Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:8]([CH3:9])[N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][NH:4][CH2:3]1.Cl[C:18]1[N:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:28])[CH:24]=2)[N:19]=1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[F:28][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([N:4]1[CH2:3][CH:2]([CH3:1])[CH:8]([CH3:9])[N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1)[N:27]=[CH:26]2
Reactant: Fc1ccc2nc(Cl)ncc2c1
Reactant: CC1CNCCN(C(=O)OC(C)(C)C)C1C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN(c2ncc3cc(F)ccc3n2)CCN(C(=O)OC(C)(C)C)C1C
Temperature: 130 °C

Procedure:
The amine 1-4 (270 mg, 1.18 mmol) was combined with 2-chloro-6-fluoroquinazoline 1-8 (216 mg, 1.18 mmol; see example 1-D), and triethylamine (412 uL, 2.96 mmol), in DMF (5 mL) and heated to 130° C. for 3 hours. The reaction was diluted with EtOAc, washed with saturated sodium bicarbonate solution and brine and the organic layer concentrated in vacuo and the residue was purified by column chromatography on silica gel (0 to 100% EtOAc in hexanes) to provide 1-10. Data for 1-10: LC/MS: m/z (M+Na)=375.2 found; 375.4 calculated.
Reaction SMILES: ClC1N=[N:6]C(NC)=C(C2C(OC)=NC=CC=2)C=1.[Cl:18][C:19]1[N:24]=[N:23][C:22]([N:25]([CH3:42])[C:26](=[O:41])[C:27]2[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:28]=2)=[C:21]([C:43]2[CH:48]=[CH:47][C:46](F)=C[C:44]=2[O:50][CH3:51])[CH:20]=1>CCCCCCC.C(OCC)(=O)C>[Cl:18][C:19]1[N:24]=[N:23][C:22]([N:25]([CH3:42])[C:26](=[O:41])[C:27]2[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[C:29]([S:37]([CH3:40])(=[O:38])=[O:39])[CH:28]=2)=[C:21]([C:43]2[C:44]([O:50][CH3:51])=[N:6][CH:46]=[CH:47][CH:48]=2)[CH:20]=1
Reactant: COc1cc(F)ccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1
Reactant: CNc1nnc(Cl)cc1-c1cccnc1OC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ncccc1-c1cc(Cl)nnc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 1, from [6-chloro-4-(2-methoxy-pyridin-3-yl)-pyridazin-3-yl]-methyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 1, intermediate d) after a reaction time of 27 hours and using a gradient of n-heptane:ethyl acetate (100:0 to 20:80) for the chromatographic purification. Light yellow solid (10%). MS (ESI+): m/z=501.060 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+:25]>CCOCC>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([NH:10][C:11]2[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:9])=[CH:22][CH:23]=1.[Na+:25]
Reactant: O=C(O)COc1ccc(NC(=O)C=Cc2ccc(O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C([O-])COc1ccc(NC(=O)C=Cc2ccc(O)cc2)cc1

Procedure:
156 Milligrams of 4-(4'-hydroxycinnamoylamino)phenoxyacetic acid were dissolved in an alcohol and an equivalent amount of sodium hydroxide was added to the solution. The solution was warmed for 30 minutes. After cooling, ether was added to the solution and the precipitated crystals were collected by filtration to obtain sodium 4-(4'-hydroxycinnamoylamino)phenoxyacetate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F)([O-:3])=[O:2].CO[C:16]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19](OC)=[CH:18][C:17]=1[OH:26]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[O:26][C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[C:21]([CH3:22])[CH:16]=1)([O-:3])=[O:2]
Reactant: COc1cc(O)c(OC)c(C)c1C
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(F)c1
Product: Cc1ccc(Oc2cc([N+](=O)[O-])ccc2[N+](=O)[O-])cc1C

Procedure:
The process was carried out as described in point 5.4 above, using 0.293 g (1.575 mmol) of 2,5-dinitrofluorobenzene and 0.287 g (1.575 mmol) of 2,5-dimethoxy-3,4-dimethylphenol. The title product was obtained in the form of an orange solid (0.415 g, 76%) after column chromatography using, as eluent, an 85:15 mixture of light mineral spirit (60-80° C.):ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=[C:11]([CH:14]=O)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:20][OH:21]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=[C:11]([CH:14]=[N:20][OH:21])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=CC1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Reactant: NO
Solvent: CCO
Solvent: O
Product: ON=CC1=NOC(c2cc(Cl)cc(Cl)c2)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3-carbaldehyde (2 g) in EtOH (4 mL) and H2O (2 drops), was added aqueous NH2OH (50% in water, 0.48 mL). The solution was stirred at room temperature for 3 hours then allowed to stand at room temperature for 16 hours. Then the solution was stirred again and more hydroxylamine (0.04 mL) was added. After 3 hours, the reaction was quenched by addition of water. After extraction with ethylacetate, the organic phase was separated, dried over magnesium sulfate and concentrated to give 2.02 g of a yellow solid which was used in the next step without further purification. 1H-NMR (CDCl3, 400 MHz) shows a mixture of diastereoisomers: 8.07 and 7.94 (s, 1H), 7.43-7.38 (m, 3H), 3.88 (d, 1H), 3.50 (d, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:19])[O:9][C:10]=1[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5])C.[OH-].[Na+].Cl>C1COCC1>[C:15]([O:14][C:12]([NH:11][C:10]1[O:9][C:8]([CH3:19])=[N:7][C:6]=1[C:4]([OH:5])=[O:3])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1nc(C)oc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)c(NC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of 314 mg (1.163 mmol) 5-tert-butoxycarbonylamino-2-methyl-oxazole-4-carboxylic acid ethyl ester in 1.16 ml THF was added at 0° C. 5.82 ml (5.82 mmol) 1N sodium hydroxide, the mixture was allowed to warm to room temperature and stirring was continued for 6 days. At 0° C. 5.82 ml (5.82 mmol) 1N HCl was added and the solvents were evaporated. The residue was suspended in DCM and filtered, the solvent was evaporated to provide the title compound as colorless solid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][Si:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]3)=[C:13]([F:25])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].O.O1CCO[CH2:29][CH2:28]1>>[N:1]1([CH2:4][C@@H:5]2[O:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][Si:20]([CH3:23])([CH3:24])[CH2:19][CH2:18]4)=[C:13]([F:25])[CH:12]=3)[CH2:6]2)[CH:29]=[CH:28][N:3]=[N:2]1
Reactant: C1COCCO1
Reactant: C[Si]1(C)CCN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Solvent: O
Product: C[Si]1(C)CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)CC1

Procedure:
A solution of azide 19 (0.60 mmol) and bicyclodiene 20 (0.31 mL, 3.03 mmol) in dioxane (4.0 mL) is refluxed for 5 h. Water (5 mL) is added and extracted with DCM (2×5 mL), dried and concentrated. The product is further purified by column chromatography on silica using hexane-EtOAc mixtures to obtain the product as a brown solid (60 mg) in 26% over 3 steps.
Reaction SMILES: N1C2OC3C=CC=CC=3NCC=2C=CC=1.BrC1C=C(F)C=CC=1C(Cl)=O.[Br:27][C:28]1[CH:33]=[C:32](F)[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[N:48]=[CH:49][CH:50]=[CH:51][C:39]=2[CH2:38]1)=[O:36].[Na].[CH3:53][C:54]1[CH:58]=[CH:57][NH:56][N:55]=1>>[Br:27][C:28]1[CH:33]=[C:32]([N:56]2[CH:57]=[CH:58][C:54]([CH3:53])=[N:55]2)[CH:31]=[CH:30][C:29]=1[C:35]([N:37]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][C:40]2[N:48]=[CH:49][CH:50]=[CH:51][C:39]=2[CH2:38]1)=[O:36]
Reactant: Cc1cc[nH]n1
Reactant: O=C(c1ccc(F)cc1Br)N1Cc2cccnc2Oc2ccccc21
Agent: O=C(Cl)c1ccc(F)cc1Br
Agent: [Na]
Agent: c1cnc2c(c1)CNc1ccccc1O2
Product: Cc1ccn(-c2ccc(C(=O)N3Cc4cccnc4Oc4ccccc43)c(Br)c2)n1

Procedure:
The title compound may be prepared in a manner analogous to that of the 2-chloro analog of Example 16, by reacting 6H-pyrido[2,3-b][1,5]benzoxazepine of Example 16, Step A, with 2-bromo-4-fluorobenzoyl chloride of Example 3, Step A. Subsequent reaction of the intermediate (2-bromo-4-fluoro-phenyl)-(11H-5-oxa-4,10-diaza-dibenzo[a,d]cyclohepten-10-yl)-methanone with the sodium salt of 3-methylpyrazole in a manner analogous to that of Example 16, Step C will provide the title compound.
Reaction SMILES: CN(C)C1C=CC=CC=1.[NH2:10][C:11]1[C:12]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[N:13][C:14]([CH3:23])=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20].[Br:30][CH2:31][C:32](Br)=[O:33]>ClCCl.O>[Br:30][CH2:31][C:32]([NH:10][C:11]1[C:12]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[N:13][C:14]([CH3:23])=[CH:15][C:16]=1[O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[O:33]
Reactant: O=C(Br)CBr
Reactant: Cc1cc(OCC(F)(F)F)c(N)c(OCC(F)(F)F)n1
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Solvent: O
Product: Cc1cc(OCC(F)(F)F)c(NC(=O)CBr)c(OCC(F)(F)F)n1
Yield: 85 %

Procedure:
N,N-Dimethylaniline (20.46 g, 168.8 mmol) was added to a solution of 3-amino-2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridine (42.29 g, 139.0 mmol) in dichloromethane (600 mL). While the mixture was stirred under cooling with ice, a solution of bromoacetyl bromide (28.73 g, 142.3 mmol) in dichloromethane (100 mL) was added thereto, followed by stirring for ten minutes. The reaction mixture was diluted with water and then extracted with chloroform. The organic layer was washed with saturated brine and then dried over sodium sulfate anhydrate, followed by concentration under reduced pressure. The thus-obtained crystals were recrystallized from chloroform-hexane, to thereby yield 2-bromo-N-[2,4-bis(2,2,2-trifluoroethoxy)-6-methylpyridin-3-yl]acetamide (50.25 g, yield 85%) as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4](OS(C(F)(F)F)(=O)=O)[N:3]=1.[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[C:26]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=4)[N:5]=3)[N:41]=2)[CH:35]=1)(=[O:33])=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(OS(=O)(=O)C(F)(F)F)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)n1
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2)n1
Temperature: 25 °C

Procedure:
A stirred mixture of trifluoro-methanesulfonic acid 4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl ester (Example A.62) (0.418 g, 1.08 mmol), N-tert-butyl-3-(6-tributylstannanyl-pyridin-2-yl)-benzenesulfonamide (Example F.6) (0.570 g, 0.98 mmol), tetrakis(triphenyl-phosphine)palladium (0.057 g, 5 mol %) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, extracted with ethyl acetate and water, dried the organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the title compound after trituration with diethyl ether as a white solid (260 mg, 50%). MS (ISP) 527.3 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:7][OH:8])[CH3:2].[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>CCCCCC>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([OH:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:22]
Reactant: CC(C)CCCCCCC(=O)O
Reactant: CCOc1cc(CO)ccc1O
Solvent: O
Solvent: CCCCCC
Product: CCOc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 89.1 %

Procedure:
3-Ethoxy-4-hydroxybenzyl alcohol (733 mg, 4.35 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 3-ethoxy-4-hydroxybenzyl 8-methylnonanoate (1.25 g, yield 88.8%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[C:21]([N:23](C)C)=O>O.[C-]#N.[Zn+2].[C-]#N.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>[C:21]([C:2]1[CH:3]=[C:4]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)#[N:23]
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1cccc(Br)c1
Reactant: CC(=O)N(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1cc2c([nH]1)CCC2c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(3-bromophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.103 g, 0.32 mmol) was combined with zinc cyanide (0.046 g, 0.39 mmol) and dissolved in dimethyl acetamide (3 mL). Then the solution was evacuated and back-flushed with N2 four times and sparged with N2 for an additional 5-10 min. Tetrakis(triphenylphosphine)palladium(0) (0.091 g, 0.08 mmol) was added and the reaction placed in a preheated (85° C.) heating block and stirred for 2 hour. The reaction was then cooled to room temperature and diluted with aqueous H2O (40 mL) and extracted three times with ethyl acetate. The organic layer was washed once with brine, then dried over Na2SO4. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-40% EtOAc/heptane afforded the title compound. 0.021 g. LCMS-MS (ESI+) 289.2 (M+Na).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH3:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: Cc1cc(COC2CCCCO2)ccc1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
4-bromo-3-methylbenzyl alcohol (2 g, 0.01 mol) was dissolved in methylene chloride (10 ml). Under ice-cooling, to the obtained solution was added 3,4-dihydropyran (1 ml, 0.011 mol) and 10-camphorsulfonic acid (120 mg, 0.5 millimol), and the mixture was stirred at room temperature for 1.5 hours. After diluting with methylene chloride, the mixture was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was distilled away, and the residue was separated and purified by using a silica-gel column chromatography (ethyl acetatee:n-hexane=1:3) to give the title compound (2.8 g, 0.01 mol).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]([O:21][CH3:22])=[N:19][CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C1COCC1>[NH2:14][C:15]1[CH:16]=[C:17]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]([O:21][CH3:22])=[N:19][CH:20]=1
Reactant: COc1ncc(N=C(c2ccccc2)c2ccccc2)cc1NS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1ncc(N)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 150 mL round-bottomed flask, N-(5-(diphenylmethyleneamino)-2-methoxypyridin-3-yl)methanesulfonamide (0.100 g, 0.262 mmol) and 1 N hydrochloric acid (0.30 mL, 0.30 mmol) were mixed into THF (2 mL). The yellow mixture was stirred at room temperature for 20 min. The reaction mixture was partitioned between tris-HCl buffer (1 M, pH 7.0) (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (10 mL). The aqueous phase was acidified to about pH 5 and the aqueous phase was extracted with
Reaction SMILES: [CH:1](=[N:8][N:9]([C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([CH:26]([C:34]#[N:35])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:21]([Cl:36])[CH:20]=1)[C:10]([NH:12]CC(OC)OC)=[O:11])[C:2]1C=CC=CC=1.Cl>C(#N)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:26]([C:22]2[C:23]([Cl:25])=[CH:24][C:19]([N:9]3[C:10](=[O:11])[NH:12][CH2:2][CH:1]=[N:8]3)=[CH:20][C:21]=2[Cl:36])[C:34]#[N:35])=[CH:32][CH:31]=1
Reactant: COC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1)OC
Agent: Cl
Solvent: CC#N
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(N2N=CCNC2=O)cc1Cl
Reaction time: 1 h
Yield: 91.1 %

Procedure:
In 30 ml of acetonitrile was suspended 3.5 g of 1-benzylidene-2-[4-(4-chloro-α-cyanobenzyl)-3,5-dichlorophenyl]-4-(2,2-dimethoxyethyl)semicarbazide produced in Working Example 2. To the suspension was added 0.7 g of 35% hydrochloric acid, and the reaction was allowed to proceed for one hour at room temperature. After completion of the reaction, the reaction mixture was cooled for 30 minutes at temperatures ranging from 0 to 10° C., then resulting crystalline precipitate was collected by filtration to afford 2.3 g of the titled compound as colorless crystals, m.p. 166-167° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[CH2:21](O)[CH3:22]>>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([CH3:14])=[CH:7][C:3]=1[C:4]([O:6][CH2:21][CH3:22])=[O:5]
Reactant: Cc1cc(C(=O)O)c(O)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1cc(C)cc([N+](=O)[O-])c1O

Procedure:
2-Hydroxy-5-methyl-3-nitrobenzoic acid (10.0 g) was dissolved in absolute ethanol (50 ml) and the solution was treated with concentrated sulphuric acid (3.0 ml), slowly with stirring. The mixture was heated at reflux for 20 hours and then poured into water (250 ml). The resulting yellow solid was recrystallised from ethanol to give ethyl 2-hydroxy-5-methyl-3-nitrobenzoate (7.5 g), m.p. 97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH2:18][C:10]2[S:9][C:8]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:11]=2)[CH:20]=1
Reactant: COc1cccc2ccsc12
Reactant: O=Cc1cc(Br)ccc1Cl
Product: COc1cccc2cc(Cc3cc(Br)ccc3Cl)sc12

Procedure:
7-Methoxybenzo[b]thiophene (see WO 02/094262) and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 367/369 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl.Cl.CCOCC>C1COCC1.C(Cl)Cl.CCOC(C)=O>[ClH:24].[Cl:24][C:20]1[CH:19]=[C:18]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:12]3[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:26][CH:25]=4)[CH:9]=[N:10][CH:11]=3)[C:35]2=[O:37])[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: N#Cc1ccc(Cn2cncc2CNCCNc2cccc(Cl)c2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CN2CCN(c3cccc(Cl)c3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a solution of the product from Step B (500 mg, 1.37 mmol) in 9.6 mL of THF at 0° C. was added triethylamine (1.2 mL, 8.6 mmol), followed by triphosgene (251 mg, 0.847 mmol). The reaction was stirred at 0° C. for one hour, then poured into EtOAc and washed with sat. aq. NaHCO3 and brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by silica gel chromatography (2.5-5% MeOH/CH2Cl2), then taken up in methanol and injected onto a preparative HPLC column and purified with a mixed gradient of 25%-55% acetonitrile/0.1% TFA; 75%-45% 0.1% aqueous TFA over 50 minutes. After concentration in vacuo, the resultant product was partitioned between dichloromethane and aq. NaHCO3 soln., and the aqueous phase was extracted with CH2Cl2. The organic solution was washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to provide the product free base, which was taken up in CH2Cl2 and treated with excess 1M HCl/ether solution. After concentrated in vacuo, the titled product (57.3 mg) was isolated as a white powder.
Reaction SMILES: [C:1]([O:5][CH:6]1[O:9][CH:7]1[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH3:10]>>[NH2:10][CH2:8][CH:7]([OH:9])[CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1OC1OC(C)(C)C
Reactant: N
Product: CC(C)(C)OCC(O)CN
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 g of 1,2-epoxypropyl tert.-butyl ether are added dropwise to 500 ml of conc. aqueous ammonia under ice-cooling and the mixture is stirred at room temperature for 20 hours. The reaction mixture is evaporated under reduced pressure to remove the aqueous ammonia. Chloroform is added to the residue. The mixture is dried with potassium carbonate. Insoluble materials are filtered off and the filtrate is evaporated to remove the solvent. The residue is distilled under reduced pressure. 49.3 g of 1-amino-3-tert.-butoxy-2-propanol are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([CH2:16][SH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C.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>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:16]([S:17][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COc1ccnc(Cl)c1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(SCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 26 h
Yield: 35.9 %

Procedure:
To a solution of 2-chloro-4-methoxypyridine (786 mg) in toluene (10 mL) were added phenylmethanethiol (683 mg), N,N-diisopropylethylamine (1.56 g), tris(dibenzylideneacetone)dipalladium(0) (202 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (256 mg), and the mixture was stirred at 80° C. for 26 hr under an argon atmosphere. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane→hexane-ethyl acetate=19:1) to give the title compound as an orange oil (yield 454 mg, 38%).