Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:33][C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:38][CH:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(NCCc1ccccc1)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(=O)NCCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 23 %

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.226 mmol), 4-[(phenethylamino)carbonyl]phenylboronic acid (60 mg, 0.249 mmol), palladium tetrakistriphenyphosphine (16 mg, 0.014 mmol) and sodium carbonate (58 mg, 0.544 mmol) were mixed with ethylene glycol dimethyl ether (3 mL) and water (1.5 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative thin layer column chromatography using dichloromethane/methanol (80:20) as mobile phase to give cis-N1-phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide (28 mg, 23%). 1H NMR (DMSO-d6) δ 1.62 (m, 4H), 2.24 (m, 16H), 2.88 (m, 2H), 3.54 (m, 2H), 4.82 (m, 1H), 7.29 (m, 7H), 8.73 (d, J=8.10 Hz, 2H), 7.99 (d, 8.17 Hz, 1H), 8.67 (m, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =539.3, Rt=2.50 min.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:24]1C(C2C=CC=CC=2)=CS[C:25]=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=CC(C=C)=CC=1>C(O)(=O)C>[C:17]1([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([CH:24]=[CH2:25])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2)c1N
Agent: C=Cc1ccc(N)cc1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: C=Cc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1
Yield: 7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1 ml), 4-aminostyrene (97 mg, 0.81 mmol), and acetic acid (0.1 ml) were used to give 10 mg (0.030 mmol, 7% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=[O:21].[Cl-].[NH4+]>C(OCC)C.CCCCCC>[Br:8][C:6]1[C:5]([F:9])=[CH:4][C:3]([F:10])=[C:2]([CH:20]([C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=2)[OH:21])[CH:7]=1
Reactant: Fc1cc(F)c(Br)cc1Br
Reactant: O=Cc1cccc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1cccc(F)c1)c1cc(Br)c(F)cc1F
Temperature: -70 °C

Procedure:
A total of 2.02 g of 1,5-dibromo-2,4-difluorobenzene obtained in Production Example II-5-a was dissolved in 38 ml of diethyl ether, and 4.9 ml of a 1.58 M solution of n-butyllithium in hexane was added under stirring at −70° C. After stirring for 1 hour, 4.9 ml of m-fluorobenzaldehyde was added and the mixture was stirred for 15 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extracting with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 0.96 g of the title compound.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=[CH:16][C:17]([OH:19])=[O:18].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:23][CH2:22][CH2:21][CH2:20][CH:2]([OH:1])/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: CCCCC(O)CCCCCCC=CC=CC=CC=CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CCCCC(O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Temperature: 0 °C
Yield: 75 %

Procedure:
An equimolar mixture of 16-hydroxyeicosatetraenoic acid (16 HETE) and N-hydroxysuccinimide in anhydrous tetrahydrofuran (THF) was cooled to 0° C. To this was added 1 equivalent of dicyclohexylcarbodiimide (DCC) with stirring. After 12h at room temperature, the solvent was removed in vacuo and the residue was purified by SiO2 chromatography to afford the corresponding 16-HETE N-hydroxysuccimide ester in 75% yield as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:30].O>C(Cl)Cl>[Br:30][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc(CCCNc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CCCNc2nc(Nc3cccc(CBr)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of {3-[(5-chloro-4-{[3-(3-methoxyphenyl)propyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.75 mmol) in methylene chloride (4.8 mL) was added slowly a solution of boron tribromide in methylene chloride (3.8 mL, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. After methylene chloride layer was separated, water and EtOAc were added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as an off-white powder (252 mg, 75%). LCMS for C20H21BrClN4O (M+H)+: m/z=447.0, 449.0. 1H NMR (400 MHz, CD3OD): δ 7.92 (s, 1H), 7.63 (s, 1H), 7.39 (s, 1H), 7.38 (m, 2H), 7.03 (t, J=7.2 Hz, 1H), 6.61 (m, 2H), 6.58 (s, 1H), 4.56 (s, 2H), 3.60 (t, J=7.6 Hz, 2H), 2.58 (t, J=7.6 Hz, 2H), 1.96 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH3:22])=[N:19]2)=[CH:14][CH:13]=1>C(OC(=O)C)(=O)C>[Cl:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18](/[CH:22]=[CH:6]/[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:10]=[CH:9][CH:8]=3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: COc1cccc(C=O)c1
Reactant: Cc1ccc2ccc(Cl)cc2n1
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 110 °C

Procedure:
7.1 mL of 3-methoxybenzaldehyde (58 mmoles), 9.953 g of 7-chloroquinaldine (56 mmoles) and 50 mL of acetic anhydride were mixed together and heated at 110° C. for 16 hours. After hydrolysis on ice, the product was extracted with ethyl acetate, washed with 5% sodium bicarbonate and brine and partially purified by flash chromatography using 10% ethyl acetate in hexane. Recrystallisation from ether: hexane yielded the title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:34]=[CH:33][C:10]([O:11][C:12]2[CH:13]=[C:14]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:32])[CH2:29][O:30][CH3:31])[CH:26]=2)[C:15]([NH:17][C:18]2[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=2)=[O:16])=[CH:9][CH:8]=1)=O.O.[NH2:37]N>C(O)C>[CH3:31][O:30][CH2:29][C@H:28]([CH3:32])[O:27][C:25]1[CH:24]=[C:14]([CH:13]=[C:12]([O:11][C:10]2[CH:33]=[CH:34][C:7]([C:5]3[CH:4]=[CH:3][NH:2][N:37]=3)=[CH:8][CH:9]=2)[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16]
Reactant: NN
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)/C=C/N(C)C)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Solvent: O
Solvent: CCO
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3cc[nH]n3)cc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
A mixture of 3-{4-[(2E)-3-(dimethylamino)prop-2-enoyl]phenoxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (100 mg, 0.209 mmol) and hydrazine hydrate (0.204 mL, 4.18 mmol) in ethanol (3 mL) was heated to 100° C. for 5 minutes in a ‘Smith Creator’ microwave. The volatiles were removed in vacuo to give the product as a colourless foam (92 mg).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:35]2[CH2:37][CH2:36]2)[C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.C([O-])=O.[Na+]>[Pd].CN(C=O)C.O.CO>[C:29]1([C:8]2[N:6]3[N:7]=[CH:2][CH:3]=[C:4]([CH2:35][CH2:36][CH3:37])[C:5]3=[N:10][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([C:17]3([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(C5CC5)cc(Cl)nn4c3-c3ccccc3)cc2)CCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCCc1ccnn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a mixture of tert-butyl {1-[4-(6-chloro-8-cyclopropyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-14.6 (0.136 g, 0.26 mmol) and 5% palladium on carbon (0.026 g) in DMF (1 mL) was added a solution of sodium formate (0.18 g, 2.6 mmol, 10.0 eq) in water (0.4 mL). The resulting mixture was stirred at 80° C. for 3 h, diluted with MeOH (10 mL) and stirred at room temperature for 1 h. The resulting solution was filtered through a membrane filter and concentrated under reduced pressure. The resulting material was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to 80% hexane/20% EtOAc 4.0 min, 80% hexane/20% EtOAc 2.5 min, gradient to 70% hexane/30% EtOAc 2.5 min, 70% hexane/30% EtOAc 9.6 min) to give tert-butyl {1-[4-(3-phenyl-8-propylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.12 g, 93%):
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[F:15][C:12]([F:13])([F:14])[C:8]1[N:7]=[C:6]2[C:11]([C:2]([OH:1])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnc2nc(C(F)(F)F)ccc2c1O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: Oc1ccnc2nc(C(F)(F)F)ccc12
Temperature: 25 °C

Procedure:
4-Hydroxy-7-trifluoromethyl[1,8]-naphthyridine-3-carboxylic acid (14.0 g, 54.2 mmol) was added in portions to refluxing Dowtherm A (250 mL)—Care! Effervescence!—and the mixture was stirred at reflux for 80 min. The mixture was allowed to cool to room temperature, and a buff coloured solid precipitated from solution. The slurry was diluted with diethyl ether (250 mL) and the solid was separated by filtration, was washed with plenty of diethyl ether and was dried. This was 7-trifluoromethyl[1,8]naphthyridin-4-ol (11.6 g, 100%). δH (360 MHz, d6-DMSO) 6.15 (1H, d, J 7.4), 7.76 (1H, d, J 8.1), 8.06 (1H, d, J 7.4), 8.70 (1H, d, J 8.1). m/z (ES+) 215 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH3:9])[CH:5]=[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:8]([C:6]1[CH:5]=[C:4]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[N:3]=[C:2]([CH3:1])[CH:7]=1)[CH3:9])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cc(C)nc(OCC(F)(F)F)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cc(OCC(F)(F)F)n1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (50 mg, colorless oil) from 1-(2-methyl-6-(2,2,2-trifluoroethoxy)pyridin-4-yl)ethanone (44 mg, 0.19 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][C:3]=1[Cl:20].[F:21][C:22]([F:32])([F:31])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24]>CN(P(N(C)C)(N(C)C)=O)C>[F:32][C:22]([F:21])([F:31])[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][C:3]=2[Cl:20])[CH2:27][CH2:26]1)=[O:24]
Reactant: CC1CCc2c(Cl)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Reactant: O=C(N1CCNCC1)C(F)(F)F
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCN(C(=O)C(F)(F)F)CC3)c(Cl)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 160 °C
Yield: 50.6 %

Procedure:
A mixture of 3.1 g of 8,9-dichloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.1 g of 1-trifluoroacetylpiperazine and 50 ml of HMPTA was heated at 160° C. for 4 hours under atmosphere of argon. After completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was washed with water. Recrystallization of the residue from dimethylformamide gave 2.3 g of 8-(4-trifluoroacetyl-1-piperazinyl)-9-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 300° C. or more.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:13]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31]CCCC2C=CC([N+]([O-])=O)=CC=2)[O:14][Si:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.BrCCCCCCOC[CH2:53][C:54]1[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=1>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:13]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:53][C:54]2[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=2)[O:14][Si:15]([CH3:20])([CH3:21])[C:16]([CH3:17])([CH3:19])[CH3:18])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCCCCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=[N+]([O-])c1ccc(CCOCCCCCCBr)cc1
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCOCCc1ccc([N+](=O)[O-])cc1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 106, using Intermediate 53 in place of Intermediate 52. ES/MS calcd. for C31H46N3O6Si+ 584.3. Found m/z=584.4 (M+H)+.
Reaction SMILES: O.O.[O:3]=[C:4]1[CH:9]=[C:8]([CH3:10])[NH:7][CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14].[Cl:16]N1C(=[O:23])N(Cl)C(=O)N(Cl)C1=O>CO.O>[OH2:3].[OH2:23].[O:3]=[C:4]1[C:9]([Cl:16])=[C:8]([CH3:10])[NH:7][CH:6]=[C:5]1[O:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: Cc1cc(=O)c(OCC(=O)O)c[nH]1
Solvent: CO
Solvent: O
Product: Cc1[nH]cc(OCC(=O)O)c(=O)c1Cl

Procedure:
2-(4-oxo-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid dihydrate (2.2 g) was dissolved in a mixture of methanol (120 ml) and water (170 ml) under heating on a water bath. The solution was stirred at 65° to 70° C. and trichloroisocyanuric acid (1.1 g) was added thereto. The resultant mixture was stirred for 65° to 70° C. for 1.5 hours. The reaction mixture was left to cool to room temperature with removal of the water bath and filtered. The obtained precipitates were washed with water and dried. The resultant crystals (2.0 g) were dried at 100° C. for 6 hours in vacuo over phosphorus pentoxide to give crystals of 2-(4-oxo-5-chloro-6-methyl-1,4-dihydropyridin-3-yloxy)acetic acid dihydrate, mp 240° to 242° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:7]=1)[C:8]([C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:15]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)CC(=O)c1cc(Cl)ccc1C
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Cl)ccc1C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
A solution of ethyl 3-(5-chloro-2-methylphenyl)-3-oxopropanoate (28.4 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (10.0 mL, 75.3 mmol, 2.6 equiv) was heated at 90° C. After 3 hours, the reaction mixture was concentrated in vacuo, and the resultant residue was purified by flash column chromatography on silica gel (0 to 80% ethyl acetate in dichloromethane) to yield 2.87 g (34%) of ethyl 2-(5-chloro-2-methylbenzoyl)-3-(dimethylamino)acrylate. LCMS (ESI) m+H=296.3.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1.Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:10][C:11](=[O:21])[CH:12]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: BrCC1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CC1CCCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 103.9 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (16.3 mL of a 0.31 M stock solution, 5.04 mmol) cooled to −78° C. was treated with (3,4-dichloro-phenyl)-acetic acid methyl ester (1.0 g, 4.58 mmol) in tetrahydrofuran/hexamethylphosphoramide (8.6 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of bromomethylcyclohexane (1.92 mL, 13.76 mmol) in hexamethylphosphoramide (1 mL). The reaction mixture was stirred at −78° C. for 3 h. The reaction was warmed to 25° C. and stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (20 mL). This mixture was poured into water (100 mL) and extracted with ethyl acetate (3×50 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate) afforded 3-cyclohexyl-2-(3,4-dichloro-phenyl)-propionic acid methyl ester (1.5 g, quant.) as a clear oil: EI-HRMS m/e calcd for C16H20Cl2O2 (M+) 314.0840, found 314.0836.
Reaction SMILES: [N+:1]([C:4]1[CH:47]=[CH:46][C:7]([C:8]([NH:10][C:11]2[CH:41]=[CH:40][C:14]([C:15]([NH:17][C:18]3[CH:19]=[C:20]([S:36]([OH:39])(=[O:38])=[O:37])[CH:21]=[C:22]4[C:27]=3[C:26]([S:28]([OH:31])(=[O:30])=[O:29])=[CH:25][C:24]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:23]4)=[O:16])=[C:13]([S:42]([OH:45])(=[O:44])=[O:43])[CH:12]=2)=[O:9])=[C:6]([S:48]([OH:51])(=[O:50])=[O:49])[CH:5]=1)([O-])=O>[Pd].O>[NH2:1][C:4]1[CH:47]=[CH:46][C:7]([C:8]([NH:10][C:11]2[CH:41]=[CH:40][C:14]([C:15]([NH:17][C:18]3[CH:19]=[C:20]([S:36]([OH:39])(=[O:37])=[O:38])[CH:21]=[C:22]4[C:27]=3[C:26]([S:28]([OH:31])(=[O:29])=[O:30])=[CH:25][C:24]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:23]4)=[O:16])=[C:13]([S:42]([OH:45])(=[O:43])=[O:44])[CH:12]=2)=[O:9])=[C:6]([S:48]([OH:51])(=[O:50])=[O:49])[CH:5]=1
Reactant: O=C(Nc1ccc(C(=O)Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(S(=O)(=O)O)c23)c(S(=O)(=O)O)c1)c1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Agent: [Pd]
Solvent: O
Product: Nc1ccc(C(=O)Nc2ccc(C(=O)Nc3cc(S(=O)(=O)O)cc4cc(S(=O)(=O)O)cc(S(=O)(=O)O)c34)c(S(=O)(=O)O)c2)c(S(=O)(=O)O)c1

Procedure:
A reaction mixture comprising 17.5 g of 8-[4-(4-nitro-2-sulfobenzamido)-2-sulfobenzamido]-1,3,6-naphthalenetrisulfonic acid, pentasodium salt, 1.0 g of 10% palladium on carbon catalyst and 100 ml of water was hydrogenated in a Parr shaker for one hour and then filtered through diatomaceous earth. The filtrate was concentrated to about 65 ml and then poured with vigorous stirring into 500 ml of absolute ethanol. The granular precipitate was collected by filtration, washed with ethanol, then ether and dried for three days at 110° C., giving 8-[4-(4-amino-2-sulfobenzamido)-2-sulfobenzamido]-1,3,6-naphthalenetrisulfonic acid, pentasodium salt.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH2:18])=[C:13]([NH2:19])[CH:12]=1>>[NH2:19][C:13]1[CH:12]=[C:11]([Cl:10])[C:16]([Cl:17])=[CH:15][C:14]=1[NH:18][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1N
Product: Cc1cscc1NC(=S)Nc1cc(Cl)c(Cl)cc1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 4,5-dichloro-1,2-diaminobenzene. Crystalline solid, m.p. 310-320° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Br:17])[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:31]=1>CN(C)C=O.O>[Br:17][C:4]1[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=[C:2]([C:30]2[CH:29]=[N:28][CH:27]=[C:26]([O:25][CH3:24])[CH:31]=2)[CH:3]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCNC(=O)Nc1nc2cc(Br)cc(Br)c2s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cncc(OC)c3)cc(Br)c2s1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
A stirred mixture of 1-(5,7-dibromo-benzothiazol-2-yl-3-ethyl urea (300 mg, 0.79 mmol), sodium carbonate (167 mg, 1.58 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloro-palladium(II) (45 mg, 0.05 mmol), 3-methoxy-5-pyridineboronic acid pinacol ester (186 mg, 0.79 mmol) in dimethyl formamide (8 ml) and water (2 ml), was purged with nitrogen for 5 min and heated at 100° C. for 1 h. The reaction mixture was concentrated in vacuo then partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 0 to 5% methanol in ethyl acetate to give 1-[7-Bromo-5-(5-methoxy-pyridin-3-yl)-benzothiazol-2-yl]-3-ethyl-urea 1 as a white solid (49 mg, 15%).