Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:42])[CH:17]([N:24]2[C:28]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=3[N:26]=[C:25]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:11]([F:43])[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:25]2[N:24]([CH:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:16]([NH:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:44])=[O:5])=[CH:10][C:11]=3[F:43])=[O:42])[C:28]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:27]=3[N:26]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Reaction time: 2 h

Procedure:
To a solution of (4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-phenoxy)-acetic acid tert-butyl ester (120 mg, 0.19 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (1.5 ml). After 2 h, the solvent was removed under reduced pressure. The resulting oil (78 mg, 71%) solidified upon standing in the refrigerator.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[C:13]([OH:22])=[C:14]([CH2:19][CH:20]=O)[CH:15]=[C:16]([Cl:18])[CH:17]=1)([O:10][CH3:11])=[O:9]>>[C:8]([C:12]1[C:13]2[O:22][CH:20]=[CH:19][C:14]=2[CH:15]=[C:16]([Cl:18])[CH:17]=1)([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(Cl)cc(CC=O)c1O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2ccoc12
Yield: 63.2 %

Procedure:
A trifluoroacetic acid (25 ml) solution of 3-carbomethoxy-5-chloro-2-hydroxyphenylacetaldehyde (5c) (5.20 g, 22.7 mmol) was refluxed for 2 hours under argon, and then poured into saturated Na2CO3The resulting precipitate was collected by filtration, and then purified by column chromatography (100% CH2Cl2) to give 6c as a cream colored solid (3.02 g, 63.2% yield). Analytical sample was prepared by recrystallization from ethyl ether, mp 144°-145° C. IR (nujol) 1710 (ester) cm-1. NMR (CDCl3) δ7.87-6.70 (m, 4H, aromatic protons) and 4.0 (s, 3H, CH3).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](I)=[C:7]([CH:34]=1)[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH:15][CH:14]=1)#[N:2].[NH:36]([C:40](=[CH2:45])[C:41]([O:43][CH3:44])=[O:42])[C:37]([CH3:39])=[O:38].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:37]([NH:36][C:40](=[CH:45][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:34][C:7]=1[O:8][CH2:9][CH2:10][NH:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]2)=[CH:15][CH:14]=1)[C:41]([O:43][CH3:44])=[O:42])(=[O:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)NCCOc3cc(C#N)ccc3I)cc2)CC1
Reactant: C=C(NC(C)=O)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CC#N
Product: COC(=O)C(=Cc1ccc(C#N)cc1OCCNC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1)NC(C)=O

Procedure:
2.72 g (4.60 mmol) of N-[2-(5-cyano-2-iodophenoxy)ethyl]-4-(1-t-butoxycarbonyl-4-piperidyloxy)benzamide and 1.32 g (9.22 mmol) of methyl 2-acetaminoacrylate were dissolved in 80 ml of acetonitrile. 272 mg (1.21 mmol) of palladium (II) acetate, 630 mg (2.07 mmol) of tri-o-tolylphosphine and 1.71 g (9.23 mmol) of tributylamine were added to the solution, and they were heated under reflux for 3 days. The solvent was evaporated, and the residue was treated with ethyl acetate as the extractant in an ordinary manner to obtain the crude product, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([C@H:25]5[CH2:29][C@@H:28]([OH:30])[CH2:27][N:26]5C(OC(C)(C)C)=O)=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:38][CH3:39])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([C@H:25]5[CH2:29][C@@H:28]([OH:30])[CH2:27][NH:26]5)=[O:24])[CH2:21][CH:22]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(C(=O)[C@H]4C[C@@H](O)CN4C(=O)OC(C)(C)C)CC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(C(=O)[C@H]4C[C@@H](O)CN4)CC3)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 240A (100 mg, 0.186 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.2 mL, 2.60 mmol) and the mixture was stirred at room temperature for 4 hours and concentrated. The residue was dissolved in dichloromethane (2 mL) and treated with 2M hydrogen chloride in ether (2.5 mL) and filtered. The solid was washed with diethyl ether and concentrated to obtain the title compound as the hydrochloride salt. 1H NMR (500 MHz, DMSO-d6) δ 1.70-1.80 (m, 1H), 2.53-2.79 (m, 2H), 3.09-3.32 (m, 2H), 4.60-4.06 (m, 7H) 4.37-4.43 (m, 2H), 4.44 (dd, J=38.4, 9.5 Hz, 1H), 4.57-4.77 (m, 1H), 6.44 (bs, 1H), 6.62-6.69 (m, 1H), 7.01-7.38 (m, 3H), 8.29 (d, J=5.3 Hz, 1H), 8.46-8.80 (m, 1H), 10.24 (bs, 1H), 12.57-12.65 (m, 1H). MS (ESI(+)) m/e 437 (M+H)+.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:18][C@@H:19]([CH2:36][CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>O.C(O)C>[CH3:18][C@@H:19]([CH2:36][CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1
Reactant: CC[C@H](C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC[C@H](C)CCCCCOc1ccc(OCc2ccccc2)cc1
Yield: 83.5 %

Procedure:
A solution of NaOH (40 g) dissolved in water (18 ml) was added to a solution of p-benzyloxyphenol (12 g, 0.060 mol) dissolved in ethanol (60 ml), followed by dropwise adding to the mixture, (S)-6-methyloctyl-p-toluenesulfonate (16.7 g, 0.055 mol) obtained above, refluxing the resulting mixture for 12 hours, distilling off ethanol after completion of the reaction, extracting the residue with toluene, washing the resulting ortanic layer with 6N-hydrochloric acid, then with 2N-NaOH aqueous solution, further with water until the washing water became neutral, drying the layer, distilling off the organic solvent to obtain an oily product, and subjecting this product to column chromatography with activated alumina (17 g) to obtain (S)-p-benzyloxyphenyl 6-methyloctyl ether (15 g), dissolving this product (15 g, 0.046 mol) in ethanol (43 ml), subjecting the solution to hydrogenolysis in the presence of paradium-carbon (1.5 g) to obtain (S)-p-6-methyloctyloxyphenol (XII) (8.2 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(=O)([O-])[O-].[Na+].[Na+].[O:17]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCOCC1>[O:17]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
This compound was prepared from trans-2-amino-1-cyclohexanecarboxylic acid (1.0 g, 7.0 mmol) by reacting it with sodium carbonate (1.48 g, 14.0 mmol) and 4-phenoxybenzenesulfonyl chloride (2.25 g, 8.38 mmol) in dioxane:water (40:20 mL) in the same manner as described in Example 1. This yielded 1.275 g (48%). The melting point was 192-194° C. Mass spectrometry revealed a molecular ion (MH)+ peak at m/z 376.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>O1CCCC1>[CH:31]1([C:36]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CCCC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 56.9 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), cyclopentanecarbonyl chloride (53 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (105 mg, 57%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:29][CH3:30])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22]C)=[O:21])=[CH:11][CH:10]=1.O.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[CH:31][C:3]=1[CH2:4][N:5]([CH2:29][CH3:30])[C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][S:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([OH:22])=[O:21])=[CH:13][CH:14]=1
Reactant: CCN(Cc1ccccc1Cl)C(=O)COc1ccc(CCSc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1ccccc1Cl)C(=O)COc1ccc(CCSc2ccccc2C(=O)O)cc1
Yield: 95.5 %

Procedure:
Methyl 2-{[2-(4-{2-[(2-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}-benzoate was dissolved in a mixture of THF (freshly distilled)/water (2/1, 3 ml), Lithium hydroxide (0.015 g, 0.629 mmol) was added. The reaction was performed in a single node microwave oven (5 min, 150 deg). THF was removed by evaporation. Water was added (10 ml) and the basic water phase was washed with diethyl ether (2×10 ml). Addition of HCl (2 ml, 1 M, pH 1). The water phase was extracted with two portions of DCM (20 ml). The organic phase was dried (MgSO4) and the solvent was removed by evaporation to give 0.103 g of 2-{[2-(4-{2-[(2-chlorobenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethyl]thio}-benzoic acid (yield 95.5%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[N:3]1.O1CCCC1.C([Li])CCC.CCCCCC.C(O[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1)(C)C>>[CH3:1][N:2]1[C:6]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[C:5]([CH3:7])[CH:4]=[N:3]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cnn(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
A solution of 1,4-dimethyl-1H-pyrazole (480.0 mg, 4.993 mol) in tetrahydrofuran (20 mL, 300 mmol) at 0° C. was added 1.6 M n-butyllithium in hexane (4.7 mL, 7.5 mmol). The solution was stirred at room temperature for 1 h and then cooled to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.63 mL, 7.99 mmol). The reaction mixture was stirred at −78° C. for 0.5 h, then warmed up to 0° C. (taking 0.5 h). The reaction was quenched with brine and extracted with EtOAc (3×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by combi-flash chromatography and eluted with EtOAc/hexane (0-60%). The purification gave 142 mg of product as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[C:5]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20](O)=[O:21])[N:18]=2)[CH:4]=[N:3]1.[O:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH2:30])[CH2:25][CH2:24]1>>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[C:5]([C:14]2[S:15][CH:16]=[C:17]([CH2:19][C:20]([NH:30][CH2:29][CH:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)=[O:21])[N:18]=2)[CH:4]=[N:3]1
Reactant: Cc1ccccc1-c1c(-c2nc(CC(=O)O)cs2)cnn1C
Reactant: NCC1CCOCC1
Product: Cc1ccccc1-c1c(-c2nc(CC(=O)NCC3CCOCC3)cs2)cnn1C

Procedure:
Using the compound obtained in step 3 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: CS([C:5]1[N:6]=[C:7]([CH2:31][CH2:32][CH3:33])[C:8]2[N:13]=[C:12]([C:14]3[CH:28]=[C:27]([CH3:29])[C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:16]([CH3:30])[CH:15]=3)[O:11][C:9]=2[N:10]=1)(=O)=O.[Cl:34][C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:36]=[C:37]([CH:38]=[CH:39][CH:40]=1)[O:41][C:5]1[N:6]=[C:7]([CH2:31][CH2:32][CH3:33])[C:8]2[N:13]=[C:12]([C:14]3[CH:28]=[C:27]([CH3:29])[C:17]([O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:16]([CH3:30])[CH:15]=3)[O:11][C:9]=2[N:10]=1
Reactant: CCCc1nc(S(C)(=O)=O)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Reactant: Oc1cccc(Cl)c1
Product: CCCc1nc(Oc2cccc(Cl)c2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Yield: 100 %

Procedure:
Analogously to example 1 (i), the reaction of 104 mg of tert-butyl [4-(5-methanesulfonyl-7-propyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with 3-chlorophenol gave 115 mg (100%) of the title compound.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[NH:19]([C:23]1[S:24][CH:25]=[C:26]([CH2:28][S:29][CH2:30][CH2:31][NH2:32])[N:27]=1)[C:20]([NH2:22])=[NH:21]>CN(C)C=O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][C:6]1[C:7](=[O:9])[NH:8][C:3]([NH:32][CH2:31][CH2:30][S:29][CH2:28][C:26]2[N:27]=[C:23]([NH:19][C:20]([NH2:22])=[NH:21])[S:24][CH:25]=2)=[N:4][N:5]=1
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Solvent: CN(C)C=O
Product: COc1cccc(Cc2nnc(NCCSCc3csc(NC(=N)N)n3)[nH]c2=O)c1
Temperature: 135 °C
Reaction time: 192 h
Yield: 5.9 %

Procedure:
A mixture of 3-methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.0 g) and 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole (0.924 g) was heated at 135° C. for 3 hours. The residue was dissolved in dimethyl formamide (20 ml) and the solution was allowed to stand at room temperature for 8 days. A yellow brown solid precipitated out of solution, and this was filtered off and dried in air, then purified using pressure assisted short bed column chromatography (Kieselgel 60) with chloroform/methanol/ammonia (s.g. 0.880) 8:2:0.3 v/v/v as eluant, to give 6-(3-methoxybenzyl)-3-[2-(2-guanidinothiazol-4-yl-methylthio)ethylamino]-1,2,4-triazin-5-one (0.1 g). The n.m.r. spectrum of the product in d4 acetic acid using tetramethylsilane as an internal standard (δ=0) had the following resonances (δ): 2.8 (2H, multiplet); 3.5 (2H, multiplet); 3.75 (5H, singlet); 3.9 (2H, singlet); 6.8-6.9 (4H, multiplet); 7.2 (1H, broad doublet).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[OH:25])=[CH:4][CH:3]=1.Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Cl)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: O=C(OCc1ccccc1)N1CCC(Sc2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 71(b), from benzyl (3RS,4RS)-4-(4-chloro-phenylsulphanyl)-3-hydroxy-piperidine-1-carboxylate by alkylation with 2-bromomethyl-naphthalene there was obtained benzyl (3RS,4RS)-4-(4-chloro-phenylsulphanyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 518 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[O:9][C:8]([CH3:12])=[N:7][C:6]=2[CH:13]=1.[OH-].[NH4+:15]>>[Br:1][C:2]1[CH:13]=[C:6]2[C:5]([C:10](=[O:9])[NH:15][C:8]([CH3:12])=[N:7]2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Cc1nc2cc(Br)ccc2c(=O)o1
Agent: [OH-]
Product: Cc1nc2cc(Br)ccc2c(=O)[nH]1
Temperature: 80 °C
Yield: 56.4 %

Procedure:
7-bromo-2-methyl-4H-benzo[d][1,3]oxazin-4-one 7.25 (400 mg, 1.58 mmol) was taken up in 26% aqueous ammonium hydroxide (5 mL, 33.38 mmol) and heated in a sealed tube at 80° C. for 4 hours. Mixture was cooled to room temperature and solid was filtered, washing with water. Solid was dried in-vacuo to yield 7-bromo-2-methylquinazolin-4(3H)-one 7.26 (213 mg), which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:17]([Cl:18])=[CH:16][C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:8])=[C:5]([O:19][CH3:20])[CH:4]=1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].Cl>CN(C)C=O>[ClH:18].[NH2:2][C:3]1[C:17]([Cl:18])=[CH:16][C:6]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12][CH2:11]2)=[O:8])=[C:5]([O:19][CH3:20])[CH:4]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCNCC1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(NC(=O)c2cc(Cl)c(N)cc2OC)CC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of-3.20 g of 4-amino-5-chloro-2-methoxy-N-(4-piperidinyl)benzamide hydrochloride, 1.22 ml of ethyl bromoacetate, 3.04 g of porassium carbonate, and 32 ml of N,N-dimethylformamide was stirred for 2.5 hours with heating at 60° C. The reaction mixture was concentrated under reduced pressure, and then the residue was added with water and extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give brown oil. The result was converted to the hydrochloride by an ordinary method to afford 3.31 g of pale yellow crystals. Recrystallization from ethanol gave colorless plates, m.p. 196.5°-198.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:15]4[CH:17]=[C:18]([NH:21][C:22](=[O:30])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[Cl:29])[CH:19]=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[C:10]([C:31]([NH2:33])=[O:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][N:35](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:14]2[CH2:13][CH2:12][C:11]3[C:10]([C:31]([NH2:33])=[O:32])=[N:9][N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:34]#[N:35])=[CH:3][CH:4]=4)[C:16]=3[C:15]=2[CH:17]=1)=[O:30]
Reactant: NC(=O)c1nn(-c2ccc(Br)cc2)c2c1CCc1ccc(NC(=O)c3ccccc3Cl)cc1-2
Reactant: CN(C)C=O
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]
Product: N#Cc1ccc(-n2nc(C(N)=O)c3c2-c2cc(NC(=O)c4ccccc4Cl)ccc2CC3)cc1
Temperature: 100 °C

Procedure:
1-(4-Bromophenyl)-8-[(2-chlorobenzoyl)amino]-4,5-dihydro-1H-benzo[g]indazole-3-carboxamide (5.2g) and Zn(CN)2 (0.9g) were dissolved in 100 ml DMF under N2. Then Pd(Ph3P)4 (1.38 g) was added. The reaction mixture was heated up to 100° C. under N2 for 12 hours. After the reaction is completed by HPLC, the solvent was evaporated, and the residue was suspended in ethyl acetate and water. After filtration, and washing with water and ethyl acetate, the filtrate of the organic layer was separated and dried with Na2SO4. After filtration and evaporation of solvent, the residue was triturated with ether. Solid obtained was filtered and washed with ether, then dried under vacuum. The desired compound (3.4 g) was obtained and characterized by 1H NMR, LC-MS (468, M+1), and CHN analysis. IKK-2 resin IC50≦1 μM.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH3:12]>C(O)(C)C>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CC(C)O
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
There were led into a solution of 21.3kg of 2,6-dichloro-3-nitropyridine (90%, water wet) in 100 liters of isopropanol with stirring at 20°-30° C. 6.8 kg (400 moles) of ammonia gas (there can also be dropped in liquid ammonia). Then stirring was carried out for 24 hours at room temperature. The 2-amino-3-nitro-6-chloro-pyridine formed was further reacted in suspension after the testing for unreacted 2,6-dichloro-3-nitro-pyridine by means of thin layer chromatography or gas chromatography is negative.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CO[C:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C(O)C>[ClH:1].[CH3:2][CH:3]([N:18]=[C:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]1)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: COC1=NCCCCC1
Agent: Cl
Solvent: CCO
Product: CC(N=C1CCCCCN1)c1ccc(CCc2ccccc2)cc1
Temperature: -20 °C
Reaction time: 96 h
Yield: 76 %

Procedure:
A mixture of 15.0 g of α-methyl-p-phenethylbenzylamine hydrochloride and 25 ml of O-methylcaprolactim is stirred into a slurry and allowed to stand at room temperature for 4 days with occasional stirring. Small portions of absolute ethanol are added to keep the slurry stirrable. The mixture is then cooled to -20° C., the precipitate is collected, washed with small portions of absolute ether and recrystallized from a mixture of acetone-methanol to yield 15.7 g (76% yield) of the desired product, M.P. 230°-231° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][N:4]=1>ClCCl.O=[Mn]=O>[F:11][C:2]([F:1])([F:12])[C:3]1[N:4]=[CH:5][CH:6]=[CH:7][C:8]=1[CH:9]=[O:10]
Reactant: OCc1cccnc1C(F)(F)F
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cccnc1C(F)(F)F
Temperature: 50 °C

Procedure:
MnO2 (6.10 g, 70.6 mmol) was added portionwise to a solution of the above (2-(trifluoromethyl)pyridin-3-yl)methanol (I-29A) (2.5 g, 14.1 mmol) in dry dichloromethane (300 mL), and the resulting suspension was heated to 50° C. for 72 hours. After this time the mixture was filtered through Celite® and the filtrate concentrate in vacuo to afford a brown oil. This crude oil was purified by silica gel chromatography using a gradient of 0-30% ethyl acetate-hexane to furnish 2-(trifluoromethyl)nicotinaldehyde (I-29B) as clear oil. 1H-NMR (400 MHz, CDCl3) δ 10.4 (m, 1H), 8.89 (dd, J=4.8 and 1.2 Hz, 1H), 8.45 (dd, J=8.0, and 1.6 Hz, 1H), 7.70 (dd, J=8.0 and 4.8 Hz, 1H). MS m/z 176.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH3:24][C:25]1([NH2:29])[CH2:28][O:27][CH2:26]1>>[CH3:24][C:25]1([NH:29][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:28][O:27][CH2:26]1
Reactant: CC1(N)COC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2(C)COC2)cn1
Yield: 8 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mmol) was converted, using 3-methyl-3-oxetanamine instead of methylamine, to the title compound (22 mg, 8%) which was obtained as a white solid. MS: m/e=380.2 [M+H]+.