Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)([O-:22])=[O:21]>C1COCC1.CCCCCC>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:13]2=[O:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: O=C1CCCCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1CCCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of diisopropylamine (342 μL, 2.45 mmol, 1.2 equiv) in 5 mL of anhydrous THF at 0° C. was added n-butyllithium (1.63 mL of a 1.6M solution in hexane), and the mixture was stirred at this temperature for 15 minutes before cooling to -78 ° C. Cyclohexanone (221 μL, 2.04 mmol, 1.0 equiv) in 2 mL of anhydrous THF was then added dropwise, stirred at -78 ° C. for 1 h followed by p-nitrobenzyl bromide (880 me, 4.08 mmol, 2.00 equiv) in 2 mL of THF, added dropwise to the resulting enolate. The reaction mixture was stirred at room temperature for 17 h, and then quenched with aqueous saturated NH4C1, and extracted with ether. The organic phase was dried over Na2SO4 and concentrated under diminished pressure to a solid residue that was purified by flash chromatography (silica gel, hexanes/ethyl acetate, 85:15), which afforded 300 mg (64%) of the desired ketone as a yellow solid. 1H NMR (400MHz, CDCl3) δ1.41 (m, 1H), 1.66 (m, 2H), 1.88 (m, 1H), 2.08 (m, 2H), 2.33 (m,, 1H), 2.45 (m, 1H), 2.57 (m, 1H, 2-H), 2.59 and 3.29 (d of ABq, 2H, benzylic-CH2), 7.34 (d, 2H, Ar--H), 8.12 ppm (d, 2H, Ar--H). [Compound 44 is hereinafter also referred to as COMPOUND "G" or 1201381]
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([O:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]#[N:27])[CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:26]([C:22]2[CH:21]=[C:20]([NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:25]=[CH:24][N:23]=2)=[N:27]1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 45.6 %

Procedure:
A mixture of methyl thiosalicylate (0.61 g, 3.7 mmol), 4-tert-butoxycarbonylamino-2-cyanopyridine (0.80 g, 3.7 mmol), triethylamine (0.80 ml, 5.7 mmol) and toluene (2.0 ml) was refluxed for 9 hrs. After cooling, the precipitated crystals were collected by filtration and dried to give the titled compound (0.60 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:32]3[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2ccc(C(C)(C)C)cc2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 51.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 4-tert-butyl phenol (40 mg, 0.26 mmol) to give the title compound (33 mg, 51%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:26])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])[CH2:3][CH2:2]1.[BH3-]C#N.[Na+].[CH:31]([C:34]1[C:39]([CH:40]=O)=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:37]([CH2:49][O:50][CH3:51])=[C:36]([CH:52]([CH3:54])[CH3:53])[N:35]=1)([CH3:33])[CH3:32].O>CO>[CH:31]([C:34]1[C:39]([CH2:40][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:26])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:17])[CH2:3][CH2:2]2)=[C:38]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[C:37]([CH2:49][O:50][CH3:51])=[C:36]([CH:52]([CH3:54])[CH3:53])[N:35]=1)([CH3:32])[CH3:33]
Reactant: COCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Reactant: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCNC(=O)Nc1ccccc1C(=O)NC1CCN(Cc2c(C(C)C)nc(C(C)C)c(COC)c2-c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
Step 2): N-(Piperidin-4-yl)-2-(N'-n-heptylureido)benzamide (0.96 g, 2.7 mmol) and NaBH3CN (0.17 g, 2.7 mmol) were added into a solution of 2.6-diisopropyl-4-(4-fluorophenyl)-3-formyl-5-methoxymethylpyridine (0.9 g, 2.7 mmol) in MeOH (30 ml). The mixture was stirred at room temperature for 72 hours, and then water was added at 0° C. extracted with dichloromethane, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (10 to 50% ethyl acetate in hexane) to give N-[1-[2,6-diisopropyl-4-(4-fluorophenyl)-5-(methoxymethyl)pyridin-3-yl]methylpiperidin-4-yl]-2-(N'-n-heptylureido)benzamide (0.65 g, 35.7%): mp 123° C.: 1NMR (CDCl3)ppm: 0.88 (3H, t), 1.17-1.46 (22H, m), 1.49-1.66 (2H, m), 1.80-2.00 (4H, m), 2.57 (2H, d), 3.09-3.53 (9H, m), 3.68-3.89 (1H, m), 3.49 (2H, s), 4.53 (1H, t), 5.98 (1H, d), 6.93 (1H, t), 7.05-7.24 (4H, m), 7.33-7.48 (2H, m), 8.41 (1H, d), 10.30 (1H, s).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[I-].[Mg+2].[I-].C(OCC)C>C(OCCCC)(=O)C>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: CCCCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 120 °C
Yield: 94.5 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.69 g, 18.14 mmol, 1.05 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in butyl acetate (70 mL) respectively, heated to 120° C. Then a solution of magnesium iodide in diethyl ether (0.3 mmol, 0.3 mL) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.88 g yield: 94.50%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]1[N:22]([C:23](=[O:33])[C:24]2[C:29]([F:30])=[CH:28][C:27]([F:31])=[CH:26][C:25]=2[F:32])[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[S:19]1)=[O:4].[Li+].[OH-].Cl>C1COCC1.CO.O>[F:40][C:37]1[CH:36]=[CH:35][C:34]([C:20]2[S:19][CH:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH2:10][C:6]3[O:7][CH:8]=[CH:9][C:5]=3[C:3]([OH:4])=[O:2])[N:22]([C:23](=[O:33])[C:24]3[C:29]([F:30])=[CH:28][C:27]([F:31])=[CH:26][C:25]=3[F:32])[N:21]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccoc1COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccoc1COc1ccccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 12 h

Procedure:
To a solution of 2-{2-[5(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylic acid methyl ester (0.49 mmol) in THF/MeOH/H2O (3:2:1), is added LiOH (3 N) (4.9 mmol). After stirring for 12 hours, the reaction is acidified with HCl (1 N) and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered, and concentrated. The residue is purified using preparative LC/MS to give 2-{2-[5(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-furan-3-carboxylic acid as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.26-7.23 (m, 3H), 7.20 (d, J=1.9, 1H), 7.10-7.05 (m, 1H), 7.03-6.99 (m, 1H), 6.86 (d, J=8.1, 1H), 6.78-6.74 (m, 3H), 6.55 (d, J=1.9, 1H), 6.55-6.50 (m, 2H), 5.38-5.21 (m, 2H); LC/MS (ES+): 557.1 (M+1)+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=C)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:26].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=[O:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(c1)OCCc1sc(-c3ncnn3C(C)C)nc1-2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C=O)ccc1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-vinyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.200 g, 0.591 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was added osmium tetraoxide (0.0473 mmol, 4% wt in water, 0.3 ml) followed by sodium metaperiodate (0.253 g, 0.00118 mol) slowly. The mixture was stirred at room temperature for 6 hours. The reaction was quenched with saturated sodium thiosulfate, then diluted with ethyl acetate and extracted 3 times with ethyl acetate. The organic phases were combined, dried with Na2SO4 and concentrated to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carbaldehyde. MS(ESI+) 341.1
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:17]([CH3:41])/[CH:18]=[CH:19]/[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:10][C:11](N(OC)C)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:42]([O:49][C@H:50]([C@@H:55]([CH3:67])[CH2:56][CH2:57][CH2:58][O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[C@@H:51]([CH3:54])[C:52]#[CH:53])([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43].[Li]CCCC.CCOC(C)=O.CCCCCC>C(Cl)(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH2:10][C:11](=[O:12])[C:53]#[C:52][C@H:51]([CH3:54])[C@H:50]([O:49][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:55]([CH3:67])[CH2:56][CH2:57][CH2:58][O:59][Si:60]([C:63]([CH3:65])([CH3:64])[CH3:66])([CH3:62])[CH3:61])[C@H:17]([CH3:41])[CH:18]=[CH:19][CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)/C=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#C[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@H](C=CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@H](CC(=O)C#C[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCCO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C

Procedure:
The procedure for 32 was used with 15 (1.31 g, 2.28 μmol), 64 (1.20 g, 3.01 mmol) and n-BuLi (1.88 mL, 1.20 mmol) to yield the ynone (1.79 g, 86%) after flash column chromatography (EtOAc/hexane 1:19) as a colorless oil: IR (CHCl3) 2929, 2856, 2209, 1675, 1471, 1462, 1385, 1254, 1093, 836, 775, 705 cm−1; 1H NMR (300 MHz, CDCl3) ε7.56-7.53 (m, 6H), 7.38-7.25 (m, 9H), 5.79 (dd, J=15.6, 7.2 Hz, 1H), 5.67 (dt, J=15.6, 4.9 Hz, 1H), 4.36 (m, 1H), 3.69-3.66 (m, 4H), 3.63 (t, J=4.1 Hz, 1H), 2.86 (m, 1H), 2.72 (m, 1H), 2.45 (m, 1H), 1.76 (m, 1H), 1.67-1.51 (m, 3H), 1.34 (m, 1H), 1.29 (d, J=7.1 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H), 1.00-0.97 (m, 28H), 0.18-0.13 (m, 18H); 13C NMR (75 MHz, CDCl3) δ 186.0, 144.2, 132.8, 128.6, 127.9, 127.7, 126.8, 96.7, 86.8, 83.1, 77.8, 71.6, 64.8, 63.2, 50.1, 42.3, 37.2, 31.7, 30.9, 30.2, 26.0, 25.9, 25.8, 18.3, 18.2, 18.0, 17.3, 15.4, 14.8, −3.9, −4.1, −4.6, −4.7, −5.3; LRMS (ESI) 933.6 [M+Na]+, 795.5, 665.2, 496.1, 413.2, 243. 1; HRMS (ESI) calcd for C55H86O5Si3Na 933.5681 [M+Na]+, found 933.5692; [α]20D−9.5 (c 0.55, CHCl3).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[C:6]([CH3:12])[CH:5]=1.CC[O:15][C:16]([CH2:18][CH:19]1[C:24](=O)[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:17]>>[Cl:1][C:9]1[CH:8]=[CH:7][C:6]([CH2:12][N:10]2[C:20]3[CH:19]([CH2:18][C:16]([OH:15])=[O:17])[CH2:24][CH2:23][CH2:22][C:21]=3[C:8]3[C:7]2=[C:6]([CH3:12])[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=3)=[CH:5][CH:4]=1
Reactant: Cl
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: COc1ccc(NN)c(C)c1
Product: COc1cc(C)c2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 34, but using 1-(4-methoxy-2-methylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared. m.p. 188°-188.5° C.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18].O>>[OH:1][CH:2]([CH2:16][NH:20][CH:17]([CH3:19])[CH3:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: COC(=O)Cc1ccc(OCC2CO2)cc1
Solvent: O
Product: COC(=O)Cc1ccc(OCC(O)CNC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-[(2,3-epoxy)propoxy]phenylacetate (2.00 g, 9.00 mmol), isopropylamine (23 ml, 0.27 mol) and water (1.35 ml, 74.7 mmol) was stirred at room temperature overnight. The reaction mixture was concentrated (rotavapor) and the oily residue was dissolved in chloroform and dried (Na2SO4). Filtration and concentration gave quantitative yield of a yellow oil that was used in the next step without further purification. The structure was verified by 1H and 13C MR analysis.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=1.[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:32][NH2:33])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].O>C1(C)C=CC=CC=1>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][CH2:32][NH:33][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][CH3:21])[N:12]=[CH:11][N:10]=2)=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1ccc(CCN)cc1
Reactant: CCOC(=O)c1c(Cl)ncnc1CC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)OCC)cc1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Triethylamine (1.89 g, 18.68 mmol) was added to a solution of ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (2.00 g, 9.32 mmol) in toluene (50 ml). The mixture was stirred at room temperature. Then, 4-butoxyphenethylamine (2.16 g, 11.18 mmol) was added. After stirring for 18 hours, water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl acetate and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (2.00 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)[CH:15]=[CH:16][CH:17]=1)(=[O:10])=[O:9].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[O-]S(C(F)(F)F)(=O)=O.[Ga+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:13]([C:25]([O:27][CH3:28])=[O:26])=[C:14]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[C:15]2=[CH:16][CH:17]=1)(=[O:9])=[O:10]
Reactant: COC(=O)c1c(CCCCC(=O)O)cccc1NS(=O)(=O)c1ccccc1F
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ga+3]
Solvent: CC(Cl)Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CCCCC2=O
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
A solution of Example 510E (3.74 g, 9.13 mmol) in dichloroethane (183 mL) was treated with trifluoroacetic anhydride (2.58 mL, 18.3 mmol) and gallium (III) triflate (0.944 g, 1.83 mmol), stirred at 90° C. for 1.5 hours, and cooled to room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate (200 mL), and the aqueous layer was extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography (7:3 hexanes/ethyl acetate) to provide the desired product (2.73 g, 76%). MS (ESI(+)) m/e 392 (M+H)+, 409 (M+NH4)+, 414 (M+Na)+; MS (ESI(−)) m/e 390 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 10.46 (br s, 1H), 7.74 (m, 2H), 7.52 (d, 1H), 7.43 (dd, 1H), 7.35 (td, 1H), 7.25 (d, 1H), 3.70 (s, 3H), 2.67 (t, 2H), 2.61 (m, 2H), 1.72 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([C:19]#[N:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:21]1([C:16](=[O:18])[CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][C:11]=2[C:19]#[N:20])[CH2:24][CH2:23][CH2:22]1
Reactant: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(OCc2ccccc2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[4-(benzyloxy)-2-cyanophenyl]acetic acid (0.40 g, 1.50 mmol) was dissolved in DMF (5 ml) and azetidine (0.128 g, 2.25 mmol), DIEA (0.78 ml, 4.49 mmol), and HATU (1.14 g, 2.99 mmol) added. The mixture was stirred at RT for 1 hr. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 307 (M+H)+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C)C=O.[N+:26]([O-:34])([O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)=[O:27]>ClCCl>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:18]([O:20][CH2:32][CH2:31][CH2:30][CH2:29][O:28][N+:26]([O-:34])=[O:27])=[O:19])=[O:2])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=[N+]([O-])OCCCCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(O)cc1)C(=O)OCCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
To a solution of Boc-(L)-tyrosine (5.0 g, 17.77 mmol) in N,N-dimethylformamide (40 ml) cesium carbonate (5.79 g, 17.77 mmol) was added. The reaction was cooled at 0° C. and a solution of 4-bromobutyl nitrate (17.77 mmol) in dichloromethane (20% w/w, 17.06 g) was added drop wise. The reaction was stirred at 0° C. for 20 minutes and then at room temperature for 22 hours. The mixture was poured into a 5% aqueous NaH2PO4 solution and extracted with diethyl ether (40×4 ml), the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 65+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 9/1 (500 ml), to n-hexane/ethyl acetate 1/1 during 4000 ml, n-hexane/ethyl acetate 1/1 (1000 ml)). The product (3.91 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[C:36]([O:41][CH3:42])[CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[C:36]([O:41][CH3:42])[CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: COc1cccc2c1CCC2N
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NC2CCc3c(OC)cccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-4-methoxy-indane
Reaction SMILES: CSCS(C)=O.[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][C:16]=1[CH:17]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.[C:28]([O:31][CH2:32]C)(=[O:30])C>[OH-].[Na+]>[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][C:16]=1[CH2:17][C:28]([O:31][CH3:32])=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(C)=O
Reactant: CCOc1ccc(OCc2ccccc2)c(C=O)c1
Agent: CSCS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(OCc2ccccc2)c(CC(=O)OC)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of methyl methylthiomethyl sulfoxide (1.94 g) and finely triturated sodium hydroxide (0.01 g) was stirred at 70° C. for 30 min. 2-Benzyloxy-5-ethoxybenzaldehyde (2.0 g) and methanol (10 mL) were added to the reaction mixture, and the mixture was further heated under reflux for 24 hrs. To the reaction mixture was added ethyl acetate, and the organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. A mixture of the obtained residue and 10% hydrogen chloride-methanol (100 mL) was heated under reflux for 24 hrs. The reaction mixture was concentrated, and then ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-(2-benzyloxy-5-ethoxyphenyl)acetate as a yellow oil (1.60 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16](Br)[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>C(OCCOCCO)C.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([N:19]=[N+:20]=[N-:21])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)N1CCc2cc(CC(C)Br)cc(C#N)c21
Agent: [Na+]
Solvent: CCOCCOCCO
Solvent: O
Product: CC(=O)N1CCc2cc(CC(C)N=[N+]=[N-])cc(C#N)c21
Yield: 88.5 %

Procedure:
1-Acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (1.42 g) and sodium azide (0.30 g) were dissolved in diethylene glycol monoethyl ether (1.4 ml) and water (3.2 ml), and the mixture was stirred at 90° C. for 9.5 hours.-To the reaction mixture was added water, and the mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of ethyl acetate and hexane (3/1) as eluent to give 1.10 g of 1-acetyl-5-(2-azidopropyl)indoline-7-carbonitrile as an oil.