Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[F:14][C:15]1[CH:20]=[C:19]([CH2:21][C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH3:23])[CH:18]=[C:17]([F:30])[C:16]=1OB(O)O.C1([C@H](C)CC2C=CC(OB(O)O)=CC=2)C=CC=CC=1>>[F:14][C:15]1[CH:20]=[C:19]([CH2:21][C@H:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:23])[CH:18]=[C:17]([F:30])[C:16]=1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Reactant: C[C@H](Cc1cc(F)c(OB(O)O)c(F)c1)c1ccccc1
Agent: C[C@H](Cc1ccc(OB(O)O)cc1)c1ccccc1
Product: C[C@H](Cc1cc(F)c(-c2ccc(S(F)(F)(F)(F)F)cc2)c(F)c1)c1ccccc1
Yield: 42.8 %

Procedure:
A reaction was carried out in the same manner as in second step of Example 4-3 except that 3.08 g (10.9 mmol) of 4-bromophenyl sulfur pentafluoride [Br-Ph-SF5] was employed instead of 1-bromo-3,5-difluorobenzene in second step of Example 4-3 and 3.00 g (10.9 mmol) of (R)-2,6-difluoro-4-(2-phenylpropyl)phenylboric acid [H-Ph-CH(CH3)—CH2-PhFF-B(OH)2] obtained in third step of Example 4-5 was employed instead of (R)-4-(2-phenylpropyl)phenylboric acid [H-Ph-CH(CH3)—CH2-Ph-B(OH)2] to obtain 2.03 g (4.67 mmol) of (R)-4-(2,6-difluoro-4-(2-phenylpropyl)phenyl)phenyl sulfur pentafluoride [H-Ph-CH(CH3)—CH2-PhFF-Ph-SF5] (yield: 43%). MS m/e: 434(M+)
Reaction SMILES: [NH2:1][C:2](=[N:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=2[F:35])[C:11]2[NH:15][C:14](=[O:16])[N:13]([C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:12]=2)=[CH:5][CH:4]=1.C(=O)([O-])O.[K+].[C:50](=[O:62])([O:55][CH:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1)[O:51][CH:52](Cl)[CH3:53]>CN(C=O)C>[CH:56]1([O:55][C:50](=[O:62])[O:51][CH:52]([O:16][C:14]2[N:13]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[N:12]=[C:11]([CH:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:2]([NH2:1])=[N:36][C:37](=[O:44])[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:4][CH:5]=3)[C:23]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH2:32][CH2:33][OH:34])[C:24]=3[F:35])[N:15]=2)[CH3:53])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nc(OC(C)OC(=O)OC3CCCCC3)n(-c3ncccn3)n2)c1
Temperature: 55 °C
Reaction time: 26 h
Yield: 52.9 %

Procedure:
To a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 1.0 g) and DMF (20 mL), potassium hydrogen carbonate (1.67 g) and 1-chloroethyl cyclohexyl carbonate (2.76 g) were added, and the resulting mixture was stirred at 55° C. for 26 hours. The reaction solution was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (680 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C@@H:9]1[CH2:13][C@@H:12]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][N:10]1[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])(O)=[O:7].[CH3:32][NH:33][C:34](=[S:37])[NH:35][NH2:36].[OH-].[Na+]>O1CCCC1.O.CN(C)C=O>[CH3:18][S:15]([O:14][C@H:12]1[CH2:11][N:10]([C:19]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:20])[C@H:9]([C:6]([NH:36][NH:35][C:34]([NH:33][CH3:32])=[S:37])=[O:7])[CH2:13]1)(=[O:17])=[O:16]
Reactant: CNC(=S)NN
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=S)NNC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a mixture of dimethylformamide (2.9 ml) and tetrahydrofuran (6 ml) was dropwise added phosphorus oxychloride (2.8 ml) at -5°~5° C. and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added a solution of (2S,4R)-2-carboxy-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (9.65 g) in tetrahydrofuran (20 ml) at -5°~5° C., followed by stirring at the same temperature for 30 minutes. The mixture was dropwise added to a solution of 4-methylthiosemicarbazide (25 g) in a mixture of water (200 ml) and tetrahydrofuran (200 ml) at 0°-10° C. with sitrring, keeping the pH between 8-9 with 1N aqueous sodium hydroxide. The mixture was stirred at the same condition for 2 hours. Tetrahydrofuran was evaporated under reduced pressure to give precipitates. The precipitates were collected by filtration, washed with water and diisopropyl ether successively, and dried over phosphorus pentoxide to give (2S,4R)-4-methanesulfonyloxy-2-(4-methylthiosemicarbazidocarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (9.61 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=1)[C:11](OC)=[O:12].O.[OH-].[Na+]>C1COCC1>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:11][OH:12])[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:17]=1
Reactant: COC(=O)c1cc(Cl)cc(-c2ccccn2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Cl)cc(-c2ccccn2)c1
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
A cooled (−10° C.) suspension of LiAlH4 (50 mg; 1.34 mmol) in anh. THF (2 ml) was treated with a solution of methyl 3-chloro-5-(pyridin-2-yl)benzoate (302 mg; 1.21 mmol) in anh. THF (1 ml). The mixture was further stirred at −10° C. for 20 min. Water (50 μl), 15% aq. NaOH (50 μl), and water (0.15 ml) were then successively added, and the resulting mixture was further stirred at rt for 1 h. Filtration, concentration to dryness under reduced pressure, and additional drying under HV afforded (3-chloro-5-(pyridin-2-yl)phenyl)methanol as a yellow oil. LC-MS (conditions A): tR=0.48 min.; [M+H]+: 220.08 g/mol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.[Cl:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:9][CH2:10]2)(=[O:24])=[O:25])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)N1CCN(c2ccccc2F)CC1
Yield: 85.8 %

Procedure:
Sulfonylation of 1-(2-fluorophenyl)piperazine.HCl (325 mg, 1.5 mmol) with 3,4-dichlorobenzene-1-sulfonyl chloride (368.3 mg, 1.5 mmol) was carried out according to a similar procedure described for step 1A using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (0.575 mL, 3.3 mmol) as base. 1-[(3,4-dichlorophenyl)sulfonyl]-4-(2-fluorophenyl)piperazine was obtained in 85.8% yield (501 mg) as white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:48]=[CH:47][C:26]([C:27]([N:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3/[C:33](=[CH:40]\[C:41]([O:43][CH3:44])=[O:42])/[C:32]([F:46])([F:45])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:46][C:32]1([F:45])[CH2:31][CH2:30][N:29]([C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:48][CH:47]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2/[C:33]/1=[CH:40]\[C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)/C=C1\c2ccccc2N(C(=O)c2ccc(N)cc2)CCC1(F)F
Reactant: O=C(O)c1ccccc1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: COC(=O)/C=C1\c2ccccc2N(C(=O)c2ccc(NC(=O)c3ccccc3-c3ccccc3)cc2)CCC1(F)F
Yield: 96.7 %

Procedure:
Using 127 mg of o-phenylbenzoic acid, 0.141 ml of oxalyl chloride and 200 mg of methyl (E)-[1-(4-aminobenzoyl)-4,4-difluoro-2,3,4,5-tetrahydro-1H-1-benzazepin-5ylidene]acetate, a similar procedure as in Reference Example 8 was repeated to obtain 287 mg of methyl (E)-[4,4-difluoro-1-[4-(2-phenylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-ylidene]acetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]([CH3:24])[N:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.ClC1C=CC2N(C(C(C3C=[C:39]4[C:43](=CC=3F)[N:42]([CH3:47])[N:41]=[CH:40]4)C)=CN=2)N=1.[I-].O[PH2]=O.[OH-].[Na+]>C(O)(=O)C>[F:23][C:22]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][N:19]2[CH3:24])=[CH:15][C:14]=1[CH:11]([C:8]1[N:6]2[N:7]=[C:2]([C:39]3[CH:40]=[N:41][N:42]([CH3:47])[CH:43]=3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)[CH3:12]
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Reactant: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: O=[PH2]O
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(-c3cnn(C)c3)nn12

Procedure:
(rac)-6-Chloro-3-[1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethanol (Stage 278.2, 2 g, 5.78 mmol) was dissolved in acetic acid (80 mL) and introduced in 4 microwave reactors. Iodide (1.84 g×4, 29 mmol), followed by H3PO2 50% (2.36 mL×4, 87 mmol) were then added into each reactor. Then they were submitted to microwave irradiations 5 min at 150° C. After combination, it was basified by a 2.5 M NaOH solution and extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 120 g RediSep® silica gel column, DCM/MeOH=100:0->94:6 in 30 min). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound (tR 1.15 min (conditions 2), MH+=330).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:17]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:17]1([NH:1][C:2]2[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCCC1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(F)(F)F)cc(NC2CCCC2)c1C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (2.5 g, 10.7 mmol) and cyclopentanone (4.5 g, 53.49 mmol) in methanol (25 mL) was added acetic acid (1.98 g, 21.44 mmol). After 3 h, sodium cyanoborohydride (1.68 g, 24.3 mmol) was added and the reaction stirred overnight. On completion, the solvent was removed under reduced pressure and crude material was purified by column chromatography to afford methyl 3-(cyclopentylamino)-2-methyl-5-(trifluoromethyl)benzoate (1.8 g, 55.9%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.ClCCl.C(OCC)C>[ClH:24].[F:23][C:19]1[CH:18]=[C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(F)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(c1cccc(F)c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(3-Fluoro-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (919 mg) was dissolved in methanol (10 ml) and dichloromethane (5 ml), 2M HCl in diethyl ether (12 ml) was added and the reaction mixture was stirred at room temperature overnight. Volatiles were removed in vacuo to yield 4-(3-fluoro-benzenesulfonyl)-piperazine hydrochloride salt (807 mg).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]([CH3:20])[C:5]([C@@:7]1([NH2:19])[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:8]1[CH2:16][O:17][CH3:18])=[O:6].[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[S:32][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:30][CH:29]=2)[CH:24]=1>N1C=CC=CC=1>[CH3:2][O:3][N:4]([CH3:20])[C:5]([C@@:7]1([NH:19][S:33]([C:31]2[S:32][C:28]([C:25]3[CH:24]=[C:23]([C:22]([F:21])([F:37])[F:38])[O:27][N:26]=3)=[CH:29][CH:30]=2)(=[O:34])=[O:35])[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:8]1[CH2:16][O:17][CH3:18])=[O:6]
Reactant: O=S(=O)(Cl)c1ccc(-c2cc(C(F)(F)F)on2)s1
Reactant: COC[C@@H]1[C@H](c2ccccc2)[C@]1(N)C(=O)N(C)OC
Agent: Cl
Solvent: c1ccncc1
Product: COC[C@@H]1[C@H](c2ccccc2)[C@]1(NS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)on2)s1)C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
The (1R*,2R*,3R*)-1-amino-2-methoxymethyl-3-phenyl-cyclopropanecarboxylic acid methoxy-methyl-amide hydrochloride (22 mg, 0.082 mmol) was dissolved in 1 mL of pyridine. To this solution was added 5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonyl chloride (25 mg, 0.079 mmol) and the mixture was stirred at room temperature overnight. After concentration, the reaction mixture was diluted with EtOAc and washed with sat. NaHCO3 (2×) and brine. After drying over MgSO4, the solution was concentrated and purified using prep-TLC (1:1 hexanes/EtOAc) to afford 13 mg of the desired product (32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]2[CH2:18][O:17]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>CO.C(O)C.C(O)(C)C>[CH3:1][O:2][C:3]1[C:13]([O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[CH:12][C:6]2[CH:7]=[CH:8][C:9](=[O:11])[O:10][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)ccc2cc1OCC1CO1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Solvent: CO
Product: COc1cc2oc(=O)ccc2cc1OCC(O)CN1CCN(c2ccccc2)CC1
Yield: 99 %

Procedure:
Method C (5 d at 40° C.); starting materials: 7-methoxy-6-(oxiranylmethoxy)-2H-1-benzopyran-2-one and 1-phenylpiperazine; yield 99%; fusion point 160°-162° C. (from isopropanol and ethanol). Hydrochloride: method F; yield 78%; fusion point 222°-225° C. (from isopropanol, ethanol and methanol).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.C(N(CC)CC)C.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1>CN(C)C=O.C(O)(C)C.CO>[C:28]([NH:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(C)O
Product: O=C(NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21)c1cccnc1
Reaction time: 2 h
Yield: 32 %

Procedure:
To a suspension of 0.6 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 30 ml of anhydrous dimethylformamide are added successively, at a temperature in the region of 20° C., 0.6 g of triethylamine and 0.42 g of nicotinoyl chloride hydrochloride. The mixture is stirred for 2 hours at the same temperature, the insoluble product formed is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 80° C. The product obtained (1.04 g) is suspended for 10 minutes in 20 ml of boiling isopropanol and, after cooling and storing at 5° C. for 1 hour, is isolated by filtration, washed with 1 ml of chilled isopropanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 60° C. The product obtained (0.43 g) is suspended in 5 ml of methanol, isolated by filtration, washed with 2 ml of methanol and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.24 g of 10-nicotinoylamino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are thus obtained, decomposing without melting above 260° C. (NMR spectrum: [200 MHz; (CD3)2SO-d6 ; δ in ppm]: 6.42 (d, J=8.5 Hz, 1H: --CH 10); 7.40 and 7.51 (2 broad t, J=8 Hz, 1H each: --H7 and --H8); 7.58 and 7.92 (2 broad d, J=8 Hz, 1H each: --H6 and --H9); 7.62 and 7.74 (2s, 1H each: --H of the imidazole); 7.62 (dd, J=8.5 and 5 Hz, 1H: --H at 5 of the pyridine); 8.33 (broad d, J=8.5 Hz, 1H: --H at 4 of the pyridine); 8.79 (broad d, J=5 Hz, 1H: --H at 6 of the pyridine); 9.11 (mt, 1H: --H at 2 of the pyridine); 9.38 (d, J=8.5 Hz, 1H: --NHCO-- at 10); 12.63 (broad s, 1H: --CONH of the ring)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11]Br>C(O)(=O)C.O>[Br:11][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][OH:1])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: BrBr
Reactant: OCCc1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: OCCc1ccc(O)c(Br)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(2-hydroxyethyl)phenol 9.50 g in acetic acid 60 ml is dropped bromine 3.54 ml over a period of 10 minutes on a water bath, and the mixture is stirred for 15 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is dissolved in methanol 120 ml and thereto is added potassium carbonate 25 g. The mixture is stirred at room temperature for 5 hours. and then diluted with water and with ethyl acetate. The solution is acidified with concentrated sulfuric acid. The organic layer is extracted with ethyl acetate, washed, dried and concentrated in vacuo. The residue is crystallized from chloroform to give 2-bromo-4-(2-hydroxyethyl)phenol as a slightly brown crystalline powder 9.37 g. mp 83–85° C.
Reaction SMILES: [Cl-].[CH3:2]/[C:3](=[C:9](/[CH3:13])\[C:10]([O-:12])=[O:11])/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:14][C:15]([CH3:22])([CH:19]([CH3:21])[CH3:20])[C:16]([NH2:18])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([O:6][C:4](=[O:5])/[C:3](/[CH3:2])=[C:9](\[CH3:13])/[C:10]([O-:12])=[O:11])[CH3:8].[NH2:18][C:16]([C:15]([NH-:14])([CH3:22])[CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)C(C)(N)C(N)=O
Agent: CCOC(=O)/C(C)=C(\C)C(=O)[O-]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C)([NH-])C(N)=O

Procedure:
A solution of 13 g of monoethyl 2,3-dimethylfumarate chloride in 20 ml of methylene chloride was added dropwise, while stirring and cooling with ice, to a solution of 12 g of 2-amino-2,3-dimethyl-butyric acid amide and 12 ml of triethylamine in 80 ml of methylene chloride. The mixture was stirred for 2 hours at room temperature, the resulting solution was extracted with water, with 2N hydrochloric acid and again with water, then dried and evaporated. The residue was triturated with diethyl ether, suction-filtered and recrystallized from a little ethanol. 8.0 g (41% of theory) of monoethyl-2,3-dimethylfumarate-N-(1-aminocarbonyl-1-methylisobutyl)-amide were obtained, m.p. 122°-125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH3:14])[C:9]=2[NH:15][C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH2:13][CH3:14])[C:9]=4[NH:15][C:16]4[O:17][C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: CCc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4Nc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-ethyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester. (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].N1CCCCC1.C(O)(=O)C>C1C=CC=CC=1>[C:15]([C:14](=[CH:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])[C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[O:18])(=[O:16])[CH3:17]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COCCOC(=O)CC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COCCOC(=O)C(=Cc1ccccc1C(F)(F)F)C(C)=O
Yield: 70.1 %

Procedure:
A mixture of 12.2 g of 2-trifluoromethylbenzaldehyde, 11.2 g of 2-methoxyethyl acetoacetate, 1 ml of piperidine, 2 ml of acetic acid and 150 ml of benzene is refluxed under the condition of azeotropic dehydration for 3.5 hours. The solvent is distilled off under reduced pressure to give red brown oil. The oil is distilled under reduced pressure to give 15.5 g of 2-methoxyethyl α-acetyl-2-trifluoromethylcinnamate, boiling at 145°-151° C./0.5 mmHg.
Reaction SMILES: [Br-].[CH:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:4])[CH3:3].C([Li])CCC.[CH:29]([C:31]1[CH:32]=[CH:33][C:34]([N:37]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][C:63]([F:66])([F:65])[F:64])=[CH:58][CH:57]=2)[CH2:38][CH2:39][C:40]2[CH:54]=[CH:53][C:43]([O:44][C:45]([CH3:52])([CH3:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47])=[CH:42][CH:41]=2)=[N:35][CH:36]=1)=O>C1COCC1.CCCCCC>[CH3:52][C:45]([O:44][C:43]1[CH:53]=[CH:54][C:40]([CH2:39][CH2:38][N:37]([C:34]2[CH:33]=[CH:32][C:31]([CH:29]=[C:2]([CH3:4])[CH3:3])=[CH:36][N:35]=2)[CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][C:63]([F:65])([F:64])[F:66])=[CH:58][CH:57]=2)=[CH:41][CH:42]=1)([CH3:51])[C:46]([O:48][CH2:49][CH3:50])=[O:47]
Reactant: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=O)cn2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(OC(F)(F)F)cc2)c2ccc(C=C(C)C)cn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 33.1 %

Procedure:
A solution of isopropyltriphenylphosphonium bromide (326 mg; 0.75 mmol) in 1.5 ml of dry THF was treated in an ice bath, under nitrogen, with n-butyl lithium (0.425 ml of a 1.6M solution in hexane; 0.68 mmol), dropwise. After stirring for 15 minutes, this mixture was added, via syringe, into an ice-cold solution of ethyl 2-[4-(2-{(5-formylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]-2-methylpropanoate (200 mg; 0.38 mmol) in 2 ml of dry THF. After stirring at rt overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification by radial chromatography using ethyl acetate-hexane mixtures (5–20% gradient) afforded ethyl 2-methyl-2-[4-(2-{[5-(2-methylprop-1-enyl)pyridin-2-yl][4-(trifluoromethoxy)benzyl]amino}ethyl)phenoxy]propanoate (70 mg; 33% yield).