Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:22])[CH3:21])=[C:13]3[NH:23][C:24]2[CH:25]=[N:26][C:27]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[Cl:36]C1C=C(B2OC(C)(C)C(C)(C)O2)C=C(Cl)C=1O>>[ClH:1].[ClH:36].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:22])[CH3:21])=[C:13]3[NH:23][C:24]2[CH:25]=[N:26][C:27]([NH:30][CH2:31][CH2:32][N:33]([CH3:34])[CH3:35])=[CH:28][CH:29]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(NCCN(C)C)nc1
Product: Cl

Procedure:
Following general procedure II, 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-{6-[2-(dimethylamino)ethylamino]pyridin-3-ylamino}-1,5-naphthyridin-3-yl]ethanone (69 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) followed by formation of the trihydrochloride salt to afford the desired product (87 mg, 78%) as a yellow-orange solid: 1H NMR (500 MHz, D2O) δ 9.22 (s, 1H), 8.22 (d, J=8.9 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.59-7.53 (m, 1H), 6.98 (s, 2H), 6.79 (d, J=9.4 Hz, 1H), 3.67 (t, J=6.4 Hz, 2H), 3.23 (t, J=6.4 Hz, 2H), 2.82 (s, 6H), 2.80 (s, 3H); ESI MS m/z 511 [M+H]+; HPLC>99% (AUC), tR=9.13 min.
Reaction SMILES: [CH2:1]([C@@:3]1([CH2:13][CH2:14][C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)O)[CH2:12][CH2:11][CH2:10][CH2:9][C:4]21OCC[O:5]2)[CH3:2].O>C(O)(=O)C>[C:17]1([C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH2:13][C@:3]2([CH2:1][CH3:2])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]2=[O:5])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC[C@@]1(CCC(O)(c2ccccc2)c2ccccc2)CCCCC12OCCO2
Solvent: CC(=O)O
Solvent: O
Product: CC[C@@]1(CC=C(c2ccccc2)c2ccccc2)CCCCC1=O

Procedure:
A solution of (S)-6-ethyl-α,α-diphenyl-1,4-dioxaspiro[4.5]decane-6-propanol (175 g) in 1 L of acetic acid containing 50 mL of water was refluxed for 3.5 hours. Most of the acetic acid was removed on a rotary evaporator, and the oily residue was poured into 300 mL of water. It was extracted with ether (2×300 mL) and the extracts were combined. They were washed with 1M sodium hydroxide (2×150 mL, first wash neutral, second wash basic) and brine (300 mL). Concentration afforded 140 g of cloudy brown oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([CH3:10])=[N:3]1.[F:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH:26][C:7]([C:5]2[C:4]([CH3:10])=[N:3][N:2]([CH3:1])[CH:6]=2)=[O:8])[CH:15]=[C:16]([F:19])[C:17]=1[F:18]
Reactant: Nc1ccccc1-c1cc(F)c(F)c(F)c1
Reactant: Cc1nn(C)cc1C(=O)Cl
Solvent: Cc1ccccc1
Product: Cc1nn(C)cc1C(=O)Nc1ccccc1-c1cc(F)c(F)c(F)c1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
79.1 g (0.494 mol, 99% pure) of 1,3-dimethyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 257.2 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 3 hours, 483.0 g (0.489 mol, 23% strength) of toluenic 3′,4′,5′-trifluorobiphenyl-2-ylamine solution were metered in and the reaction mixture was stirred for a further 1 hour. After venting and cooling to 70° C., the mixture was cooled to 20° C. with a cooling ramp of 5° C./h and stirred overnight. Subsequently, the mixture was cooled to 0° C., and the solids were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 155.4 g (92%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=O)[CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CC#N>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:3]=1
Reactant: COc1ccc(C(=O)c2cc(Br)sc2C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(Cc2cc(Br)sc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a solution of methanone 9 (11.7 g, 37.6 mmol) in CH2Cl2/CH3CN (90 mL/90 mL) were added triethylsilane (15.0 mL, 94.0 mmol) and boron trifluoride diethyl etherate (12.0 mL, 94.0 mmol) at 0° C. The mixture was warmed up to room temperature slowly and stirred at room temperature for 15 hours. To the mixture was added aq. saturated K2CO3 solution (100 mL) slowly and extracted with EtOAc (100 mL×2). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica column chromatography (Biotage) to provide the desired product 10 (11.2 g, 100%).
Reaction SMILES: [O:1]=[C:2]([CH3:29])[CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.ClCCl.[IH:33]>O>[IH:33].[O:1]=[C:2]([CH3:29])[CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1
Reactant: CC(=O)CCCn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: ClCCl
Solvent: O
Product: CC(=O)CCCn1c(NC2CCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine (1-(4-oxopentyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine, ethylene ketal (0.9 g, 2.0 mmol) and dichloromethane (20 mL). Cool in an ice bath and add hydriodic acid (0.53 mL, 57%, 4.05 mmol). Warm to ambient temperature. After 0.5 hours, add water (0.5 mL) and heat to reflux. After 18 hours, cool to ambient temperature and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:20]=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:33]([CH2:32][CH2:31][N:22]2[C:21](=[O:20])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:30])(=[O:34])=[O:35])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(NS(=O)(=O)CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.00 g (7.032 mmol) 1-Isopropyl-piperidin-4-ylamine (commercially available, or obtainable as described in EP 1479676) was dissolved in 100 ml dichloromethane. Subsequently 1.38 ml (1.1 equiv.) diisopropylethylamine (DIPEA) and 2.12 g (1.1 equiv.) 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (commercially available) were added. The resulting mixture was stirred for 5 h at room temperature. After complete conversion the mixture was diluted with 100 ml dichloromethane and washed with 150 ml water. The organic phase was then washed with 100 ml of a half saturated NaHCO3-solution and finally with brine. Drying over anhydrous MgSO4 and removal of the solvent by evaporation under reduced pressure gave crude 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid (1-isopropyl-piperidin-4-yl)-amide as a light yellow foam. Yield: 2.48 g MS (ES+): m/e=380.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>COCCOC>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:3]2[C:2]([NH2:1])=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[N:4]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Nc1ccc(C(F)(F)F)nc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(C(F)(F)F)ccc2N)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
A solution of 3-amino-2-chloro-6-trifluoromethyl-pyridine (0.890 g), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.4 g) (prepared as described in WO 2006/003494) and tetrakis(triphenyl-phosphine)palladium (0.200 g) in 1,2-dimethoxyethane (45 ml) was treated with aqueous potassium phosphate (1.1 M) (1.92 g). The reaction mixture was stirred at 80° C. for 3 hours. Aqueous workup with ethyl acetate furnished a residue which was purified by chromatography on silica gel (eluent: hexane/ethyl acetate 1:1) to give 3-amino-6-trifluoromethyl-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (1.5 g) as a white solid. MS (ES+) 288 (M-isoprene); 1H NMR (400 MHz, CDCl3) 1.50 (s, 9H), 2.61 (m, 2H), 3.67 (t, 2H), 4.10 (m, 2H), 4.21 (s, 2H), 6.11 (s, 1H), 7.03 (d, 1H), 7.33 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]([F:16])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:17][CH3:18])=[CH:9][CH:10]=3)[C@@:5]3([CH2:22][O:21][C:20]([NH2:23])=[N:19]3)[C:4]=2[CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:72]1[CH2:76][CH2:75][CH2:74][C:73]1=[O:77]>CCOC(C)=O.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].O1CCOCC1>[NH2:23][C:20]1[O:21][CH2:22][C@:5]2([N:19]=1)[C:6]1[CH:7]=[C:8]([O:17][CH3:18])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:4]2=[CH:3][C:2]([N:72]2[CH2:76][CH2:75][CH2:74][C:73]2=[O:77])=[CH:15][C:14]=1[F:16]
Reactant: O=C1CCCN1
Reactant: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(Br)cc(F)c1O2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(N3CCCC3=O)cc(F)c1O2
Temperature: 100 °C
Reaction time: 60 h

Procedure:
Resealable tube was charged with solids: (S)-2′-bromo-4′-fluoro-7′-methoxy-5H-spiro[oxazole-4,9′-xanthen]-2-amine (500 mg, 1.32 mmol, prepared as described in Method BB40 but using 4-bromo-2-fluorophenol and 2-bromo-5-methoxybenzoic acid)), Pd2 dba3 (121 mg, 0.13 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (229 mg, 0.40 mmol), cesium carbonate (859 mg, 2.64 mmol). pyrrolidin-2-one (152 μL, 1.98 mmol) and dioxane (5 ml) were added and the mixture was stirred at 100° C. for 60 h. The mixture was diluted with EtOAc, filtered through celite, concentrated and purified on 12 g RediSep Gold column using 10-80% of DCM/MeOH/NH4OH 90:10:1 in DCM to afford (S)-1-(2-amino-5′-fluoro-2′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)pyrrolidin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[C@@H:10]([CH3:24])[NH:11][C:12](=[O:23])[C@H:13]([CH3:22])[NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>O1CCOCC1>[ClH:26].[CH2:1]([O:8][C:9](=[O:25])[C@@H:10]([CH3:24])[NH:11][C:12](=[O:23])[C@H:13]([CH3:22])[NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)N[C@H](C)C(=O)OCc1ccccc1

Procedure:
To a slurry of 28.7 g. of N-t-butoxycarbonyl-L-alanyl-D-alanine benzyl ester in 150 ml. of dioxane saturated with hydrogen chloride and the mixture stirred for 4 hours at room temperature. The solvent was removed in vacuo and the residue triturated with diethyl ether. The resulting solids were filtered, redissolved in methylene chloride and the solution concentrated to about 150 ml. Ether was added and the solids filtered under nitrogen, 22.0 g.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][CH2:7][C:8]3[C:17](C)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:9]=3[C:10](=[O:13])[C:11](=O)[C:4]=2[CH:3]=1.[CH3:23][NH:24][C:25]([NH2:27])=[NH:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(O)C.O>[NH2:27][C:25]1[N:24]([CH3:23])[C:10](=[O:13])[C:11]2([C:9]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][C:8]=3[CH2:7][CH2:6][C:5]3[CH:21]=[CH:22][C:2]([Br:1])=[CH:3][C:4]2=3)[N:26]=1
Reactant: COc1ccc2c(c1C)CCc1ccc(Br)cc1C(=O)C2=O
Reactant: CNC(=N)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCc1ccc(Br)cc1C21N=C(N)N(C)C1=O
Temperature: 85 °C
Yield: 57 %

Procedure:
A solution of 8-bromo-2-methoxy-1-methyl-11,12-dihydro-dibenzo[a,e]cyclo-octene-5,6-dione 13 (2.49 g; 6.9 mmol) in dioxane and ethanol was treated with N-methylguanidine (1.52 g, 13.9 mmol), followed by a solution of sodium carbonate (1.47 g; 13.9 mmol) in water, heated at 85° C. for 3 hours, cooled and concentrated in vacuo. The resultant residue was taken up in chloroform and washed with water. The chloroform phase was separated, dried over magnesium sulfate and evaporated. This residue was crystallized from ethyl acetate and hexane to give the title product as a tan powder, 1.62 g (57% yield, identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[CH2:13]([O:15][CH2:16]Cl)[CH3:14].O>CN(C=O)C>[CH2:13]([O:15][CH2:16][O:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)[CH3:14]
Reactant: CCOCCl
Reactant: Oc1ccc2occc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCOc1ccc2occc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of benzofuran-5-ol (2) (257 mg, 1.92 mmol) in DMF (3 mL), NaH (81 mg, 1.92 mmol, 57% dispersion in oil) was added at 0° C. The reaction mixture was warmed to room temperature and stirred 1 hour. Chloromethyl ethyl ether (214 μL, 2.30 mmol) was then added drop wise to 0° C. and the mixture was stirred at room temperature for additional 1 hour. Water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (2×50 mL). The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. Purification of the crude product by flash column chromatography using 10% ethyl acetate in hexane afforded compound (3) (273 mg) as a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Cc1c(C(=O)O)cnn1C
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)cnn1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A dry flask was charged with 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid (0.144 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (101 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.177 g, 0.47 mmol, 46%).
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:28][C:26](=[O:27])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:23]1=[S:24].[Cl-].[NH4+].N>C(O)C>[C:1]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[C:28]2[S:22][C:23](=[S:24])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:26]2=[O:27])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)c2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)c2ccccc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 3.04 g of ethyl 2-benzamidothiazol-4-ylglyoxylate, 1.91 g of rhodanine-3-acetic acid, 1 g of ammonium chloride, 1 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[C:22]3[C:21]([CH3:23])=[C:20]([CH3:24])[S:19][C:18]=3[C:17]([Br:25])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:7]=[CH:6][C:5]=1[OH:26])([CH3:3])[CH3:2].C([O-])(=O)C.[K+].[Br:32]Br>C(O)(=O)C>[Br:32][C:6]1[CH:7]=[C:8]([C:10]2[C:22]3[C:21]([CH3:23])=[C:20]([CH3:24])[S:19][C:18]=3[C:17]([Br:25])=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[CH:15]3)[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[OH:26]
Reactant: BrBr
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c(C(C)C)c3)c2c1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(C(C)C)c3)c2c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a suspension of 2-isopropyl-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.35 g, 0.81 mmol) and potassium acetate (0.80 g, 8.11 mmol) in glacial acetic acid (11 mL) was added a solution of bromine (0.05 mL, 0.97 mmol) in glacial acetic acid (1.5 mL) dropwise at room temperature. An additional 1 mL of acetic acid was used to rinse the pipette and flask. After stirring at room temperature for 4 h the reaction was quenched with a small amount of dilute sodium bisulfite and diluted with water (100 mL). The white solid was collected on a sintered glass funnel, washed well with water and dried (Na2SO4) to give the title compound as a white solid (0.40 g,98%): mp 157-162° C.; (DMSO-d6): δ 9.20 (s, 1H), 8.19 (d, 1H), 7.66-7.61 (m, 1H), 7.49-7.48 (m, 2H), 7.35 (d, 1H), 7.13 (d,1H), 3.40 (septet, 1H), 2.42 (s, 3H), 1.60 (s, 3H), 1.16 (d, 6H); MS(+FAB): [M+H], 2 bromine isotope pattern, 502 (12%), 504 (30%), 506 (18%); Anal. Calc. for C23H20Br2OS: C, 54.78, H, 4.00, N, 0.00. Found: C, 53.67, H; 3.84, N, 0.03.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][N:31]([C:40](=[O:39])[CH2:41][OH:42])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CNCC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CN(C(=O)CO)CC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*)-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f39) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:35]=[C:36]=[O:37])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>O1CCCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:37])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]
Reactant: COc1ccc(N=C=O)cc1OC
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3,4-dimethoxyphenyl isocyanate (0.182 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from tetrahydrofuran to give 64.6 mg (18.7%) of the desired product as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[CH:5]=[C:4]([CH:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH3:14])[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1)[NH2:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:11]([O:10][C:8]([C:6]1[CH:5]=[C:4]([CH:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[CH3:14])[N:3]=[C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)=[C:23]([O:22][CH3:21])[CH:24]=2)[N:7]=1)=[CH2:9])[CH3:12]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: C=C(OCC)c1cc(C(C)OCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(C(C)OCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C

Procedure:
2-Chloro-4-(1-ethoxyvinyl)-6-(1-(2,2,2-trifluoroethoxy)ethyl)pyrimidine (0.35 g, 1.13 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.275 g, 1.35 mmol), palladium(II) acetate (0.038 g, 0.17 mmol), 2-(dicyclohexylphosphino)biphenyl (0.059 g, 0.17 mmol), cesium carbonate (0.734 g, 2.25 mmol) and dioxane (4 mL) were mixed in a vial. The vial was capped, evacuated and flushed with nitrogen. The reaction mixture was heated by microwave irradiation at 120° C. for 2.5 h, cooled and filtered through a pad of silica gel. The pad was eluted with 10% methanol in ethyl acetate. The solvents were evaporated and the residue was purified by column chromatography on silica gel using a gradient of 0-10% methanol in dichloromethane as eluent to yield the title product, 0.38 mg (70%).