Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7]P(=O)(OCC)OCC)=[CH:3][CH:2]=1.C(O[K])(C)(C)C.[CH:22]([C:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=2)[NH:26][N:25]=1)=O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:22]/[C:24]2[C:32]3[C:27](=[CH:28][C:29]([C:33]#[N:34])=[CH:30][CH:31]=3)[NH:26][N:25]=2)=[CH:5][CH:6]=1
Reactant: N#Cc1ccc2c(C=O)n[nH]c2c1
Reactant: CCOP(=O)(Cc1ccncc1)OCC
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 82 %

Procedure:
Diethyl pyridin-4-ylmethylphosphonate was redissolved in DMF (25 mL) and cooled to 0° C. tBuOK (3.36 g, 30 mmol) was added portion wise over 2 min and the reaction mixture turned dark brown red. After stirring for 2 min at 0° C., a solution of 3-formyl-1H-indazole-6-carbonitrile (1.71 g, 10 mmol) in DMF (15 mL) was added dropwise by pipette over 5 min. The resulting mixture was stirred for 40 min at 0° C. before quenching with ice, 2N HCl (20 mL) and H2O (20 mL). After stirring for 10 min at rt, the reaction mixture was carefully basified with sat. NaHCO3 to pH about 8 and copious amounts of yellow precipitate formed. The solid was collected by suction filtration and rinsed with H2O. After dying under high vacuum, 2.016 g (82%) of title compound was obtained as beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.90 (s, 1H, NH), 8.60-8.54 (m, 2H), 8.43 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 7.93 (d, J=16.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 1H, partially overlapping with the doublet at 7.55 ppm), 7.55 (d, J=16.0 Hz, 1H, partially overlapping with the doublet at 7.58 ppm); MS ESI 250.0 [M+H]+, calcd for [C15H11N3O+H]+ 250.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8](=[O:13])[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:6]2[OH:20].[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28]Cl)[CH2:23][CH2:22]1>>[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][O:20][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[O:9][C:8](=[O:13])[C:7]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc2oc(=O)c(-c3ccccc3)c(O)c2c1
Reactant: ClCCN1CCOCC1
Product: COc1ccc2oc(=O)c(-c3ccccc3)c(OCCN3CCOCC3)c2c1
Yield: 67.5 %

Procedure:
This compound is obtained according to the method of Example 8 from 12.1 g. (0.045 mol) of 6-methoxy-3-phenyl-4-hydroxy-coumarin and 10.9 g. (0.057 mol) of 2-morpholino-1-chlorethane. After recrystallisation from isopropanol, 11.3 g. of a beige-coloured solid are obtained. M.P. 118° C.; yield 67.5% (theoretical yield 16.7 g.).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[C:31]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]1[CH2:40][CH2:39][N:38]([C:18]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)=[O:19])[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure K, 2-(2-Ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid was coupled with 1-tert-butylpiperazine according to General Procedure K to give 567. LCMS m/z: 266.7 (2M+H+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:13][OH:14])[CH2:10][C@H:9]2[CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[C:15](OC=C)(=[O:17])[CH3:16].CC(CC(O)=O)=O>CCOC(C)=O.CCCCCCC>[C:15]([O:12][CH2:11][C@@H:9]1[CH2:10][C@:8]1([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:13][OH:14])(=[O:17])[CH3:16]
Reactant: OC[C@@H]1C[C@@]1(CO)c1cccc(F)c1
Reactant: C=COC(C)=O
Agent: CC(=O)CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)OC[C@@H]1C[C@@]1(CO)c1cccc(F)c1
Temperature: 22.5 °C
Yield: 100.6 %

Procedure:
((1S,2R)-1-(3-fluorophenyl)cyclopropane-1,2-diyl)dimethanol (5, 7.89 g, 0.040 mol, 1.0 equiv.) was dissolved in 2-methyl-THF (23.68 mL), under nitrogen. Lipase acrylic resin (Candida Antarctica Lipase B, Sigma-Aldrich, Saint Louis, Mo.) (417.5 mg, 5.0 wt %) was added. Vinyl acetate (5.56 mL, 0.060 mol, 1.5 equiv.) was added, and the reaction mixture was stirred at 20-25° C. while monitoring the ratio of mono-acetate and diacetate (8-9 h) by HPLC and TLC (EtOAc/Heptane=1/1). Upon reaction completion, the lipase was removed by filtration and rinsed with 2-methyl-THF (71.04 mL). The filtrate and the rinse were combined and washed with 15% NaCl aq. solution (27.63 mL) followed by sat. aqueous NaCl solution (23.68 mL). The solvent was removed under reduced pressure then azeotroped with 2-methyl-THF until KF is less than 1500 ppm to afford the title compound, ((1R,2S)-2-(3-fluorophenyl)-2-(hydroxymethyl)cyclopropyl)methyl acetate, 6 (9.59 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][Cl:19])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][Cl:19])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC(C)(CCl)COc1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(OCC(C)(C)CCl)ncn1
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
In 5 ml of tetrahydrofuran was suspended 0.14 g of sodium hydride (60% in oil), to which 0.5 ml of a solution containing 0.22 g of 2-butyn-1-ol in tetrahydrofuran was added dropwise at room temperature, followed by stirring for 10 minutes. To this was added dropwise 0.5 ml of a solution containing 0.62 g of 4-chloro-6-(3-chloro-2,2-dimethylpropyloxy)pyrimidine in tetrahydrofuran at 0° C., followed by stirring at the same temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.62 g of 4-(2-butynyloxy)-6-(3-chloro-2,2-dimethylpropyloxy)pyrimidine (the present compound (10)).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18](Cl)=[C:19]([F:24])[CH:20]=2)[N:15]([CH:26]=[CH2:27])[CH:14]=1)=[O:12])[CH3:9]>N1C=CC=CC=1>[CH2:8]([O:10][C:11]([C:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][C:18]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:19]([F:24])[CH:20]=2)[N:15]([CH:26]=[CH2:27])[CH:14]=1)=[O:12])[CH3:9]
Reactant: CN1CCNCC1
Reactant: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 68.6 %

Procedure:
1-Methylpiperazine (1.6 g) and 1-vinyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (1.2 g) were added to a 3 ml of pyridine, and the mixture was refluxed for 5 hrs. The reaction mixture was concentrated in vacuo, water was added to the residue, and the mixture was adjusted to pH 4 with acetic acid. After filtering, the filtrate made alkali with sodium hydroxide solution. The crude crystals were recrystallized from a mixture of chloroform and benzene to give 1.0 g (68.5% yield) of 1-vinyl-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 186.5°-187.5° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4](=[O:15])[NH:3]1.[CH2:16]=[O:17]>>[OH:17][CH2:16][N:3]1[C:2](=[O:1])[N:6]2[CH2:7][CH:8]=[CH:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:15]
Reactant: C=O
Reactant: COC(=O)C1C=CCn2c(=O)[nH]c(=O)n21
Product: COC(=O)C1C=CCn2c(=O)n(CO)c(=O)n21
Yield: 50 %

Procedure:
7.02 g (0.033 mol) of methyl 2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate and 9 ml of 40% aqueous formaldehyde were heated on a steam-bath for 4.5 hours. The mixture was evaporated in vacuo to give a colourless oil which was crystallized from dichloromethane/hexane, there being obtained 3.97 g (50%) of methyl 2-hydroxymethyl-2,3,5,8-tetrahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 123°-125° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][NH:5]C(=O)OC(C)(C)C.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:40].[N:41]12[CH2:48][CH2:47][CH:44]([CH2:45][CH2:46]1)[C@@H:43]([NH:49][C:50]([C:52]1[S:53][C:54]3[C:60](Br)=[CH:59][CH:58]=[CH:57][C:55]=3[CH:56]=1)=[O:51])[CH2:42]2.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]>[ClH:40].[ClH:40].[NH2:5][CH2:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[C:60]1[C:54]2[S:53][C:52]([C:50]([NH:49][C@@H:43]3[CH:44]4[CH2:45][CH2:46][N:41]([CH2:48][CH2:47]4)[CH2:42]3)=[O:51])=[CH:56][C:55]=2[CH:57]=[CH:58][CH:59]=1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: NCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
534.2 mg (1.87 mmol) of tert-butyl 2-bromobenzylcarbamate, 474.1 mg (1.87 mmol) of bis(pinacolato)diboron, 397.0 mg (4.04 mmol) of potassium acetate, 45.5 mg (0.06 mmol) of PdCl2(dppf), 500 mg (1.24 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 3.11 ml of 2 M sodium carbonate solution and a further 45.5 mg (0.06 mmol) of PdCl2(dppf) in 6.0 ml of DMF are reacted by general method D. Purification by preparative HPLC is followed by concentration of the combined product fractions, taking up in methanol, addition of 1N hydrochloric acid, and stirring at room temperature for 30 min. Concentration and drying under high vacuum result in 121 mg (20% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([O:7][Si](C)(C)C)=[C:4]([CH3:6])[CH3:5].[N+:12]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])([O-:14])=[O:13]>C(Cl)Cl.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:1][O:2][C:3](=[O:7])[C:4]([CH3:6])([CH3:5])[CH:17]([OH:18])[C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(O[Si](C)(C)C)=C(C)C
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
1-Methoxy-1-(trimethylsiloxy)-2-methyl-1-propene (2.4 mL, 2.092 g, 12 mmol) is added dropwise to a suspension of 2-Nitro-benzaldehyde (1.51 g, 10 mmol), Scandium (III) trifluoromethanesulfonate (148 mg, 0.3 mmol) in 30 mL of dry CH2Cl2 at −78° C. The resulting mixture is slowly warmed up to 0° C. and stirred for 1 h. The reaction is quenched with 1 M HCl and stirred for 1 h at room temperature. After extraction with ethyl acetate (20 mL×3), washed with brine, dried over anhydrous Na2SO4 and concentration, the residue is purified by flash column, and gives a yellow oil (800 mg).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/Cl)=[N:7]\[OH:8])=[O:5].[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([C:18]#[CH:19])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]([F:20])([F:21])[C:12]1[CH:13]=[C:14]([C:18]2[O:8][N:7]=[C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C(Cl)=N\O
Reactant: C#Cc1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)on1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of ethyl chlorooximidoacetate (6.68 g, 44.09 mmol) in tetrahydrofuran (90 mL) in an ice bath was added 3-(trifluoromethyl)phenylacetylene (5.0 g, 29.39 mmol) slowly, followed by triethylamine (8.19 mL, 58.78 mmol) dropwise. The resulting mixture was stirred at room temperature overnight, which was then filtered through a layer of silica gel (top) and anhydrous Na2SO4 (bottom), and washed with ethyl acetate. The filtrate was washed with water, the organic layer dried over sodium sulfate, and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:Hexanes=1:9) to afford ethyl 5-[3-(trifluoromethyl)phenyl]isoxazole-3-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([S:37][CH3:38])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:38][S:37][C:36]1[NH:35][N:34]=[C:24]2[C:23]=1[CH2:22][CH2:21][C:20]1[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:8]4([NH2:7])[CH2:9][CH2:10][CH2:11]4)=[CH:13][CH:14]=3)[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][C:25]2=1
Reactant: CSc1[nH]nc2c1CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Solvent: O=C(O)C(F)(F)F
Product: CSc1[nH]nc2c1CCc1nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc1-2
Reaction time: 0.01 h
Yield: 55.8 %

Procedure:
tert-butyl(1-(4-(3-(methylthio)-8-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (53 mg, 0.098 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and freeze-dried to give the desired product as an off-white solid (24 mg, 37% yield). 1H-NMR (500 MHz, CD3OD) δ 8.14 (1H, br s), 7.48 (2H, d), 7.43 (2H, d), 7.27-7.34 (3H, m), 7.21-7.27 (2H, m), 3.26 (2H, t), 2.97 (2H, br t), 2.72-2.82 (2H, m), 2.53-2.63 (2H, m), 2.49 (3H, s), 2.19-2.30 (1H, m), 1.91-2.02 (1H, m). LCMS (Method A) RT=4.06 min, M+H+=439.14.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:10]=1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[N:36]=2)=[CH:28][N:27]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:26]2[N:27]=[CH:28][C:29]([C:32]3[N:33]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:34]=[C:35]([C:37]([F:39])([F:40])[F:38])[N:36]=3)=[CH:30][CH:31]=2)=[CH:11][C:10]=1[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCc1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)nc1
Product: Cc1cc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cn2)ccc1OCc1ccccc1
Yield: 99.7 %

Procedure:
By using 2-(4-benzyloxy-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.08 g) and 2-bromo-5-[4-(trifluoromethyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-2-yl]pyridine (0.7 g), the procedure was carried out in the same manner as in Reference example 1-3) to obtain 2-[[2-[6-(4-benzyloxy-3-methylphenyl)-3-pyridyl]-4-(trifluoromethyl)imidazol-1-yl]methoxy]ethyltrimethylsilane (0.892 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]4[CH2:24][C:19]5(OCC[O:20]5)[CH2:18][CH2:17][CH2:16][C:13]=4[CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]4[CH2:24][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:13]=4[CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1
Reactant: c1cc(-n2ncc3cc4c(cc32)CCCC2(C4)OCCO2)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCCc2cc3c(cnn3-c3ccncc3)cc2C1
Temperature: 60 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
1-(Pyridin-4-yl)-5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (31.8 g, 99 mmol) and 4-methylbenzenesulfonic acid hydrate (23.8 g, 125 mmol) were added to a round bottom flask followed by the addition of acetone (250 mL). The mixture was heated to about 60° C. for about 2 h, then about 45° C. for about 16 h. The reaction mixture was cooled to rt, filtered and the resulting solids were collected. The solids were taken into EtOAc/MeOH and neutralized with sat. aq. NaHCO3. The mixture was extracted with EtOAc (3×100 mL) and any solids that would not dissolve were collected. The organics were dried over MgSO4 and concentrated in vacuo. The collected solids and extracted material were combined to provided 1-(pyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (26.2 g, 95%); LC/MS, method 1, Rt=1.25 min MS m/z 278 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.73-8.68 (m, 2H), 8.43-8.41 (m, 1H), 8.03 (s, 1H), 7.95-7.90 (m, 2H), 7.73 (s, 1H), 3.19 (d, J=5.5 Hz, 2H), 3.17 (d, J=4.1 Hz, 2H), 2.54-2.48 (m, 2H), 2.00-1.87 (m, 2H).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([O:15][CH:16]([CH2:19]O)[CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH2:8]([O:15][CH:16]1[CH2:17][O:18][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:19]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: O=C1CCCCC1
Solvent: c1ccccc1
Product: c1ccc(COC2COC3(CCCCC3)OC2)cc1

Procedure:
Using the procedure of Example 51, cyclohexanone and 2benzyloxy-1,3-propanediol were reacted, using benzene as solvent, to give after distillation, 3-benzyloxy-1,5-dioxaspiro[5.5]undecane, b.p. 120°-121°/0.05 mm. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[C:20]([NH:31][C:32]([C:34]3[CH:35]=[N:36][CH:37]=[C:38]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH:39]=3)=[O:33])[CH:19]=2)=[CH:10][N:9]=1>>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([OH:24])=[O:23])=[C:20]([NH:31][C:32]([C:34]3[CH:35]=[N:36][CH:37]=[C:38]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:39]=3)=[O:33])[CH:19]=2)=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cncc3ccccc23)cc1NC(=O)c1cncc(-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2cncc3ccccc23)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 4-(isoquinolin-4-yl)-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by stirring at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and ethyl acetate and water were added to the residue. After adjusting the pH to 6.5 with a 2 mol/L aqueous solution of sodium hydroxide, the solid substance was collected by filtration to obtain 81 mg of 4-(isoquinolin-4-yl)-2-(5-phenylpyridine-3-carboxamido)benzoic acid as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22]([C:10]1[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1ccc(-c2csc3ccccc23)cc1
Product: COc1ccc(-c2c(C(=O)c3cc(C)cc(C)c3)sc3ccccc23)cc1

Procedure:
3-p-Methoxyphenylbenzothiophene is acylated with 3,5-dimethylbenzoyl chloride as previously described to give 2-(3',5'-dimethylbenzoyl)-3-p-methoxyphenylbenzothiophene. Demethylation with pyridine hydrochloride followed by reaction of the hydroxy compound thus formed with diethylaminoethyl chloride as described above gives the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[CH:9][C:8]([OH:16])=[CH:7][CH:6]=2)[CH3:2].[H-].[Na+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][O:16][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:3]([CH2:1][CH3:2])=[C:11]2[CH2:12][C:13]([NH2:15])=[O:14])[CH3:34]
Reactant: CCc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCOc1ccc2c(c1)c(CC(N)=O)c(CC)n2Cc1ccccc1
Yield: 55 %

Procedure:
2-Ethyl-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide (308 mg, 1 mmol) was reacted with 40 mg (1 mmol) of 60% NaH/mineral oil and then with 0.15 mL (1 mmol) of ethyl 4-bromobutyrate as described in Example 56. Part D to give a product that was chromatographed on silica gel eluting with 50% EtOAc/hexane to give 231 mg (55% yield) of [4-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1-H-indol-5-yl]oxy]butanoic acid ethyl ester.
Reaction SMILES: CO[C:3]([N:5](C)[C:6]1[CH:7]=[C:8]([C:18]([C:20]2[C:21]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[CH:39][C:22]=3[S:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:27][CH:26]=2)=[O:19])[CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=O.C[Si](I)(C)C>C(Cl)Cl>[CH3:3][NH:5][C:6]1[CH:7]=[C:8]([C:18]([C:20]2[C:21]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)=[CH:39][C:22]=3[S:23][C:24]=2[C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:29][CH:30]=2)=[O:19])[CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)N(C)c1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CNc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reaction time: 5.5 h
Yield: 37.3 %

Procedure:
The 379 mg of 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-[(methoxycarbonyl)(methyl)amino]-4-(1-pyrrolidinylmethyl)phenyl ketone (Part G) was dissolved in 5.5 mL of dry CH2Cl2. To the solution was added 0.31 mL of trimethylsilyl iodide. The reaction mixture was stirred for 5.5 h. The reaction was quenched with 0.3 mL of MeOH and the mixture was concentrated to dryness under reduced pressure. Purification by flash chromatography (silica gel, 5% to 8% [10% conc NH4OH/MeOH]/CH2Cl2) afforded 130 mg (0.201 mmol, 37%) of a yellow foam.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]=1[CH3:13])=[C:2]=[S:3].[CH2:14]([NH2:17])[CH2:15][NH2:16]>C1(C)C=CC=CC=1>[NH2:16][CH2:15][CH2:14][NH:17][C:2](=[S:3])[NH:1][C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]=1[CH3:13]
Reactant: NCCN
Reactant: Cc1c(N=C=S)ccc2ocnc12
Solvent: Cc1ccccc1
Product: Cc1c(NC(=S)NCCN)ccc2ocnc12
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
A solution of 5-isothiocyanato-4-methylbenzoxazole (0.68 g, 3.58 mmol) in toluene (75 mL) is treated with ethylenediamine (0.84 mL, 12.53 mmol). The reaction is stirred for 30 minutes as the product precipitates. The precipitate is filtered and dried in an oven to yield 0.85 g of 5-[N'-(2-aminoethyl)thioureido]-4-methylbenzoxazole as a white solid.