Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][CH:10]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][NH:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:18].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C>O1CCCC1.[Pd]>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][NH:22][C:23]1[C:28]([NH:29][C:14]([C:12]2[S:13][C:9]([CH3:8])=[CH:10][CH:11]=2)=[O:15])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:18]
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: CCOC(=O)CNc1ncccc1N
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(C)s1
Yield: 100.8 %

Procedure:
Under a nitrogen atmosphere, triethylamine (31.41 g, 0.311 mole) and 5-methyl-2-thiophenecarbonyl chloride (50 g, 0.311 mole) were added simultaneously, dropwise, to a stirred and chilled solution of freshly prepared N-[[3-amino]-2-pyridinyl] glycine ethyl ester (0.296 mole) by palladium/carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester (66.98 g, 0.296 mole) in dry tetrahydrofuran (~1 liter). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers separated and the aqueous layer was again extracted with ethyl acetate. The combined organic layers were washed twice with a 5% potassium hydroxide solution, twice with a saturated sodium bicarbonate solution, twice with water, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 95.3 g of a tan solid in quantitative yield. A 1.5-g portion of the solid was dissolved in hot absolute ethanol, filtered while hot, and brought to its cloud point by addition of water. Cooling to room temperature gave a solid which was collected by filtration, rinsed with water, and dried under high vacuum at room temperature overnight to give 1.11 g of title compound, mp 112°-115° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]([NH2:30])=[S:29])[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:27][C:28]2[S:29][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[N:30]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]1
Reactant: COc1ccccc1C(=O)CBr
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Product: COc1ccccc1-c1csc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 2-bromo-2′-methoxyacetophenon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude product was purified through stirring with methylene chloride at room temperature yielding 104 mg (88%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(2-methoxy-phenyl)-thiazol-2-yl]-amine as a light yellow solid. MS ISP (m/e): 393.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.65 (s, 1H), 9.32 (s, 1H), 8.17 (d, 1H), 8.05 (s, 1H), 7.70 (s, 1H), 7.53 (d, 1H), 7.51 (s, 1H), 7.32-7.29 (m, 2H), 7.15 (d, 1H), 7.07 (t, 1H), 3.94 (s, 3H), 3.93 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.C[O:7][C:8](=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.[Na+].[Cl-].[NH4+:21].[OH-]>O.[Cl-].[Na+].O>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:8]([NH2:21])=[O:7])=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: [NH4+]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: NC(=O)CCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a suspension of 3-(4-amino-phenyl)-propionic acid methyl ester sulfuric acid salt (as prepared in the previous step, 277 mg, 1.00 mmol) in 8 mL of conc NH4OH was added 0.75 g of NaCl in 3 mL of H2O. After stirring at RT for 16 h, the resulting mixture was treated with 10 mL of brine and extracted with EtOAc (5×25 mL). The combined organic layers were dried (Na2SO4) and concentrated to give 133 mg (81%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C9H12N2O, 165.1 (M+H). found 165.0.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][N:18]([CH2:29][C:30]1([CH2:33][CH2:34][N:35]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:32][CH2:31]1)[CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.O.NN>C(O)C>[NH2:35][CH2:34][CH2:33][C:30]1([CH2:29][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)n1c(CN(CC2(CCN3C(=O)c4ccccc4C3=O)CC2)C2CCCc3cccnc32)nc2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCC1(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)CC1
Yield: 51.9 %

Procedure:
To a solution of 2-{[{1-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-cyclopropylmethyl}-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (0.121 g, 0.20 mmol) in ethanol (4 mL) was added hydrazine monohydrate (0.20 mL, 4.12 mmol) and the resultant mixture was stirred at room temperature overnight. The mixture was filtered through filter paper and concentrated. Purification of the cnide material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 39 mg (50%) of the free base of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[NH4+:11]>>[NH2:11][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncc(Cl)cc1Cl

Procedure:
2,3,5-Trichloropyridine (20 g, 0.11 moles) was placed in a steel bomb and treated with ammonium hydroxide (300 mL) at 190° C. in similar manner as described in Example 2 to give 2-amino-3,5-dichloropyridine (15 g) as a white solid. 1H NMR (CDCl3) δ 7.92 (d, 1H), 7.48 (d, 1H), 5.1 (broad s, 2H); MS m/z 163 (M+H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@H:24]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[C:35]([F:43])[CH:34]=4)[O:25][C:26]4([CH2:31][CH2:30][O:29][CH2:28][CH:27]4I)[C:11]=3[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2]>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]3[C@H:24]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[C:35]([F:43])[CH:34]=4)[O:25][C:26]4([CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[C:11]=3[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c3c1[C@H](c1ccc(C(F)(F)F)c(F)c1)OC31CCOCC1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: [Pd+2]
Agent: [OH-]
Product: CC(C)c1nc2c(c3c1[C@H](c1ccc(C(F)(F)F)c(F)c1)OC31CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (3S,9S)-9-(tert-butyldimethylsilyloxy)-3-(3-fluoro-4-(trifluoromethyl)phenyl)-3′-iodo-4-isopropyl-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]. 10% palladiumhydroxide on charcoal is used instead of 10% palladium on charcoal.
Reaction SMILES: C([NH:4][C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)[CH:8]=1)=[O:6])(C)C.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].C1(C#C)C=CC=CC=1>>[CH3:25][Si:26]([C:29]#[C:30][C:20]1[CH:19]=[C:18]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][N:11]=3)[C:16](=[O:17])[C:7]([C:5]([NH2:4])=[O:6])=[CH:8]2)[CH:23]=[CH:22][CH:21]=1)([CH3:28])[CH3:27]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Solvent: C#Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cccc(-n2cc(C(N)=O)c(=O)c3cccnc32)c1

Procedure:
Following the procedure of Step 5 of EXAMPLE 1, but substituting the 1-(3-Bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from present Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for phenylacetylene, the 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide product was obtained as a solid.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH:11]=[O:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.[C:19]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:11]([C:9]1[N:10]=[C:6]2[C:5]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:4][CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:25])=[CH:27][CH:28]=3)[N:7]2[CH:8]=1)=[O:12]
Reactant: O=Cc1cn2c(Br)cnc(N3CCOCC3)c2n1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(C=O)cn23)cc1
Temperature: 80 °C

Procedure:
A mixture of compound 2a (1.0 g, 3.2 mmol), 4-(tert-butoxycarbonyl)phenylboronic acid pinacol ester (1.2 g, 3.9 mmol), PdCl2(dppf) (260 mg, 0.30 mmol), 2M Na2CO3 (8.0 mL, 16 mmol) in dioxane (10 mL) was heated to 80° C. for 2 h. The reaction was cooled, filtered through a diatomaceous earth-filled cartridge (2.5 g), and the filter cake was rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure. The residue was diluted with DCM and extracted with water, brine, then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with MeOH, filtered and dried to give compound 67a. Mass Spectrum (LCMS, ESI pos.) Calcd. for C22H24N4O4: 409.4 [M+H]. found 409.4.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27](O)=[O:28]>>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:28]
Reactant: Cc1ccccc1CC(=O)O
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: Cc1ccccc1CC(=O)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(2-methylphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.31 (d, J=7.8, 1H), 8.03 (d, J=7.7, 1H), 8.01-7.96 (m, 1H), 7.94-7.87 (m, 1H), 7.33-7.30 (m, 1H), 7.24-7.14 (m, 3H), 3.84-3.81 (m, 4H), 3.68 (s, 2H), 3.15-3.06 (m, 4H), 2.35 (s, 3H); MS (ESI+) M/Z 379 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH2:48][CH:49]([OH:61])[CH2:50][N:51]1[CH2:60][CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:52]1[C:53]2[C:58](=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:59][CH2:60][N:51]1[CH2:50][CH:49]([OH:61])[CH2:48][NH:47][C:17]([C:16]1[CH:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[CH:22]=[CH:21][CH:20]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)O)c2)CC1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C(=O)NCC(O)CN3CCc4ccccc4C3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.3 %

Procedure:
The solution of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (300 mg, 1.0 mmol) and HATU (381 mg, 1.0 mmol) in DCM (10 mL) was stirred at 25° C. for 30 min. Then 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (200 mg, 1.0 mmol) and DIPEA (259 mg, 2.00 mmol) was added and the resulting solution was stirred at 25° C. for 16 h. The solution was concentrated and the residue was purified by column chromatography to give the title product (140 mg, Yield 28.8%). LCMS (m/z): 495.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:51]1[CH:55]=[CH:54][N:53]=[C:52]1[NH:56][C:57]([C:59]1[C:67]2[NH:66][C:65]([NH2:68])=[N:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]>O.CN(C=O)C>[NH:53]1[CH:54]=[CH:55][N:51]=[C:52]1[NH:56][C:57]([C:59]1[C:67]2[N:66]=[C:65]([NH:68][C:14]([C:13]3[CH:12]=[N:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:17]=3)=[O:16])[NH:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=C(O)c1cncc(OCc2ccccc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cncc(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
0.07 g (0.30 mmol) of 5-benzyloxy-nicotinic acid and 0.12 g (0.32 mmol) of HBTU were combined in a flask charged with 2 mL DMF and 0.25 mL of DIEA. This reaction mixture was then treated with 0.05 g (0.20 mmol) of 2-Amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B) and stirred at 80° C. for 1 h. The reaction mixture was diluted with water, and the resultant solid precipitate was filtered and washed with saturated NaHCO3. The solid was dissolved with MeOH, evaporated onto silica gel and isolated by flash column chromatography (500 mL DCM/20 mL NH3/MeOH) to yield 10 mg (10%) of 2-[(5-benzyloxy-pyridine-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 455.0 (M+1)+.
Reaction SMILES: P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)([O-:12])=[O:11].N1([C:28](=[O:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])CCCCC1>>[CH2:32]([O:31][C:29](=[O:30])[C:28]([C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])[NH:17][CH:16]=1)=[O:34])[CH3:33]
Reactant: CCOC(=O)C(=O)N1CCCCC1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Product: CCOC(=O)C(=O)c1c[nH]c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diphosphoryl chloride (23.5 mL, 170 mmol) was added dropwise to a stirred mixture of 4-nitroindole (25.0 g, 154 mmol) and ethyl 1-piperidineglyoxylate (29.0 g, 170 mmol) at 0° C. The mixture was allowed to warm slowly to ambient temperature and stirring was continued for 18 h. The reaction mixture was cooled to 0° C. and quenched carefully by addition of EtOH (50 mL), followed by saturated aqueous NaBCO3 until no further effervescence was observed. The precipitated yellow solid was isolated by filtration, washed with H2O, and dried in vacuo to give the title compound. MS: m/z=263 (M+1).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:29])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:29])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:14]([O:27][CH3:28])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCC(=O)O
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCCCC(=O)O

Procedure:
Using 0.2 g of N-(trans-4-methylcyclohexyl )-4-(5-carboxypentyloxy) -3-methoxycinnamamide, 0.01 g of 10% palladium-carbon, and 35 mR of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 0.14 g of N-(trans-4methylcyclohexyl) -3-[4-(5-carboxypentyloxy )- 3methoxyphenyl]propionamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([N+:14]([O-])=O)=[CH:9][C:10]=1[CH2:11][CH:12]=[CH2:13])[CH2:6][OH:7].[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:14][C:8]1[CH:9]=[C:10]([CH2:11][CH:12]=[CH2:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:6][OH:7]
Reactant: C=CCc1cc([N+](=O)[O-])c(CO)cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C=CCc1cc(N)c(CO)cc1OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
24 ml of ethanol-water (5:1) was added to 1.00 g of 3-methoxy-6-nitro-4-(2-propenyl)benzylalcohol, 1.00 g of iron, and 2.00 g of ammonium chloride. The reaction solution was stirred at 90° C. for 1 hour. Thereafter, the reaction solution was cooled to a room temperature, and insoluble matters were then removed by filtration. The filtrate was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure, so as to obtain 793 mg of the subject compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C(N(CC)CC)C.[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>C1COCC1.CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:27][CH2:26][CH:22]1[CH2:23][CH2:24][CH2:25][N:21]1[CH3:20])=[O:8])([O-:3])=[O:2]
Reactant: CN1CCC[C@H]1CO
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCCC1COC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a solution of 3-nitrobenzoylchloride (2.5 g; 13.5 mmol) in THF (25 ml) was added triethylamine (1.87 ml; 13.5 mmol), a catalytic amount of 4-(N,N-dimethylamino)pyridine and (S)-(−)-1-methyl-2-pyrrolidinemethanol (1.61 ml; 13.5 mmol). The mixture was heated to reflux for 1.5 hours and left with stirring at ambient temperature overnight. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and diluted hydrochloric acid (4 M). The aqueous phase was rendered alkaline by addition of aqueous sodium hydroxide (4 M) and extracted with dichloromethane. The organic extract was dried over sodium sulphate and evaporated to leave 6r (2.8 g; 78%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][C:18]([O-:20])=O.Cl>O>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[N:10]1[C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:17][C:18]1=[O:20]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na]
Solvent: O
Product: O=C1Cc2ccccc2N1c1c(Cl)cccc1Cl
Reaction time: 0.17 h

Procedure:
1.5 g sodium-[2-(2,6-dichloro-phenylamino)-phenyl]-acetate are dissolved in 6 ml of water, combined with 5.2 ml 1 N hydrochloric acid and the precipitated solid is suction filtered after stirring for 10 minutes. After drying in vacuo the solid is taken up in 6 ml of tetrahydrofuran, combined with 990 μl triethylamine and 1.17 g N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride and stirred for 3 hours. Then it is divided between water and ethyl acetate, the aqueous phase is extracted twice with ethyl acetate and the combined organic phases are dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 70:30 to 20:80).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Cl)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccc2)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
Dichlorobis(triphenylphosphine)palladium (29 mg, 0.04 mmol) was added to a solution of methyl 4-chloro-2-methoxybenzoate (904 mg, 4.5 mmol), phenylboronic acid (500 mg, 4.1 mmol) and cesium carbonate (2.7 g, 8.2 mmol) in N,N-dimethylformamide (15 mL) under argon atmosphere, and the mixture was stirred at 120° C. for 8 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (410 mg, 41.2%) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[CH3:13][N:14]([S:18][S:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[C:15](F)=[O:16].C(N(CC)CC)C>O1CCOCC1.O>[CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][C:15](=[O:16])[N:14]([CH3:13])[S:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:22][CH:21]=3)[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)Oc1cccc2c1OC(C)(C)C2
Yield: 39.9 %

Procedure:
To a solution of 4.0 g (0.024 m) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol and 6.56 g (0.024 m) of N-methyl-N-(p-tert-butylphenylthiosulfenyl)carbamoyl fluoride in 25 ml of dioxane was added 2.45 g (0.024 m) of triethylamine. After 24 hours the reaction mixture was diluted with 200 ml of water and the product was extracted in ethylacetate. The organic extract was washed in turn with diluted sodium hydroxide and water, dried over MgSO4 and concentrated under reduced pressure. The product was crystallized from isopropyl ether to yield 4.0 g of a white solid, m.p. 150°-151° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][C:3]=1[O:12][CH3:13].Br[CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]1=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:23]3[CH2:24][CH2:25][CH2:26][CH:21]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:15][CH:16]=4)[C:22]=3[N:11]=2)=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: COc1cc(NC(N)=S)ccc1Br
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1Br
Yield: 61.9 %

Procedure:
(4-Bromo-3-methoxy-phenyl)-thiourea (1.20 g, 4.59 mmol) and 2-bromo-6-phenyl-cyclohexanone (1.29 g, 5.10 mmol) in 20 ml ethanol were stirred overnight at reflux. The brown solution was evaporated to dryness; the brown residue was dissolved in chloroform, washed three times with water and dried with magnesium sulfate. The solvent was evaporated in vacuo. Column chromatography (70 g silica, dichloromethane) afforded the title compound (1.18 g, 62%) as a light brown foam. MS ISP (m/e): 417.1 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): □ (ppm)=7.25 (m, 7H), 6.90 (s broad, 1H), 6.50 (dd, 1H), 4.04 (m broad, 1H), 3.58 (s, 3H), 2.75 (m broad, 2H), 2.20 (m broad, 1H), 1.77 (m broad, 3H).