Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:22])[C:8]=1[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]([CH3:21])[CH3:20])[NH2:5].C([O-])(=O)C.[Na+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:7]([CH3:22])[C:8]=1[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]([CH3:20])[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(N)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNc1cc(C)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(Cl)c1
Yield: 37 %

Procedure:
120 mg of 3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylaniline (Example III) are heated to reflux with 62 mg of sodium acetate and 63 mg of ethyl bromoacetate in 5 ml of ethanol for 17 hours. A further 21 mg of ethyl bromoacetate are added and the mixture is refluxed for 3 hours. The solvent is removed in vacuo, the residue is taken up with water and dichloromethane, the organic phase is washed with saturated sodium chloride solution, dried and the solvent is removed in vacuo. Chromatographic purification (cyclohexane/ethyl acetate) affords 56 mg of ethyl N-{3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylphenyl}glycinate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[C:11]2=[O:26])=[CH:6][CH:5]=1
Reactant: O=c1n(-c2ccc(OC(F)(F)F)cc2)ccn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCN(c3ccc(OC(F)(F)F)cc3)C2=O)cc1
Reaction time: 5 h
Yield: 85.6 %

Procedure:
To a solution of 1-(4-nitrophenyl)-3-(4-trifluoromethoxyphenyl)-1,3-dihydroimidazol-2-one (144 mg, 0.395 mmol) in EtOH (40 mL) was added 10% Pd/C (100 mg). The mixture was evacuated and flushed with nitrogen three times. The Parr vessel was pressurized to 45 psi of hydrogen and shaken for 5 h. The depressurized solution was filtered through a pad of Celite® and the pad was washed with EtOH (25 mL). The ethanol was removed under reduced pressure to afford the title product (114 mg, 95%): 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=9.2 Hz, 2H), 7.33 (d, J=9.2 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 6.71 (d, J=9.2 Hz, 2H), 3.92 (s, 4H), 3.61 (br s, 2H); EIMS m/z 307 (M+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11]N3CCN(C(C)(C)C(N(C)C)=O)CC3)=[CH:8][C:6]=2[N:7]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@@H:40]1[CH:45]([CH3:47])[CH3:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[CH:8]=2)[CH2:41][C@@H:40]1[CH:45]([CH3:47])[CH3:46])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CN(C)C(=O)C(C)(C)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC(C)[C@H]1CNCCN1C(=O)OC(C)(C)C
Product: CC(C)[C@H]1CN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CCN1C(=O)OC(C)(C)C

Procedure:
Prepared using the method used in the preparation of 2-[4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazin-1-yl]-N,N-dimethyl-isobutyramide using (S)-2-isopropyl-piperazine-1-carboxylic acid tert-butyl ester in place of N,N-dimethyl-2-piperazin-1-yl-isobutyramide. The title compound was obtained as an off-white solid (182 mg, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1B(O)O.O=O.Cl[C:17]1[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25]([NH2:27])=[O:26])[CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:17]1[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25]([NH2:27])=[O:26])[CH:18]=1
Reactant: COc1cccc(OC)c1B(O)O
Reactant: CSc1nc(Cl)cc(C(N)=O)n1
Agent: O=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1cccc(OC)c1-c1cc(C(N)=O)nc(SC)n1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A 7 mL teflon-faced screw-cap vial was charged with 2,6-dimethoxyphenyl-boronic acid (218 mg, 1.2 mmol, 2 eq.) and dichloro-bis-(diphenylphosphinoferrocene)-palladium-dichloromethane adduct (49 mg, 60 μmol, 10 mol %). In a glove box under a nitrogen atmosphere (O2 content<=0.5%), the vial was charged with a solution of the 6-chloro-2-methylsulfanyl-pyrimidine-4-carboxylic acid amide (122 mg, 0.6 mmol) in degassed DMF/DME (1/1, 4.5 mL), and a degassed aqueous 1 M solution of potassium phosphate (1.0 mL, 1 mmol, 1.7 eq.). The vial was sealed, withdrawn from the glove box, and agitated in an incubator shaker at 75° C. for 16 hours. The cooled mixture was then diluted with chloroform (15 mL), and washed with brine (20 mL, 2×10 mL), and aqueous 1 M potassium carbonate (10 mL). The organic layer (solution of 6-(2,6-dimethoxy-phenyl)-2-methylsulfanyl-pyrimidine-4-carboxylic acid amide in chloroform) was then used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>C(OCC)(=O)C>[Br:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[NH:17][C:24](=[O:25])[NH:18][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Br)c(Oc2ccc(F)cc2F)cc1N
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Br)c(Oc3ccc(F)cc3F)cc2[nH]1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
A solution of 4-bromo-5-(2,4-difluorophenoxy)benzene-1,2-diamine (0.371 g, 1.18 mmol) in ethyl acetate (5.20 mL) was treated with N,N-carbonyldiimidazole (0.23 g, 1.4 mmol) and stirred at 50° C. for 30 min. The reaction mixture was treated with additional N,N-carbonyldiimidazole (1.2 eq) and stirred at 50° C. for 1 h. The reaction mixture was cooled to 20° C. and the heterogeneous mixture was filtered to give the desired product (156 mg, 39%) as a light grey solid. LCMS calculated for C13H8BrF2N2O2 (M+H)+: m/z=341.0, 343.0. found: 341.0, 342.9.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:25][O:26][C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:16]2[N:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:29][C:28]5[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=5[O:26][CH3:25])[S:3][C:4]=4[CH:10]=3)[CH:13]=[N:14][C:15]=2[CH:20]=1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Reactant: COc1ccccc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccccc1Nc1nc2ccc(Cn3cnc4cc(OC)c(OC)cc43)cc2s1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
To a suspension of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (26 mg, 0.063 mmol) from Example 2 and 2-methoxyaniline (15.5 mg, 0.13 mmol) in anhydrous 1,4-dioxane (0.30 mL) at rt was added Cs2CO3 (41 mg, 0.13 mmol). Argon was bubbled into the mixture for 5 min followed by the addition of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.0 mg, 0.005 mmol) and tris(dibenzylideneacetone)dipalladium (0) (2.3 mg, 0.003 mmol). Argon was bubbled into the mixture for an additional 5 min and then the mixture was heated in a sealed tube at 100° C. for 4 h. After cooling to rt, the reaction mixture was filtered through a Celite plug and the filtrate was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)-N-(2-methoxyphenyl)benzo[d]thiazol-2-amine (9.4 mg, 33%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.42 (d, J=7.3 Hz, 1H), 8.18 (s, 1H), 7.76 (d, J=1.1 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.28 (dd, J=1.5, 8.3 Hz, 1H), 7.19 (d, J=2.1 Hz, 2H), 6.92-7.09 (m, 3H), 5.46 (s, 2H), 3.86 (s, 3H), 3.76 (d, J=0.8 Hz, 6H). LCMS (ESI) m/z 447 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])[C:6]=2[CH:18]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:21].C(Cl)(Cl)Cl.CO>CS(C)=O>[C:10]([C:7]1[C:6]2[C:18](=[O:21])[C:2](=[O:1])[CH:3]=[CH:4][C:5]=2[O:9][CH:8]=1)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: O=C(c1ccccc1)c1coc2ccc(O)cc12
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CS(C)=O
Product: O=C1C=Cc2occ(C(=O)c3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of compound 3 (100 mg, 0.42 mmol) in DMSO (1 mL) was added Dess-Martin periodinane (356 mg, 0.84 mmol) at 0° C. The resulting mixture was stirred at room temperature for 20 min and poured into ice water (2 mL). The resulting precipitate was filtered, washed with water, and dried under high vacuum to furnish compound SKC-BF-01 (50 mg, 50%) as a red solid. TLC Rf=0.6 (CHCl3-MeOH, 9:1). NMR (CDCl3) δ 7.88-7.85 (m, 3H), 7.61 (d, J=6.33 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.41 (d, J=10.3 Hz, 1H), 6.34 (d, J=10.3 Hz, 1H); MS (ES) m/z 253 (M+H)+.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[CH3:16])=O>>[CH3:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[Cl:1]
Reactant: [Cl-]
Reactant: Cc1ccc(OC(=O)Cl)c(C)c1
Agent: [Al+3]
Product: Cc1ccc(Cl)c(C)c1
Temperature: 200 °C
Yield: 20 %

Procedure:
0.5 g of anhydrous aluminium chloride was added to 15 g of 2,4-dimethylphenyl chloroformate and the mixture was heated at 200° C. for 3 hours at normal pressure. The reaction mixture was cooled and worked up as described in Example 1. 2,4-Dimethylchlorobenzene was obtained in a yield of 20%, which is considerable despite the unfavourable substitution pattern.