Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)=[O:27])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1>CO.C1COCC1.C(Cl)Cl.[Pd]>[N:13]1([C:11]2[N:12]=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=4)=[O:27])=[CH:21][CH:20]=3)[N:10]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(C3=CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(C3CCOCC3)nc(N3CCOCC3)n2)cc1
Reaction time: 3 h
Yield: 24.8 %

Procedure:
1-{4-[4-(3,6-dihydro-2H-pyran-4-yl)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (130 mg, 0.28 mmol) and Pd—C (10%, wet) (113 mg) were suspended in methanol/THF/CH2Cl2 (4:1:1) (30 mL) and hydrogenated (at 1 atm pressure) for 3 h. After completion, the catalyst was removed by filtration over Celite™ and the solvents were removed in vacuo to obtain the crude product, which was purified by semi-prep-HPLC (TFA-method), to give (32 mg=20% yield) of 1-{4-[4-Morpholin-4-yl-6-(tetrahydro-pyran-4-yl)-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea; MS (ESI) m/z 462.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@H:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=O.[CH3:18][NH:19][CH3:20].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C1COCC1>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@@H:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:19]([CH3:20])[CH3:18]
Reactant: CNC
Reactant: O=C[C@H]1CCC[C@@H]1c1c[nH]c2ccc(I)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C[C@@H]1CCC[C@H]1c1c[nH]c2ccc(I)cc12
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a room temperature solution of (1S,2S)-2-(5-iodo-1H-indol-3-yl)-cyclo-pentanecarbaldehyde (17.5 g, 51.6 mMol) in 200 mL of methanol was added with stirring dimethylamine (64 mL of a 2.0 M solution in THF, 128 mMol) followed by acetic acid (0.5 mL). After 15 min, NaBH(OAc)3 (12 g, 57 mMol) was added slowly. The resulting mixture was stirred 18 h and was then concentrated under vacuum. The residue was partitioned between ethyl acetate (400 mL) and aqueous NaHCO3 (300 mL). The organic layer was washed twice with aqueous NaHCO3 (250 mL). Every aqueous layer was extracted with ethyl acetate (50 mL) to make sure no product was left in aqueous. The combined organic extracts were then dried over MgSO4. Solvent was removed under vacuum and the residue was pump dried overnight to give crude trans [2-(5-iodo-1H-indol-3-yl)-cyclopentylmethyl]-dimethylamine (19.4 g, 100%) which was used directly for the next reaction without further purification. An analytical sample was prepared by crystallization from ethyl acetate. 1H NMR (400 MHz, methanol-d4) δ 7.86 (s, 1H), 7.30 (d, 1H), 7.14 (d, 1H), 7.02 (s, 1H), 2.80 (m, 1H), 2.27 (m, 3H), 2.12 (s, 6H), 2.10 (m, 2H), 1.79 (m, 3H), 1.46 (m, 1H); 13C NMR (400 MHz, methanol-d4), δ 137.6, 131.1, 130.5, 128.9, 123.2, 119.0, 114.6, 82.3, 66.2, 46.0, 45.6, 43.4, 35.0, 33.0, 25.2; HRMS (EI), exact mass calc'd for C16H21IN2 (M+H) 369.0828, found 369.0836.
Reaction SMILES: Cl[CH2:2][C:3]([CH2:5]Cl)=[O:4].[SH:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(N([CH2:20][CH3:21])CC)C>O1CCCC1>[CH2:13]([O:12][C:10]([CH2:9][CH2:8][S:7][CH2:2][C:3]([CH2:5][S:7][CH2:8][CH2:9][C:10]([O:12][CH2:20][CH3:21])=[O:11])=[O:4])=[O:11])[CH3:14]
Reactant: O=C(CCl)CCl
Reactant: CCOC(=O)CCS
Reactant: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCSCC(=O)CSCCC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
To a stirred solution of 1,3-dichloroacetone (6.85 g, 54 mmol) and ethyl 3-mercaptopropionate (13.9 mL, 108 mmol) in anhydrous tetrahydrofuran (150 mL) was dropwise added triethylamine (15.0 mL, 108 mmol) at 0° C. and stirred at room temperature for 24 h. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The ethyl acetate phase was washed with 5% hydrochloric acid and then brine, dried over sodium sulfate, and concentrated to dryness, affording 17.4 g of the crude 1,3-bis(2-ethoxycarbonylethylthio)acetone.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([Cl:13])=[CH:11][C:10]([F:14])=[C:9]([C:15]3[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)[C:7]=2[CH:8]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH2:32](O)[CH3:33]>>[Cl:13][C:12]1[C:6]2[O:5][C:4]([C:1]([O:3][CH2:32][CH3:33])=[O:2])=[CH:8][C:7]=2[C:9]([C:15]2[C:16](=[O:26])[N:17]([CH3:25])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)=[C:10]([F:14])[CH:11]=1
Reactant: CCO
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(=O)O)cc23)c1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Yield: 99 %

Procedure:
0.08 g (0.21 mmol) of 3-(2-carboxy-7-chloro-5-fluorobenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 10 ml of ethanol, and 4.0 mg (0.04 mmol) of sulfuric acid was added thereto, followed by refluxing for 2 hours. Ethanol was distilled off under reduced pressure. Then, the obtained residue was poured into water and extracted with diethyl ether. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.09 g (yield: 99%) of the desired product. Melting point: 118-120° C. 1H-NMR (300 MHz, CDCl3) δ value: 1.41(3H,t), 3.75(3H,s), 4.43(2H,q), 6.82(1H,d), 7.34(1H,d), 7.38(1H,s), 7.57(1H,d)ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[NH:22]1[CH2:27][CH2:26][S:25][CH2:24][CH2:23]1.[CH2:28]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:28][N:22]4[CH2:27][CH2:26][S:25][CH2:24][CH2:23]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: C1CSCCN1
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Reactant: C=O
Solvent: CCO
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1ccc(O)c2CN1CCSCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.050 g, 0.18 mmol) obtained in Example A1, Step 1 in ethanol (2.0 mL) was added with thiomorpholine (0.023 g, 0.22 mmol), and 37% aqueous formaldehyde (0.020 g, 0.24 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-7-(thiomorpholinomethyl)benzofuran-3(2H)-one (0.031 g, 44%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][C:9]=1[C:18]#[N:19].[F:26][C:27]1[C:32]([OH:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37].CCN(CC)CC>ClCCl>[F:26][C:27]1[C:32]([O:33][S:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[C:9]([C:18]#[N:19])[CH:10]=2)(=[O:16])=[O:15])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Oc1ccccc1-c1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1Oc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride (Preparation 55, 500 mg, 1.35 mmol) in dichloromethane (5 ml) was added slowly to pentafluorophenol (249 mg, 1.35 mmol) and Et3N (137 mg, 1.35 mmol) in dichloromethane (5 ml) and stirring continued overnight at ambient temperature. The reaction was concentrated in vacuo and purified using silica gel column chromatography (dichloromethane/heptane 40/60, then 60/40, then 80/20, then dichloromethane) to furnish the title compound. LCMS Rt=1.92 minutes 1H NMR (400 MHz; CDCl3) δ (ppm): 6.69 (d, J=8.98 Hz, 1 H) 7.21-7.30 (m, 2 H) 7.31-7.38 (m, 2 H) 7.43-7.53 (m, 4 H) 7.53-7.58 (m, 1 H) 7.79 (dd, J=8.98, 2.34 Hz, 1 H) 8.06 (d, J=2.34 Hz, 1 H) 19F NMR (376 MHz, CDCl3) δ (ppm): 160.82 (t, J=19.50 Hz) −154.87 (t, J=21.80 Hz) −151.09 (d, J=17.21 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14].[OH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>CO>[OH:17][C:18]1[CH:19]=[C:20]([NH:21][S:13]([C:4]2[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])(=[O:15])=[O:14])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(N)cc1O
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c(OC)c2OC)cc1O
Reaction time: 1 h

Procedure:
To a solution of 2,3,4-trimethoxybenzenesulfonyl chloride (500 mg, 1.88 mmol) in methanol (mL) is added 3-hydroxy-4-methoxyaniline (523 mg, 3.76 mmol) at ambient temperature. The reaction is stirred for 1 h, the solvent is then evaporated and the crude product is purified by flash chromatography over silica.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:13]2=[O:37])[CH2:8]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O>[OH:6][C@H:7]1[CH2:11][CH2:10][C@H:9]([N:12]2[C:17]3=[N:18][C:19]([NH:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[C:13]2=[O:37])[CH2:8]1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)C3)C2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N([C@H]3CC[C@H](O)C3)C2=O)cc1
Reaction time: 0.5 h

Procedure:
(−)-(1S,3S)-1-[3-(tert-Butyl-dimethyl-silanyloxy)-cyclopentyl]-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (445 mg, 0.82 mmol) (from Example 29g supra) was dissolved in a 25% trifluoroacetic acid in dichloromethane solution (5 mL) and water (300 μL) at 0° C. After stirring for 30 minutes the mixture was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide and the pH of the aqueous layer was adjusted to 12 via the addition of solid sodium hydroxide. The organic layer was collected, dried over sodium sulfate, filtered and concentrated to a residue that was purified by chromatography with a silica gel column and a 0–100 ethyl acetate in hexanes to 0–40% tetrahydrofuran in ethyl acetate gradient to give (−)-(1S,3S)-1-(3-hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 307 mg, 86%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[N:7][NH:8][C:9]2=[O:14])([O-:3])=[O:2].[C:15](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:15][N:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:9]1=[O:14]
Reactant: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ncc2c([N+](=O)[O-])cccc2c1=O
Reaction time: 8 h
Yield: 91.4 %

Procedure:
1.6 g of 5-nitro-phthalazin-1-one and 2.31 g of potassium carbonate are stirred for 10 minutes at room temperature in 60 ml of DMF. 1.1 ml of methyl iodide is added, and it is stirred overnight. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. 1.57 g of 2-methyl-5-nitro-phthalazin-1-one is obtained as a yellow solid.
Reaction SMILES: C1(C)C=CC(S(C[N+:11]#[C-])(=O)=O)=CC=1.[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C[C:21]([CH3:24])([O-])C.[K+]>O1CCCC1>[NH:11]1[CH:21]=[CH:24][C:15]([C:14]([O:18][CH3:19])=[O:17])=[CH:16]1
Reactant: CC(C)(C)[O-]
Reactant: C=CC(=O)OC
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc[nH]c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
A solution (250 mL) of p-toluenesulfonylmethyl isocyanide (15.0 g) and methyl acrylate (6.92 mL) in tetrahydrofuran was added dropwise to a suspension (100 mL) of potassium tert-butoxide in tetrahydrofuran over 30 min. The reaction mixture was stirred at room temperature for 1 hr, and filtered through a glass filter filled with silica gel (diameter 8 cm, height 4 cm), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow solid (yield 4.69 g, 49%).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[Cl:6][C:7]1[C:16]2[C:11]3=[C:12]([C:17](=[O:21])N[C:19](=[O:20])[C:10]3=[CH:9][CH:8]=1)[CH:13]=[CH:14][CH:15]=2>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:17](=[O:21])[C:12]2=[C:11]3[C:16](=[CH:15][CH:14]=[CH:13]2)[C:7]([Cl:6])=[CH:8][CH:9]=[C:10]3[C:19]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1NC(=O)c2ccc(Cl)c3cccc1c23
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCN1C(=O)c2cccc3c(Cl)ccc(c23)C1=O
Yield: 76.4 %

Procedure:
This compound has been reported previously. This preparation is similar to previously reports (see e.g. Daffy et al. Chem-Eur J 1998, 4, 1810-1815; de Silva et al., Chem Rev 1997, 97, 1515-1566). A portion of n-butylamine (5.00 mL, 50.6 mmol) was added to a suspension of 4-chloronaphthalene-1,8-dicarboximide (11.7 g, 50.5 mmol) in 160 mL of toluene. This mixture was brought to reflux for 17 hours to give a dark black-brown solution. Crystallization from hexanes/toluene at −10° C. gave 1ax as a pure brownish-yellow powder (11.1 g, 76%). 1H NMR: δ=8.65 (d, 1H, J=7.4 Hz), 8.58 (d, 1H, J=8.6 Hz), 8.49 (d, 1H, J=7.9 Hz), 7.85 (t, 1H, J=7.9 Hz), 7.81 (d, 1H, J=7.9 Hz), 4.18 (t, 2H, J=7.6 Hz), 1.72 (m, 2H), 1.45 (m, 2H), 0.98 (t, 2H, J=7.4 Hz). 13C{1H} NMR: δ=163.8, 163.5, 139.0, 132.0, 131.2, 130.6, 129.3, 129.1, 127.9, 127.5, 123.2, 121.7, 40.5, 30.3, 20.5, 14.0. ESI/MS m/z.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10](Cl)(=[O:14])[CH2:11][CH2:12][CH3:13]>N1C=CC=CC=1>[C:10]([O:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5])(=[O:14])[CH2:11][CH2:12][CH3:13]
Reactant: OCC(CO)(CO)CO
Reactant: CCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCC(=O)OCC(CO)(CO)CO
Yield: 47 %

Procedure:
In this example, the stoichiometry of Example 1 was modified using pentaerythritol (1.92 g; 14 mmol) and butyryl chloride (0.75 mL; 0.5 equiv) and pyridine (100 mL) to produce pentaerythritol monobutyrate (0.74 g; 47%).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH:9]([OH:12])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14]CCOC.C(=O)(OCC)OCC.C[O-].[Na+]>O>[OH:11][CH2:10][CH:9]1[O:12][C:13](=[O:14])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1
Reactant: COCCOC
Reactant: OCC(O)CNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(=O)OCC
Product: O=C1OC(CO)CN1c1ccccc1

Procedure:
A mixture of 83.6 g (0.5 mole) of 3-phenylamino-1,2-propanediol, 250 ml of 1,2-dimethoxyethane and 61 ml of diethyl carbonate was refluxed in a nitrogen atmosphere. Solid sodium methoxide (about 0.15 g) was added and refluxing continued for approximately 21/2 hours. The mixture was cooled, stirred with water and filtered to yield 41.1 g of 5-(hydroxymethyl)-3-phenyl-2-oxazolidinone, m.p. 122°-124° C. The 41.1 g was recrystallized from 100 ml of absolute ethanol to give 38.0 g, m.p. 125.5°-126° C. A further crop of 25.3 g (m.p. 124.5°-125° C.) was obtained from the water filtrate by concentrating and recrystallizing from ethanol.
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[S:16][C:17]([C:37]([F:40])([F:39])[F:38])=[CH:18][C:19]=1[C:20]1[N:35]([CH3:36])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH:27]=[C:22]2[N:21]=1)C.[S:41]([O-:45])([O-])(=[O:43])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:41]([C:15]1[S:16][C:17]([C:37]([F:39])([F:40])[F:38])=[CH:18][C:19]=1[C:20]1[N:35]([CH3:36])[C:23]2=[N:24][CH:25]=[C:26]([C:28]([F:33])([F:34])[C:29]([F:32])([F:31])[F:30])[CH:27]=[C:22]2[N:21]=1)(=[O:45])=[O:43])[CH3:11]
Reactant: O=S([O-])([O-])=S
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1sc(C(F)(F)F)cc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1sc(C(F)(F)F)cc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.08 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to 3 ml of a solution of 0.07 g of 2-(2-ethylthio-5-trifluoromethylthiophen-3-yl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5,b]pyridine in chloroform under ice cooling, and the mixture was stirred for 2 hours and at room temperature for 1 hour. A 10% aqueous sodium thiosulfate solution was poured into the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.07 g of 2-(2-ethylsulfonyl-5-trifluoromethylthiophen-3-yl)-3-methyl-6-pentafluoroethyl-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (10)).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[CH:29]1([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[O:40][CH3:41])[CH2:32][CH2:31][CH2:30]1>O.CC(O)=O.C1COCC1>[CH:29]1([C:33]2[CH:38]=[CH:37][C:36]([B:16]([OH:21])[OH:17])=[C:35]([F:39])[C:34]=2[O:40][CH3:41])[CH2:30][CH2:31][CH2:32]1
Reactant: COc1c(F)cccc1C1CCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C2CCC2)ccc(B(O)O)c1F
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 89.7 %

Procedure:
To a 500 mL round-bottomed flask were added a stir bar, dry THF (60 mL) and 2,2,6,6-tetramethylpiperidine (8.0 mL, 47 mmol). The flask was cooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (18.0 mL, 45 mmol) over 2 min. The resultant mixture was stirred for 5 min and then allowed to warm to 0° C. After 35 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)3 (10.20 mL, 44 mmol) over 4 min. After 16 min, a solution consisting of 1-cyclobutyl-3-fluoro-2-methoxybenzene (7.24 g, 40.2 mmol) and dry THF (20.0 mL) was added over the course of 6 min and stirring continued for 3.5 h before adding HOAc (8 mL). The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL), the extract dried over MgSO4, filtered and concentrated to dryness to give (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid as an off-white solid (8.08 g, 90%). The crude product was used directly in the next synthetic step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([CH3:23])[C:19]([CH3:24])=[N:18][C:17]=2[C:16]([C:25]([OH:27])=O)=[CH:15][CH:14]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:25]([C:16]3[C:17]4[N:18]=[C:19]([CH3:24])[C:20]([CH3:23])=[N:21][C:22]=4[C:13]([C:3]4[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[Cl:12])=[CH:14][CH:15]=3)=[O:27])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3nc(C)c(C)nc23)c1Cl
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nc(C)c(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2,3-dimethyl-quinoxaline-5-carboxylic acid (Step 122.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture 18 h at rt. Title compound: ESI-MS: 595.0 [M+H]+; tR=3.86 min (System 1); TLC: Rf=0.15 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[K+].Cl[CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14]>[Cl-].CO[Si](OC)(OC)CCC[N+]1C=CC(N(C)C)=CC=1>[C:1]([O:6][CH2:9][CH2:10][CH2:11][Si:12]([O:17][CH3:18])([O:15][CH3:16])[O:13][CH3:14])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)[O-]
Reactant: CO[Si](CCCCl)(OC)OC
Agent: CO[Si](CCC[n+]1ccc(N(C)C)cc1)(OC)OC
Agent: [Cl-]
Agent: [K+]
Product: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Temperature: 135 °C
Yield: 90.6 %

Procedure:
124 g (1 mol) of potassium methacrylate were admixed with 198.5 g (1 mol) of 3-chloropropyltrimethoxysilane, 2.7 g of 1-(3'-trimethoxysilylpropyl)-4-dimethylaminopyridinium chloride and 0.5 g of N,N'-diphenyl-p-phenylamine, and the mixture was heated to 135° C. while stirring. After 1 hour at this temperature the mixture was cooled and the potassium chloride which had precipitated was filtered off and washed with 60 g of methanol. The methanol was evaporated from the combined filtrates, and the residue was distilled under reduced pressure. 225 g of 3-methacryloxypropyltrimethoxysilane having a boiling point of 82° C. (0.4 mbar) were obtained. The yield was 90.7% of theory, based on the amount of potassium methacrylate which was used. The purity of the product was 99.0%. In the gas chromatogram only traces of 4-dimethylaminopyrrdine were detectable. A 2% solution of the product in water with a pH of 4 contained no oily separation of any kind.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](Cl)=[O:36]>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=3)=[O:36])[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)c4ccccn4)cccc3C2=O)C(=O)N1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
Triethylamine (0.7 g, 7.4 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and picolinoyl chloride hydrchloride (0.5 g, 2.5 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with H2O (30 mL). The mixture was filtered, and the solid was slurried with hot methanol (15 mL) to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.6 g, 78%): mp 254-256° C.; 1H NMR (DMSO-d6) δ 2.01-2.06 (m, 1H), 2.32-2.66 (m, 2H), 2.86-3.01 (m, 1H), 4.43-4.65 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.7 and 13.0 Hz, 1H, CH), 7.45-7.64 (m, 4H, Ar), 7.97-8.07 (m, 2H, Ar), 8.65 (d, J=4.2 Hz, 1H, Ar), 9.51 (t, J=5.8 Hz, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.59, 31.17, 46.30, 51.57, 121.63, 122.02, 126.60, 128.28, 130.77, 131.58, 134.73, 137.79, 140.08, 148.44, 149.80, 164.16, 168.06, 170.99, 172.82; Anal. calcd. for C20H18N4O4: C, 63.49; H, 4.79; N, 14.81. Found: C, 63.32; H, 4.66; N, 14.80.