Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH:27]1([NH:30][C:31](=[O:49])[C:32]2[CH:37]=[C:36](B3OC(C)(C)C(C)(C)O3)[C:35]([CH3:47])=[C:34]([F:48])[CH:33]=2)[CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH:27]1([NH:30][C:31](=[O:49])[C:32]2[CH:33]=[C:34]([F:48])[C:35]([CH3:47])=[C:36]([C:2]3[C:3]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[C:4]=4[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=3)[CH:37]=2)[CH2:28][CH2:29]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 100 °C
Yield: 9.8 %

Procedure:
4-Chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one (0.056 g, 0.17 mmol), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.065 g, 0.17 mmol), K2CO3 (0.07 g, 0.51 mmol) and tetrakis triphenyl phosphine palladium (10 mg, 0.05 eq) are dissolved in dioxane/water (3:1, 10 mL) and heated to about 100° C. for about 3 h. The mixture is concentrated and purified via reverse phase HPLC to afford the title compound (9 mg, yellow powder, mp 214.2-217.5): LC-MS m/z 540 (M+H)+, 1.69 min (ret time). HPLC indicates 96% pure.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)C=C.[Cl:39]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:39][CH:5]1[N:8]([C:9](=[C:23]([S:30][C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1
Reactant: ClCl
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Sc1ccc(C)cc1)C(=O)C(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccc(SC(C(=O)C(C)(C)C)=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2Cl)cc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To a solution of 2.28 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-methylthiophenoxy)-3-trimethylacetylthiopropenate in dichloromethane at -20° , was added solution of 7.6 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 1.48 g of the title compound as a yellow foam (69% of the theoretical yield).
Reaction SMILES: COC([C:5]1([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])[C:9](=[O:10])[CH:8]=[CH:7][CH:6]1[CH2:11][C:12]([O:14][CH3:15])=[O:13])=O.[Cl-].[Na+]>CS(C)=O.O>[CH3:15][O:14][C:12]([CH2:11][CH:6]1[CH:5]([CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])[C:9](=[O:10])[CH:8]=[CH:7]1)=[O:13]
Reactant: CC/C=C\CC1(C(=O)OC)C(=O)C=CC1CC(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC/C=C\CC1C(=O)C=CC1CC(=O)OC
Temperature: 175 °C
Yield: 91 %

Procedure:
A 360 mg quantity of 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone is dissolved in 8 ml of dimethyl sulfoxide containing 23 mg of water. The solution is reacted in a sealed tube with addition of 20 mg of sodium chloride. After the solution has been heated at 175° C. for 4 hours, the product is cooled to room temperature and then extracted with ethyl ether. The ethereal layer is washed, dried and distilled for the removal of the solvent. Purification of the residue by a silica gel column affords a compound (1-a) and compound (1-b) (R2 =CH3 in each). Yield of compound (1-a): 62.5%. Yield of compound (1-b): 28.5%. Combined yield: 91%. B.p. 87°-91° C./2.5 mm Hg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]3([OH:23])[CH2:21][CH2:22][O:18][CH2:19]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Reactant: O=C1CCOC1
Product: OC1(c2ccc3c(c2)CN(Cc2ccccc2)C3)CCOC1

Procedure:
Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and tetrahydrofuran-3-one. Brown oil. MS (m/e): 296.4 ([M+H]+, 100%).
Reaction SMILES: [C:1]([C:3]1([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][C:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2].[OH-].[K+].O>CC(O)C>[C:1]([C:3]1([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][C:12]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)#[N:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCN(C2CCC(C#N)(c3ccc(F)cc3)CC2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: N#CC1(c2ccc(F)cc2)CCC(N2CCC(C(=O)O)(c3ccccc3)CC2)CC1
Yield: 66.4 %

Procedure:
A mixture of 10.9 parts of ethyl 1-[4-cyano-4-(4-fluorophenyl)-1-cyclohexyl]-4-phenyl-4-piperidinecarboxylate, 11.2 parts of potassium hydroxide, 50 parts of water and 96 parts of 2-propanol is stirred and refluxed for 4 hours. The reaction mixture is filtered hot over Hyflo and the filtrate is poured onto 300 parts of water. The whole is neutralized with acetic acid to pH 6-7. The precipitated product is filtered off, washed three times with water and converted into the hydrochloride salt in ethanol and 2-propanol. The salt is filtered off and suspended in a solution of 1.4 parts of potassium hydroxide in 150 parts of water. The free base is extracted four times with 70 parts of 1,1'-oxybisethane. The aqueous phase is separated and stirred for a while on a rotavapor to remove all traces of 1,1'-oxybisethane. The clear aqueous phase is acidified with a 10% acetic acid solution to pH 6. The precipitated product is filtered off, washed with water and dried overnight at about 105° C., yielding 5.4 parts (66.4%) of 1-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-4-phenyl-4-piperidinecarboxylic acid; mp. 281.1° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([CH:16]=O)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:18]1[C:27]2[CH:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]3[C:41](=[O:42])[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]3=[O:43])[CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C:10]1[C:11]([CH2:16][N:28]([CH:26]2[C:27]3[N:18]=[CH:19][CH:20]=[CH:21][C:22]=3[CH2:23][CH2:24][CH2:25]2)[CH2:29][CH2:30][CH2:31][CH2:32][N:33]2[C:34](=[O:43])[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:41]2=[O:42])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccnc1C=O
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1CN(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21

Procedure:
Using General Procedure B, reaction of 3-(tert-Butyldimethylsilanyloxymethyl)-pyridine-2-carbaldehyde, 2-[4-(5,6,7,8-Tetrahydroquinolin-8-ylamino)-butyl]-isoindole-1,3-dione and NaBH(OAc)3 in CH2Cl2 gave 2-{4-[[3-(tert-Butyldimethylsilanyloxymethyl)-pyridin-2-ylmethyl]-(5,6,7,8-tetrahydroquinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a light brown solid. 1H NMR (CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H), 1.31 (m, 2H), 1.49 (quintet, 2H, J=7.5 Hz), 1.59 (m, 1H), 1.85-2.08 (m, 3H), 2.47 (m, 1H), 2.59 (m, 2H), 2.67 (m, 1H), 3.49 (t, 2H, J=7.5 Hz), 3.90 (m, 1H), 3.96 (d, 1H, J=12.0 Hz), 4.11 (d, 1H, J=12.0 Hz), 4.98 (d, 1H, J=15.0 Hz), 5.20 (d, 1H, J=15.0 Hz), 6.99 (m, 1H), 7.13 (m, 1H), 7.28 (d, 1H, J=7.5 Hz), 7.68 (m, 2H), 7.80 (m, 2H), 7.82 (d, 1H, J=7.5 Hz), 8.32 (d, 1H, J=3.0 Hz), 8.42 (d, 1H, J=3.0 Hz).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[N:16]3[C:11]([C:12]([NH2:17])=[N:13][CH:14]=[N:15]3)=[C:10]([C:18]3[CH:19]=[CH:20][C:21]4[C:25]([CH:26]=3)=[N:24][N:23]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:22]=4)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:27]([N:23]1[CH:22]=[C:21]2[C:25]([CH:26]=[C:18]([C:10]3[CH:9]=[C:8]([CH:4]4[CH2:5][CH2:6][CH2:7][N:1]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:2][CH2:3]4)[N:16]4[C:11]=3[C:12]([NH2:17])=[N:13][CH:14]=[N:15]4)[CH:19]=[CH:20]2)=[N:24]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C3CCCNCC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 20.4 %

Procedure:
To a solution of 7-azepan-4-yl-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.20 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (17 pt, 0.22 mmol) and N,N-diisopropylethylamine (136 μL, 0.78 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 21 mg (21%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.90 (s, 1 H), 7.78 (dd, 1 H), 7.58 (s, 1 H), 7.28-7.38 (m, 5 H), 7.14 (dd, 1 H), 6.61 (s, 1 H), 5.64 (s, 2 H), 3.19-3.56 (m, 4 H), 2.90 (s, 3 H), 1.66-2.20 (m, 7 H); ES-MS m/z 516.30 [M+H]+, HPLC RT (min) 3.07.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][NH2:15])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:16]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(CC)CC)C>CN(C)C=O>[CH2:5]([O:4][C:2]([NH:12][CH2:13][CH2:14][NH:15][C:26](=[O:27])[C@H:24]([CH3:25])[NH:23][C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCNC(=O)OCc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCNC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A solution of 10.0 g (0.043 mol) of (1f) and 10.3 g (0.036 mol) of N-BOC-L-alanine, N-hydroxysuccinimide ester in anhydrous N,N-dimethylformamide (50 ml) was cooled with an ice bath. To this was added 7.6 ml (0.054 mol) of triethylamine in anhydrous N,N-dimethylformamide (20 ml) over a period of 30 minutes. The reaction was stirred at ca. 5° C. for 1 hour, then at room temperature for 1 hour. The N,N-dimethylformamide was removed in vacuo and the resulting residue was dissolved in 300 ml of ethyl acetate. The solution was washed with 1M HCl (3×100 ml), water (100 ml), saturated sodium bicarbonate solution (3×100 ml) and finally, with brine (100 ml). After drying over anhydrous magnesium sulfate, the solution was filtered and concentrated in vacuo to give 12.4 g (94% yield) of N-BOC-L-alanine, 2-(benzyloxycarbonylamino)ethyl amide (1g) as a white solid. TLC: Rf 0.67 (chloroform-isopropanol 9:1); 1H NMR(CDCl3) δ 1.27(d, 3H), 1.40(s, 9H), 3.32(m, 4H), 4.15(m, 1H), 5.06(s, 2H), 5.51(d, 1H), 5.90(m, 1H), 7.19(m, 1H), 7.31(bs, 5H); 13C NMR (CDCl3) δ 18.5, 28.2, 39.6, 40.5, 50.1, 66.5, 79.8, 127.9, 128.3, 136.3, 155.4, 156.9, 173.7.
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Reactant: Brc1cccc2ccccc12
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)P(c1cccc2ccccc12)C(C)(C)C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
In a 500 ml four-necked flask thoroughly purged with nitrogen, 18.1 g (0.1 mol) of di-tert-butylphosphinous chloride, 0.20 g (0.002 mol (corresponding to 2% by mol)) of copper(I) chloride, 20 ml of tetrahydrofuran and 20 ml of toluene were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 24.8 g (0.12 mol) of 1-bromonaphthalene and 3.5 g (0.14 mol) of metallic magnesium in 180 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at 65° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 30 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance. The oily substance was recrystallized from 150 ml of methanol to obtain 23.6 g (purity: 98.5%) of the aimed di-tert-butyl(1-naphthyl)phosphine as white crystals. The yield was 85.4%. Melting point: 95-97° C.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:9]([C:10]([OH:12])=O)[C:8]=1[C:16]([OH:18])=O)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[NH2:20][CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28]>C(O)(=O)C>[O:28]=[C:22]1[CH:21]([N:20]2[C:16](=[O:18])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:10]2=[O:12])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: NC1CCC(=O)NC1=O
Reactant: CCCCCNc1cccc(C(=O)O)c1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Yield: 53 %

Procedure:
To a stirred solution of 3-pentylamino-phthalic acid (2.51 g, 10 mmol) in acetic acid (50 ml) was added 3-amino-piperidine-2,6-dione hydrochloride (1.81 g, 11 mmol). The reaction mixture was heated to reflux overnight. The solvent was evaporated in vacuo and the residue dissolved in ethyl acetate (100 ml). The ethyl acetate mixture was washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (1×100 ml), and dried (MgSO4). The solvent was evaporated in vacuo and the solid residue was purified by chromatography (25% ethyl acetate/hexane) to give 1.82 g (53%) of product as a yellow solid: mp 141-143° C.; 1H NMR (DMSO-d6) d 11.09 (s, 1H); 7.58 (t, J=8.3 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.519 (t, J=5.7 Hz, 1H), 5.06 (dd, J=5.3 and 12.4 Hz, 1H), 3.32-3.25 (m, 2H), 2.97-2.82 (m, 1H), 2.62-2.46 (m, 2H), 2.06-2.01 (m, 1H), 1.61-1.55 (m, 2H), 1.35-1.32 (m, 4H), 0.88 (t, J=6.7 Hz, 3H); 13C NMR (DMSO-d6) d 172.72, 170.01, 168.92, 167.25, 146.39, 136.21, 132.14, 117.08, 110.31, 108.99, 48.52, 41.77, 30.94, 28.46, 28.33, 22.12, 21.82, 13.85; Anal. Calcd. For C18H21N3O4: C, 62.96; H, 6.16; N, 12.24. Found: C, 62.92; H, 6.17; N, 12.15.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O.[Cl-].[Na+].O>[CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCNC(=O)OCc1ccccc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN(C)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Methyl 6-benzyloxycarbonylamino-hexanoate (4.15 g) is dissolved in N,N-dimethylformamide (2.5 mL) and thereto is added sodium hydride (63%) (552 mg) under ice-cooling and the mixture is stirred at the same temperature for 1 hour and thereto is added methyl iodide (1.72 ml), and the mixture is stirred at the same temperature for an additional 2 hours. To the reaction mixture is added a saturated brine, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 6-(benzyloxycarbonyl-methyl-amino)-hexanoate (2.25 g). MS (m/z): 294 [M+H]+
Reaction SMILES: [OH:1][N:2]=C(C1C=CC2NC=NC=2C=1)N.[C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19]2)#[N:15]>>[NH2:15][C:14](=[N:2][OH:1])[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][C:20]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19]2
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: CCOC(=O)c1cc2cc(C#N)c(OC)cc2[nH]1
Product: CCOC(=O)c1cc2cc(C(N)=NO)c(OC)cc2[nH]1

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from ethyl 5-cyano-6-methoxy-1H-indole-2-carboxylate obtained in step 1 (120 mg; 0.49 mmol) as a beige solid (135 mg, 99%). 1H NMR (DMSO-d5) δ 9.25 (s, 1H), 7.60 (s, 1H), 7.11 (s, 1H), 6.90 (s, 1H), 5.53 (bs, 2H), 4.31 (q, J=7 Hz, 2H), 3.80 (s, 3H), 1.32 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1)[NH:6][C:5]2=[O:21].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[OH:19][C:15]1[C:16]([CH3:18])=[CH:17][C:12]([C:7]2[NH:6][C:5](=[O:21])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:22](=[O:24])[CH3:23])[CH:3]=3)[N:8]=2)=[CH:13][C:14]=1[CH3:20]
Reactant: Cc1cc(-c2nc3ccc(N)cc3c(=O)[nH]2)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2nc(-c3cc(C)c(O)c(C)c3)[nH]c(=O)c2c1
Reaction time: 4 h
Yield: 17 %

Procedure:
To a round-bottomed flask were added 2-amino-5-nitro-benzamide (0.681 g, 3.76 mmol), 4-hydroxy-3,5-dimethyl-benzaldehyde (0.565 g, 3.76 mmol), sodium bisulfite (0.747 g, 4.2 mmol), p-toluenesulfonic acid, monohydrate (0.072 g, 0.376 mmol) and N,N-dimethylacetamide (60 mL). The reaction mixture was refluxed at 155° C. for 16 h before being cooled to room temperature. Water was added and the precipitated solid was filtered off, washed with water and methanol to obtain a crude which was purified by column chromatography (silica gel (50 g) employing 1-20% methanol in dichloromethane as eluents, to obtain 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 19%). The compound 2-(4-hydroxy-3,5-dimethyl-phenyl)-6-nitro-3H-quinazolin-4-one (0.220 g, 0.71 mmol) was hydrogenated in dimethyl formamide (20 mL) using palladium on activated carbon (0.076 g, 0.071 mmol) at room temperature for 14 h. The solvent was evaporated and the crude was purified by column chromatography (silica gel 25 g) employing 1-5% methanol in dichloromethane as eluents to obtain 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one (0.132 g). The compound 6-amino-2-(4-hydroxy-3,5-dimethyl-phenyl)-3H-quinazolin-4-one was dissolved in pyridine under nitrogen. Acetic anhydride was added at room temperature and stirred for 4 h. Pyridine was removed and the residue was dried. Methanol was added to the flask and a solution of potassium carbonate in water was added and stirred for 4 h. The solvent was removed, acidified with 1 N hydrochloric acid and the precipitated solid was filtered off and dried to obtain N-(2-(4-hydroxy-3,5-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl)acetamide (0.037 g, 17%). Selected data: MS (ES) m/z: 324.1; MP 336.5° C. (decomposed).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:10]([Si:17]1(C2C=CC=CC=2)[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:10]([Si@H:17]1[CH2:18][CH2:19][C@H:20]([C:23]([O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:24])[CH2:21][CH2:22]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Oc1ccc(F)c(F)c1
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: CCCCCCC[Si@H]1CC[C@H](C(=O)Oc2ccc(F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using 3,4-difluorophenol and 4-n-heptyl-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:14][C:15](=[O:19])[C:16](=O)[CH3:17])C>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[C:16]([CH3:17])[C:15]([OH:19])=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)=O
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: O
Product: CC(=NNc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension in water (150 ml) of 4-nitrophenylhydrazine (15 g, 23 mmol) and 2-oxo-propionic acid ethyl ester (12 g, 100 mmol) was left under stirring at room temperature for 6 hours. The obtained precipitate was filtered and washed to give the ethyl ester of the 2-[(4-nitrophenyl)-hydrazono]-propionic acid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([CH2:34][N:35]([CH3:40])[CH:36]2[CH2:39][O:38][CH2:37]2)[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:31][CH:32]([CH2:34][N:35]([CH3:40])[CH:36]5[CH2:37][O:38][CH2:39]5)[CH2:33]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN(CC1CNC1)C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(CN(C)C4COC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.2 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (78 mg, 0.2 mmol), (azetidin-3-ylmethyl)methyloxetan-3-yl-amine (47 mg, 0.3 mmol), and 4 Å molecular sieves (250 mg) in 1,2-dichloroethane (2 mL) was stirred at RT for 6 h. Sodium triacetoxyborohydride (85 mg, 0.4 mmol) was added and the resulting reaction mixture was stirred at RT under nitrogen atmosphere for 16 h. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The crude residue was loaded on an Isolute® SCX-2 cartridge (5 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 8:92) to afford 421 as an off-white foam (63 mg, 59%). LCMS (Method I): RT 2.11 min, [M+H]+ 532. 1H NMR (400 MHz, CDCl3): δ 7.97-7.96 (1 H, m), 7.72-7.71 (1 H, m), 7.23 (2 H, t, J=3.78 Hz), 4.61 (2 H, t, J=6.53 Hz), 4.53 (2 H, t, J=6.23 Hz), 4.32 (4 H, s), 3.82-3.81 (9 H, m), 3.51-3.50 (3 H, m), 3.32 (2 H, q, J=7.48 Hz), 3.03-2.89 (2 H, m), 2.68-2.57 (1 H, m), 2.40 (2 H, d, J=7.26 Hz), 2.04 (3 H, s), 1.41 (3 H, t, J=7.47 Hz)