is heated at reflux for 24 hours. An additional 1 mL of triethylamine and 4 mL of benzene are added and the reaction is heated at reflux for 6 hours. The mixture is cooled to room temperature and 2 mL of methanol are added. The solvents are removed in vacuo and the residue is treated with 10 mL of ethyl acetate. The insoluble material is removed by filtration, washing with ethyl acetate. The filtrate is washed with 10% aqueous hydrochloric acid, water, and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 4:1 hexane:ethyl acetate to provide 92 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[(4-methoxyphenyl)ethynyl]thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 249-250° C.; 1H NMR (DMSO-d6) δ 3.81 (s, 3H), 3.86 (s, 3H), 7.01 (d, J=7 Hz, 2H), 7.40 (s, 1H), 7.55 (d, J=7 Hz, 2H), 7.70 (s, 1H), 7.79 (s, 1H), 8.65 (s, 1H), 9.81 (s, 1H); MS 477.9, 479.9 (M−H)−.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]([F:19])[CH:8]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH:29]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>CN(C=O)C.CCOC(C)=O>[NH3:6].[CH2:20]([CH:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([CH:29]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:30](=[O:31])[N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[CH2:17][CH2:18]2)=[C:9]([F:19])[CH:8]=1)=[O:5])[CH3:21]
Reactant: CCC(CC)C(=O)Nc1ccc(N2CCNCC2)c(F)c1
Reactant: O=C(C(Br)c1ccccc1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)C(=O)Nc1ccc(N2CCN(C(C(=O)N3CCCC3)c3ccccc3)CC2)c(F)c1
Product: N
Reaction time: 18 h
Yield: 0.1 %

Procedure:
To a solution of 2-ethyl-N-(3-fluoro-4-piperazin-1-yl-phenyl)-butyramide (0.08 g, 0.27 mmol) and Na2CO3 (0.03 g, 0.30 mmol) in DMF (2 mL) was added 2-bromo-2-phenyl-1-pyrrolidin-1-yl-ethanone (0.09 g, 0.30 mmol). After 18 h of stirring the mixture was diluted with EtOAc (30 mL) and washed with water (3×30 mL). The organic layer was dried (MgSO4) and concentrated. Chromatography of the resulting residue (SiO2; 2 M NH3 in MeOH/DCM) gave the title compound (0.08 mg, 51%). MS (ESI): mass calcd. for C28H37FN4O2, 480.29. m/z found, 481.4 [M+H]+. 1H NMR (DMSO): 7.52-7.47 (m, 3H), 7.36-7.29 (m, 3H), 7.07-7.05 (m, 1H), 6.87-6.83 (m, 1H), 3.42-3.38 (m, 1H), 3.09 (br s, 4H), 2.69 (s, 4H), 2.10-1.45 (m, 12H), 0.96-0.94 (m, 6H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].O>CN(C=O)C>[N:29]([C:10]1[C:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[C:11]=1[F:27])=[N+:30]=[N-:31]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(F)c(F)c1Nc1ccccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(SCc2ccccc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of methyl 5-(benzylthio)-3,4-difluoro-2-((2-chlorophenyl)amino)benzoate (12.44 g, 29.64 mmol) in DMF (100 mL) was added NaN3 (2.89 g, 44.46 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 9.84 g, 75.1% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.72 (s, 1H), 7.65 (s, 1H), 7.45 (m, 1H), 7.33 (m, 4H), 7.24 (m, 2H), 6.95 (m, 2H), 4.20 (s, 2H), 3.81 (s, 3H).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([CH:20]=1)[C:17]([O-:19])=[O:18])=[O:10])([CH3:5])[CH3:4])#[N:2].[OH-].[Li+].Cl>C1COCC1.O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:22]=[CH:23][CH:24]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18])=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1C(=O)O
Temperature: 40 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
To a solution of 5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylbenzoate 103 (7.13 mmol, 2.5 g) in THF (30 mL), lithium hydroxide (28.5 mmol, 0.683 g) in (20 mL) water was added and the reaction was stirred overnight at 40° C. The reaction mixture was acidified with 2N HCl solution and extracted with ethyl acetate (2×). Organic layer was washed with 2N NaOH (3×), aqueous layer was acidified with 2N HCl solution and the milky mixture was extracted with ethyl acetate (3×), dried and concentrated under reduced pressure. Crude product was triturated with ACN to give 5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylbenzoic acid 104 (550 mg, 23%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 2.50 (s, 3H), 7.30 (d, J=8.6 Hz, 1H), 7.60 (t, J=7.4 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.90 (dd, J=8.2 Hz and 2.3 Hz, 1H), 7.96 (d, J=7.8 Hz, 1H), 8.06 (t, J=2.0 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H), 10.40 (s, 1H). (m/z)=323 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([Br:14])[CH:8]=1.[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)#N.Cl.CC[O:26]CC>CCCCCC>[Br:14][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([Br:13])[CH:10]=1)[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:26]
Reactant: CCOCC
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: N#Cc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(c1cccnc1)c1cc(Br)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5M solution of n-butyllithium in hexane (40.0 ml) was added dropwise to a stirred mixture of 1,3,5-tribromobenzene (31.5 g) and dry ether (1000 ml) at -78° C. under an atmosphere of dry nitrogen. The resulting solution was stirred at -78° C. for 30 minutes and then a solution of 3-cyanopyridine (10.4 g) in dry ether (100 ml) was added dropwise. The mixture was stirred at -78° C. for 1 hour and then the temperature was allowed to reach 0° C. 2N Hydrochloric acid (200 ml) was added, with stirring, and the ether layer was decanted off and then extracted several times with 2N hydrochloric acid. The acidic extracts were combined and warmed on a steam bath for 20 minutes, then the solution was cooled and basified with aqueous potassium hydroxide solution. The resulting solid was filtered off, washed with water, dried and combined with the solid obtained by evaporation under vacuum of the ether solution. The crude product was chromatographed on silica gel using dichloromethane as eluent; the earlier fractions contained impurity and the later fractions were combined and evaporated under vacuum. The solid obtained from the latter fractions was crystallised from ethyl acetate-hexane to give the title compound (23.33 g), m.p. 124°-126° C. Found: C,42.50; H,2.23; N,4.21. C12H7Br2NO requires C,42.26; H,2.07; N,4.11%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.C([O-])([O-])=O.[Ca+2].[I:18]Cl>CO.C(Cl)Cl>[NH2:1][C:2]1[C:11]([I:18])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[C:3]=1[I:18]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(I)c(N)cc1Cl
Product: COC(=O)c1ccc(N)c(I)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of compound 23b (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monochloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methy 4-amino-2-chloro-5-iodo-benzoate 23c as the major the product and methy 4-amino-2-chloro-3-iodo-benzoate 23d as the minor product.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[Cl:23].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>O>[Cl:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
Potassium carbonate (10.4 g) was added to a mixture composed of 50 mL of N,N-dimethylacetamide, 19.2 g of 1,2-dichloro-4-nitrobenzene, and 14.5 g of 4-chlorobenzenethiol. This mixed solution was stirred at 35 to 40° C. for 2.5 hr. This reaction solution was poured into 500 mL of iced water, and the precipitated crystals were collected by filtration to give 27.8 g of 2-chloro-1-(4-chlorophenylthio)-4-nitrobenzene (yield 92.5%).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH3:20].C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>>[CH2:19]([O:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:30][CH2:31][N:32]([C:2]3[CH:18]=[CH:17][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:14]=[CH:13][C:12]([I:15])=[C:11]([Cl:16])[CH:10]=4)=[CH:4][N:3]=3)[CH2:33][CH2:34]2)=[CH:27][CH:28]=1)[CH3:20]
Reactant: O=C(Nc1ccc(I)c(Cl)c1)c1ccc(Cl)nc1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(I)c(Cl)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(3-Chloro-4-iodo-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester was prepared from 6-chloro-N-(3-chloro-4-Iodo-phenyl)-nicotinamide and 4-(piperazin-1-yl)-benzoic acid ethyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid ethyl ester above. HRMS m/z calcd for C25H24N4O3ClI [M+H]+: 591.0655. Found: 591.0657.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:8][NH:7][C:6]2[N:9]=[CH:10][CH:11]=[CH:12][C:5]=2[CH2:4][NH:3]1.[Br:14]Br>CN(C=O)C>[Br:14][C:11]1[CH:10]=[N:9][C:6]2[NH:7][CH2:8][C:2]([CH3:13])([CH3:1])[N:3]=[CH:4][C:5]=2[CH:12]=1
Reactant: BrBr
Reactant: CC1(C)CNc2ncccc2CN1
Solvent: CN(C)C=O
Product: CC1(C)CNc2ncc(Br)cc2C=N1
Temperature: 0 °C
Yield: 56.8 %

Procedure:
A solution of 3,3-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine (0.43 g, 1.8 mmol) in DMF (20 mL) was cooled in an ice bath and treated drop-wise with Br2 (0.19 mL, 3.7 mmol). After stirring in the ice bath for 2.5 h, the reaction was quenched with H2O (25 mL) and NaHCO3 (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with H2O (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated to an orange oil. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2 to 96:4) gave the title compound (0.26 g, 54%) as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=2.3 Hz, 1H), 8.03 (s, 1H), 7.73 (d, J=2.3 Hz, 1H), 5.93 (br s, 1H), 3.09 (d, J=4.9 Hz, 2H), 1.30 (s, 6H); MS (ESI) m/e 254 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.FBF.[NH:25]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][NH2:37])[CH2:26]1>>[NH2:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:27]1[CH2:28][CH2:29][N:25]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:26]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: NCc1ccccc1C1CCNC1
Agent: FBF
Product: COc1c(N2CCC(c3ccccc3CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
Starting from difluoroborane 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline -carboxylate (1.13 g, 3.3 mmol) and 2-(3-pyrrolidinyl) benzenemethanamine, a procedure analogous to that given in Example 1, provided the fluoroborate ester of the title compound.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Cl:7].[F:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>ClCCl>[Br:1][C:2]1[S:3][C:4]([C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([F:8])=[CH:10][CH:11]=2)=[CH:5][C:6]=1[Cl:7]
Reactant: Clc1ccsc1Br
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1cc(Cl)c(Br)s1
Temperature: 18 °C
Reaction time: 0.83 h
Yield: 97.1 %

Procedure:
Ferric chloride (301.2 g) was added to a stirred solution of 2-bromo-3-chlorothiophene (148.5 g) and 4-fluorobenzoyl chloride (169.7 g) in dichloromethane (2230 ml), cooled to 18° C. in an icetwater bath. The temperature of the reaction mixture rose to 22° C. and was then cooled to 12° C. Cooling was removed and the reaction mixture was stirred for a further 50 min during which time the internal temperature rose to 16° C. The reaction mixture was re-cooled to 10° C., water (700 ml) was added carefully, keeping the internal temperature below 15° C., and the mixture was then stirred for 1 h. The dichloromethane layer was separated and the aq layer was washed with dichloromethane. The combined dichloromethane layer was washed with water and saturated sodium bicarbonate solution. The dichloromethane was separated and the aq. layer filtered through dicalite and extracted with dichloromethane. The extract was washed with water, dried (Na2SO4) and evaporated to dryness to give 2-bromo-3-chloro-5-(4-fluorobenzoyl)-thiophene as a solid (233.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1.COC1C=CC(CNC2CCC2)=CC=1>CO>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc(N)nc1
Agent: COc1ccc(CNC2CCC2)cc1
Solvent: CO
Product: COc1ccc(CNc2ccc(OC)cn2)cc1

Procedure:
5A was prepared from 4-methoxybenzaldehyde and 5-methoxypyridin-2-amine following the procedure employed for the preparation of 4A. HPLC: Rt=1.30 min (PHENOMENEX® Luna C18 4.6×30 mm 3 u, A10-90% aqueous methanol containing 0.1% TFA in 2 min; 4 mL/min flow). MS (ES): m/z=244.9 [M+H]+.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([C:44]2([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=3)[CH2:47][CH2:46][CH2:45]2)=[O:43])=[CH:37][CH:36]=1>O1CCCC1>[Br:1][CH:41]([C:38]1[CH:37]=[CH:36][C:35]([Cl:34])=[CH:40][CH:39]=1)[C:42]([C:44]1([C:48]2[CH:53]=[CH:52][C:51]([Cl:54])=[C:50]([Cl:55])[CH:49]=2)[CH2:47][CH2:46][CH2:45]1)=[O:43]
Reactant: O=C(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C(Br)c1ccc(Cl)cc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 109.9 %

Procedure:
Phenyltrimethylammonium tribromide (6.59 g) was added in portions at −5° C. to a stirred solution of 2-(4-chlorophenyl)-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (6.2 g) in tetrahydrofuran (150 ml). The mixture was stirred at ambient temperature for 4 hours, allowed to stand at ambient temperature for a further 48 hours, then it was filtered, and the solvent removed in vacuo. The residue was purified via flash chromatography over silica using a 3:97 mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined, and the solvents removed in vacuo. The residue was triturated with petroleum ether (b.p. 60-80° C.) (30 ml) and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 2-bromo-2-(4-chlorophenyl)1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as a colourless solid (4.83 g), m.p. 109-110° C.