Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].N1CCCC1.[C:16]([OH:19])(=O)[CH3:17].[OH:20][CH2:21][C:22]1C=CO[C:23]=1[CH:24]=O>>[OH:20][CH2:21][C:22]1[O:19][C:16](/[CH:17]=[CH:6]/[C:4](=[O:5])[CH2:3][CH2:2][C:1]([O:8][CH2:9][CH3:10])=[O:7])=[CH:24][CH:23]=1
Reactant: O=Cc1occc1CO
Reactant: CC(=O)O
Reactant: CCOC(=O)CCC(C)=O
Solvent: C1CCNC1
Product: CCOC(=O)CCC(=O)/C=C/c1ccc(CO)o1
Yield: 429 %

Procedure:
11.3 mL of ethyl levulinate (79.2 mmol) was placed in a ground glass single necked, 24/40, round bottom flask and stirring was begun. This was then chilled with an ice bath. In air, the pyrrolidine (1.25 mL, 15.8 mmol) and acetic acid (0.91 mL, 15.8 mmol) was then added. Hydroxymethyl furfural (HMF) (10.01 g, 79.2 mmol) was then added and solution darkened. The cooling bath was then removed and the solution was stirred at ambient temperature until the reaction was complete (by 1H and 13C NMR). The reaction was then purified by silica gel chromatography (using an ethyl acetate/hexane gradient). 17.1 g of product was obtained (85%). δH(CDCl3) 1.21 (t, J=7 Hz, 3H), 2.60 (t, J=6.6 Hz, 2H), 2.86 (t, J=6.6 Hz, 2H), 4.09 (q, J=7 Hz, 2H), 4.56 (s, 2H), 6.19 (m, 1H), 6.56 (m, 2H), 7.25 (m, 1H). δ13C (CDCl3) 197.6, 172.6, 157.1, 150.0, 128.6, 120.0, 116.7, 109.8, 60.3, 56.8, 35.1, 27.8, 13.6.
Reaction SMILES: N#N.C([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[C:8]=1C(N)=O)CCC.[CH2:19]([C:23]1C=CN=C(C(N)=O)C=1C(N)=O)[CH2:20][CH2:21]C.C[N:36](C)[CH:37]=[O:38].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4]>O>[CH2:23]([N:15]1[C:13](=[O:14])[C:9]2[N:10]=[CH:11][CH:12]=[CH:7][C:8]=2[NH:36][C:37]1=[O:38])[CH2:19][CH2:20][CH3:21]
Reactant: CN(C)C=O
Reactant: CCCCc1ccnc(C(N)=O)c1C(N)=O
Agent: CC(=O)[O-]
Agent: N#N
Agent: [Pb+4]
Solvent: O
Product: CCCCn1c(=O)[nH]c2cccnc2c1=O
Reaction time: 2 h

Procedure:
A 100 ml. flask was charged with 9.0 g. of a mixture of N2 -n-butyl-2,3-pyridine-dicarboxamide and N3 -n-butyl-2,3-pyridine-dicarboxamide suspended in 70 g. dimethylformamide. An 18.0 g. portion of lead tetra-acetate was added, and the reaction mixture stirred at 60° for 2 hours. The reaction mixture was poured into 200 ml. water. The precipitate was filtered from the water, recrystallized from dioxane, and dried at 100°, for about 1 hour. The final yield of 3-n-butyl-pyrido[3,2-d] and 3-n-butyl-pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione amounted to 8.4 g., melting point 200°-210°, and represented 93 percent of theory based on the dicarboxamide starting material. The structure was determined by nuclear magnetic resonance spectroscopy to consist of 78 percent of the [3,2-d]isomer and 22 percent of the [2,3-d]isomer.
Reaction SMILES: [CH2:1]([N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:19]([Br:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(O)CC>[Br-:27].[CH2:1]([N:13]1[CH:17]=[CH:16][N:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]1[CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCCCCCn1ccnc1C
Solvent: CCCO
Product: CCCCCCCCCCCCN1C=CN(CCCCCCCC)C1C
Product: [Br-]
Temperature: 100 °C

Procedure:
1 mole of 1-n-dodecyl-2-methylimidazole is dissolved in 500 ml of n-propanol and reacted with 1.1 moles of n-octyl bromide. The reaction mixture is heated at 100° C for 5 hours. Upon removing the solvent, the remaining residue is washed with ether, suctioned off, and dried.
Reaction SMILES: [F:1][B-](F)(F)F.N#[O+].[CH3:8][N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32][CH3:33])=[C:25](N)[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12]>ClCCl>[CH3:8][N:9]([C:14](=[O:36])[C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[C:26]([O:32][CH3:33])=[C:25]([F:1])[CH:24]=2)=[C:17]([Cl:35])[CH:16]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: F[B-](F)(F)F
Reactant: COc1c(N)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Agent: N#[O+]
Solvent: ClCCl
Product: COc1c(F)cc(Oc2c(Cl)cc(C(=O)N(C)CC(=O)O)cc2Cl)cc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of nitrosonium tetrafluoroborate (55 mg, 0.47 mmol) in dichloromethane (5 mL) was cooled to 0° C. and methyl-N-[3,5-dichloro-4-(3-amino-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine (189 mg, 0.43 mmol) was added. The reaction mixture was further stirred at 0° C. for 1 h. Dichloromethane was removed from nitrogen and o-xylene (10 mL) was added to the reaction mixture. The reaction mixture was refluxed for 1 h and the solvent was removed. The crude reaction mixture was purified on column (silica gel, n-heptane/ethyl acetate, gradient elution from 98:2 to 60:40) to give 50 mg (26%) of methyl-N-[3,5-dichloro-4-(3-fluro-5-isopropyl-4-methoxyphenoxy)benzoyl]glycine.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[CH3:13][O:14][C:15](=[O:27])[C:16]1[C:17](=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)[C:18]([O:20][CH3:21])=[O:19].Cl>CO>[CH3:13][O:14][C:15](=[O:27])[C:16]1[C:17](=[CH:22][C:23]([NH:26][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1C(=O)OC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(NCc2ccccc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 38.8 %

Procedure:
Benzaldehyde (1.64 ml, 16.2 mmol) and sodium cyanoborohydride (1.02 g, 16.2 mmol) were added to a solution of 4-aminophthalic acid dimethyl ester (1.7 g, 8.1 mmol) in dry methanol (50 ml) and pH was adjusted to 5.5-5 with 2 M hydrogen chloride in methanol (approx. 1 ml). The reaction mixture was stirred at room temperature for 20 hours and evaporated to dryness in vacuo. The residue was partitioned between methylene chloride (50 ml) and water (30 ml). pH was adjusted to 8 and the organic phase was isolated, dried over magnesium sulphate and evaporated to dryness in vacuo. The crude product was purified on silica gel (eluent: ether:heptane (1:1)) to give 4-benzylaminophthalic acid dimethyl ester as a golden oil (yield: 0.94 g, 39%). 1H—NMR (CDCl3) in ppm: γ 3.82 (3H,s); 3.88 (3H,s); 4.35 (2H,d); 4.66 (1H, broad d); 6.57 (1H,d.d.); 6.65 (1H,d); 7.23-7.35 (5H,m); 7.73 (1H,d).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:25][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>C1COCC1.N1C=CC=CC=1>[CH:26]1([C:32]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:25][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]5[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)C4CCCCC4)ncc3[nH]2)cc1
Reactant: O=C(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCC4)cc3)[nH]c2cn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.2 %

Procedure:
To a stirring solution of 10 (0.080 g, 0.24 mmol) in dry THF/Pyridine (10 ml/0.300 ml) cyclohexane carbonyl chloride (0.060 ml, 0.38 mmol) was added and stirred at room temperature for 4 h. The reaction mixture was quenched with water and stirred for 30 min. The yellow solid was filtered, dried, and purified through a bed of SiO2 gel. Elution with ethyl acetate afforded the desired product 11 as light yellow solid 0.055 g (51%). Mp. 235° C.; 1HNMR (DMSO-d; 500 MHz): δ 12.99 (1H, brs, NH), 10.27 (1H, brs, NH), 10.07 (1H, brs, NH), 8.61 (1H, brs), 8.27 (1H, brs), 8.07 (2H, d, J=8.0 Hz), 7.79 (2H, d, J=9.0 Hz); 2.52 (1H, m), 2.36 (1H, m), 1.83-1.17 (20H, m); EIMS m/z: 446.5 (M+1) 444.6 (M−1); Anal. (C26H31N5O2.0.91H2O) C, H, N
Reaction SMILES: [CH2:1]([N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:18]([NH2:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:11]1[C:12](=[O:17])[CH2:13][CH:14]([NH:28][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]1=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN
Reactant: CCCCCCCCCCN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCCCNC1CC(=O)N(CCCCCCCCCC)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of N-decyl maleimide (0.01 M) prepared as described in Example 11 above, decylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:4]=2[S:5][C:6]=1C(O)=O.[NH:15]1[CH2:21][CH2:20][CH2:19]N[CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN1CCCC1=O.C(OCC)(=O)C>[F:14][C:11]1[CH:12]=[CH:13][C:3]2[C:2]([N:1]3[CH2:19][CH2:20][CH2:21][NH:15][CH2:16][CH2:17]3)=[CH:6][S:5][C:4]=2[CH:10]=1
Reactant: C1CNCCNC1
Reactant: Nc1c(C(=O)O)sc2cc(F)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc2c(N3CCCNCC3)csc2c1
Temperature: 25 °C

Procedure:
Heat a solution of 3-amino-6-fluoro-benzo[b]thiophene-2-carboxylic acid (5.0 g, 24 mmol) in 1-methyl-2-pyrrolidinone (5 ml) to 100° C. for 2 h., and then, introduce a stream of nitrogen, to cool the solution to room temperature. Add homopiperazine (9.5 g, 95 mmol) and p-toluene sulfonic acid monohydrate (9.0 g, 47 mmol) and heat the mixture to 145° C. for 4 h. After that time, cool the reaction mixture to room temperature, dilute with ethyl acetate (30 mL) and wash with brine (3×15 mL). Separate the organic layer and dry over MgSO4. Evaporate the solvent and purify the crude product by column chromatography (SiO2, 100 g CH2Cl2/MeOH 9:2, then
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][C:7]=1[O:13][CH3:14].Cl.[C:16]([CH2:18][C:19]([NH2:21])=[O:20])#[N:17].O.O.O.C([O-])(=O)C.[Na+]>O.C(O)C>[Br:5][C:6]1[CH:12]=[CH:11][C:9]([N:10]=[N:1][CH:18]([C:16]#[N:17])[C:19]([NH2:21])=[O:20])=[CH:8][C:7]=1[O:13][CH3:14]
Reactant: N#CCC(N)=O
Reactant: O=N[O-]
Reactant: COc1cc(N)ccc1Br
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(N=NC(C#N)C(N)=O)ccc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
Sodium nitrite (8.54 g, 123.7 mmol) dissolved in water (100 ml) was added to an ice-cold suspension of 4-bromo-3-methoxyaniline (25 g, 123.7 mmol) in concentrated HCl (46 ml, 1514 mmol) and water (100 ml). After stirring for 10 minutes, 2-cyanoacetamide (10.40 g, 123.7 mmol) and sodium acetate trihydrate (84 g, 617 mmol) in water (1.8 L) was added and the reaction was allowed to stir overnight. The resulting solid was collected by filtration, washed with water, dried, giving an orange solid which was refluxed in 1.4 L of ethanol for 30 min. The mixture was cooled to room temperature, the solid was collected by filtration, washed with ethanol (100 ml×3), and dried to yield the title compound as a yellow solid (34.4 g, 94%). 1H NMR: 11.70 (s, 1H), 7.90 (s, 1H), 7.50 (m, 2H), 7.35 (s, 1H), 7.20 (d, 1H), 3.90 (s, 3H); m/z: 296.
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].C(N(CC)P1OCCO1)C.C[Si](C)(C)Cl.[C:34]([CH2:36][C:37](Cl)=[O:38])#[N:35]>C(Cl)Cl>[CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH:13][C:37]([CH2:36][C:34]#[N:35])=[O:38])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: N#CCC(=O)Cl
Agent: CCN(CC)P1OCCO1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CC#N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.72 g (10 mmol) of 7-aminocephalosporanic acid are suspended in 50 ml of dry methylene chloride. 1.5 ml (10 mmol) of 2-diethylamino-1,3,2-dioxaphospholane and 1.33 ml (10.5 mmol) of trimethylchlorosilane are added under nitrogen at room temperature. The reaction mixture is stirred for 16 hours at room temperature. After cooling to 0° C, a solution of 10 mmol of cyanoacetyl chloride in 6 ml of methylene chloride is added over 5 minutes.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[C:19](/[CH:22]=[CH:23]/[C:24]([O:26]C(C)(C)C)=[O:25])[CH:20]=[N:21][C:15]=2[NH:14][C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:40]>CCOCC>[ClH:40].[CH2:1]([O:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[C:19](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])[CH:20]=[N:21][C:15]=2[NH:14][C:13](=[O:31])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of (E)-7-(2-tert-butoxycarbonyl-vinyl)-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepine-4-carboxylic acid benzyl ester (0.31 g, 0.73 mmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL). After stirring at room temperature for 30 min, the clear tan solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl (10 mL of a 4.0 M solution in dioxane, 40 mmol) to give a cloudy mixture. The mixture was diluted with Et2O (200 mL) to give an off-white precipitate. After stirring for 15 min, the solid was isolated by filtration, washed with Et2O, and dried under vacuum for 1.5 h to give the title compound (0.27 g, 91%) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.50-10.47 (m, 1H), 8.49 (s, 1H), 8.09-8.15 (m, 1H), 7.53-7.59 (m, 1H), 7.15-7.33 (m, 5H), 6.51-6.65 (m, 1H), 5.42 (bs, 2H), 5.05-5.08 (m, 2H), 4.63 (s, 2H), 4.43 (s, 2H); MS (ESI) m/e 368 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1.[CH3:17][Mg]Br>C1COCC1>[OH:1][C:2]1([CH3:17])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[C@H:4]([CH:14]([CH3:16])[CH3:15])[CH2:3]1
Reactant: CC(C)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)[C@@H]1CC(C)(O)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (2S)-4-oxo-2-(propan-2-yl)pyrrolidine-1-carboxylate (500 mg, 2.2 mmol) in THF (10 mL) at −78° C. was added methylmagnesium bromide (1.65 mL, 4.95 mmol) dropwise. The reaction was stirred at −78° C. for 2 hours before warming to room temperature and stirring for an additional 2 hours. The reaction was quenched by slowly adding saturated aqueous ammonium chloride at 0° C. The mixture was acidified with HCl (1N) and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (0-80% ethylacete/hexanes, linear gradient) to afford tert-butyl (2S)-4-hydroxy-4-methyl-2-(propan-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:13](=[O:16])([O-])[O-:14].[K+].[K+].C(O[C:24](=O)[N:25]([CH2:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1)C)(C)(C)C>CC(N(C)C)=O.O>[C:3]([O:14][C:13]([CH2:24][NH:25][CH2:27][C:28]1[CH:29]=[C:30]([C:34]2[CH:39]=[CH:38][C:37]([O:40][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=1)=[O:16])([CH3:9])([CH3:4])[CH3:2]
Reactant: CCOC(=O)c1ccccc1F
Reactant: O=C([O-])[O-]
Reactant: CN(Cc1cccc(-c2ccc(O)cc2)c1)C(=O)OC(C)(C)C
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccccc1Oc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1
Yield: 104.9 %

Procedure:
2.15 g (12.8 mmol) of ethyl 2-fluorobenzoate and 1.9 g (14 mmol) of potassium carbonate are successively added to a solution of 4 g (12.8 mmol) of tert-butyl(4′-hydroxybiphenyl-3-ylmethyl)methylcarbamate in 45 ml of dimethylacetamide. The reaction medium is refluxed for 48 hours, cooled, diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under vacuum. The residue obtained is purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 3.1 g of ethyl 2-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yloxy}benzoate are obtained in the form of a colorless oil, in a yield of 53%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[C:22](Br)[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH3:28])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cncc(Br)c1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cncc(-c2ccccc2C)c1
Temperature: 80 °C

Procedure:
The procedure described in Example 1: step c was followed using {[4-(5-Bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.08 mmol), 2-methyl phenyl boronic acid (23 mg, 0.17 mmol), Pd(PPh3)4 (19 mg, 0.02 mmol), aqueous Na2CO3 (2M, 800 μL, 0.4 mmol), ethanol (800 μL) and toluene (1600 μL). The reaction was heated to 80° C. for 12 hours. The residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo resulted in a crude mixture of the product that was used without further purification or characterization.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([C:14]3[C:15]([NH2:26])=[N:16][CH:17]=[C:18]([C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=4)[N:19]=3)=[N:11][N:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>C(Cl)Cl>[NH2:26][C:15]1[N:16]=[CH:17][C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:36](=[O:39])[CH2:37][CH3:38])[CH2:24][CH:25]=2)=[N:19][C:14]=1[C:12]1[O:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][Br:1])=[CH:8][CH:7]=2)=[N:10][N:11]=1
Reactant: CCC(=O)Cl
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1nnc(-c2ccc(CBr)cc2)o1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CC=C(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Reaction time: 0.25 h
Yield: 60.9 %

Procedure:
To a solution of 3-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (34 mg, 0.07 mmol) in anhydrous DCM (500 μL) cooled in an ice water bath under an atmosphere of nitrogen was added DIEA (49 mg, 66 μL, 0.38 mmol) followed by the dropwise addition of a solution of propanoyl chloride (8 mg, 7 μL, 0.08 mmol) in DCM (0.2 mL). The reaction mixture was stirred for 15 minutes. The reaction mixture was diluted with DCM and washed three times with 1M aqueous HCl solution, twice with saturated aqueous NaHCO3 solution and then twice with a solution of brine. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to yield 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,6-dihydro-2H-pyridin-1-yl]propan-1-one (20 mg, 57%). LC/MS m/z 471.3 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:17]([N:19](CC)CC)[CH3:18].ClCC#N>CN1CCCC1=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:18][C:17]#[N:19])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CN1CCCC1=O
Product: N#CCN1CCN(c2cccc3c2OCCO3)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 1-(1,4-benzodioxan-5-yl)piperazin (11 g) and triethylamine (7 ml) in N-methyl-2-pyrrolidinone was treated dropwise with chloroacetonitrile (4.5 g). After stirring for 2 h at 100° C. the mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product, 1-(1,4-benzodioxan-5-yl)-4-cyanomethylpiperazine, was obtained as an oil (17.4 g) which was sufficiently pure for use in the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.F[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[C:18]([F:21])([F:20])[F:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[C:18]([F:19])([F:21])[F:20])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(N2CCC(CO)CC2)c(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
To a solution of piperidin-4-ylmethanol (2.19 g) in DMSO (40 mL) were added 4-fluoro-3-(trifluoromethyl)benzonitrile (3.00 g) and potassium carbonate (3.21 g). The reaction mixture was stirred at 100° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.59 g).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[N:13]=2)=[CH:8][CH:7]=1)([OH:3])=[O:2].O[N:30]1[C:51](=[O:52])[NH:50][C@H:49]2[C@@H:31]1[CH2:32][S:33][C@H:34]2[CH2:35][CH2:36][CH2:37][CH:38](N1C(=O)CCC1=O)[C:39](=[O:41])O.CO.CCOCC>CN(C=O)C>[C:39]([NH:13][CH2:14][CH2:19][NH-:20])(=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]1[C@@H:49]2[C@@H:31]([NH:30][C:51]([NH:50]2)=[O:52])[CH2:32][S:33]1.[C:1]([CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:20][C:19]3[C:18](=[O:21])[N:17]([CH2:22][CH2:23][CH3:24])[C:16](=[O:25])[N:15]([CH2:26][CH2:27][CH3:28])[C:14]=3[N:13]=2)=[CH:10][CH:11]=1)([OH:3])=[O:2]
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Agent: CCCn1c(=O)c2[nH]c(-c3ccc(OCC(=O)O)cc3)nc2n(CCC)c1=O
Solvent: CO
Solvent: CCOCC
Solvent: CN(C)C=O
Product: [NH-]CCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21

Procedure:
Compound 6d (24.1 mg, 0.056 mmol) was suspended in 1 ml DMF. N-Hydroxysuccinimido-d-biotin (Sigma, 23.6 mg, 0.069 mmol) was added with stirring. A solution formed after several minutes, and a precipitate appeared soon thereafter. After one day methanol (1 ml) and ether were added. The precipitate was collected and dried (yield 26.6 mg, 73%).