Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].B([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=[O:34].[Na+].[Na+].[CH2:51]([O:58][CH2:59]/[CH:60]=[CH:61]/[CH2:62][C@@H:63]([CH2:67][CH2:68][CH3:69])[C:64]([OH:66])=[O:65])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.COCOC.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(#N)C>[CH2:51]([O:58][CH2:59][C@H:60]([C@H:61]1[O:65][C:64](=[O:66])[C@H:63]([CH2:67][CH2:68][CH3:69])[CH2:62]1)[OH:34])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Reactant: CCC[C@H](C/C=C/COCc1ccccc1)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: COCOC
Solvent: CC#N
Solvent: O
Product: CCC[C@@H]1C[C@@H]([C@H](O)COCc2ccccc2)OC1=O
Reaction time: 0.17 h
Yield: 66 %

Procedure:
400 ml of a solution of a sodium tetraborate buffer solution (0.05 M) in a 0.4 mM disodium ethylenediaminetetraacetate aqueous solution, 0.600 g of tetrabutylammonium bisulfate (1.77 mmol) and 10.3 g of 1,2:4,5-di-O-isopropylidene-β-D-erythro-2,3-hexodiuro-2,6-pyranose (39.9 mmol) were added to 10.5 g of (2R,4E)-6-benzyloxy-2-propylhex-4-enoic acid obtained in Example (116b) (40.0 mmol) in a mixed solvent of acetonitrile (150 ml) and dimethoxymethane (300 ml) at room temperature, and the mixture was stirred for 10 minutes. The reaction mixture was cooled in an ice bath. Then, a solution of 34.0 g of Oxone (trade mark) (55.2 mmol) in a 0.4 mM disodium ethylenediaminetetraacetate aqueous solution (200 ml) and a solution of 31.8 g of potassium carbonate (230 mmol) in water (200 ml) were separately added dropwise over seven hours. The mixture was stirred at the same temperature for one hour and then diluted with 200 ml of water, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1-1/1) to obtain 7.30 g of the title compound (total yield over two steps: 66%).
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.C1C=CC2N(O)N=NC=2C=1.NC1C=CC=CN=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][CH:4]=[CH:5][N:6]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2ccccn2)cc1
Reaction time: 1 h

Procedure:
The product from Example 1, Part C (200 mg, 0.6 mmol) was dissolved in 25 mL CH3CN, HOBt (48 mg, 0.3 mmol) was added, and stirring continued for 1 h. 2-Aminopyridine (88 mg, 0.9 mmol), triethylamine (0.18 mL, 1.26 mmol), and HATU (250 mg, 0.66 mmol) were added and the mixture was stirred at room temperature for 2 h. Solvent was evaporated and the title compound was isolated as a white solid by silica gel chromatography (140 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 8.41 (br s, 1H), 8.29 (m, 1H), 8.13 (d, J=8 Hz, 1H), 7.70 (m, 1H), 7.22 (d, J=9 Hz, 2H), 7.06 (m, 1H), 6.83 (d, J=9 Hz, 2H), 5.07 (d, J=15 Hz, 1H), 4.62 (s, 1H), 4.15 (d, J=15 Hz, 1H), 3.77 (s, 3H), 2.90 (m, 2H), 1.95 (s, 3H), 1.84 (s, 3H). MS: m/z (MH+) 398.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[CH:9]([C:15](=O)[CH3:16])[C:10]([O:12]CC)=[O:11]>C(O)C>[CH3:16][C:15]1[N:7]=[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]2[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: Cc1nc2ccccn2c1C(=O)O
Temperature: 80 °C
Reaction time: 48 h
Yield: 44.5 %

Procedure:
A mixture of pyridin-2-amine (10 g, 106 mmol), ethyl 2-chloro-3-oxobutanoate (16 g, 97 mmol) and ethanol (200 mL) was stirred at 80° C. for 2 days. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. The collected organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (25 mL), water (75 mL) and ethanol (200 mL) were added to the obtained residue, and the mixture was stirred at 70° C. for 1 hr. 6N Hydrochloric acid (34 mL) was added dropwise to the reaction mixture under ice-cooling. The resulting precipitate was collected by filtration, washed with water, ethanol and diethyl ether and dried to give the title compound (7.6 g, 44%) as a pale-pink solid.
Reaction SMILES: [C:1](OCC12CC3CC(CC(O)(C3)C1)C2)(=[O:4])[CH:2]=[CH2:3].[OH:18][C:19]12[CH2:29][C:23]3([OH:30])[CH2:24][C:25]([OH:28])([CH2:27][C:21]([OH:31])([CH2:22]3)[CH2:20]1)[CH2:26]2>>[OH:18][C:19]12[CH2:20][C:21]3([OH:31])[CH2:22][C:23]([O:30][C:1](=[O:4])[CH:2]=[CH2:3])([CH2:24][C:25]([OH:28])([CH2:27]3)[CH2:26]1)[CH2:29]2
Reactant: C=CC(=O)OCC12CC3CC(CC(O)(C3)C1)C2
Reactant: OC12CC3(O)CC(O)(C1)CC(O)(C2)C3
Product: C=CC(=O)OC12CC3(O)CC(O)(CC(O)(C3)C1)C2
Yield: 83 %

Procedure:
The reaction was conducted in the same manner as the step of Example 36 (2) except that 1,3,5,7-tetrahydroxyadamantane was used instead of the 1,3-dicarboxy-5-adamantanol, and, as a result, a 1,3,5-trihydroxy-7-acryloyloxyadamantane (yield: 83%, white solid) was obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=1.N1C=CN=C1>CN(C)C=O.CCOCC>[C:1]([Si:5]([O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][C:12]=1[CH3:17])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(F)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cc(F)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.2 %

Procedure:
t-Butyldimethylchlorosilane (14.34 g, 93.24 mmol) is combined with 4-fluoro-2-methylphenol (10.00 g, 77.70 mmol) and 1H-imidazole (13.32 g, 194.24 mmol) in dimethylformamide (100 mL) and stirred at room temperature overnight. The reaction is diluted with ether (200 mL) and washed with water (2×100 mL) and brine. The organic portion is dried with sodium sulfate, filtered, and concentrated to afford 18.9 g (100%) of the title compound. GC-ES m/z 240 [M]+, TR=4.06 min.
Reaction SMILES: [F:1][C:2]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:14])[C:10]2[C:5](=[C:6]([C:15]#[N:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.S(=O)(=O)(O)[OH:26].C(=O)(O)[O-].[Na+]>O>[F:24][C:2]([F:1])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:3]1[N:12]=[C:11]([S:13][CH3:14])[C:10]2[C:5](=[C:6]([C:15]([NH2:16])=[O:26])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=S(=O)(O)O
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C#N)cccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C(N)=O)cccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carbonitrile from Example 35 step C (200 mg, 0.57 mmol) were added concentrated sulfuric acid (2.88 mL) and water (0.32 mL). The mixture was stirred at 65° C. for 1 h and then allowed to cool to rt. The mixture was neutralized by slow addition of saturated aq sodium bicarbonate and then extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carboxamide (191 mg, 92%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.60 (s, 3H) 7.89-8.15 (m, 4H) 8.36-8.44 (m, 1H) 8.62-8.69 (m, 1H) 8.71-8.79 (m, 1H) 9.28-9.39 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH:19]1([CH:22]2[NH:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH2:21][CH2:20]1>N1C=CC=CC=1>[CH:19]1([CH:22]2[NH:27][CH2:26][CH2:25][N:24]([C:10]3[CH:11]=[C:12]4[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]4[CH2:1][CH3:2])=[CH:8][C:9]=3[F:14])[CH2:23]2)[CH2:21][CH2:20]1
Reactant: C1CNC(C2CC2)CN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C4CC4)C3)cc21
Temperature: 100 °C
Yield: 10 %

Procedure:
A mixture of 1.265 g of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.86 g of 3-cyclopropylpiperazine and 15 ml of pyridine was heated at 100° C. in a pressure bottle for 3 hours, then cooled and evaporated. The residue was purified by silica gel flash chromatography, eluting with chloroform:methanol:water:triethylamine (9:0.5:0.02:0.02), giving 180 mg of the desired product, mp 250° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:11]([C:3]1[C:4]2[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[S:6][C:2]=1[NH:1][C:25](=[O:27])[CH3:26])(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Temperature: 50 °C
Yield: 78 %

Procedure:
To a stirred solution of 1.04 g (4.04 mmol) (2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-phenyl-methanone in 25 ml acetic anhydride was added 0.2 ml pyridine. The mixture was heated at 50° C. for 35 minutes and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to afford 1.35 g (78%) N-(3-benzoyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-acetamide as an orange oil. ES-MS m/e (%): 300 (M+H+, 100).
Reaction SMILES: [N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH2:19][OH:20])\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Mn]([O-])([O-])(=O)=O.[Ba+2]>ClCCl>[N:1]1([CH2:6]/[CH:7]=[C:8](/[C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=[O:20])\[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(CO)c2)cc1
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(C=O)c2)cc1
Reaction time: 7 h
Yield: 99.7 %

Procedure:
To a stirred solution of the above 3-(3-pyrrolidino-1-(4-tolyl)-prop-1E-enyl)benzyl alcohol (1.1 g) in dichloromethane (75 mL) was added barium manganate (Firouzabadi and Ghaderi, Tetrahedron Letters, 1978, 839) and the mixture was kept at 40° for 7 hours, and left at room temperature for 16 hours. The solid was removed by filtration and the filtrate was evaporated to give the crude 3-(3-pyrrolidino-1-(4-tolyl)prop-1E-enyl)benzaldehyde (1.09 g) which was not further purified. To a stirred suspension of sodium hydride (107 mg; 80% oil suspension) in 1,2-dimethoxyethane (3.7 mL) was added diethyl methoxycarbonylmethyl-phosphonate (740 mg) in 1,2-dimethoxyethane (3.7 mL). After 15 minutes' stirring, a solution of the above (E)-aldehyde (1.09 g) in 1,2-dimethoxyethane (3.7 mL) was added dropwise and the mixture was stirred for 18 hours at room temperature. After addition of water and acidification with dilute hydrochloric acid, the suspension was washed with ether, and the clear aqueous solution was basified with sodium carbonate solution and the precipitated oil was extracted into ether. The washed and dried ether solution was evaporated to leave a solid (800 mg) which was dissolved in ethanol and refluxed with Girard reagent P (200 mg) for 1 hour. The solvent was evaporated, water and ether were added and the ether extract was washed, dried and evaporated to leave methyl (E)-3-(3-pyrrolidino-1-(4-tolyl)prop-1E-enyl)cinnamate, m.p. 102°-107° (620 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[OH:25])[CH:18]=1)=[C:10]([CH3:33])[CH:9]=2)=[O:5])C>CO.O.[OH-].[K+]>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:24]([OH:25])[C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=2[OH:23])[O:16][C:11]2[C:12]([CH3:15])=[C:13]3[C:8](=[CH:9][C:10]=2[CH3:33])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(O)c4ccc(F)cc4)c3)c(C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc2[nH]c(C(=O)O)cc2c(C)c1Oc1ccc(O)c(C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.1 %

Procedure:
To a solution of 5-{3-[(4-Fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (17.5 mg, 0.039 mmol) in a mixture of methanol (0.5 mL) and water (0.5 mL) at room temperature was added potassium hydroxide (3M, 0.078 mL), and the resulting solution was stirred at room temperature for 20 hours. The reaction solution was diluted with 0.1M potassium hydroxide (10 mL) and washed with ethyl acetate (3 times 5 mL). The aqueous solution was acidified with hydrochloric acid and then extracted with ethyl acetate (3 times 10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the title compound (13 mg) as a solid. 1H NMR (400 MHz, CD3OD) δ11.0 (s, 1H), 7.30-7.26 (m, 2H), 7.12 (s, 2H), 6.93 (t, 2H), 6.73 (d, 1H), 6.60 (d, 2H), 6.43-6.40 (dd, H), 5.97 (s, 1H), 2.23 (s, 3H), 2.13 (s, 3H). MS (APCI−) Calc:421. 1, Found: 420.1 (M−1).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[C:12](B(O)O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:19]1[CH:20]=[C:21]([C:26]2[N:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:27]=2)[CH:22]=[C:23](Br)[CH:24]=1.[OH-].[Na+]>O1CCCC1.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>[CH:1]1[C:14]2[CH:13]=[C:12]([C:19]3[CH:20]=[C:21]([C:26]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:29]=[C:28]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[N:27]=4)[CH:22]=[C:23]([C:13]4[C:14]5[C:5]([C:6]6[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=6[CH:12]=4)=[CH:4][CH:3]=[CH:2][CH:1]=5)[CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1cc2ccccc2c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4cc5ccccc5c5ccccc45)cc(-c4cc5ccccc5c5ccccc45)c3)n2)cc1
Yield: 66 %

Procedure:
In a stream of argon, 1.37 g (6.16 mmol) of 9-phenanthreneboronic acid, 1.20 g (2.57 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 72.1 mg (0.103 mmol) of dichlorobis(triphenylphosphine)palladium were suspended in 75 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 4.81 mL (19.3 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 5 hours. The resultant reaction mixture was left to stand to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was recrystallized from o-xylene to give 1.13 g of the target 2-[3,5-di(9-phenanthryl)phenyl]-4,6-diphenyl-1,3,5-triazine as grayish white solid (yield: 66%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:15])[CH2:10][CH2:9]3.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=[O:34]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([O:26][C:27](=[O:28])[C:4]=2[CH:3]=1)[CH2:9][CH2:10][N:11]([C:14]([C:16]1[C:24]2[C:19](=[CH:20][C:21]([Cl:25])=[CH:22][CH:23]=2)[N:18]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([F:29])[CH:31]=2)[CH:17]=1)=[O:15])[CH2:12][CH2:13]3
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21
Product: O=C1OC2(CCN(C(=O)c3cn(C(=O)c4cccc(F)c4)c4cc(Cl)ccc34)CC2)c2ccc(Br)cc21

Procedure:
Following the general procedure VII as described above, the acylation of 5-bromo-1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one with commercially available 3-fluorobenzoyl chloride gave the title compound. ES-MS m/e (%): 581.2(M+H+).
Reaction SMILES: C([NH:9][C:10]([NH:20][CH2:21][CH2:22][N:23]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:11][CH2:12][CH2:13][CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)(=O)C1C=CC=CC=1.[ClH:37]>>[ClH:37].[ClH:37].[ClH:37].[NH:18]1[CH:19]=[C:15]([CH2:14][CH2:13][CH2:12][NH:11][C:10]([NH2:9])=[N:20][CH2:21][CH2:22][N:23]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:16]=[CH:17]1
Reactant: O=C(NC(=NCCCc1c[nH]cn1)NCCN(Cc1ccccc1)c1ccccc1)c1ccccc1
Agent: Cl
Product: NC(=NCCN(Cc1ccccc1)c1ccccc1)NCCCc1c[nH]cn1
Yield: 57 %

Procedure:
1.60 g (3.3 mmol) of N1 -benzoyl-N2 [3-(4-imidazolyl) propyl]-N3 [2-(N-benzyl-N-phenylamino)ethyl]-guanidine (Example 100) are boiled in 30 m1 conc.hydrochloric acid for 1.4 hours. After cooling, the reaction mixture is concentrated by evaporation to one third of its original quantity and the aqueous solution obtained is extracted three times with 30 ml of ether. The aqueous phase is then filtered and concentrated by evaporation under vacuum. The residue is taken up twice with 20 ml portions of ethanol and again concentrated by evaporation. The residue finally obtained is recrystallised from absolute ethanol. 0.92 g (57%) of the title compound is obtained in the form of a colourless, hygroscopic solid.
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[NH:14][C:15]2[O:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][N:19]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[NH:14][C:15]3[O:16][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:18][N:19]=3)=[CH:6][CH:7]=2)=[CH:33][CH:32]=1)=[O:30])[CH3:27]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1Nc1nnc(-c2ccccc2)o1
Product: CCOC(=O)c1ccc(-c2ccc(-c3onc(C)c3Nc3nnc(-c4ccccc4)o3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 4-ethoxycarbonylphenylboronic acid.
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:24][CH:23](O)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:26])[CH:21]=3)[O:16]2)=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:26])[CH:21]=3)[O:16]2)=[CH:11][CH:10]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(F)cc1)O2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCC(c1ccc(F)cc1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylsilane (14 ml) was added slowly into a solution of 2-(4-fluorophenyl)chroman-4,6-diol (2.9 g) in dichloromethane (58 ml). Trifluoroacetic acid (27 ml) was then added dropwise into a reaction mixture and it was stirred at room temperature for 1 hour. The reaction mixture was poured on ice-water and extracted with dichloromethane. The residue was evaporated under reduced pressure with toluene to obtain 2-(4-fluorophenyl)chroman-6-ol. 1H NMR (400 MHz, CDCl3) δ: 7.38 (m, 2H), 7.06 (m, 2H), 6.77 (d, 1H, J 8.6 Hz), 6.61 (dd, 1H, J 8.6, 2.9 Hz) 6.57 (d, 1H, 8.6 Hz), 4.97 (dd, 1H, J 10.2, 2.4 Hz), 2.95 (ddd, 1H, J −16.8, 11.4, 6.2 Hz), 2.74 (ddd, 1H, J −16.8, 5.3, 3.1 Hz), 2.15 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: O.NN.[C:4]([O:8][C:9](=[O:28])[CH2:10][O:11][C@H:12]1[CH2:16][C@H:15]([N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:14]=[CH:13]1)([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9](=[O:28])[CH2:10][O:11][CH:12]1[CH2:16][CH:15]([NH2:17])[CH:14]=[CH:13]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)CO[C@@H]1C=C[C@@H](N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)COC1C=CC(N)C1

Procedure:
Add 22 μl (0.545 mmol) of hydrazine monohydrate to 120 mg (0.349 mmol) of trans-{[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)cyclopent-2-en-1-yl]oxy}acetic acid tert-butyl ester in 0.3 ml of ethanol. Heat the mixture under reflux for 15 min. This forms a voluminous precipitate. After cooling, remove it by filtration and wash it with a little ethanol. Concentrate the filtrate under reduced pressure and use the resulting product (74 mg) without further purification.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:23])=O)[S:19][CH:20]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>CC(N(C)C)=O>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]#[N:23])[S:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (25 mg) obtained in Example 13 in DMA (5 mL) was added trifluoroacetic anhydride (240 mg) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 1 hr. To the reaction mixture was added water, the precipitate was collected by filtration, and the obtained solid was crystallized from ethyl acetate and hexane to give the title compound (16.7 mg).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]#N)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=CC=CC=1.C(OC([C:31]1C2C(=CC=CC=2)C=C[N:32]=1)(C)C)(=O)C1C=CC=CC=1>>[CH2:1]([C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:31]#[N:32])[C:11]=2[CH:10]=[CH:9][N:8]=1)[CH3:6]
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Reactant: N#Cc1cccc2c(-c3ccccc3)nccc12
Product: CCc1nccc2c(CC#N)cccc12

Procedure:
1-Ethylisoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-ethyl-5-dichloroacetylaminomethylisoquinoline. The product was reacted successively in the same way as in steps (c), (d), (e) and (f) of Example 18 to afford 1-ethylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-ethylisoquinoline-5-acetic acid having a melting point of 166.2° to 180.8° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:13][NH:14][C:15](=N)[CH:16]([CH3:18])[CH3:17]>>[CH:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[O:13][N:14]=1)([CH3:18])[CH3:17]
Reactant: N#CN1CCC2(CC1)OCCO2
Reactant: CC(C)C(=N)NO
Product: CC(C)c1noc(N2CCC3(CC2)OCCO3)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-isobutyramidine following a procedure analogous to that described in Intermediate 2. LC (method 17): tR=1.56 min; Mass spectrum (ESI+): m/z=254 [M+H]+.