Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].B(OCC)(OCC)OCC.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OC(=O)C)C.C1CCCCC1>[CH2:20]([O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(O)c1O
Agent: CCOB(OCC)OCC
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Oc1cccc(OCc2ccccc2)c1O

Procedure:
Using the procedure of Example 13, 25.22 g of pyrogallol, 35.1 ml of triethyl borate and 23.76 ml of benzyl bromide were reacted to obtain 33.8 g of the expected product in the form of a thick red oil after chromatography on silica eluting with a cyclohexane - ethyl acetate (6-4) mixture (Yield: 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].[C:43](O)(=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)=[CH:32][CH:31]=2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:23][CH2:24][N:25]([C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:26][CH2:27]2)[C:19]=1[CH3:20])=[O:13]
Reactant: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Reactant: CC(C)(C)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)C(C)(C)C)CC1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(piperidin-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide (0.2 g, 0.34 mmol) was dissolved in DMSO (2 mL) and pivalic acid (0.107 g, 1.04 mmol) and triethyl amine (0.106 g, 1.04 mmol) was added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (0.27 g, 0.52 mmol) was added to it and stirring was continued for overnight. After completion of the reaction, reaction mixture was poured into ice, extracted with 10% MeOH/DCM. Combined organic layers were dried, concentrated to obtain crude; which then purified by column chromatography to afford the title compound (0.14 g, 60.86%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[S:11][CH3:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:20](=[O:21])[NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: O=C=Nc1cccnc1
Reactant: CSc1cc2c(cc1Br)NCC2
Product: CSc1cc2c(cc1Br)N(C(=O)Nc1cccnc1)CC2
Yield: 71 %

Procedure:
6-Bromo-5-methylthioindoline (D85) (0.26 g, 1.06 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol to afford the title compound (0.27 g, 71%) as a white crystalline solid m.p. 242°-244° C.
Reaction SMILES: CN(C=O)C.[NH:6]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:7]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:32][C@H:33]([C:36]([OH:38])=[O:37])[CH2:34][OH:35].CCN(CC)CC>>[NH:6]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:7]([C:15]([NH:32][C@H:33]([C:36]([OH:38])=[O:37])[CH2:34][OH:35])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CO)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)O
Yield: 31 %

Procedure:
In a 10 ml solution of DMF containing 500 mg (1.38 mmol) of Boc-Phe-OSu was added 5 ml of an aqueous solution of H-Ser-OH.Et3N [preparation from 290 mg (2.76 mmol) of H-Ser-OH and 384 μl (2.76 mmol) of Et3N] and the mixture was stirred for 14 hr. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate and washed with 1N-HCl and saturated sodium chloride aqueous solution, successively, together with salting out. The resultant solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the resulting residue was purified with a silica gel column chromatography (CHCl3:MeOH). The eluate was mixed with ether and n-hexane to give crystals of 150 mg of the title compound with yield of 31%.
Reaction SMILES: O1CCOCC1.[F:7][C:8]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[CH:13][C:9]=1[C:10](Cl)=[O:11].[CH3:20][N:21]([CH3:28])[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:28])[CH:22]=[C:23]([C:10](=[O:11])[C:9]1[CH:13]=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:8]=1[F:7])[C:24]([O:26][CH3:27])=[O:25]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: COC(=O)C=CN(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To dioxane (80 ml) solution of 2,3,4,5-tetrafluorobenzoyl chloride (21.25 g) was added dioxane (25 ml) solution of methyl 3-dimethylaminoacrylate (12.92 g) with ice-cooling, and triethylamine (14.46 ml) was added thereto with ice-cooling. The mixture was stirred for 30 minutes at the same temperature, then for 3 hours at room temperature, and then for one hour at 50° to 60° C. The mixture was concentrated under reduced pressure, then dissolved in methylene chloride (200 ml), washed with water (200 ml) and brine (100 ml) in order, then dried with sodium sulfate and concentrated under reduced pressure to obtain a syrup product. The syrup product was subjected to column chromatography with silica gel and eluted with a mixed liquid of methanol/methylene chloride (3/97, V/V) to obtain methyl 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (15.47 g) as a syrup product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])([CH3:14])[N:13]=1)(C)(C)C.[N+:27]([O-])([OH:29])=[O:28].[OH-].[Na+]>S(=O)(=O)(O)O>[NH2:7][C:8]1[N:9]([CH3:25])[C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[C@:12]([C:15]2[CH:20]=[C:19]([N+:27]([O-:29])=[O:28])[CH:18]=[CH:17][C:16]=2[F:21])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2ccccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C1N
Temperature: 0 °C

Procedure:
To a solution of [(S)-4-(2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E7, 0.27 g) in sulfuric acid (98%, 3.1 ml) was added at 0° C. fuming nitric acid (0.05 ml) and the reaction mixture was allowed to warm to 22° over 30 min. The mixture was slowly added to 20 ml ice cold water, the pH was adjusted to 7 using aqueous 4N NaOH and extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated to give crude (S)-2-amino-6-(2-fluoro-5-nitro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (0.19 g) as a pale orange amorphous solid. MS (ESI): m/z=309.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[O:32][CH:33]=[CH:34][N:35]=1>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[O:32][CH:33]=[CH:34][N:35]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Fc1ccccc1-c1ncco1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2CCN(c3ccccc3-c3ncco3)CC2)cc1
Temperature: 0 °C
Yield: 37.3 %

Procedure:
A mixture of N-benzylpiperazine (3.56 g, 20.2 mmol) and THF (25 mL) was cooled to 0° C. and n-butyllithium (2.5M in hexanes, 7.6 mL, 19 mmol) was added. The mixture was cooled 30 minutes with stirring at 0° C., stirred 1 hour at 25° C., then cooled to 0° C. and 2-fluoro-1-oxazol-2-ylbenzene (1.1 g, 6.75 mmol) was added slowly. The reaction mixture was allowed to warm to 25° C., then stirred 90 minutes and diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (9:1) to give 4-benzyl-1-(2-oxazol-2-ylphenyl)piperazine (0.805 g, 2.52 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](Br)[CH:11]=[CH2:12].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C(=O)C.C(OCC)C>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[CH:11]=[CH2:10]
Reactant: O=Cc1cccc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: C=CCOc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.6 %

Procedure:
3-Hydroxybenzaldehyde (1.00 g, 8.19 mmol) and allyl bromide (0.780 mL, 9.01 mmol) in N,N-dimethylacetamide (35 mL) was treated with Cs2CO3 (4.01 g, 12.3 mmol) and allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with diethyl ether (150 mL), washed with 1N HCl, saturated NaHCO3, brine, dried (MgSO4), filtered and the filtrate concentrated. The residue was purified by flash chromatography (silica gel, using 7% ethyl acetate/hexanes as eluent) to provide the title compound as a clear oil (1.19 g, 89%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH3:14])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pt](=O)=O.[H][H]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH3:14])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CN1CCCC1Cc1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CN1CCCC1Cc1ccc(N)cc1

Procedure:
Hydrogenate 18 g of 2-(4-nitrobenzyl)-1-methylpyrrolidine in ethanol with 300 mg of platinum dioxide/hydrogen. Filter the catalyst from the reaction mixture, concentrate the latter and recrystallize the thus-produced residue from n-hexane to obtain the title compound at a yield of 12.7 g (82% of theory).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/C.[CH:6]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])OCC.[N+]([O-])([O-])=O.[NH4+]>CCO.CCOC(C)=O>[CH2:14]([O:13][CH:6]([O:10][CH2:11][CH3:12])[CH:1]=[CH:2][CH3:3])[CH3:15]
Reactant: C/C=C/C=O
Reactant: CCOC(OCC)OCC
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC=CC(OCC)OCC
Reaction time: 22 h
Yield: 88.7 %

Procedure:
Crotonaldehyde (23.64 mL, 285.35 mmol), triethyl orthoformate (57.02 mL, 342.42 mmol) and ammonium nitrate (2.28 g, 28.54 mmol) were combined in 60 mL EtOH. After 22 h at ambient temperature, the reaction was diluted with EtOAc (60 mL) and washed with saturated sodium bicarbonate solution (40 mL). The aqueous layer was back extracted with EtOAc (20 mL). The combined organics were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 36.5 g (89%) of 1,1-diethoxybut-2-ene. 1H NMR (CDCl3, 400 MHz) 5.84 (m, 1H); 5.54 (m, 1H); 4.82 (d, J=5.7 Hz, 1H); 3.64 (m, 2H); 3.49 (m, 2H); 1.73 (m, 3H); 1.21 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:35].[CH3:36][Mg]Br>C1COCC1.C(OCC)C>[F:29][C:26]([F:27])([F:28])[C:25]([C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[N:16]([CH2:15][C:3]1[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([CH:11]([OH:12])[CH3:36])=[CH:13][CH:14]=3)[O:6][C:2]=1[CH3:1])[C:17]([CH3:35])=[CH:18]2)([OH:34])[C:30]([F:33])([F:32])[F:31]
Reactant: C[Mg]Br
Reactant: Cc1oc(-c2ccc(C=O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1oc(-c2ccc(C(C)O)cc2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 50 mg (0.1 mmol) of 4-{5-methyl-4-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-oxazol-2-yl}-benzaldehyde in 1 ml of THF was cooled to 0° C. and treated with 0.13 ml (0.4 mmol) of a 3M methylmagnesium bromide solution in diethylether. The mixture was stirred and allowed to reach RT within 1 hr. Distribution of the crude between a saturated aqueous solution of NH4Cl and EtOAc, drying of the combined organic phases over Na2SO4, evaporation of the solvent, and chromatography on silica gel with heptane/EtOAc 4:1 gave 44 mg (85%) of 1,1,1,3,3,3-hexafluoro-2-(1-{2-[4-(1-hydroxy-ethyl)-phenyl]-5-methyl-oxazol-4-ylmethyl}-2-methyl-1H-indol-5-yl)-propan-2-ol, off-white solid, MS: 513 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH2:13])[CH:5]=1.CCN(CC)CC.[Cl:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][Cl:22])[CH:5]=1
Reactant: CCOc1cc(N)cc(C(=O)OC)c1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(NC(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 113.9 %

Procedure:
3-Amino-5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv) was suspended in CH2Cl2 (40 ml) and treated at room temperature with NEt3 (2.32 g, 23 mmol, 1.1 equiv). The resulting solution was cooled to 0° C. and 4-chlorobutyryl chloride (3.1 g, 22 mmol, 1.1 equiv) was added dropwise. The resulting mixture was stirred at 0° C. for 3 h then allowed to warm to room temperature. The solution was washed with 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo to give of 3-(4-chloro-butanoylamino)-5-ethoxy-benzoic acid methyl ester (D51) (7.0 g, 115%) as a brown oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1.I[CH2:43][CH3:44].O>CN(C)C=O>[CH2:43]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([O:29][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:41]=[N:40][CH:39]=[CH:38][N:37]=3)[S:34][CH:35]=2)[CH:28]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]1)[CH3:44]
Reactant: CCOC(=O)CCc1cn(Cc2cc(O)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2cc(OCC)cc(OCc3csc(-c4cnccn4)n3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
Sodium hydride (60%, oily, 28.0 mg) was added to a solution of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (378 mg) in N,N-dimethylformamide (5 ml) at 0° C., which was stirred at room temperature for 15 minutes. Iodoethane (0.0672 ml) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (385 mg, yield: 97%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-])=O)=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I.CS[C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32]>C(O)C.C(OCC)C.[Pd]>[CH2:1]([C:8]1[N:9]([CH2:20][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([NH:17][C:31]([C:33]1[S:34][CH:35]=[CH:36][CH:37]=1)=[NH:32])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Solvent: CCOCC
Product: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
Compound 4 (125 mg, 0.344 mmol) was dissolved in anhydrous ethanol (7 mL) in a dry argon purged flask. Palladium, 10 wt % on activated carbon (36.2 mg, 0.034 mmol) is quickly added and the atmosphere from the flask evacuated by vacuum pump and replaced with hydrogen from a balloon. The atmosphere is evacuated from the flask and replaced with hydrogen twice more and the mixture stirred under a hydrogen atmosphere at room temperature. After 3 hours, thin layer chromatography in a solvent system of 2M NH3 in methanol:CH2Cl2, 5:95 shows complete conversion to compound 5, which is utilized without isolation. The mixture is filtered through a pad of celite to remove insolubles, the pad washed with anhydrous ethanol (7 mL) and the ethanolic solution of the amine 5 is charged to a small, argon purged flask fitted with a magnetic stirbar. Thiophene-2-carboximidothioic acid methyl ester hydroiodide (127.5 mg, 0.447 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 48 hours, at which time the solution was diluted with diethyl ether (100 ml) resulting in the formation of a off-white precipitate that was collected on a sintered glass funnel and washed with ether. The solid was partitioned between H2O and ethyl acetate and 3M sodium hydroxide solution added to adjust pH to 8-9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95) to afford beige foam 6 (75 mg, 49.3%); 1H NMR (DMSO-d6) δ 7.71 (d, 1H, J=3.7 Hz), 7.58 (d, 1H, J=5.2 Hz), 7.35-7.20 (m, 6H), 7.09 (m, 1H), 6.92 (s, 1H), 6.64 (d, 1H, J=8.5 Hz), 6.23 (brs, 2H), 6.10 (s, 1H), 4.14 (s, 2H), 3.99 (t, 2H, J=8.0 Hz), 2.90 (quintet, 1H, J=4.6 Hz), 2.10 (s, 3H), 2.05-1.97 (m, 2H), 1.91-1.80 (m, 1H), 1.69-1.56 (m, 3H), 1.49-1.35 (m, 2H); ESI-MS (m/z, %): 443 (M+1, 70%), 219 (100%).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH:13]1[C:21](=[O:22])[C:19](=[O:20])[C:17](=[O:18])[NH:16][C:14]1=[O:15].Cl>C(O)C>[OH:20][C:19]1([C:8]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=[CH:10][CH:9]=2)[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: c1ccc(-n2cccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1NC(=O)C(O)(c2cccn2-c2ccccc2)C(=O)N1
Yield: 80.6 %

Procedure:
1-Phenylpyrrole (1.4 g., 0.01 mole), alloxan hydrate (1.6 g., 0.01 mole) and 50 ml. of ethanol were combined and refluxed for 15 minutes. No reaction was noted by tlc. 1N Hydrochloric acid (10 ml., 0.01 mole) added and the acidified mixture refluxed for 15 minutes. Incomplete reaction was noted by tlc. A second portion of alloxan hydrate (1.6 g., 0.01 mole) was added and the mixture refluxed another 15 minutes, cooled and evaporated to dryness. Trituration of the residue with water gave title product [2.3 g.; m/e 285; m.p. 232°-234° C. (dec); Rf 0.3 (1:1 ethyl acetate:hexane)].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:27])[C:15]([F:26])([F:25])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][CH:37]=2)[CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1([C:36]2[CH:41]=[CH:40][C:39]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:27])[C:15]([F:25])([F:26])/[CH:16]=[CH:17]/[C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[CH:6][CH:7]=3)=[CH:38][CH:37]=2)[CH2:34][CH2:35]1)=[O:32])[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(F)(F)/C=C/c1ccc(F)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(F)(F)/C=C/c4ccc(F)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-2,2-difluoro-4-(4-fluoro-phenyl)-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].CI.[C:23](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:23])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: Cc1cc(Cl)c(N2C(=O)C3=CCCCN3C2=O)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC#N
Solvent: CI
Product: COc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1C
Yield: 64.6 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2-chloro-4-methyl-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, 1.11 mmol), methyliodide (0.08 mL, 1.22 mmol) and potassium carbonate (0.15 g, 1.11 mmol) was stirred for 30 minutes under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a white solid of 2-(2-chloro-4-methyl-5-methoxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.22 g, yield:61.1%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:9]=[O:10])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([CH:9]=[O:10])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)CCCBr
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCC(=O)O)c(Cl)c1Cl

Procedure:
A mixture of 2,3-dichloro-4-formylphenol (5.73 g., 0.03 mole), ethyl 4-bromobutyrate (11.7 g., 0.06 mole) and potassium carbonate (8.28 g., 0.06 mole) in dimethylformamide (25 ml.) is heated at 50°-60° C. for 11/2 hours. Water (50 ml.) is added and the mixture is extracted with ether. The ether extract is dried and evaporated. To the residue is added a solution composed of 48 ml. of 40% sodium bisulfite and 12 ml. of alcohol. The precipitated 4isulfite addition compound then is washed with alcohol and ether. The solid is suspended in water heated in a steam bath. An oily layer of the free aldehyde is formed. The hot water then is decanted and the oily layer is extracted with ether and the ether evaporated. The residue is heated to 80° C. in a mixture of potassium hydroxide (2.8 g.), methanol (30 ml.) and water (5 ml.), the resulting solution is evaporated to dryness and the residue dissolved in water. Upon acidification a solid separates. The solid is crystallized from benzene to obtain 2.9 g. of 4-(2,3-dichloro-4-formylphenoxy)butyric acid, M.P. 147°-148° C.