Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N+]([O-])=O)(C)(C)C.[N+:8]1([O-:22])[C:13]2[CH:14]=[C:15]3[CH2:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[N:11]=[C:10](N)[N:9]=1.C(I)[I:24]>C1COCC1.[Cu]I>[I:24][C:10]1[N:9]=[N+:8]([O-:22])[C:13]2[CH:14]=[C:15]3[CH2:20][CH2:19][O:18][C:16]3=[CH:17][C:12]=2[N:11]=1
Reactant: Nc1nc2cc3c(cc2[n+]([O-])n1)CCO3
Reactant: ICI
Agent: [Cu]I
Agent: CC(C)(C)[N+](=O)[O-]
Solvent: C1CCOC1
Product: [O-][n+]1nc(I)nc2cc3c(cc21)CCO3
Temperature: 20 °C
Yield: 48.6 %

Procedure:
tert-BuNO2 (90%, 3.8 mL, 28.8 mmol) was added to a stirred solution of 1-oxide 204 (2.0 g, 9.8 mmol), CH2I2 (3.8 mL, 46.7 mmol) and CuI (1.87 g, 9.8 mmol) in THF (40 mL), and the mixture was stirred at reflux temperature for 7 h. The mixture was cooled to 20° C., the solvent was evaporated and the residue purified by chromatography, eluting with a gradient (2-10%) of MeOH/DCM, to give iodide 213 (1.50 g, 49%) as a pale yellow solid: mp 192-194° C.; 1H NMR δ 8.19 (t, J=1.6 Hz, 1H, H-9), 7.10 (s, 1H, H-5), 4.83 (t, J=8.4 Hz, 2H, H-7), 3.44 (dt, J=8.4, 1.6 Hz, 2H, H-8); 13C NMR δ 167.0, 150.4, 136.2, 123.3, 116.4, 105.8, 103.7, 73.4, 29.0; HRMS calcd for C9H6IN3O2(M+) m/z 314.9505, found 314.9501.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].[OH-].[Na+].Cl>CO>[C:13]([O:12][C:10]([C:9]([CH3:18])([O:8][C:7]1[CH:6]=[C:5]([CH:21]=[CH:20][CH:19]=1)[C:3]([OH:4])=[O:2])[CH3:17])=[O:11])([CH3:14])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cccc(OC(C)(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(3-methoxycarbonylphenoxy)-2-methylpropionate (17.03 g, 57.80 mmol) was dissolved in methanol (80 mL). Subsequently, an aqueous 3M sodium hydroxide solution (40 mL) was added thereto, and the mixture was stirred for three hours at room temperature. After completion of reaction, the mixture was acidified with hydrochloric acid under ice-cooling, to thereby precipitate colorless crystals. The crystals were subjected to filtration, thorough washing with water, and drying under reduced pressure, whereby colorless crystals were obtained (14.92 g, 53.22 mmol, 92.0%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@@H:13]([NH2:15])[CH2:12]1.[Cl:16][C:17]1[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=1.C(N(CC)CC)C>CS(C)=O.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:12][C@@H:13]([NH:15][C:22]2[C:17]([Cl:16])=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:14]1
Reactant: Clc1nccnc1Cl
Reactant: N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1nccnc1N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Reaction time: 6 h
Yield: 32.4 %

Procedure:
To a round bottomed flask was added cis-N1-(benzo[d]thiazol-2-yl)cyclobutane-1,3-diamine (0.5306 g, 1.816 mmol), 2,3-dichloropyrazine (0.271 g, 1.816 mmol, Pfaltz & Bauer, Inc.), and triethylamine (0.758 ml, 5.45 mmol, Sigma-Aldrich Chemical Company, Inc.) to stir at 75° C. in DMSO (1.816 ml) to stir for 6 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 100% EtOAc in hexane, to provide the title compound (0.1952 g, 0.588 mmol, 32.4% yield). LCMS showed product peak at 1.625 min (m+1=332.0). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.06-2.20 (m, 2 H) 2.75-2.87 (m, 2 H) 3.98-4.11 (m, 1 H) 4.11-4.22 (m, 1 H) 7.03 (td, J=7.53, 1.17 Hz, 1 H) 7.19-7.28 (m, 2 H) 7.40 (d, J=7.24 Hz, 1 H) 7.60 (d, J=2.54 Hz, 1 H) 7.69 (dd, J=7.82, 0.78 Hz, 1 H) 8.05 (d, J=2.74 Hz, 1 H) 8.32 (d, J=6.65 Hz, 1 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)#[CH:40]>O1CCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:40]#[C:39][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(I)cc2)cc1C
Reactant: C#Cc1ccccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(F)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (Z)-[4-[3-(4-fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.75 mmol; example 10) was dissolved in anhydrous tetrahydrofuran (10 mL). Anhydrous triethylamine (20 mL) and a solution of 2-ethynylpyridine (155 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) were added. The solution was degassed and copper(I) iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were added. A mixture was stirred at ambient temperature under nitrogen atmosphere overnight; the resulting suspension was filtered through a paddle of silica gel and silica gel was thoroughly washed with ethyl acetate. The obtained filtrate was evaporated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with water (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified using column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10) yielding methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[(pyridin-2-yl)ethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as orange oil.
Reaction SMILES: [OH:1][C:2]1([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=3)[CH:10]2O)[CH2:4][CH2:3]1.Cl.O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[OH:18][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[C:9]([CH2:8][N:5]3[CH2:6][CH2:7][C:2]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)([OH:1])[CH2:3][CH2:4]3)[CH2:17]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(CC2(O)CCN(CC3Cc4cc(O)ccc4C3O)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(CC2(O)CCN(CC3=Cc4ccc(O)cc4C3)CC2)cc1
Yield: 100 %

Procedure:
(1RS,2RS) and (1RS, 2SR)-2-[4-hydroxy-4-(4-methyl-benzyl)-piperidine-1-ylmethyl]-indan-1,5-diol (310 mg, 0.84 mmol) and ethanolic HCl (5 eq.) was heated in EtOAc (30 ml) at 65° C. for 1.5 hr. Distilled H2O (30 ml) and 10% NaHCO3 (30 ml) was added and the mixture shaken, the aqueous phase was further extracted with EtOAc (2×20 ml) and the combined organic extracts were washed with satd. NaCl solution (30 ml), dried (Na2SO4) and filtered. Evaporation of the solvent afforded 1-(6-hydroxy-1H-inden-2-ylmethyl)-4-(4-methyl-benzyl)-piperidin-4-ol as a beige solid (308 mg, 0.84 mmol, 100%) Mp. 154-157° C., MS m/e=350.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4]2[N:5]([CH:19]=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C>[I:29][C:19]1[N:5]2[CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=3)[CH:8]=[C:3]([C:2]([F:1])([F:22])[F:23])[C:4]2=[N:21][CH:20]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3nccn3c2)cc1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3c2)cc1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (1.36 g, 4.1 mmol) in 5 mL of acetic acid was added sodium acetate (0.51 g, 6.2 mmol) and a solution of iodine monochloride (2M, 2.5 mL, 5.0 mmol)-slightly exothermic. The reaction mixture was stirred for 30 min at 23° C., precipitate formed, then partitioned between 60 mL of water and 60 mL of EtOAc. The organic layer was washed with sat. NaHCO3, water, aq. sodium thiosulfate, water, then dried over Na2SO4, filtered and concentrated to give 1.36 g (72%) of an off-white solid. MS (ISP) 457.3 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][N:16]([C:17]4[N:22]=[C:21]([CH:23]5[C:28](=[O:29])[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24]5)[CH:20]=[CH:19][CH:18]=4)[C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1>[OH:29][CH:28]1[CH2:27][CH2:26][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:24][CH:23]1[C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)[N:22]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CN(C(=O)OC(C)(C)C)CCC3=O)n2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CN(C(=O)OC(C)(C)C)CCC3O)n2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
To a solution of tert-butyl 3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-4-oxo-piperidine-1-carboxylate (90 mg, 0.18 mmol) in tetrahydrofuran (8.0 ml) at 0° C. was added sodium borohydride (8.0 mg, 0.20 mmol). The reaction mixture was stirred at 0° C. for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 100% EtOAc) to give the desired product 40 mg 44% yield. MS (ESI) m/z: 488.1.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH2:22]([C@H:24]([NH:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:35]=1[O:50][CH2:51][CH2:52][NH2:53])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23].C1CCC(N=C=NC2CCCCC2)CC1.O(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([C@H:24]([NH:31][C:32]([C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:35]=1[O:50][CH2:51][CH2:52][NH:53][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23]
Reactant: O=C(O)Cc1ccncc1
Reactant: CC[C@H](NC(=O)c1c(OCCN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Product: CC[C@H](NC(=O)c1c(OCCNC(=O)Cc2ccncc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
0.41 g (2.4 mmol) of 4-pyridylacetic acid hydrochloride were suspended in 80 ml of CH2Cl2; the suspension was cooled to 0° C. and 0.33 ml (2.4 mmol) of TEA, 0.64 g (4.7 mmol) of HOBT and 1.0 g (2.4 mmol) of (S)-N-(α-ethylbenzyl)-3-(2-aminoethoxy)-2-phenylquinoline-4-carboxamide (compound of Description 4) were added. 0.58 g (2.8 mmol) of DCC, dissolved in 10 ml of CH2Cl2, were added dropwise and the reaction mixture was stirred at 0° C. for 1 h and at room temperature overnight. The precipitated dicyclohexylurea was filtered off and the filtrate was washed with 20% citric acid, sat. sol. NaCl and brine, dried over Na2SO4 and evaporated in vacuo to dryness. The crude product was purified by flash column chromatography on 230-400 mesh silica gel, eluting with a mixture of CH2Cl2/MeOH 95:5 containing 0.5% NH4OH (28%), to yield, after trituration with i-Pr2O, 0.85 g of the title compound.
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH:23](Br)([CH3:25])[CH3:24].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][S:2][C:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)([CH:23]([CH3:25])[CH3:24])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)Br
Reactant: COC(=O)C(SC)c1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(SC)(c1cccc(Oc2ccccc2)c1)C(C)C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Methyl α-methylthio-(m-phenoxyphenyl)acetate (1.77 g) was dissolved in 10 ml of dimethylformamide, and with ice cooling, 260 mg (65% content) of sodium hydride was added. The mixture was stirred for 30 minutes. Then, 0.70 ml of isopropyl bromide was added, and with ice cooling for 3 minutes, the mixture was stirred at room temperature for 2.5 hours. After adding an aqueous solution of ammonium chloride (1 g/40 ml), the mixture was extracted three times with 50 ml of diethyl ether. The organic layer was washed twice with 20 ml of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column using benzene as an eluent to afford 1.25 g of methyl α-methylthio-α-(m-phenoxyphenyl)isovalerate in a yield of 62%.
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH2:34][CH2:35][O:36][CH3:37])=[N:19][C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[N:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:38])([CH3:7])[CH3:6])C.[Li+].[OH-]>O1CCCC1.CCOCC>[CH3:37][O:36][CH2:35][CH2:34][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:39])=[O:3])=[C:10]([CH3:38])[CH:11]=2)=[C:22]([CH3:23])[N:21]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:19]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1COc1ccc(OC(C)(C)C(=O)O)c(C)c1
Yield: 81.3 %

Procedure:
A solution of 244 mg (0.446 mmol) 2-{4-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.34 ml 1N LiOH-solution in 2.5 ml tetrahydrofurane was stirred for 2 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude residue was suspended in AcOEt/heptane 1:19. The resulting crystals were filtered off providing 188 mg of pure 2-{4-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:10]2[OH:21])([CH3:5])[CH3:4].[OH2:22]>COCCOC>[CH:3]([O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:4][C:3]([O:6][CH2:7][CH3:15])=[O:22])[N:11]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:10]2=[O:21])([CH3:5])[CH3:4]
Reactant: CC(C)CN1C(=O)c2ccc(OC(C)C)cc2C1O
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)CC1c2ccc(OC(C)C)cc2C(=O)N1CC(C)C
Temperature: 20 °C

Procedure:
Ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is prepared as described in Example 2, starting with 0.149 g of 60% sodium hydride in 20 cm3 of 1,2-dimethoxyethane, 1.23 cm3 of triethyl phosphonoacetate and 1.08 g of 5-isopropyloxy-3-hydroxy-2-isobutyl-2,3-dihydro-isoindol-1-one. The mixture is refluxed for 5 hours and then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 100 cm3 of water and the mixture is then extracted with 3 times 100 cm3 of diethyl ether. The organic extracts are combined, washed with 100 cm3 of saturated brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (80 kPa) on a cartridge of silica gel (particle size 32-63 μm), eluting with a mixture of cyclohexane/ethyl acetate (90/10 by volume) and then with a mixture of cyclohexane/ethyl acetate (80/20 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.42 g of ethyl (5-isopropyloxy-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1yl)acetate is thus obtained in the form of a colorless oil. (Rf=0.57, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[OH:14][C@H:15]1[CH2:19][CH2:18][NH:17][C@H:16]1[CH3:20].C(=O)([O-])[O-].[Li+].[Li+]>>[OH:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=2)[C@H:16]1[CH3:20]
Reactant: C[C@@H]1NCC[C@@H]1O
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](O)CCN1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 4-fluoro-2-(trifluoromethyl)benzonitrile (851 mg), (2S,3S)-3-hydroxy-2-methylpyrrolidine (5 mmol) and lithium carbonate (665 mg), the title compound was obtained as a colorless solid (yield: 630 mg) by an operation similar to that in Example 3.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH2:44][O:45][CH3:46])=[CH:39][CH:38]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:26][CH2:25]2)(=[O:23])=[O:22])=[CH:7][CH:6]=1.[H-].[Na+].Cl.[CH3:50][N:51]([CH3:55])[CH2:52][CH2:53]Cl.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:37]2[CH:38]=[CH:39][C:40]([O:43][CH2:44][O:45][CH3:46])=[CH:41][CH:42]=2)[C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:53][CH2:52][N:51]([CH3:55])[CH3:50])[C:13]=2[S:21]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[CH2:26][CH2:25]2)(=[O:22])=[O:23])=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)[nH]c3ccccc23)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(S(=O)(=O)N3CCN(c4ccccc4Cl)CC3)n(CCN(C)C)c3ccccc23)cc1
Temperature: 0 °C
Yield: 82.9 %

Procedure:
To a solution of Compound 241 (1.2 g, 1.81 mmol) obtained in Example 242 in 25 ml of N,N-dimethylformamide was portionwise added sodium hydride (60% in oil, 160 mg, 3.81 mmol) with stirring at 0° C., and 2-dimethylaminoethylchloride hydrochloride (260 mg, 1.81 mmol) was added thereto, followed by heating to 80° C. and then stirring for 7 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution for neutralization, and water was added thereto followed by extraction with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was purified with silica gel column chromatography (ethyl acetate/hexane=2/1) to give 1.1 g (yield: 85%) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=O)=[O:6])[CH:2]=[CH2:3].[Cl:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>[Cl:19][C:20]1[N:25]=[C:24]([CH2:26][C:11]([C:10]2[CH:9]=[C:8]([NH:7][C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH2:3])[CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:23]=[CH:22][N:21]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OCC)c1
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
Ethyl 3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (20.0 g, 80.24 mmol) was dissolved in 1M LiHMDS in THF (260 mL) and cooled to 0° C. A solution containing 2-chloro-4-methylpyrimidine (10.32 g, 80.24 mmol) in 20 mL dry THF was added to the reaction mixture. The reaction was stirred at 0° C. for 2 h, quenched with MeOH (100 mL), dried directly onto silica, and purified via flash chromatography EtOAc/CH2Cl2 0-100% gradient run over 60 min. The desired fractions were combined and the solvent was removed to give the title compound (13.6 g, 51% yield); ES-LCMS m/z 332 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([N+:20]([O-])=O)[CH:3]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[NH2:20][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCc1nccn1-c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCc1nccn1-c1ccc(F)cc1N
Reaction time: 2.5 h

Procedure:
Ethyl 3-[1-(4-fluoro-2-nitrophenyl)-1H-imidazol-2-yl]-propanoate as synthesized in above Production Example 91, 210 mg was dissolved in 1 mL of acetic acid and 1 mL of water, to which 533 mg of 85% sodium hyposulfite was added, followed by 2.5 hours' heating under reflux. The reaction liquid was allowed to cool off and rendered weakly alkaline with saturated aqueous sodium hydrogencarbonate solution, which was extracted with ethyl acetate. The extract was washed with saturated brine and dried over sodium sulfate. Distilling the solvent off under reduced pressure, 100 mg of the title compound was obtained.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C(O)(=O)C(C)=C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 64.7 %

Procedure:
200 mg of styrene, 320 mg of triethoxysilane, and 370 mg of toluene were placed in a glass reaction tube and 0.0014 ml of methacrylic acid was added. Next, 0.002 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 66.3%, phenethyltriethoxysilane was produced at a yield of 64.7%, and the yield of (α-methylbenzyl)triethoxysilane was 1.0%.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18](O)=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1>>[N:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH:36][C:18]([C:17]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9](=[O:28])[C:10]3[C:15]([C:16]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=3)=[O:19])=[CH:31][CH:30]=1
Reactant: NCc1ccncc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Product: O=C(NCc1ccncc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (250 mg) and 4-picolylamine. Colorless crystals (17 mg).