Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:23])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH2:20][C:21]#[N:22])[N:11]=2)=[CH:5][CH:4]=1.Cl>C(Cl)Cl.CO.[Pd]>[NH2:22][CH2:21][CH2:20][C:12]1[N:11]=[C:10]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: COc1ccc(N(C)c2nc(CC#N)nc3ccccc23)cc1
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(N(C)c2nc(CCN)nc3ccccc23)cc1
Reaction time: 72 h
Yield: 8.3 %

Procedure:
A mixture of {4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-yl}-acetonitrile (250 mg, 0.82 mmol), 10% Pd/C (100 mg) and HCl (12 M, 1 mL, 12 mmol) in CH2Cl2/MeOH (1:1, 10 mL) was treated with H2 (50 psi) and shaken for three days. The Pd/C was filtered off and the filtrate concentrated and purified to give 21 mg of the title compound as a solid. 1H NMR (CDCl3) δ 7.64 (d, 1H), 7.55 (ddd, 1H), 7.13 (d, 2H), 6.95 (m, 2H), 6.93 (d, 2H), 3.85 (s, 3H), 3.62 (t, 2H), 3.56 (s, 3H), 3.4 (t, 2H); LC-MS (ESI+; 309 ([M+H]+)).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]2[CH2:8][CH2:9][CH2:10][C@@H:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:33])([F:32])[S:28](Cl)(=[O:30])=[O:29].O>CN(C=O)C>[F:26][C:27]([F:33])([F:32])[S:28]([O:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:11]2[C:4]3=[N:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6][N:5]3[CH2:8][CH2:9][CH2:10]2)=[CH:13][CH:14]=1)(=[O:30])=[O:29]
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (1.00 g) and potassium carbonate (1.23 g) in DMF (dry) (30 ml) was added trifluoromethanesulfonyl chloride (0.939 mL) at 0° C. The mixture was stirred at 0° C. for 5 min then at room temperature for 2 hr. The mixture was added with water. The resulting precipitate was collected, washed with water, and dried at 60° C. in vacuo to give the title compound (1.27 g) as a white solid.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.Cl>[OH-].[Na+]>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:7]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C(O)CCCCNc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCN(C(=O)c1ccc(Cl)cc1)c1ccccc1-c1ccccc1

Procedure:
5.4 g of 5-[N-(biphenyl-2-yl)amino]valeric acid is dissolved in 40 ml of 0.2 N caustic soda solution. Into the resulting clear solution (while vigorously stirring and constantly controlling the pH) 3.5 g of p-chlorobenzoyl chloride is added, drop by drop, while concurrently adding dilute caustic soda solution in order to maintain the pH at between 7 and 8. After the addition of acid chloride is complete, the solution is stirred for a further 30 minutes at pH 8 and then acidified to pH 3 with dilute hydrochloric acid. The precipitate, which is oily at first crystallizes after a time. It is filtered off and recrystallized from isopropyl alcohol to obtain 7.6 g (93% of thoery) of 5-[p-chloro-N-(biphenyl-2-yl)benzamido]valeric acid, MP 170° to 173°, which is identical with the compound obtained by the procedure of Example 53.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].CN(C)CCCN(C)C.[NH2:23][C:24]1[N:29]=[C:28]([OH:30])[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[CH:34][C:33]=2[O:50][CH3:51])=[C:26]([CH3:52])[N:25]=1>C1COCC1.O>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:30][C:28]1[C:27]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][O:42][Si:43]([C:46]([CH3:49])([CH3:47])[CH3:48])([CH3:44])[CH3:45])=[CH:34][C:33]=2[O:50][CH3:51])=[C:26]([CH3:52])[N:25]=[C:24]([NH2:23])[N:29]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1O
Agent: CN(C)CCCN(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(OCCCO[Si](C)(C)C(C)(C)C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Yield: 95.4 %

Procedure:
2-Mesitylenesulfonyl chloride (4.96 g, 22.7 mmol) was added to a solution of N,N,N′,N′-tetramethyl-1,3-propanediamine (3.79 mL, 22.7 mmol) and the product of example 8 step (v) (6.55 g, 15.1 mmol) in THF (66 mL) and the mixture was stirred at RT for 3 h. The resulting mixture was diluted with water and extracted with EtOAc. And the combined organic solutions were washed with brine, dried and concentrated. The residue was purified via chromatography on silica to give 8.87 g of the subtitle compound as a white solid; 1H NMR (CDCl3); 6.93 (2H, s), 6.71 (1H, d), 6.41 (1H, d), 6.33 (1H, dd), 4.66 (2H, br s), 4.02 (2H, t), 3.78 (3H, s), 3.77-3.82 (2H, m), 3.75 (2H, s), 2.59 (6H, s), 2.31 (3H, s), 2.25 (3H, s), 1.93-2.01 (2H, m), 0.89 (9H, s), 0.05 (6H, s); LC-MS: m/z 616.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])CO)[CH2:9][CH2:10][CH3:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: COc1ccsc1
Reactant: CCCCCCC(CO)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCC(CCCC)COc1ccsc1
Reaction time: 15 h
Yield: 83 %

Procedure:
Under a nitrogen atmosphere, 3-methoxythiophene (5.0 g, 44.8 mmol), 2-butyloctanol (16.7 g, 89.6 mmol), and p-toluenesulfonic acid (850 mg, 4.48 mmol) were dissolved in toluene (40 ml), and refluxing was performed for 15 hours. Then, water was added to the reaction solution. The reaction solution was then extracted with methylene chloride, and an organic layer was washed with a saturated saline solution and water. The organic layer was dried with anhydrous magnesium sulfate, and, after filtration, the solution was distilled off under reduced pressure. By separating and purifying the obtained reaction solution by silica gel column chromatography in which hexane was used as a mobile phase, a target substance was obtained as clear oil (83% yield). 1H-NMR (400 MHZ, CDCl3, TMS) δ 7.17 (dd, J=5.2 Hz, 1.6 Hz, 1 H), 6.76 (d, J=5.2 Hz, 1 H), 6.21 (d, J=1.6 Hz, 1 H), 3.81 (d, J=5.8 Hz, 2 H), 1.25 (m, 17 H), 0.88 (m, 6 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:10]2[CH3:19])=[C:4]([N+:20]([O-])=O)[CH:3]=1.O1CCCC1.[H][H]>[Ni].CO>[NH2:20][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH:10]1[CH3:19]
Reactant: [H][H]
Reactant: COC(=O)N1CCC(Nc2ccc(Cl)cc2[N+](=O)[O-])C(C)C1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N1CCC(Nc2ccc(Cl)cc2N)C(C)C1

Procedure:
A mixture of 51 parts of methyl 4-(4-chloro-2nitrophenylamino)-3-methyl-1-piperidinecarboxylate, 270 parts of tetrahydrofuran and 96 parts of methanol is hydrogenated at normal pressure and at normal temperature with 15 parts of raney-nickel catalyst. After the calculated amount of hydrogen is taken up (6 hours), the catalyst is filtered off and the filtrate is evaporated. The oily residue is triturated in warm 2,2'-oxybispropane. After cooling, the product is filtered off, pulverized in a mortar and triturated again in 2,2'-oxybispropane. The product is filtered off and dried, yielding methyl 4-(2-amino-4-chlorophenylamino)-3-methyl-1-piperidinecarboxylate.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]2[CH2:21][C@@H:20](OS(C)(=O)=O)[CH2:19][N:18]2[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=2)=[O:28])=[O:16])[CH2:11][CH2:10]1>C(#N)C>[C:1]([S:3][C@@H:20]1[CH2:19][N:18]([C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=2)=[O:28])[C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][OH:6])[CH2:10][CH2:11]2)=[O:16])[CH2:21]1)(=[O:4])[CH3:2]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@H]1C[C@@H](C(=O)N2CCN(CCO)CC2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
685 mg of potassium thioacetate were added to a solution of 2.0 g of (2S,4R)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described step 54(a)(ii), 54(a)(ii') and 54(a)(ii") above] in 20 ml of dry acetonitrile, and the resulting mixture was stirred at 80° C. for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, the residue was diluted with 200 ml of ethyl acetate, and the dilute solution was washed with an aqueous solution of sodium chloride; was then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a gradient elution method with mixtures of ethyl acetate and methanol ranging from 9:1 to 4:1 by volume as the eluent, to give 1.35 g of the title compound, as a powder.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:28][C:29]1[NH:33][C:32]2[CH:34]=[C:35]([C:38]([F:41])([F:40])[F:39])[CH:36]=[CH:37][C:31]=2[N:30]=1.C(N(CC)C(C)C)(C)C.[I-].[K+]>C(#N)C>[N:1]1[C:10]2[CH:9]([N:11]([CH2:28][C:29]3[NH:30][C:31]4[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][C:32]=4[N:33]=3)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc2nc(CCl)[nH]c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2cc(C(F)(F)F)ccc2[nH]1)C1CCCc2cccnc21
Yield: 75.4 %

Procedure:
2-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-isoindol-1,3-dione (160 mg, 0.46 mmol) and 2-chloromethyl-6-trifluoromethyl-1H-benzoimidazole (129 mg, 0.55 mmol), N,N-diisopropylethylamine (100 μL, 0.60 mmol), and potassium iodide (8 mg, 0.05 mmol) in acetonitrile were stirred at 40° C. for 3 days. Then the reaction mixture was cooled and the solvent was removed under reduced pressure to afford a red oil. Purification by flash column chromatography on silica gel using NH4OH/CH3OH/CH2Cl2 (1:2:97) afforded the product as an orange foam (190 mg, 76%). 1H NMR (CDCl3) δ 1.37-1.45 (m, 5H), 1.56-1.70 (m, 2H), 2.18-2.20 (m, 1H), 2.57-2.61 (m, 1H), 2.72-2.80 (m, 3H), 3.49-3.54 (m, 2H), 3.98-4.16 (m, 3H), 7.13-7.15 (m, 1H), 7.40-7.45 (m, 2H), 7.62-7.74 (m, 5H), 7.86 (br m, 1H), 8.62 (br m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2[N:6]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Br)cc2nc[nH]c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2ncn(C3CCCCO3)c12
Yield: 94.7 %

Procedure:
A mixture of 74 (1.09 g, 5.19 mmol), TsOH.H2O (98 mg, 0.51 mmol), 3,4-dihydro-2H-pyran (2.4 mL, 26 mmol) in THF (15 mL) was degassed and then heated to reflux overnight. The solvent was removed in vacuo. The residue was partitioned between with DCM (300 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a MeOH/DCM gradient (0.5% to 1% MeOH) to afford 1.45 g (95%) of 5-bromo-7-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (76) as yellow solid: MS (ESI) m/z=295.1 [M+1]+.
Reaction SMILES: [CH:1]1([NH:7][C@@H:8]2[CH2:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([F:18])[C:11]=3[O:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:21](=O)[CH2:22][CH3:23].[BH3-]C#N.[Na+]>CO>[CH:1]1([N:7]([C@@H:8]2[CH2:13][C:12]3[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([F:18])[C:11]=3[O:10][CH2:9]2)[CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC=O
Reactant: COc1ccc(F)c2c1C[C@@H](NC1CCCCC1)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCN(C1CCCCC1)[C@H]1COc2c(F)ccc(OC)c2C1
Reaction time: 8 h
Yield: 97 %

Procedure:
To the solution of (R)-3-(N-cyclohexylamino)-8-fluoro-5-methoxy-3,4-dihydro-2H-1-benzopyran in methanol (25 mL) were propanal (1.3 g, 23 mmol) and NaCNBH3 (0.15 g, 2.3 mmol) added. The solution was stirred overnight to give the desired compound in a 97% yield according to GC. The solvent was removed in vacuo and the residue was worked up by extraction to give 0.7 g of the title compound as a colorless oil. GC/MS (70 eV) M=321 (40%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.C(O[C:10](=[NH:17])[CH2:11][C:12](OCC)=[O:13])C.[NH:18]1[C:22]([NH2:23])=[CH:21][CH:20]=[N:19]1>C(OCC)(=O)C.C(O)C>[NH2:17][C:10]1[NH:23][C:22]2[N:18]([N:19]=[CH:20][CH:21]=2)[C:12](=[O:13])[CH:11]=1
Reactant: CCOC(=N)CC(=O)OCC
Reactant: Nc1ccn[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cc(=O)n2nccc2[nH]1
Temperature: 0 °C

Procedure:
Sodium bicarbonate (3.9 g, 46.2 mmol) is added in small portions to a mixture of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (Z-1) (8.6 g, 44.0 mmol) in crushed ice (100 g) and ethyl acetate (50 mL) until the pH value reaches 8-9. The organic layer is separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers are dried over anhydrous MgSO4 and filtered. The filtrate is concentrated in vacuo to afford a colourless oil which is added to a solution of 1H-pyrazol-5-amine (3.65 g, 44.0 mmol) in ethanol (100 mL). The resulting mixture is then degassed and backfilled with argon (three cycles) and stirred at reflux overnight. The mixture is then filtered while it was still warm. The solid is rinsed with cold ethanol (25 mL) and ether (2×25 mL), and then dried in vacuo to afford 5-aminopyrazolo[1,5-a]pyrimidin-7(4H)-one (Z-2).
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](Cl)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][CH2:19][C:20]([N:8]2[CH2:9][CH2:10][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: c1ccc(C2CCN2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
A solution of 2-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 4-phenyl-1-(2-phenylazetidin-1-yl)butan-1-one are collected and the solvent is removed in vacuo to give 488 mg of colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].B([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])([O-:10])=[O:9]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2ccncc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a degassed mixture containing 4-chloro-3-nitropyridine (3.0 g, 18.9 mmol), 3-boronobenzoic acid (3.7 g, 22.7 mmol), potassium carbonate (5.2 g, 37.8 mmol) and dioxane (189 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.30 g, 0.28 mmol) in one portion under a nitrogen atmosphere. The mixture was heated with fast stirring at 100° C. for 15 h, cooled to room temperature, filtered and concentrated to afford 3-(3-nitropyridin-4-yl)benzoic acid as a tan residue which was used without further purification. LCMS: retention time: 1.375 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 u, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 245 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23]C(OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.NC1[NH:52][N:51]=[N:50][N:49]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([NH:22][C:23]2[NH:52][N:51]=[N:50][N:49]=2)=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: Nc1nnn[nH]1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1nnn[nH]1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 5-amino-1H-tetrazole was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:10].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:10])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1
Reactant: NO
Reactant: N#Cc1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: N=C(NO)c1cccnc1
Reaction time: 0.21 h

Procedure:
To a solution of 5.012 g (72.1 mmol) of hydroxylamine hydrochloride in 55 mL of isopropyl alcohol, 8.8 g (105.7 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 5.0 g (48 mmol) of 3-cyanopyridine was added and stirred at 80° C. to 85° C. for 3-4 h. After completion of the reaction, the reaction mixture was cooled to 25° C. to 30° C., filtered and washed with 10 mL of isopropyl alcohol. The filtrate was collected and distilled to obtain a crude residue, which was chased with 5 mL of toluene to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([CH3:27])=[C:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:23]=1[CH3:33])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([CH3:27])=[C:24]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:23]=4[CH3:33])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.5 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (6.3 mg, 0.0226 mmol), 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (4.9 mg, 0.0249 mmol) and piperidine (4 drops) in ethanol (1 mL) was stirred at room temperature for 24 hours. The reaction was concentrated and purified (reversed phase HPLC) to give 5.2 mg (51%) of the title compound. MS 456.4 [M++1].
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:18][O:19][C:20](=[O:40])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C)(=O)=O>>[CH3:18][O:19][C:20](=[O:40])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COC(=O)CCc1ccccc1OCCCCCOS(C)(=O)=O
Reactant: CCCCCc1c(O)ccc2c1OCCC2=O
Product: CCCCCc1c(OCCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCCC2=O
Yield: 98 %

Procedure:
Using the procedure of example 11 and starting with 1.25 g (5.34 mmol) of 2,3-dihydro-7-hydroxy-8-pentyl-4H-1-benzopyran-4-one (from example 117) and 1.64 g (4.76 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]benzenepropanoic acid methyl ester (from example 72), 2-[5-[(3,4-dihydro-4-oxo-8-pentyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester was obtained in 98% yield (2.52 g) as a pale-yellow oil. This diester (5.18 mmol) was saponified with 7.8 mL of 3N aqueous lithium hydroxide in 25 mL of tetrahydrofuran, at room temperature, for 48 hr. Work-up as in example 4 gave 2-[5-[(3,4-dihydro-4-oxo-8-pentyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]benzenepropanoic acid as an oil. This material was flash chromatographed on silica gel eluting with ethyl acetate-hexane mixtures giving 0.69 g (28.5%) of pure acid as a solid. Recrystallization from acetonitrile gave a colorless solid, mp 86°-87° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(N(C(C)C)CC)(C)C.[CH3:19][O:20][CH2:21]Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:19][O:20][CH3:21]
Reactant: COCCl
Reactant: Oc1cc(F)ccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
2-Bromo-5-fluorophenol (30 g, 0.16 mol) is dissolved in dichloromethane (170 mL) and cooled to 0° C. To this solution is added diisopropylethylamine (36 mL, 0.20 mol) via syringe followed by chloromethyl methyl ether (16 mL, 0.20 mol) via an addition funnel. The solution is stirred and warmed to room temperature. After 2 h, the mixture is washed with saturated aqueous NH4Cl, water, and brine. The organic portion is dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 20% AcOEt/hexane) to yield 26.1 g (71%) of the title compound as a clear colorless oil. 1H NMR 400 MHz (CDCl3) δ 7.46-7.53 (m, 1H), 6.92-6.99 (m, 1H), 6.63-6.70 (m, 1H), 5.26 (s, 2H), 3.55 (s, 3H).