Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][NH:24][CH2:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>>[CH3:23][N:24]([CH2:25][C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CNCC(=O)N1CCOCC1
Product: CN(CC(=O)N1CCOCC1)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 2-(methylamino)-1-morpholinoethanone to give 225. MS: (ESI+)=454.1
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[C:8]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([NH:22][CH2:23][CH2:24][CH3:25])[CH:6]=1)C>[OH-].[Na+]>[O:15]([C:8]1[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:5]([C:4]([OH:26])=[O:3])=[CH:6][C:7]=1[NH:22][CH2:23][CH2:24][CH3:25])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCCNc1cc(C(=O)OCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
Ethyl-4-phenoxy-3-n-propylamino-5-sulphamyl-benzoate (1 g) was dissolved in 1N sodium hydroxide (15 ml), and heated on a steam bath for 1 hour. After cooling, the 4-phenoxy-3-n-propylamino-5-sulphamyl-benzoic acid was precipitated by addition of 4N hydrochloric acid until the pH was 2.5; the melting point was 223°-224° C.
Reaction SMILES: [CH3:1][NH2:2].[O:3]1[CH2:29][CH:4]1[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH2:12][C:13]([CH3:18])([CH3:17])[O:14]2)=[CH:9][CH:8]=1>C(O)C>[C:19]1([CH:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH:4]([OH:3])[CH2:29][NH:2][CH3:1])=[CH:8][CH:9]=3)[O:14][C:13]([CH3:18])([CH3:17])[CH2:12]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC1(C)CC(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Reactant: CN
Solvent: CCO
Product: CNCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
Methylamine (7ml) was added to 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)chroman 3.3g., 0.0092 moles) in ethanol (7ml) and the solution left to stand at room temperature for 48 hours. Removal of solvent gave the title compound as a dark coloured oil which was converted to the hydrochloride salt. Recrystallization from 1:1 petroleum ether: ether gave a grey solid (0.85g., 24%) m.p. 96-100° C.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:11]=1[NH2:12]>C(OCC)(=O)C>[F:9][C:10]1[CH:16]=[C:15]([Cl:17])[C:14]([O:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:11]=1[N:12]=[C:2]=[O:3]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)Oc1cc(N)c(F)cc1Cl
Solvent: CCOC(C)=O
Product: COC(=O)Oc1cc(N=C=O)c(F)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of trichloromethyl chloroformate (19 ml, 158 mmol) in ethyl acetate (200 ml) was charged into a 500 ml-three neck flask equipped with a dropping funnel and a distillation apparatus and a solution of 2-fluoro-4-chloro-5-methoxycarbonyloxianiline (21.9 g, 100 mmol) in ethyl acetate (100 ml) was added dropwise in 20 minutes. After completion of addition, the mixture was heated at 80° C. and ethyl acetate was distilled off. After cooling, carbon tetrachloride (150 ml) was added and allowed the mixture to stand overnight. After removal of indissolved substances by filtration, the solvent was distilled off from filtrate under reduced pressure, whereby light brown solid of 2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl isocyanate (20.6 g, yield 84%) was obtained.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:39][O:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:10]([NH:12][CH:13]2[C:37](=[O:38])[N:15]3[C:16]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[S:22])=[C:17]([CH3:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.C(=O)(O)[O-].[Na+]>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:39][O:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:10]([NH:12][CH:13]2[C:37](=[O:38])[N:15]3[C:16]([C:21]([O:23][CH:24]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[S:22])=[C:17]([CH3:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Yield: 79.7 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer, 2.3 g) in methanol (69 ml) was added conc. hydrochloric acid (1.44 ml) at 35° C., and the suspension was stirred for an hour at the same temperature. The reaction mixture was adjusted to pH 7.0 with an aqueous saturated solution of sodium bicarbonate. Methanol as evaporated in vacuo, and the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated in vacuo to give benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-methylthio-3-cephem-4-carboxylate (syn isomer, 1.76 g). mp. 148°-155° C.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]=2[C:24]([F:27])([F:26])[F:25])=[CH:4][C:3]=1[C:30]([O:32]C)=[O:31].O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:29]=[C:28]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:14]=2[C:24]([F:25])([F:27])[F:26])=[CH:4][C:3]=1[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc2c(cc1F)-c1noc(-c3onc(-c4ccccc4)c3C(F)(F)F)c1CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(cc1F)-c1noc(-c3onc(-c4ccccc4)c3C(F)(F)F)c1CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 8-fluoro-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carboxylate (Preparation 67C, 0.050 g, 0.109 mmol) and lithium hydroxide monohydrate (0.005 g, 0.119 mmol) in THF (4.0 mL) and water (4 mL) was stirred at room temperature for 4 h. An additional amount of lithium hydroxide monohydrate (0.005 g, 0.119 mmol) was added and the contents stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate (3×10 mL) and water (5.0 mL). The ethyl acetate extracts were combined, dried, and concentrated to give 8-fluoro-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carboxylic acid as a white solid. [40 mg, 0.090 mmol, 83%]. The product had an HPLC ret. time=4.15 min. (condition B). LC/MS M+1=445.0.
Reaction SMILES: [I-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:19][CH2:20][C:21](=[O:23])[NH2:22])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]([O:26]C)=[O:25]>N1C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:19][CH2:20][C:21](=[O:23])[NH2:22])[C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cc2c(OCC(N)=O)c(OC)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: COc1ccc2c(cc(C(=O)O)n2Cc2ccc(Cl)c(Cl)c2)c1OCC(N)=O
Temperature: 115 °C
Yield: 30.1 %

Procedure:
Lithium iodide (0.39 g) was added to stirred solution of methyl N-(3,4-dichlorobenzyl)-5-methoxy-4-carbamoylmethoxyindole-2-carboxylate (0.12 g) in pyridine (10 ml) under an atmosphere of argon. The reaction was then heated at 115° C. for 16 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and hydrochloric acid (2.0 M, 10 ml). Combined organic extracts were washed with water and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated in vacuo to give the product as a cream coloured solid (35 mg, 30%); NMR d (CD3SOCD3) 3.80 (s, 3H), 4.51 (s, 2H), 5.79 (s, 2H), 6.90 (dd, 1H), 7.18 (d, 1H), 7.25 (d, 1H), 7.34 (d, 1H), 7.39 (s, 1H), 7.42 (brs, 1H), 7.51 (d, 1H), 7.57 (brs, 1H), 13.05 (brs, 1H); M/z (−) 421 (M−H+).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([CH3:12])=[C:10]([Br:13])[CH:9]=[C:8]([CH3:14])[N:7]=1)=[O:5])C.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1>>[CH3:21][C:19]1[N:20]=[C:16]([NH:15][C:4]([C:6]2[C:11]([CH3:12])=[C:10]([Br:13])[CH:9]=[C:8]([CH3:14])[N:7]=2)=[O:5])[S:17][CH:18]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1nc(C)cc(Br)c1C
Product: Cc1csc(NC(=O)c2nc(C)cc(Br)c2C)n1

Procedure:
The title compound, white solid, MS (ISP): m/e=326.1, 328.0 (M+H)+, was prepared from 4-Bromo-3,6-dimethyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole in accordance with the general method of example 1, step 5.
Reaction SMILES: Cl[C:2]1[C:3]([C:11]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=[N:12][NH2:13])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CC(C)([O-])C.[Na+]>CN1CCCC1=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:14]1([C:11]2[C:3]3=[C:4]4[CH:10]=[CH:9][NH:8][C:5]4=[N:6][CH:7]=[C:2]3[NH:13][N:12]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CN1CCCC1=O
Product: c1cc2c(ncc3[nH]nc(C4CCC4)c32)[nH]1
Yield: 4.5 %

Procedure:
A mixture of 5-chloro-4-(cyclobutyl(hydrazono)methyl)-1H-pyrrolo[2,3-b]pyridine (0.052 g, 0.21 mmol), sodium tert-butoxide (0.048 g, 0.50 mmol), palladium acetate (0.0005 g, 0.0025 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl di-tert-butyl phosphine (0.0015 g, 0.0025 mmol) was heated in N-methyl-2-pyrrolidinone (2 mL) at about 160° C. in a CEM Discover microwave for about 30 min. The insoluble residue was removed by filtration and the filtrate was subjected to purification by preparative RP-HPLC (Table 2, Method h) to yield 1-cyclobutyl-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine as a white solid (0.002 g, 4%): LC/MS (Table 2, Method d) Rt=1.78 min; m/z: 213 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([C:16](OCC)=[O:17])[C:11](OCC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH2:16][OH:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(COCc1ccccc1)(CC(C)(C)C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)CC(CO)(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Diethyl 2-benzyloxymethyl-2-(2,2-dimethylpropyl)malonate (15 g.) in dry diethyl ether (50 ml.) was added slowly to a stirred suspension of lithium aluminium hydride (7.0 g.) in dry diethyl ether (200 ml.) at 0°, under nitrogen. The mixture was stirred at room temperature for 12 hours. Aqueous sodium hydroxide solution (25 ml., 10% solution) was added carefully. The mixture was filtered and the solid was washed with diethyl ether. The filtrates were dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with 1:4 ethyl acetate:hexane. 2-Benzyloxymethyl-2-(2,2-dimethylpropyl)-propan-1,3-diol was obtained as a colourless oil (5.5 g.).
Reaction SMILES: COC[N:4]1[CH:9]=[C:8]([CH3:10])[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][Cl:15])[C:5]1=[O:16].Cl>C(O)(C)C>[Cl:15][CH2:14][CH2:13][CH2:12][N:6]1[C:7](=[O:11])[C:8]([CH3:10])=[CH:9][NH:4][C:5]1=[O:16]
Reactant: COCn1cc(C)c(=O)n(CCCCl)c1=O
Agent: Cl
Solvent: CC(C)O
Product: Cc1c[nH]c(=O)n(CCCCl)c1=O
Temperature: 60 °C
Yield: 58.8 %

Procedure:
A mixture of 1-methoxymethyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (40.4 g, 0.16 mol) and isopropanol (200 mL) was heated to 60° C. and added to refluxing concentrated hydrochloric acid (200 mL) at a rate such that the reaction mixture remained at gentle reflux. The mixture was heated 3 hours at reflux and then distilled to remove methanol byproduct. The mixture was heated 4.5 hours at 92° C., cooled to 25° C., poured into water (650 mL), saturated with sodium hydroxide and extracted with ethyl acetate (5×300 mL). The combined extracts were washed with sodium bicarbonate and water and concentrated in vacuo. The residue was recrystallized from toluene/isopropanol (10:1, 55 mL) and the solids were collected, washed with hexanes and dried at 60° C. (15 g 1st crop). The mother liquors were concentrated and the solids were collected, dried (2nd crop) and combined with the first crop to give 3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione (19.8 g, 94 mmol), m.p. 145°-147° C.
Reaction SMILES: [CH2:1]([NH:8][CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1>>[CH2:1]([N:8]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[CH:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: O=CNCc1ccccc1
Product: Cc1cc(C)cc(N(C=O)Cc2ccccc2)c1
Yield: 99.2 %

Procedure:
Using general procedure A, N-benzylformamide (170 mg, 1.26 mmol) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×5 cm; hexane-ethyl acetate 3:1; 15 mL fractions). Fractions 7-13 provided 247 mg (99% yield) of the product as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 7.39-7.22 (m, 5H), 6.91 (s, 1H), 6.75 (s, 2H), 5.00 (s, 2H), 2.30 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:26])[C:15]([NH:17][C@@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:19])=[O:16])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:26])[C:15](=[O:16])[NH:17][C@@H:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH3:19])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)N[C@H](C)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(=O)N[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-hydroxy-N-((R)-1-phenyl-ethyl)-acetamide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26](Br)=[CH:25][C:23]=3[CH:24]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:30][S:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:33])=[O:32]>O1CCOCC1.O>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[O:21][C:22]3[CH:28]=[CH:27][C:26]([C:37]4[CH:38]=[CH:39][C:34]([S:31]([CH3:30])(=[O:33])=[O:32])=[CH:35][CH:36]=4)=[CH:25][C:23]=3[CH:24]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(Br)ccc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3o2)CC1
Temperature: 100 °C

Procedure:
An aqueous Na2CO3 solution (2 M, 0.68 mL) is added to a mixture of 4-(5-bromo-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.50 g) and 4-(methanesulfonyl)phenylboronic acid (1.97 g) in a mixture of dioxane/water (60:40). The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (500 mg) is added. The resulting mixture is heated to 100° C. for 2 h. After cooling to room temperature, ethyl acetate, brine, and activated charcoal are added. The mixture is filtered and the organic phase is separated, dried over Na2SO4, and the solvent is evaporated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→60:40) to give the title compound. LC (method 1): tR=1.80 min; Mass spectrum (ESI+): m/z=478 [M+Na]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH2:31][C:32]([N:34]([CH3:42])[C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)=[O:33])[CH3:30]>>[CH3:30][N:29]([CH2:31][C:32]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH3:42])=[O:33])[CH3:28]
Reactant: CN(C)CC(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-dimethylaminomethylcarbonyl-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C28H28N4O4
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][CH2:14][CH2:13][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:11])[CH:6]=1
Reactant: ClCCBr
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCCCl)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 4-nitro-m-cresol (2.0 g, 0.013 mol), 1-bromo-2-chloroethane (1.7 mL, 0.020 mol) and potassium carbonate (4.7 g, 0.034 mol) in N,N-dimethylformamide (21 mL) was stirred at 70° C. for 18 h. Cooled to ambient temperature, the reaction mixture was poured into ice water, extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel(hexane/ethyl acetate) to afford 4-(2-chloroethoxy)-2-methyl-1-nitrobenzene as solid (2.1 g, y. 73%).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8](=O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.C([O-])([O-])=O.[Na+].[Na+]>>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:8]1[S:1][C:2]2=[N:3][C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[N:6]2[CH:7]=1
Reactant: O=C(Cn1c(S)nc2ccccc21)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: c1ccc(-c2cn3c(nc4ccccc43)s2)nc1
Yield: 37.5 %

Procedure:
A solution of 2-mercapto-1-[2-oxo-2-(2-pyridyl)ethyl]benzimidazole (1 g.) in polyphosphoric acid was heated at 140° C. for 1 hour. The solution was neutralised with Na2CO3 solution and extracted into EtOAc (700 ml). The extracts were dried (MgSO4) and evaporated to give a solid which was recrystallised from EtOAc/EtOH to give the title compound (0.35 g.) mp 222°-4° C.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[NH:16][N:17]=[CH:18][CH:19]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:19]=[CH:18][N:17]([CH2:24][CH2:25][O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:16]=3)=[N:12][C:11]=2[CH3:20])=[O:9])=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccn(CCOc3ccccc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 90 °C
Yield: 42.3 %

Procedure:
A solution of 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid 4 fluoro-benzylamide (0.1 g, 0.33 mmol) in dimethyl sulfoxide (5 mL) was treated with (2-bromo-ethoxy)benzene (0.11 g, 0.50 mmol) and potassium carbonate (0.14 g, 1.0 mmol), and the reaction mixture was heated to 90° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed with brine (2×50 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by preparative thin layer chromatography over silica gel (methylene chloride:methanol, 95:5) to provide 4-methyl-2-[1-(2-phenoxy-ethyl)-1H-pyrazol-3-yl]-thiazole-5-carboxylic acid 4-fluoro-benzylamide as a tan solid (0.061 g, 43% yield). 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.07-7.19 (m, 5H), 6.78-6.93 (m, 3H), 6.70-6.73 (m, 2H), 5.82-5.88 (bm, 1H), 4.38-4.44 (m, 4H), 4.20 (t, J=5 Hz, 2H), 2.60 (s, 3H); MS (M+H)+=437.1; Rt=1.51 min; HRMS (M+H)+=437.14.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[S:56][CH3:57])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[S:56][CH3:57])=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: CSc1ccccc1N=C=O
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CSc1ccccc1NC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 49 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and 1-isocyanato-2-(methylthio)benzene as starting materials in 49% yield. LCMS for C32H32ClN7O2S (M+H)+: m/z=614.2.