Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCN(C(=O)OC(C)(C)C)CC6)cc5)cc34)cn2)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)c1
Yield: 27 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (108 mg, 0.197 mmol) was deprotected in TFA/toluene (5/5 ml). This afforded 30 mg (27% yield) of the titled. 1H NMR (CD3OD, 300 MHz): δ 8.627-8.622 (d, 1H), 8.56 (s, 1H), 8.20 (s, 1H), 7.94 (s, 1H), 7.75-7.71 (m, 3H), 7.44-7.42 (d, 2H), 7.25-7.20 (t, 1H), 7.13-7.07 (m, 3H), 5.37 (s, 2H), 3.55-3.51 (d, 2H), 3.21-3.13 (m, 2H), 3.03-2.94 (m, 1H), 2.31 (s, 3H), 2.14-2.10 (d, 2H), 2.03-1.89 (qd, 2H). MS: m/z=448.4 (M+1), HPLC: 98.27% in method A.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(#N)C>[CH3:21][O:20][C:3]1[C:2]([O:1][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:34][CH:35]=2)=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[O:14][CH2:13]2
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OC)c1OCc1ccc(S(C)(=O)=O)cc1
Temperature: 80 °C
Yield: 19.7 %

Procedure:
To a stirring solution of 5-(3-Hydroxy-2,4-dimethoxy-phenyl)-3H-isobenzofuran-1-one (80 mg, 0.279 mmol) in acetonitrile (10 mL) was added potassium carbonate (115 mg, 0.837 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (208 mg, 0.837 mmol) and the resultant reaction mixture was heated to 80° C. for 4 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (25 mg, 19.7%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:29]=[CH:28][C:14]([CH2:15][N:16]3[C:20]([CH:21]=O)=[C:19]([C:23]([O:25]CC)=O)[N:18]=[CH:17]3)=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1.S(=O)(=O)(O)O>C(O)C.O>[Cl:4][C:5]1[CH:31]=[CH:30][C:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[C:20]4[CH:21]=[N:3][N:2]([CH3:1])[C:23](=[O:25])[C:19]=4[N:18]=[CH:17]3)=[CH:28][CH:29]=2)=[O:10])=[CH:7][CH:6]=1
Reactant: CNN
Reactant: CCOC(=O)c1ncn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cn1ncc2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Temperature: 25 °C
Yield: 6.7 %

Procedure:
A solution of methylhydrazine (472 mg) and ethyl 1-[4-(4-chlorobenzoyl)benzyl]-5-formylimidazole-4-carboxylate (1.03 g) in ethanol (20 ml) was refluxed for 3 hours. After cooling to room temperature, concentrated sulfuric acid (0.2 ml) was added and the mixture was further refluxed for 21 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developer; chloroform:methanol=19:1) to provide the title compound as white powder (66 mg, yield 7%). 1H-NMR (CDCl3) δ: 3.90(3H,s), 5.47(2H,s), 7.31(2H,d,J=8.4Hz), 7.48(2H,d,J=8.4Hz), 7.73(2H,d,J=8.4Hz), 7.81(2H,d,J=8.4Hz), 7.92(1H,s), 8.00(1H,s).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH:18]2[CH2:20][CH2:19]2)[CH:13]=[C:14]([F:17])[CH2:15][OH:16])=[CH:8][CH:7]=1.O>C1C=CC=CC=1.N1C=CC=CC=1>[C:1]([O:16][CH2:15][C:14]([F:17])=[CH:13][CH:12]([C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][CH:10]=1)[CH:18]1[CH2:19][CH2:20]1)(=[O:3])[CH3:2]
Reactant: OCC(F)=CC(c1ccc(Cl)cc1)C1CC1
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC(F)=CC(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
Acetyl chloride (1.2 ml) was slowly added to a stirred solution of 4-(4-chlorophenyl)-4-cyclopropyl-2-fluorobut-2-enol (Example 6) (0.51 g) in benzene (30 ml) and pyridine (0.24 ml) at 0° C. and stirring was continued for 24 hours while the mixture warmed to room temperature. Water (2 ml) was added, and the mixture was extracted with diethyl ether (3×20 ml). The combined organic layers were washed with water (3×10 ml), dried and evaporated under reduced pressure. The residual oil was chromatographed on silica gel using diethyl ether/hexane (1:4) to yield 4-(4-chlorophenyl)-4-cyclopropyl-2-fluorobut-2-enyl acetate (0.46 g, 78%).
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][CH:26]=[CH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[Si:1]([O:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C=CC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CCC[C@H]1CCC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2.4 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]but-2-enoate are dissolved in 35 ml of methanol, and 200 mg of Pd (10% on activated carbon) are added. The mixture is stirred at room temperature under an atmosphere of hydrogen for 7 hours. The catalyst is filtered off through Celite and the filtrate is concentrated under reduced pressure. This gives 2.3 g of tert-butyl 4-[cis-3-(tert-butyl-diphenylsilanyloxy)cyclohexyl]butanoate as an oil. C30H44O3Si (480.75), MS(ESI): 481 (M+H+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[SH:14][C:15]1[CH:16]=[C:17]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.[Cu]Cl.O>[CH3:28][O:27][C:21]1([C:17]2[CH:16]=[C:15]([S:14][C:2]3[CH:7]=[CH:6][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=3)[CH:20]=[CH:19][CH:18]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: COC1(c2cccc(S)c2)CCOCC1
Reactant: CN(c1ccc(I)cc1)S(C)(=O)=O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC1(c2cccc(Sc3ccc(N(C)S(C)(=O)=O)cc3)c2)CCOCC1
Reaction time: 3 h

Procedure:
A solution of N-(4-iodophenyl)-N-methylmethanesulphonamide (0.31 g, 1 mmol), 4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.22 g), potassium carbonate (20 mg) and copper (I) chloride (30 mg) in DMF (20 ml) was heated to 140° C. and stirred for 3 hours. Ethyl acetate (40 ml) and water (40 ml) were added and the mixture was filtered through celite. The filtrate was washed with water (40 ml) and brine (40 ml), dried (MgSO4) and the solvent evaporated. The product was purified by column chromatography, thus N-{4-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]phenyl}-N-methylmethanesulphonamide was obtained as an oil (0.12 g, 42%). NMR Spectrum 1.85-2.10 (4H, m), 2.85 (3H, s) 3.00 (3H, s), 3.30 (3H, s), 3.75-3.90 (4H, m), 7.25-7.35 (8H, m).
Reaction SMILES: Cl[C:2]([NH:4][N:5]1[CH:13]=[C:11]([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25][C:26](=[O:39])[CH2:27][NH:28][CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH3:24]>C1COCC1.C(OCC)C>[CH2:23]([O:25][C:26](=[O:39])[CH2:27][N:28]([CH2:29][CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:2]([NH:4][N:5]1[CH:13]=[C:11]([CH3:12])[C:9](=[O:10])[NH:8][C:6]1=[O:7])=[O:3])[CH3:24]
Reactant: CCOC(=O)CNCCNC(=O)OC(C)(C)C
Reactant: Cc1cn(NC(=O)Cl)c(=O)[nH]c1=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(CCNC(=O)OC(C)(C)C)C(=O)Nn1cc(C)c(=O)[nH]c1=O
Reaction time: 12 h

Procedure:
The product from Example 5, 8, is dissolved in THF (500 mL) and diisopropylethylamine (12.9 g, 0.1 mol) is added, followed by N-(2-t-butyloxycarbonylaminoethyl)glycine ethyl ester (24.6 g, 0.1 mol) and the solution stirred for 12 hours. The reaction is diluted with 1000 mL of diethyl ether and extracted 3 times with 0.1N HC1 solution. The organic layer is washed with diluted sodium bicarbonate solution, dried, filtered and evaporated to give a solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.Cl.[CH3:12][O:13][NH2:14].C(O)(=O)C>O>[CH3:12][O:13][N:14]=[CH:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[N:5][C:6]=1[Cl:10]
Reactant: CON
Reactant: Nc1ncnc(Cl)c1C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CON=Cc1c(N)ncnc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-amino-6-chloro-pyrimidine-5-carbaldehyde Compound 1a (1.0 g), O-methyl-hydroxylamine hydrochloride (0.94 g) and a mixed solvent of acetic acid (25 mL) and H2O (4 mL) were added to a flask. The mixture was stirred at rt overnight, then concentrated. The residue was suspended in H2O and extracted with EtOAc. The organic layer was separated, dried with MgSO4, then concentrated to afford 4-amino-6-chloro-pyrimidine-5-carbaldehyde O-methyl-oxime Compound 9a (0.97 g, 92%). 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.50 (s, 1H), 8.25 (s, 1H), 7.70 (s, 1H), 3.98 (s, 3H). MS (ESI) m/z: 188 (M+H+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH:18]1([C:23](N(OC)C)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CON(C)C(=O)C1CCCC1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)C2CCCC2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with cyclopentyl-N-methoxy-N-methylcarboxamide. It is used in crude form in the following reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl)C1CC1
Agent: Cl[Sn]Cl
Solvent: O
Product: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl)C1CC1

Procedure:
The title compound was prepared from [4-chloro-5-(cyclopropyl-methyl-amino)-2-nitro-phenyl]-carbamic acid tert.-butyl ester (Example C9) (3.2 g, 9.36 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as brown solid (2.00 g).
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2([O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.Cl>[Pd].O>[O:15]1[C:11]2([CH2:18][CH2:19][NH:8][CH2:9][CH2:10]2)[C:12](=[O:17])[NH:13][C:14]1=[O:16]
Reactant: O=C1NC(=O)C2(CCN(Cc3ccccc3)CC2)O1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C2(CCNCC2)O1
Reaction time: 12 h
Yield: 69 %

Procedure:
A mixture of 8-benzyl-3,8-diaza-1-oxaspiro[4.5]decane-2,4-dione (1.1 g, 4.2 mmol), 10% palladium on carbon (330 mg), acetic acid 10 mL, concentrated hydrochloric acid (2 mL) and water (20 mL) was hydrogenated approximately 12 hours at 15 psi of pressure. The mixture was filtered and concentrated and the residue was crystallized from isopropanol to give 3,8-diaza-1-oxaspiro[4.5]decane-2,4-dione (0.6 g, 2.9 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:35])[CH3:34])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Product: CCOC(=O)C(C)(C)Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Yield: 74 %

Procedure:
The procedure of Example 3 was repeated by using 10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (500 mg) and ethyl α-bromoisobutyrate (0.22 ml) to obtain the title compound (470 mg, 74%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12](Br)Br)=[CH:7][CH:6]=1.CCCCCC.C([Li])CCC.[CH3:26][Si:27]([CH3:30])([CH3:29])Cl.O>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si:27]([CH3:30])([CH3:29])[CH3:26])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C=C(Br)Br)cc1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(2,2-dibromoethenyl)phenol methoxymethyl ether (16.56 g) in THF (350 ml) was cooled to -78° C., to which was added dropwise, under argon atmosphere, a 1.6M n-butyl lithium hexane solution (70 ml). The mixture was stirred for one hour under the same conditions, which was then warmed and stirred for one hour at room temperature. The reaction mixture was cooled with ice, to which was added dropwise trimethylchlorosilane (7.2 ml). The mixture was then stirred for 3 hours while warming up to room temperature, to which was added water to quench the reaction, followed by extraction with ethyl acetate. The organic layer was washed (a saturated aqueous saline solution) and dried (anhydrous magnesium sulfate), then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 4-(2-trimethylsilylethynyl)phenol methoxymethyl ether (10.76 g) (Compound B-26). The physical properties are shown in Table 8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:39][S:40]([CH2:43][CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)(=[O:42])=[O:41]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:47][CH2:46][N:45]([CH2:44][CH2:43][S:40]([CH3:39])(=[O:41])=[O:42])[CH2:50][CH2:49]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:33])([CH3:32])[CH2:30][OH:31])=[CH:25][C:24]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)CO)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-hydroxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (example 12g) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 701.4 [(M+H)+]
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH2:11]([C:18]1[S:22][C:21]([CH2:23][NH2:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.CO.C(OCC)(=O)C.O>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][CH2:23][C:21]2[S:22][C:18]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:19][CH:20]=2)=[O:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: NCc1ccc(Cc2ccccc2)s1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Nc1ccc(C(=O)NCc2ccc(Cc3ccccc3)s2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a solution of 6-aminonicotinic acid (340 mg, 2.4 mmol) and C-(5-benzyl-thiophen-2-yl)-methylamine described in Preparation Example 42 (450 mg, 2.2 mmol) in N,N-dimethylformamide (5 mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (1.1 g, 2.4 mmol) and triethylamine(0.62 mL, 4.4 mmol), and the solution was stirred at 60° C. for 1 hour. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed twice with water. Silica gel was added to the organic layer, the solvent was evaporated in vacuo adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate, then ethyl acetate:methanol=10:1), and 6-amino-N-(5-benzyl-thiophen-2-ylmethyl)-nicotinamide (210 mg, 0.65 mmol, 29.5%) was obtained.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[Sn](CCCC)(CCCC)CCCC.Br[C:28]1[N:33]=[C:32]2[C:34]([C:56]([NH:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[CH:35][N:36]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:31]2=[N:30][CH:29]=1>CN(C=O)C.O.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.[Cu](I)I>[C:59]([NH:58][C:56]([C:34]1[C:32]2=[N:33][C:28]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([O:3][CH:2]([F:1])[F:26])[CH:5]=4)[NH:9][N:8]=3)=[CH:29][N:30]=[C:31]2[N:36]([C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:35]=1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(Br)nc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2ccc(OC(F)F)cc12
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4ccc(OC(F)F)cc34)nc12
Temperature: 90 °C
Yield: 56.8 %

Procedure:
A mixture of 5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (250 mg, 0.57 mmol), 2-bromo-N-tert-butyl-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (280 mg, 0.58 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), copper iodide (26 mg, 1.36 mmol) in 10 mL of dry DMF was heated to 90° C. for 3 hours under N2. The reaction mixture was cooled to room temperature, diluted with 50 mL of water, product extracted with ethyl acetate (3×20 mL), organics combined dried with sodium sulfate, filtered and concentrated to give N-tert-butyl-2-(5-(difluoromethoxy)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (208 mg, crude). LCMS: (M+H)+=643.
Reaction SMILES: [Na].[N+:2]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)([O-:4])=[O:3].Cl.Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[N:14]1([CH:13]([C:7]2[N:6]=[C:5]([N+:2]([O-:4])=[O:3])[NH:9][CH:8]=2)[CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCCCC1
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CC(c1c[nH]c([N+](=O)[O-])n1)N1CCCCC1
Temperature: 140 °C
Yield: 70 %

Procedure:
The sodium salt of 2-nitroimidazole (0.01 mole) was reacted with a mixture of 0.01 mole of N-(2-chloroethyl)piperidine hydrochloride and 0.01 mole of sodium methoxide in 20 ml of xylene. The mixture was heated at 140° C. under reflux for 8 hours. The mixture was filtered, the filtrate was concentrated under vacuum. The residue was crystallized from a mixture of ethyl ether and hexane to yield 0.007 mole of 1-piperidinoethyl-2-nitroimidazole, m.p. 61°-62° C. The 1-piperidinoethyl-2-nitroimidazole (0.01 mole) was treated with 0.01 mole of m-chloroperbenzoic acid (m--CPBA) at room temperature for 30 minutes in 100 ml of chloroform as solvent. The resulting N-oxide was purified by recrystallization from chloroform and benzene, and had a m.p. of 108°-109° C. 'H-nmr: (CD3OD) 7.12 and 7.47 (S, C4,5 -H), ##STR16## 3.60 (t, NCH2) ppm.ir: (KBr) 1485 and 1360 (NO2), 1270 cm-1 (N→O).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:40]=[CH:39][C:13]([CH2:14][N:15]([C:26]3[CH:38]=[CH:37][C:29]4[O:30]C(C)(C)[O:32][C:33](=[O:34])[C:28]=4[CH:27]=3)[C:16](=[O:25])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:16](=[O:25])[C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:26]3[CH:38]=[CH:37][C:29]([OH:30])=[C:28]([CH:27]=3)[C:33]([OH:34])=[O:32])=[CH:39][CH:40]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)c2ccc(O)c(C(=O)O)c2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-chlorophenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-4-methoxybenzamide and NaOH as a white powder (45%). 1H NMR (MeOD, 300 MHz) δ 7.53-7.42 (m, 5H), 7.41-7.28 (m, 6H), 7.09 (m, 1H), 6.77 (m, 3H), 5.11 (s, 2H), 3.73 (s, 3H). M− (ESI): 510; M+ (ESI): 511.9. HPLC, Rt: 4.89 min (Purity: 97.6%).