Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([C:17]3[C:18]([CH3:34])=[C:19]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=[CH:21][CH:22]=3)[CH:12]([N+:14]([O-])=O)[CH3:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.O1CCCC1.C(OCC)(=O)C.[Zn]>[NH2:14][CH:12]([CH3:13])[CH:11]([C:17]1[C:18]([CH3:34])=[C:19]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:20]=[CH:21][CH:22]=1)[C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:8][CH:7]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(c1c[nH]c2cc(Br)ccc12)C(C)N
Yield: 94.9 %

Procedure:
A solution of benzyl (3-(1-(6-bromo-1H-indol-3-yl)-2-nitropropyl)-2-methylphenyl)carbamate (4.47 g, 8.56 mmol), ammonium chloride (6.87 g, 128 mmol), and zinc dust (8.40 g, 128 mmol) in methanol (100 mL) and tetrahydrofuran (100 mL) was stirred overnight under nitrogen. The reaction was diluted with ethyl acetate and filtered through a pad of CELITE®. The filtrate was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate (70 mL), and washed with brine (70 mL). The organic layer was collected, and the aqueous layers were sequentially extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give benzyl (3-(2-amino-1-(6-bromo-1H-indol-3-yl)propyl)-2-methylphenyl)carbamate (4.00 g, 8.12 mmol, 95% yield) as a light brown semi-solid and as a ˜1:1 diastereomers. LC/MS M+1=492.1 and 494.1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:14][S:15]([O-:17])=[O:16].[Na+].C=O.[CH2:21](N(CC)CC)C>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:14][S:15]([CH3:21])(=[O:17])=[O:16]
Reactant: CCN(CC)CC
Reactant: CS(=O)[O-]
Reactant: CSc1ccc2c(O)ccnc2c1
Agent: C=O
Agent: [Na+]
Solvent: O
Product: CSc1ccc2c(O)c(CS(C)(=O)=O)cnc2c1
Temperature: 25 °C

Procedure:
A mixture of 4-hydroxy-7-methylthioquinoline (4.2 g.), sodium methanesulphinate (8.2 g.), aqueous formaldehyde (37%, 9.0 ml.), triethylamine (2.85 ml.), industrial methylated spirit (130 ml.) and water (50 ml.) was stirred and boiled under reflux for 96 hours. The mixture was cooled to room temperature and filtered. The residue was washed with hot industrial methylated spirit to give the novel compound 4-hydroxy-3-methylsulphonylmethyl-7-methylthioquinoline, m.p. 290°-292°.
Reaction SMILES: [N+:1]([CH: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])([O-:3])=[O:2].O.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][C:12]([CH:4]([N+:1]([O-:3])=[O:2])[C:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:14])=[O:13])[CH3:17]
Reactant: CCO
Reactant: O=C1c2ccccc2C(=O)C1[N+](=O)[O-]
Solvent: O
Product: CCOC(=O)C(C(=O)c1ccccc1)[N+](=O)[O-]
Reaction time: 8 h

Procedure:
2-Nitroindane-1,3-dione (20.5g; 0.107 moles) in ethanol (100 ml) was heated under reflux for 4 hours, cooled, poured into water (1 liter). allowed to stand overnight and filtered. The solid was extracted with 5% sodium bicarbonate solution (3 × 100 ml) and filtered. The insoluble solid was predominantly the ψ-ethyl ester, 3-ethoxy-3-nitromethylphthalide, contaminated with some α-ethyl ester. Acidification of the combined sodium bicarbonate filtrates, filtration and recrystallisation from ethanol gave the α-ethyl ester, 2-ethoxycarbonyl-ω-nitroacetophenone, m.p. 81°.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[C:6]([C:11]([N:13]([CH2:29][CH2:30][CH3:31])[CH:14]2[CH2:17][N:16]([C:18]3[S:19][C:20]([C:24]([O:26]CC)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:15]2)=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10].O>CO.C1COCC1>[Cl:3][C:4]1[N:5]=[C:6]([C:11]([N:13]([CH2:29][CH2:30][CH3:31])[CH:14]2[CH2:15][N:16]([C:18]3[S:19][C:20]([C:24]([OH:26])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:17]2)=[O:12])[NH:7][C:8]=1[CH2:9][CH3:10]
Reactant: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(C)c(C(=O)OCC)s2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CN(c2nc(C)c(C(=O)O)s2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
A 2 N aqueous lithium hydroxide solution (1.30 mL, 2.59 mmol) was added to a mixed solution of ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl](n-propyl)amino}azetidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (227d) (114 mg, 0.26 mmol) in methanol/THF (3 mL/0.5 mL), and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (4.5 mL) was added to the aqueous layer, followed by extraction with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The resulting solid was suspended and washed in diethyl ether to obtain 58 mg of the title compound as a white solid (54%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([S:44]([CH3:47])(=[O:46])=[O:45])=[C:40]([Br:48])[CH:39]=2)/[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[S:51][CH:52]=[CH:53][N:54]=1>C(Cl)Cl>[Br:48][C:40]1[CH:39]=[C:38](/[C:34](=[CH:33]\[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)/[C:35]([NH:49][C:50]2[S:51][CH:52]=[CH:53][N:54]=2)=[O:37])[CH:43]=[CH:42][C:41]=1[S:44]([CH3:47])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1Br
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
A solution of triphenylphosphine (467 mg, 1.78 mmol) in methylene chloride (8 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (317 mg, 1.78 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution (E)-3-cyclopentyl-2-[3-bromo-4-(methanesulfonyl)-phenyl]-acrylic acid (334 mg, 0.89 mmol) in methylene chloride (4 mL). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (713 mg, 7.12 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (40 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×25 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotaoe chromatography (FLASH 40S, Silica, 3/1 hexanes/ethyl acetate) afforded the pure (E)-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-acrylamide (71 mg, 17.5%) as an amorphous white solid: EI-HRMS m/e calcd for C18H19BrN2O3S2 (M+) 454.0020, found 454.0025.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][N:15]([CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([CH3:23])[CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CSc1ncnc2cc(N)ncc12
Product: CN(C)c1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 190 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (245 mg, 1.28 mmol) (described in a previous experimental) and N,N-dimethyl-1,3-phenylenediamine (1.60 g, 11.8 mmol) is stirred under N2 at 190° C. for 1 h, and the resulting product is chromatographed (twice) over alumina (3% EtOH/CHCl3) to give 7-amino-4-(3-dimethylaminoanilino)pyrido[4,3-d]pyrimidine (113 mg, 32%) as a pale yellow solid. 1H NMR (DMSO) δ 9.66 (1H, brs), 9.33 (1H, s), 8.36 (1H, s), 7.22 (1H, brd, J=7.8 Hz), 7.16 (2H, m), 6.57 (2H, brs), 6.51 (1H, ddd, J=8.0, 2.3, 1.2 Hz), 6.42 (1H, s), 2.91 (6H, s).
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:24][C:23]([CH3:25])=[CH:22][C:5]=2[N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([O:18]COC)[CH:9]=2)[CH:7]=1)#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.C(O)C.O>[C:1]([C:3]1[C:4]2[S:24][C:23]([CH3:25])=[CH:22][C:5]=2[N:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([OH:18])[CH:9]=2)[CH:7]=1)#[N:2]
Reactant: COCOc1cc(-n2cc(C#N)c3sc(C)cc32)ccc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(s1)c(C#N)cn2-c1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a mixed solution of methyl 4-(6-cyano-2-methyl-thieno[3,2-b]pyrrol-4-yl)-2-(methoxymethoxy)benzoate (0.63 g) in tetrahydrofuran (10 mL), ethanol (5.0 mL) and water (5.0 mL) was added lithium hydroxide monohydrate (0.22 g), and the mixture was stirred at room temperature for 4 hours. Then 1 mol/L hydrochloric acid (10.6 mL) was added to the reaction solution and the resulting mixture was stirred at 50° C. for 5 hours. The reaction solution was concentrated under reduced pressure. To the residue was added water. The precipitated solid was collected by filtration, washed with water, and dried under reduced pressure at 50° C. to give the title compound (0.52 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27].O>N1C=CC=CC=1>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 550 mg, 0.189 mmol) was dissolved in pyridine (18 mL), added with anhydrous trifluoromethanesulfonic acid (0.758 ml, 3 eq.), and stirred at room temperature for 30 min. The reaction solution was added to water and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white powder, 641 mg, 81%).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([C:13]2(Br)[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]2=[O:21])[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CO>[OH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH:29]1[C:13]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:24])[CH3:23])[CH:8]=2)[C:18](=[O:19])[NH:17][C:16](=[O:20])[NH:15][C:14]1=[O:21]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C2(Br)C(=O)NC(=O)NC2=O)c1
Reactant: OCCN1CCNCC1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C2(C3CNCCN3CCO)C(=O)NC(=O)NC2=O)c1
Yield: 14.1 %

Procedure:
A solution of 5-[3-(tertbutyldimethylsilyloxy)phenyl]-5-bromobarbituric acid (444 mg) and N-(2-hydroxyethyl)piperazine (420 mg) in 10 ml of methanol is stirred at room temperature for 5 hours, then the solvent is evaporated off and the residue is purified by silica gel chromatography (13 g; eluent: ethyl acetate/methanol 3:1), to give 70 mg of the product.
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([O:17]C)=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)[Br:20].CO>ClCCl>[BrH:20].[NH2:2][C:3]1[C:4]([OH:17])=[C:5]([C:9]2[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrB(Br)Br
Reactant: COc1c(N)cccc1-c1csc(C(=O)O)c1
Agent: Br
Solvent: ClCCl
Solvent: CO
Product: Nc1cccc(-c2csc(C(=O)O)c2)c1O
Reaction time: 0.5 h
Yield: 17.5 %

Procedure:
4-(3-Amino-2-methoxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 19b (360 mg, 1.45 mmol) was dissolved in 5 mL of dichloromethane followed by dropwise addition of boron tribromide (2.8 mL, 5.6 mmol). The reaction mixture was reacted at room temperature for 4.5 hours. The reaction mixture was added with 5 mL of methanol and concentrated under reduced pressure. The residue was diluted with 10 mL of ethyl acetate and stirred for 0.5 hours. The mixture was filtered and the filter cake was dried to obtain the title compound 4-(3-amino-2-hydroxy-phenyl)-thiophene-2-carboxylic acid hydrobromide 19c (80 mg, yield 17.5%) as a grey solid.
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH:6]1([CH2:12][NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[NH:18])=[NH:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:28][C:29]([CH3:31])=[O:30]>>[C:29]([OH:2])(=[O:30])[CH3:31].[CH2:20]([NH:19][C:17]1[NH:16][C:14]([NH:13][CH2:12][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]2)=[N:15][C:29]([CH3:31])([CH3:28])[N:18]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CO
Reactant: CC(C)=O
Reactant: CCCCCCCCNC(=N)NC(=N)NCC1CCCCC1
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCNC1=NC(C)(C)N=C(NCC2CCCCC2)N1

Procedure:
100 ml of methanol, 80 ml of acetone and 0.6 ml of concentrated hydrochloric acid were added to 9.0 g (23.5 mmol) of N1-cyclohexylmethyl-N5-octyl-biguanide dihydrochloride. The mixture was refluxed for 21 hours, and the solvent was distilled off under reduced pressure. To the residue were added 120 ml of ethanol, 80 ml of water, and 9.5 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with methyl ethyl ketone. The extract was washed with water, and 1.7 g of acetic acid was added thereto. The solvent was distilled of f under reduced pressure, and the residue was dried well, and recrystallized from methyl ethyl ketone two times to obtain 4.9 g of colorless crystals having a melting point of 70 to 73° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][C:33](O)=[O:34])[C:26]2=[N:27][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]4[CH:8]=[CH:9][C:10]([S:13]([NH:16][C:17]5[S:18][CH:19]=[CH:20][N:21]=5)(=[O:14])=[O:15])=[CH:11][CH:12]=4)[CH2:5][CH2:6]3)=[O:34])[C:26]2=[N:27][CH:28]=1
Reactant: O=C(O)Cn1ccc2cc(Cl)cnc21
Reactant: O=S(=O)(Nc1nccs1)c1ccc(C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cn1ccc2cc(Cl)cnc21)N1CCC(c2ccc(S(=O)(=O)Nc3nccs3)cc2)CC1
Yield: 46.7 %

Procedure:
Synthesized according to general procedure 17, method C using THF as solvent. To a solution of 4-(piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.35 g, 1.08 mmol) and 2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetic acid (0.25 g, 1.19 mmol) in THF (6 mL) was added HATU (0.533 g, 1.40 mmol) followed by the addition of DIEA (0.279 g, 2.16 mmol) at 0° C. under inert atmosphere. The reaction was quenched with water after 15 minutes, the layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography using 0-3% methanol in DCM gave 4-(1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)acetyl)piperidin-4-yl)-N-(thiazol-2-yl)benzenesulfonamide (0.26 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.57 (d, J=3.5 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.26 (d, J=4.6 Hz, 1H), 6.83 (d, J=4.6 Hz, 1H), 6.49 (d, J=3.5 Hz, 1H), 5.25 (d, J=2.6 Hz, 2H), 4.44 (d, J=12.9 Hz, 1H), 4.16 (d, J=12.8 Hz, 1H), 3.24 (t, J=11.7 Hz, 1H), 2.95-2.88 (m, 1H), 2.70 (t, J=11.7 Hz, 1H), 1.91-1.66 (m, 3H), 1.55-1.45 (m, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=516.5; tR=1.57 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:9][CH:10]2[CH2:13][CH:12]([NH2:14])[CH2:11]2)=[N:5][CH:6]=[CH:7][N:8]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:2][C:3]1[C:4]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: NC1CC(Oc2nccnc2Cl)C1
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccnc1OC1CC(Nc2nc3ccccc3s2)C1
Temperature: 180 °C
Yield: 95.5 %

Procedure:
A mixture of 3-(3-chloro-pyrazin-2-yloxy)-cyclobutylamine hydrochloride (1.2 g, 6.28 mmol), 2-chloro-benzothiazole (purchased from ALDRICH™) (1.07 g, 6.28 mmol) and DIEA (1.8 g, 12.56 mmol) in NMP (12 mL) was heated to 180° C. for 2 hours in microwave. The reaction mixture was extracted with EtOAc (40 mL) and water, the organic phase was washed with brine and dried over Na2SO4. The organic layers were concentrated and purified by column chromatography on silica gel to give N-(3-((3-chloropyrazin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine (3.0 g, 6 mmol, 95.5%). ESI-MS (M+1): 333 calc. for C15H13ClN4OS 332.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: Clc1cc(Cl)cc(Sc2ccc(Br)cc2)c1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
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: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(Cl)cc(Cl)c3)cc2)c1C
Yield: 31.1 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-3,5-dichlorobenzene (0.2 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3,5-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.083 g, 31%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[CH:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].Br[C:23]1[C:24]([Cl:49])=[C:25]2[C:31]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=3[O:39][CH3:40])=[CH:30][N:29]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:26]2=[N:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:12]=[CH:11][C:10]([C:23]2[C:24]([Cl:49])=[C:25]3[C:31]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=4[O:39][CH3:40])=[CH:30][N:29]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:26]3=[N:27][CH:28]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5]
Reactant: CN(C)C(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: COc1cc(Cl)ccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(Cl)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1-c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc(N)c(C(=O)N(C)C)c3)c(Cl)c12
Yield: 55 %

Procedure:
Into a 20 mL Personal Chemistry microwave reaction vial were added 2-Amino-N,N-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-nicotinamide (1.55 g, 5.35 mmol), 5-Bromo-4-chloro-3-(4-chloro-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (1.58 g, (3.15 mmol), bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (129 mg, 0.158 mmol), sodium carbonate solution (3.15 mL, 6.30 mmol, 2.0 M solution in water) and N,N-dimethylformamide (15 mL). The vial was purged with nitrogen, sealed, and irradiated in a Personal Chemistry Optimizer at 120° C. for 30 minutes. The mixture was concentrated in vacuo. The crude was taken up in dichloromethane (150 mL) and washed with aqueous saturated sodium carbonate solution (1×150 mL) and brine (1×150 mL). The organ phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford 2-Amino-5-[4-chloro-3-(4-chloro-2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-nicotinamide (1.02 g, 1.74 mmol, 55% yield). 1H-NMR [500 MHz, d6-DMSO] δ: 8.26 (s, 1H), 8.06 (d, 1H), 7.72 (s, 1H), 7.48 (d, 1H), 7.26 (d, 1H), 7.11 (d, 1H), 7.03 (dd, 1H), 6.18 (s, 2H), 5.66 (s, 2H), 3.71 (s, 3H), 3.59 (t, 2H), 2.94 (s, 6H), 0.85 (s, 2H), −0.08 (s, 8H); MS [MH+] m/z: 486