Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[OH2:28].[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:32][CH2:31]2)=[CH:16][CH:17]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=3[N:21]=[C:20]2[CH2:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:32][CH2:31]2)=[CH:16][CH:17]=1
Reactant: BrCCSc1ccccc1
Reactant: Oc1ccc2c(c1)nc(CC1CCNCC1)n2Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: Oc1ccc2c(c1)nc(CC1CCN(CCSc3ccccc3)CC1)n2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
A mixture of 6.48 parts of [(2-bromoethyl)thio]benzene, 6.8 parts of 1-[(4-fluorophenyl)methyl]-2-(4-piperidinylmethyl)-1H-benzimidazol-5-ol, 4.2 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone was stirred for 2 hours at reflux temperature using a water separator. After cooling to room temperature, the reaction mixture was poured into water. The layers were separated. The organic layer was washed with 500 parts of water, dried, filtered and evaporated. The residue was taken up in a mixture of trichloromethane and methanol (95:5 by volume) and 25 parts of silica gel. After stirring for 15 minutes, the whole was filtered, washed with the eluent and the filtrate was evaporated. The residue was boiled in 160 parts of 2-propanone. The mixture was stirred overnight at room temperature. The product was filtered off, washed with 2-propanone and crystallized from 280 parts of 2-propanone. The product was filtered off, washed with 2-propanone and dried in vacuo at 50° C., yielding 2.7 parts (27.8%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(phenylthio)ethyl]-4-piperidinyl]methyl]-1H-benzimidazol-5-ol hemihydrate; mp. 193.8° C. (570).
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[CH:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]3[CH2:26][C@H:25]([S:27][C:28]4[C@H:29]([CH3:52])[C@@H:30]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]5[C:32]=4[C:33]([O:35]CC4C=CC([N+]([O-])=O)=CC=4)=[O:34])[CH2:24][N:23]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:21])[CH2:16][C@@H:15]2[CH3:66])=O)=CC=1)([O-])=O>O1CCCC1.O>[CH:13]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C@@H:22]2[CH2:26][C@H:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([OH:35])=[O:34])[CH2:24][NH:23]2)=[O:21])[CH2:16][C@@H:15]1[CH3:66])=[NH:12]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C=NC(=O)OCc5ccc([N+](=O)[O-])cc5)[C@@H](C)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCN(C=N)[C@@H](C)C4)C3)[C@H](C)[C@H]12
Yield: 37.9 %

Procedure:
87 mg of 4-nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[(3S)-4-(N-4-nitrobenzyloxycarbonylformimidoyl)-3-methylpiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 4.5 ml of a 2:1 by volume mixture of tetrahydrofuran and water, and were hydrogenated by bubbling hydrogen through the solution at room temperature for 2 hours in the presence of 220 mg of 10% w/w palladium-on-charcoal. The reaction mixture was then worked up and purified by the same procedure as that described in Example 1(b), to give 16 mg of the title compound, as a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:16])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:7]=1[CH3:8].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>CN(C1C=CN=CC=1)C.O.CS(C)=O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:16][C:4]1[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2nccc(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
Dimethyl sulfoxide (2.8 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (60 mg), 4-chloro-6,7-dimethoxyquinoline (184 mg), cesium carbonate (274 mg), 4-(N,N-dimethylamino)-pyridine (51 mg), and cesium fluoride (64 mg) to prepare a solution which was then stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (33 mg, yield 29%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH2:16])[CH3:12].Cl.CN(C)CCCN=C=NCC.[CH:31]1(/[CH:36]=[C:37](\[C:48]2[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=2)/[C:38]2[NH:39][C:40](=[O:47])[C:41]([CH:44]3[CH2:46][CH2:45]3)=[CH:42][CH:43]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C)C=O.O.C(N(CC)CC)C>[CH:31]1(/[CH:36]=[C:37](\[C:48]2[CH:56]=[CH:55][C:51]([C:52]([NH:16][CH2:15][CH2:14][N:13]([CH2:17][CH3:18])[CH2:11][CH3:12])=[O:53])=[CH:50][CH:49]=2)/[C:38]2[NH:39][C:40](=[O:47])[C:41]([CH:44]3[CH2:45][CH2:46]3)=[CH:42][CH:43]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCN(CC)CCN
Reactant: O=C(O)c1ccc(/C(=C\C2CCCC2)c2ccc(C3CC3)c(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccc(/C(=C\C2CCCC2)c2ccc(C3CC3)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
1-Hydroxybenzotriazole (39 mg), triethylamine (0.04 mL), N,N-diethylethylenediamine (0.061 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg) were sequentially added to a solution of 4-[(E)-2-cyclopentyl-1-(5-cyclopropyl-6-oxo-1,6-dihydropyridin-2-yl)ethenyl]benzoic acid (50 mg) in N,N-dimethylformamide at room temperature, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform:methanol=20:1) and the resulting solid was washed with diethyl ether to give the title compound as a white solid (17 mg, 26%).
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cccc2ccccc12
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)P(c1cccc2ccccc12)C(C)(C)C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
In a 500 ml four-necked flask thoroughly purged with nitrogen, 18.1 g (0.1 mol) of di-tert-butylphosphinous chloride, 0.20 g (0.002 mol (corresponding to 2% by mol)) of copper(I) chloride, 20 ml of tetrahydrofuran and 20 ml of toluene were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 24.8 g (0.12 mol) of 1-bromonaphthalene and 3.5 g (0.14 mol) of metallic magnesium in 180 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at 65° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 30 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance. The oily substance was recrystallized from 150 ml of methanol to obtain 23.6 g (purity: 98.5%) of the aimed di-tert-butyl(1-naphthyl)phosphine as white crystals. The yield was 85.4%. Melting point: 95-97° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].Cl>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:13][C@H:12]1[C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (50 g) and triethylamine (63.1 ml) in tetrahydrofuran (250 ml) was dropwise added methanesulfonyl chloride (35.0 ml) with stirring at -5°-0° C. for 2 hours. After stirring for 1 hour, the mixture was poured into ice-water (500 ml) and the solution was adjusted to pH 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (250 ml). The organic layer was washed in turn with 1N hydrochloric acid (250 ml×2) and brine (250 ml), dried over magnesium sulfate, and evaporated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-2-carboxy-4-methanesulfonyloxypyrrolidine (66.21 g).
Reaction SMILES: Br[CH:2]([C:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][CH2:18][CH2:17][C:16]=3[CH:21]=2)=[C:10]([CH3:22])[S:9][C:8]=1[CH3:23])[C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:30][C:31]([SH:34])([CH3:33])[CH3:32]>CN(C)C=O>[C:31]([S:34][CH:2]([C:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][CH2:18][CH2:17][C:16]=3[CH:21]=2)=[C:10]([CH3:22])[S:9][C:8]=1[CH3:23])[C:3]([O:5][CH3:6])=[O:4])([CH3:33])([CH3:32])[CH3:30]
Reactant: CC(C)(C)S
Reactant: COC(=O)C(Br)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)C(SC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
A mixture of methyl 2-bromo-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethylthiophen-3-yl]acetate (32a) (50 mg, 0.126 mmol), cesium carbonate (82 mg, 0.253 mmol) and 2-methyl-2-propanethiol (23 mg, 0.253 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 5 hours. The reaction mixture was quenched with water (6 mL) and extracted with ethyl acetate (4×5 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (cyclohexane/ethyl acetate 80/20) to provide the desired thio-ether (32b) (28 mg, 0.07 mmol, 55%) as a clear yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C(#N)C.I([O-])(=O)(=O)=[O:25].[Na+].Cl>C(Cl)(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:25])=[O:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: CCCCCC(C(=O)O)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.27 g, 0.98 mmole, from Example 1, step 6) in a mixture of 2 mL of carbon tetrachloride, 2 mL acetonitrile and 3 mL water, containing 3-5 mg of ruthenium chloride, was added 0.85 g of sodium periodate. The mixture was stirred at room temperature for 2 hours, diluted with 10 mL of water, and pH was adjusted to 2 with 10% hydrochloric acid. The mixture was extracted with three 10 mL portions of dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a dark oil. The product was purified by flash chromatography (SiO2, gradient from 0 to 20% ethyl acetate in hexanes) to yield 0.16 g of 2-(4,4-dimethyl-chroman-7-yl)-heptanoic acid as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)[C:6]=1[CH3:11]
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc(Br)cc2)c1C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (6 g, 36 mmol) and 4-bromobenzyl bromide (8.9 g, 36 mmol) in 80 ml acetonitrile was added K2CO3 (4.9 g, 36 mmol). The mixture was stirred for 12 h at room temperature, 12 h at 50° C., and after addition of an additional 1 g of K2CO3 the mixture was stirred for another 12 h at room temperature. The mixture was concentrated by under reduced pressure, poured into water and extracted twice with ethyl acetate, dried with MgSO4 and evaporated under reduced pressure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.[CH:21]([O:23][CH3:24])=O.[H-].[Na+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2/[C:16](=[CH:21]\[O:23][CH3:24])/[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1CCc1ccc(F)cc1
Reactant: COC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 81 %

Procedure:
A solution of methyl 2-(2-[4-fluorophenyl]ethyl)phenylacetate (2.83g) and methyl formate (12.8ml) in dry DMF (20ml) was added dropwise over 20 minutes to a stirred suspension of sodium hydride (0.50g) in dry DMF (30ml) cooled in an ice bath. Effervescence and foaming built up slowly, and, when it had subsided, the mixture was allowed to warm to room temperature and stir for 3.5 hours. The mixture was diluted with water, acidified with concentrated hydrochloric acid and extracted with ether. The extracts were washed with water, dried and concentrated. A stirred solution of the resulting viscous yellow oil (3.34g) in DMF (30ml) was treated successively with potassium carbonate (3.05g) and dimethyl sulphate (1.54g). After 2 hours, the reaction mixture was poured into water and extracted with ether. The extracts were washed with water, dried, concentrated and chromatographed using 30% ether in petrol to give (E)-methyl 2-(2-[2-(4-fluorophenyl)ethyl]phenyl)-3-methoxypropenoate (2.64g, 81% yield) as a colourless solid m.p. 411/2°-421/2° C., lH NMR (CDCl3); delta 2.76 (4H,br s), 3.70 (3H,s), 3.82 (3H,s), 7.58 (1H,s), ppm.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br)([O-:27])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][CH:35]=[C:28]([N+:25]([O-:27])=[O:26])[CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[N+]([O-])c1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c1
Yield: 4.5 %

Procedure:
The title compound (0.005 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-nitrobenzyl bromide (0.09 g) in place of benzyl chloride and Cs2CO3 (0.2 g) in place of NaH. MS (ESI): exact mass calculated for C20H19ClN4O2, 382.12. found, m/z 383.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.07-8.05 (m, 1H), 7.91-7.87 (m, 1H), 7.50 (t, J=7.9 Hz, 1H), 7.44-7.38 (m, 3H), 7.36-7.33 (m, 2H), 5.41 (s, 2H), 2.88-2.85 (m, 4H), 2.82-2.79 (m, 2H), 2.73-2.71 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C@H:12]([CH:17]([CH3:19])[CH3:18])[C:13]([O:15][CH3:16])=[O:14])[CH2:5]2.CC1(C)C(C)(C)OB([C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=3)=[O:36])=[CH:30][CH:29]=2)O1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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].O>[CH3:18][CH:17]([CH3:19])[C@@H:12]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:28]3[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=4)=[O:36])=[CH:32][CH:33]=3)[CH:3]=2)[C:7]1=[O:11])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Temperature: 82.5 °C
Reaction time: 1.25 h

Procedure:
The compound of example 359 (288 mg, 0.886 mmol), compound of example 357 (300 mg, 0.738 mmol) and Pd(dppf)Cl2: CH2Cl2 (18 mg, 0.022 mmol) were taken in DMF (5 mL) under an argon atmosphere. To this reaction mixture, 2M solution of Na2CO3 (234 mg, 2.214 mmol, 1.1 mL) was added and the reaction mixture was stirred at 80-85° C. for 1 to 1.5 h. After completion of the reaction, water was added to the reaction mixture and the product obtained was extracted with ether. The combined ether layers were washed with water and brine, dried over anhydrous Na2SO4 or MgSO4. The solvent was evaporated and the product was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:16][C@H:17]([NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[CH3:18])=[CH:11][C:12]=2[C:14]#[N:15])[CH2:7][CH2:6]1.[OH-].[Na+].OO.S([O-])([O-])=[O:40].[Na+].[Na+]>CS(C)=O.O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([CH2:16][C@H:17]([NH:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][C:31]([F:34])([F:32])[F:33])[CH3:18])=[CH:11][C:12]=2[C:14]([NH2:15])=[O:40])[CH2:7][CH2:6]1
Reactant: C[C@H](Cc1cc(C#N)c2c(c1)CCN2CCCO)NCCOc1ccccc1OCC(F)(F)F
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2)NCCOc1ccccc1OCC(F)(F)F
Temperature: 22.5 °C
Reaction time: 5 h

Procedure:
1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carbonitrile(6.00 g) was dissolved in dimethylsulfoxide (75 mL), and to the solution was added 5 mol/L aqueous sodium hydroxide solution(4.50 mL). To the reaction mixture, 30% hydrogen peroxide (2.63 mL) was added little by little at not more than 25° C. The reaction mixture was stirred at 20 to 25° C. for 5 hours. To the reaction mixture, an aqueous sodium sulfite solution of sodium sulfite (2.1 g) dissolved in water (150 mL) was added carefully. The reaction mixture was extracted twice with ethyl acetate (50 mL). The combined ethyl acetate layer was extracted twice with 2 mol/L hydrochloric acid. The aqueous hydrochloric acid solution extracted was neutralized with sodium bicarbonate, and extracted twice with ethyl acetate (50 mL). The combined ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was cooled to give 1-(3-hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxy)phenoxy]-ethyl}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide (4.49 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:4]=1[CH:5]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCC1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:4]=1/[CH:5]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: COc1c(C)cc(C)cc1C=O
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNC1
Solvent: c1ccncc1
Solvent: O
Product: COc1c(C)cc(C)cc1/C=C/C(=O)O
Yield: 81.4 %

Procedure:
A solution of 2-methoxy-3,5-dimethylbenzaldehyde (9.40 g, 57.2 mmol), malonic acid (8.90 g, 85.8 mmol), and pyrrolidine (730 mg, 8.58 mmol) in pyridine (80 mL) was refluxed for 14 hours. This reaction mixture was poured in iced water and extracted with ethyl acetate. The extract was washed with 2N-hydrochloric acid, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 9.60 g of the title compound. Yield 81%.
Reaction SMILES: N1(C2N=C(CC([O-])=O)NC(=O)C=2)CC[O:4]CC1.[Na+].Cl[C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:45])[N:24]2[C:29](=[O:44])[CH2:30][C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:32]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[OH:4][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH2:22][CH:23]([CH3:45])[N:24]2[C:29](=[O:44])[CH2:30][C:31]1[NH:36][C:35](=[O:37])[CH:34]=[C:33]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:32]=1
Reactant: CC1Cc2c(Cl)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(O)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 107.5 %

Procedure:
The product is prepared by following the procedure described in example 1c using 1.2 g of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 0.82 g of 2-methyl-2,3-dihydro-1H-indol-4-ol [reference example 1c] and 1.17 g of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 1.1 ml of pyridine and 25 ml of N,N-dimethylformamide. After purification of the residue by chromatography on a 90 g cartridge of 15-40 μm silica, elution being carried out with pure dichloromethane and then with 98/2 then 95/5 v/v dichloromethane/methanol mixtures at a flow rate of 80 ml/min, 0.84 g of 2-[2-(4-hydroxy-2-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one is obtained in the form of a very pale pink powder, the characteristics of which are the following: