Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:64]([N:66]1[CH2:71][CH2:70][N:69]([CH:72]2[CH2:77][CH2:76][CH:75]([NH2:78])[CH2:74][CH2:73]2)[CH2:68][CH2:67]1)[CH3:65]>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][C@H:75]5[CH2:74][CH2:73][C@H:72]([N:69]6[CH2:68][CH2:67][N:66]([CH2:64][CH3:65])[CH2:71][CH2:70]6)[CH2:77][CH2:76]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN1CCN(C2CCC(N)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCN([C@H]2CC[C@H](NC(=O)c3ccc(Nc4ncc5c(n4)N(C4CCCC4)CC4(CC4)C(=O)N5C)c(OC)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1.5 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-ethylpiperazin-1-yl)cyclohexanamine (Intermediate 13) as the trihydrochloride salt (58 mg, 0.18 mmol, 1.2 eq) and DIPEA (78 μL, 0.45 mmol, 3 eq). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-ethylpiperazin-1-yl)cyclohexyl)-3-methoxybenzamide (colourless glass, 26 mg, 28%).
Reaction SMILES: [CH2:1]([C:4]1[C:17]([OH:18])=[C:16]([CH3:19])[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:20])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:21])[C:6]=2[CH:5]=1)[CH:2]=C.ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl.[C:37](=[O:40])([O-])[O-:38].[K+].[K+]>O>[F:20][C:9]1[C:8]2[C:7](=[O:21])[C:6]3[CH:5]=[C:4]4[CH2:1][CH:2]([C:37]([OH:38])=[O:40])[O:18][C:17]4=[C:16]([CH3:19])[C:15]=3[O:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: C=CCc1cc2c(=O)c3c(F)cccc3oc2c(C)c1O
Reactant: O=C([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1c2c(cc3c(=O)c4c(F)cccc4oc13)CC(C(=O)O)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.3 %

Procedure:
A mixture of 2-allyl-8-fluoro-3-hydroxy-4-methyl-9-oxo-9H-xanthene (9.0 g), m-chloroperbenzoic acid (8.0 g) and chloroform (1,000 ml) was stirred at room temperature for 5 hours and left to stand overnight. To the mixture, potassium carbonate (20 g) and water (500 ml) were added and the resulting mixture was extracted with chloroform. The chloroform layer was dried and the solvent was distilled off. The residue was dissolved in acetone (1,000 ml) and to the stirred solution, a mixture of chromium trioxide (21 g), water (120 ml) and concentrated sulfuric acid (36 g) was added dropwise at room temperature. After leaving it to stand overnight, the mixture was filtered and the filtrate was evaporated to dryness under vacuum. After addition of water, the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 5.0 g of 6-fluoro-2,3-dihydro-11-methyl-5-oxo-5H-furo[3,2-b]xanthene-2-carboxylic acid. m.p. 292°-295° C. This compound produced a mass spectrum having a molecular ion peak at m/e 314.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:50][CH2:49][CH2:48][N:47]([C:51](=[N:53][C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[CH:60][CH:59]=4)=[O:55])[CH3:52])[CH2:46][CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:50][CH2:49][CH2:48][N:47]([C:51](=[N:53][C:54]([O:56][CH2:57][C:58]3[CH:59]=[CH:60][C:61]([N+:64]([O-:66])=[O:65])=[CH:62][CH:63]=3)=[O:55])[CH3:52])[CH2:46][CH2:45]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
2.1 ml of trifluoroacetic acid and 67 μl of trifluoromethanesulfonic acid were added to a solution of 285 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)homopiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (ii) above] in 414 μl of anisole, and the resulting mixture was stirred for 1 hour, whilst ice-cooling. At the end of this time, the reaction mixture was worked up by the same procedure as described in Preparation 1(iv), to give 296 mg of the title compound, as a powder.
Reaction SMILES: Cl[C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][OH:10])[N:7]=1.C(N(CC)CC)C.Cl.[CH3:29][O:30][CH2:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:3]3[C:2]([N:35]4[CH2:36][CH2:37][CH:32]([CH2:31][O:30][CH3:29])[CH2:33][CH2:34]4)=[N:7][C:6]([CH2:8][CH2:9][OH:10])=[N:5][C:4]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: COCC1CCNCC1
Reactant: OCCc1nc(Cl)c2c(-c3ccc(F)cc3)csc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCC1CCN(c2nc(CCO)nc3scc(-c4ccc(F)cc4)c23)CC1
Temperature: 55 °C
Yield: 89.7 %

Procedure:
2-[4-Chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]ethanol (150 mg, 0.0005 mol), triethylamine (0.214 mL, 0.00154 mol) and 4-(methoxymethyl)piperidine hydrochloride (0.091 g, 0.00055 mol) were dissolved in ethanol (5 mL) and warmed to 55° C. for 2 hrs. The reaction was then poured over ice and extracted with DCM. The organics were dried by passage through a PTFE frit and concentrated in vacuo to give 2-[5-(4-fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-yl]ethanol (180 mg). LCMS RT=4.33 min. M+1=402.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCC>[F:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: CCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1F
Temperature: 145 °C
Reaction time: 28 h
Yield: 89.2 %

Procedure:
Potassium fluoride (244 g; 4.2 moles) and tetradecyltrimethylammonium bromide (67.2 g; 0.2 moles) were added to molten 2-chloronitrobenzene (630 g; 4.0 moles). After stirring at 145° C. for 28 hours and a similar work-up to Example 1, 2-fluoronitrobenzene was obtained in 89.2% yield, together with 4.1% recovered 2-chloronitrobenzene. Corrosion tests carried out during this reaction indicated negligible attack on stainless steel or glass enamel test pieces and very low corrosion rate on mild steel test pieces. In comparison when this reaction was carried out at 240° C. severe corrosion of the test pieces occurred.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].Cl.CC1C=C(C=CC=1)CC1(CO)CCNCC1.Cl.[CH3:36][C:37]1[CH:51]=[CH:50][CH:49]=[CH:48][C:38]=1[CH2:39][C:40]1([CH2:46][OH:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[OH:47][CH2:46][C:40]1([CH2:39][C:38]2[CH:48]=[CH:49][CH:50]=[CH:51][C:37]=2[CH3:36])[CH2:45][CH2:44][N:43]([C:13]([C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:17][CH:16]=3)[CH:9]=[N:10][CH:11]=2)=[O:15])[CH2:42][CH2:41]1
Reactant: N#Cc1ccc(Cn2cncc2C(=O)O)cc1
Reactant: Cc1ccccc1CC1(CO)CCNCC1
Agent: Cc1cccc(CC2(CO)CCNCC2)c1
Agent: Cl
Product: Cc1ccccc1CC1(CO)CCN(C(=O)c2cncn2Cc2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared as white solid according to the procedure described in Example 38, Step A-B substituting 1-(4-cyanobenzyl)imidazole-5-acetic acid·lithium chloride with 1-(4-cyanobenzyl)imidazole-5-carboxylic acid and 4-(3-methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt with 4-(2-methylbenzyl)-4-hydroxymethylpiperidine hydrochloride salt (Example 35) in Step B. The crude product was purified with column chromatography on silica gel eluting with 2-5% methanol in chloroform.
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:22][C:23](=O)[CH2:24][C:25](=O)[CH3:26]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH3:26])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:4]=2)[N:2]=1
Reactant: Cn1cnc2c(Nc3ccc(C#N)cc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(C#N)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from 4-(2-hydrazino-9-methyl-9H-purin-6-ylamino)-benzonitrile and 2,4-pentanedione.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:20]O>>[NH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH3:20])=[O:11])=[CH:5][CH:4]=1
Reactant: CO
Reactant: CC(C)(C(=O)O)c1ccc(N)nc1
Agent: Cl
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)(C)c1ccc(N)nc1
Temperature: 25 °C

Procedure:
A solution of 2-(6-aminopyridin-3-yl)-2-methylpropanoic acid hydrochloride (35.0 g, 0.162 mmol) and concentrated H2SO4 (5 mL) in MeOH (250 mL) was heated at reflux overnight. After cooling to ambient temperature, the reaction was quenched cautiously with saturated aqueous NaHCO3 and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organic phase separated and the aqueous phase re-extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue (31.6 g, 100%) was judged pure by a combination of TLC and 1H nmr analysis and was used without further purification in the subsequent reaction.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[CH2:14][CH2:13][C@@:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([OH:15])[C:11]([CH3:24])([CH3:23])[CH2:10]1)=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38].CS(C)=O>CCOC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@:12]2([OH:15])[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C@H:6]([NH:5][C:3](=[O:4])[CH2:2][O:34][C:35]3[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=3[C:37]([O:39][CH3:40])=[O:38])[CH:25]([CH3:27])[CH3:26])[CH2:10][C:11]2([CH3:23])[CH3:24])=[CH:17][CH:18]=1
Reactant: CC(C)[C@@H](NC(=O)CCl)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1OCC(=O)N[C@@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Yield: 40.5 %

Procedure:
2-Chloro-N-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)acetamide (35 mg, 0.084 mmol), potassium carbonate (35 mg, 0.253 mmol), methyl 2-hydroxybenzoate (13 mg, 0.084 mmol) and DMSO (3 mL) were mixed with stirring at 25° C. The reaction was stirred for 20 hours, diluted with EtOAc, and then rinsed 4 times with water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give an amber oil which was purified over silica gel in (3:1 to 1:1 hexanes/EtOAc to 100% EtOAc) to obtain methyl 2-(2-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethoxy)benzoate (18 mg, 0.034 mmol, 40% yield) as a white glass. MS found: (M+H)+=531.21.
Reaction SMILES: BrC[C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Ca+2]>O1CCOCC1.O>[CH3:13][C:10]1[CH:9]=[C:4]2[C:3]([CH2:8][O:7][C:5]2=[O:6])=[CH:12][CH:11]=1
Reactant: COC(=O)c1cc(C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2c(c1)C(=O)OC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.9 %

Procedure:
A heterogeneous, colorless solution of methyl 2-(bromomethyl)-5-methylbenzoate and regioisomer (27.2 mmol) and calcium carbonate (16.33 g, 163 mmol) in 1,4-dioxane (194 mL) and water (194 mL) was refluxed. After 5 hr, the reaction was cooled to room temperature. The insolubles were filtered, and the filtrate was concentrated in vacuo. The residue was extracted with CH2Cl2 (2×200 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give an oil which was purified by flash chromatography using an ISCO 220 g column eluting with 10-50% EtOAc/hexanes. Appropriate fractions were collected and concentrated in vacuo to give the desired product (1.205 g, 8.13 mmol, 29.9% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH:21]=O)=[CH:8][CH:7]=1.[CH:24]([NH2:26])=[O:25].[OH-].[Na+]>C(O)=O>[CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[C:9]([CH2:21][NH:26][CH:24]=[O:25])=[CH:8][CH:7]=1
Reactant: CN(C)CCNc1ccc(C=O)c2sc3ccccc3c(=O)c12
Reactant: NC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C)CCNc1ccc(CNC=O)c2sc3ccccc3c(=O)c12
Temperature: 170 °C

Procedure:
A mixture of 1-[[2-(dimethylamino)ethyl]amino]-9-oxothioxanthen-4-carboxaldehyde (4.75 g) , formamide (66.5 mL) and formic acid (7.6 mL) was heated at 170° C. for 4 hours. The mixture was poured into ice water (250 mL) , basified with 35% NaOH and extracted with chloroform. The organic layer was washed with water (2×), then brine (1×) and the solvent was dried over Na2SO4 and concentrated in vacuo to afford 6.2 g of N-[[1-[[2-(dimethylamino) ethyl]amino]-9-oxothioxanthen-4-yl ]methyl ]formamide.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22])[CH:2]=[CH2:3].I[CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:24][CH3:25])=[CH:7][C:6]=1[N:12]1[C:13](=[O:22])[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]1=[O:21])[CH:2]=[CH2:3]
Reactant: CCI
Reactant: C=CCOc1ccc(O)cc1N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(OCC)cc1N1C(=O)c2ccccc2C1=O

Procedure:
A mixture of Example 84A (0.63 g, 2.13 mmol), iodoethane (0.68 mL, 8.52 mmol) and K2CO3 (1.47 g, 10.65 mmol) in acetone (50 mL) were stirred, and refluxed for 3 hours, and cooled. The solution was filtered, and dried with silica gel powder (10 g). 15% Ethyl acetate in hexanes (1 L) and 20% ethyl acetate in hexanes (1 L) were used to run flash chromatography. The title compound was obtained (320 mg, 46%). MS (DCI) m/z 324.07 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (t, J=7.12 Hz, 3 H) 4.00 (q, J=7.12 Hz, 2 H) 4.46–4.55 (m, 2 H) 5.07–5.30 (m, 2 H) 5.88 (m, 1 H) 6.82 (dd, J=2.54, 0.85 Hz, 1 H) 6.93–6.96 (m, 2 H) 7.75–7.80 (m, 2 H) 7.94 (dd, J=5.42, 3.05 Hz, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([CH:18]=[CH2:19])[CH:15]=[C:14]([C:20]#[N:21])[CH:13]=2)[O:9][N:8]=1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.B1([O-])O[O:43]1.O.O.O.O.[Na+]>ClCCl.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][OH:43])[CH:15]=[C:14]([C:20]#[N:21])[CH:13]=2)[O:9][N:8]=1
Reactant: [O-]B1OO1
Reactant: C=Cc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: N#Cc1cc(CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 3.9 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-vinylphenyl)-1,2,4-oxadiazole (83 mg, 0.30 mmol) in dichloromethane (2 mL) was treated with 9-BBN dimer (40 mg, 0.16 mmol) and the reaction mixture stirred at room temperature for 4 hours. Sodium perborate tetrahydrate (157 mg, 1.02 mmol) and water (1 mL) were added and the resulting biphasic mixture was stirred vigorously for 18 hours. The mixture was diluted with dichloromethane and water and the organic layer dried by filtration through an EX-TUBE. Silica gel chromatography using a gradient of 20% to 75% ethyl acetate in hexane, followed by trituration in 10% ethyl acetate in hexane afforded 3.4 mg (3.7%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-hydroxyethyl)phenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), δ (ppm): □□ 8.85 (d, 1H), 8.43 (s, 2H), 8.22 (d, 1H), 7.90 (t, 1H), 7.80 (s, 1H), 7.48 (m, 1H), 3.99 (m, 2H), 3.02 (t, 2H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[NH:7]([C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]2[C:26]3[C:21](=[C:22]([C:27]([NH2:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:30][CH:31]=1)=[O:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: NC(=O)c1cccc2c(NCc3ccc(N)cc3)ncnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1cccc2c(NCc3ccc(NC(=O)Nc4ccccc4)cc3)ncnc12
Reaction time: 8 h
Yield: 27 %

Procedure:
Phenyl isocyanate (240 μL, 0.5 M in anhydrous DCM, 0.11 mmol, 1.1 equiv.) was added to a solution of 4-[(4-aminobenzyl)amino]quinazoline-8-carboxamide (32 mg, 0.1 mmol, 1.0 equiv.) and triethylamine (40 μL, 0.3 mmol, 3.0 equiv.) in anhydrous DCM (2 mL). The resulting mixture was stirred at it overnight. The title compound was obtained by pre-HPLC in 27% yield. Mass: M+H+: 413.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[C:12]([N+:21]([O-:23])=[O:22])=[CH:13][C:14]2[O:18][C:17](=[O:19])[NH:16][C:15]=2[CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24]([C:29]1[CH:43]=[C:42]([C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:30]=1[O:31][C:32](=[O:39])[CH:33](Cl)[CH2:34][CH2:35][CH2:36][CH3:37])([CH2:27][CH3:28])([CH3:26])[CH3:25]>>[C:24]([C:29]1[CH:43]=[C:42]([C:44]([CH2:47][CH3:48])([CH3:45])[CH3:46])[CH:41]=[CH:40][C:30]=1[O:31][C:32](=[O:39])[CH:33]([N:16]1[C:15]2[CH:20]=[C:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:12]([N+:21]([O-:23])=[O:22])=[CH:13][C:14]=2[O:18][C:17]1=[O:19])[CH2:34][CH2:35][CH2:36][CH3:37])([CH2:27][CH3:28])([CH3:25])[CH3:26]
Reactant: CCCCC(Cl)C(=O)Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC
Reactant: O=c1[nH]c2cc(OCc3ccccc3)c([N+](=O)[O-])cc2o1
Agent: [H-]
Agent: [Na+]
Product: CCCCC(C(=O)Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)n1c(=O)oc2cc([N+](=O)[O-])c(OCc3ccccc3)cc21
Yield: 72.8 %

Procedure:
60% sodium hydride in oil dispersion (3 g, 0.075 mole) was added to the benzoxazolone ((d), 18.12 g, 0.063 mole) and α-(2,4-ditert.-pentylphenoxy)-hexanoylchloride (23.23 g, 0.063 mole) in dry refluxing toluene (400 ml) and the resulting solution was refluxed for further 2 hours. Water (100 ml) was added and azeotropically distilled. The organic solution was filtered and evaporated to dryness under vacuum. The oily residue was purified by column chromatography on silica gel using toluene as eluant. The obtained yellow oil was crystallized from methanol (150 ml) to give the acylated benzoxazolone ((e), 28.3 g, 72.5%) as white prisms. The product structure was confirmed by NMR and IR spectra.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[OH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[OH:36])=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: OB(O)c1ccccc1O
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3O)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 2-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (45 mg, yield 93%).
Reaction SMILES: B(F)(F)F.[N:5]1([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:7][C@H:6]1[C:8]([O:10][CH3:11])=[O:9].[CH:22]([OH:25])([CH3:24])[CH3:23].ClCCl>ClCCl>[CH2:15]([O:14][C:12]([NH:5][C@H:6]([C:8]([O:10][CH3:11])=[O:9])[CH2:7][O:25][CH:22]([CH3:24])[CH3:23])=[O:13])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H]1CN1C(=O)OCc1ccccc1
Reactant: CC(C)O
Agent: FB(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](COC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
16 syringe drops of boron trifluoride diethyletherate (catalyst) was added to a stirred solution of 1-benzyl 2-methyl (2S)-aziridine-1,2-dicarboxylate (0.50 g, 2.1 mmol) in isopropanol/dichloromethane (30 ml, 1:2) at room temperature. The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (20 ml), washed with a saturated aqueous sodium bicarbonate (5 ml), water (5 ml), dried over magnesium sulfate, filtered and concentrated to give methyl N-[(benzyloxy)carbonyl]-O-isopropyl-L-serinate as a clear colourless oil, (0.432 g, 68%); 1H NMR Spectrum: (CDCl3) 1.09 (m, 6H), 3.56 (m, 1H), 3.65 (m, 1H), 3.79 (s, 3H), 3.82 (m, 1H), 4.46 (m, 1H), 5.16 (s, 2H), 5.60 (d, 1H), 7.38 (m, 5H).