Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:20]=O)=[C:9]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[C:10]=1[CH2:11]C)=[O:5])C.[CH2:22]([O:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:39]=[C:38]3[C:34]([CH2:35][C:36](=[O:40])[NH:37]3)=[CH:33][CH:32]=2)[CH:28]=[CH:29][CH:30]=1)[CH3:23]>N1CCCCC1.C(O)C>[C:15]([CH2:14][CH2:13][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:20]=[C:35]1[C:34]2[C:38](=[CH:39][C:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH2:22][CH3:23])[CH:26]=3)=[CH:32][CH:33]=2)[NH:37][C:36]1=[O:40])([OH:17])=[O:16]
Reactant: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1CC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C(=O)O)c(C)c2CCC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-ethyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 6-(3-ethoxyphenyl)-2-oxindole (304 mg), and piperidine (2 drops) in ethanol (5 mL) were held at 90° C. overnight. The precipitate that formed was filtered, washed with ethanol. The precipitate, an orange solid, was stirred with potassium hydroxide (4 pellets) in ethanol (3 mL) at 90° C. for 2.5 hours. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 370 mg of 4-(2-Carboxyethyl)-5-[6-(3-ethoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.C(OC([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C@@H:9]([N:13]([CH2:14][CH2:15][CH3:16])[CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([C:38]([CH:35]4[CH2:36][CH2:37][NH:32][CH2:33][CH2:34]4)=[O:39])[CH2:21][CH2:20]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CCCN(CCC1CCNCC1)[C@@H]1CCc2ccc(OC)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC1CCN(C(=O)C2CCNCC2)CC1)[C@@H]1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.5 %

Procedure:
Under an inert atmosphere ((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-(2-piperidin-4-yl-ethyl)-propyl-amine (200 mg, 0.61 mmol), piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (139 mg, 0.61 mmol), EDCl (117 mg, 0.61 mmol), HOBT (82 mg, 0.61 mmol), triethylamine (0.17 mL, 1.2 mmol), and dichloromethane (35 mL) were combined. The mixture was stirred at room temperature for 48 h and then concentrated in-vacuo. The residue was taken-up in EtOAc (50 mL) and washed with water (30 mL), 1 N NaOH (30 mL), brine (30 mL), and dried (MgSO4). The solution was filtered and concentrated to afford an oil. The oil was flash chromatographed on silica gel eluting with 20% acetone in hexanes to afford the protected amine (260 mg) which was deprotected with 10 mL trifluoroacetic acid, as described herein, to afford (4-{2-[((R)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-ethyl}-piperidin-1-yl)-piperidin-4-yl-methanone (200 mg) 116[M+H]+=478.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[CH2:11]([O:13][C:14](=[O:17])[CH2:15][Br:16])[CH3:12]>CC(C)=O>[BrH:16].[CH2:11]([O:13][C:14](=[O:17])[CH2:15][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][C:2]1=[NH:10])[CH3:12]
Reactant: Nc1nc2ccccc2s1
Reactant: CCOC(=O)CBr
Solvent: CC(C)=O
Product: Br
Product: CCOC(=O)Cn1c(=N)sc2ccccc21
Temperature: 50 °C
Yield: 86 %

Procedure:
A mixture of benzothiazol-2-ylamine (1.0 g, 6.6 mmol) and bromoacetic acid ethyl ester (0.86 mL, 7.9 mmol) in 30 mL of acetone was heated at 50° C. for 6 hours. The mixture was cooled to ambient temperature and the solid was triturated with ethanol, collected by filtration, and dried under vacuum to provide 1.8 g (86%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.25 (t, J=7.1 Hz, 3 H), 4.22 (q, J=7.1 Hz, 2 H), 5.28 (s, 2 H), 7.44 (td, J=7.6, 1.0 Hz, 1 H), 7.55 (td, J=7.8, 1.4 Hz, 1 H), 7.68 (d, J=7.8 Hz, 1 H), 8.01 (dd, J=8.1, 1.0 Hz, 1 H), 10 3 (s, 1H); MS (DCI/NH3) m/z 237 (M+H)+.
Reaction SMILES: O.[C:2]([O-:9])(=[O:8])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[NH4+].[NH4+].[C:12]1([CH3:22])[CH:17]=[CH:16]C(S(O)(=O)=O)=CC=1>C(O)CCC>[C:2]([O:9][CH2:22][CH2:12][CH2:17][CH3:16])(=[O:8])[CH2:3][CH2:4][C:5]([O:7][CH2:2][CH2:3][CH2:4][CH3:5])=[O:6]
Reactant: O=C([O-])CCC(=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Solvent: CCCCO
Solvent: O
Product: CCCCOC(=O)CCC(=O)OCCCC

Procedure:
For the esterification reaction, a three-neck flask (500 ml) with a water separator is used, in which n-butanol, 52 g of diammonium succinate and 0.45 g of para-toluenesulfonic acid are initially charged. The mixture is brought to boiling with stirring. During the reaction, the dibutyl succinate formed is enriched in the flask (together with butanol). The water/n-butanol azeotrope and NH3 are distilled off via the top and condensed in the water separator. The condensate is separated into a butanol phase and a water phase. The butanol phase is recycled into the flask. The reaction ran for a total of 240 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[F:18][C:19]([F:29])([F:30])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4C(F)(F)F)cc23)CC1

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 13.0 mg (0.062 mMol) 2-trifluoromethylbenzoyl chloride, 20.3 mg 89%) of the title compound were recovered.
Reaction SMILES: [OH:1]O.[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][C@H:15]5[C:16]([O:22]C)=[CH:17][CH:18]=[C:19]2[C@:7]5([C:8]=34)[CH2:6][CH2:5]1.[NH4+].[OH-]>C(O)=O.OS(O)(=O)=O.O>[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][CH:15]5[C:16]([CH:17]=[CH:18][C@:19]2([OH:1])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:22]
Reactant: OO
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 40 °C
Yield: 86 %

Procedure:
Hydrogen peroxide (30%, 1.3 mL, 13 mmol) is added to a solution of thebaine O-1 (3.11 g, 10 mmol) in a mixture of formic acid (88%, 1.3 mL) and H2SO4 (0.7%, 4.1 mL). The mixture is heated at 40° C. (bath temperature) for 6.5 h, cooled, diluted with water (10 mL), and made basic with concentrated NH4OH. The precipitate is filtered, washed with H2O and dried (MgSO4). The product is recrystallized from EtOH—CHCl3 to yield O-5 (2.70 g, expected yield 86%). See Iijima, I.; Minamikawa, J.; Jacobson, A. E.; Brossi, A.; Rice, K. C.; J. Med. Chem. (1978) 21, 398.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(O)C.C(=O)([O-])O.[Na+].[NH2:18][C:19]1[N:20]=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=1>Br.O>[F:27][C:25]([F:26])([F:28])[C:23]1[CH:22]=[N:21][N:20]2[CH:8]=[CH:9][N:18]=[C:19]2[N:24]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1nncc(C(F)(F)F)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: FC(F)(F)c1cnn2ccnc2n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 22.5 %

Procedure:
A stirred mixture of bromoacetaldehyde diethyl acetal (2.30 ml, 14.8 mmol) in concentrated hydrobromic acid (0.73 ml) and water (0.73 ml) was heated at reflux for 2 h, then poured into ethanol (25 ml). The solution was neutralised to pH 7 with solid sodium hydrogencarbonate, then filtered. To the filtrate was added 3-amino-5-trifluoromethyl-1,2,4-triazine (1.0079 g, 6.14 mmol) and the mixture was stirred at 60° C. for 20 h, then 80° C. for 23 h. The mixture was evaporated in vacuo, and the residue was purified by flash chromatography (silica gel, 35-50% EtOAc/isohexane) to give 0.2593 g (22%) of the title compound: 1H NMR (360 MHz, CDCl3) δ8.20 (1H, d, J 0.8 Hz), 8.30 (1H, d, J 0.9 Hz), 8.73 (1H, s).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]4[CH2:33][O:32]C5(CCCCC5)[O:30]4)[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].O.Cl>C(O)C>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[C:11]([NH:23][C:24]3[S:28][N:27]=[C:26]([C@H:29]([OH:30])[CH2:33][OH:32])[N:25]=3)=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Yield: 82.6 %

Procedure:
(S)-N-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.600 g, 1.09 mmol) was dissolved in ethanol (25 ml) and water (600 mg) and concentrated HCl (600 mg) were added. The mixture was heated to reflux for 2 hours, concentrated in vacuo, dissolved and concentrated with EtOH (2×50 mL). The material was triturated from acetonitrile to afford (S)-1-(5-(3-(2-ethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol (0.420 g, 0.90 mmol, 82%) as a solid. Mass Spectrum (apci) m/z=469.1 (M+H—HCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([OH:18])=O)[NH:7]2.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:16]([N:19]1[CH2:24][CH2:23][N:22]([C:16]([C:6]3[NH:7][C:8]4[C:4]([CH:5]=3)=[C:3]([O:2][CH3:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=4)=[O:18])[CH2:21][CH2:20]1)=[O:18])[NH:7]2
Reactant: COc1cc2[nH]c(C(=O)O)cc2c(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc2[nH]c(C(=O)N3CCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5[nH]4)CC3)cc2c(OC)c1OC

Procedure:
4,5,6-Trimethoxyindole-2-carboxylic acid (290 mg) and piperazine (50 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [CH:1]([CH:3]=[O:4])=[O:2].[NH2:5][C:6]([NH2:8])=[O:7]>>[OH:2][C@@H:1]1[C@H:3]([OH:4])[N:5]2[C:6](=[O:7])[N:8]1[C@H:3]([OH:4])[CH:1]2[OH:2]
Reactant: O=CC=O
Reactant: NC(N)=O
Product: O=C1N2C(O)[C@@H](O)N1[C@H](O)[C@@H]2O
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To 290 g of a 40% solution of glyoxal (116 g active) in a three neck round bottom flask equipped with stirrer, condenser and temperature control added 60 g urea (1 mole) at ambient temperature. After all urea dissolved, the temperature was increased to 90° C. and kept for 60 min until all reactants were consumed and (2R,3S,6R)-2,3,5,6-tetrahydroxy-1,4-diazabicyclo[2.2.1]heptan-7-one product was formed as determined by HPLC. This solution was added to a 50% solution of six moles of dextrose (1080 g) in water at 60° C. After the two solutions mixed, enough water was added to bring the final concentration to 50%.
Reaction SMILES: N1C=CC=CC=1NC1C=CC=CN=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:21]#N.[CH3:29][O:30][CH:31]([O:34][CH3:35])CBr>>[CH3:29][O:30][CH:31]([O:34][CH3:35])[CH2:21][CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1
Reactant: N#CC(c1ccccn1)c1ccccn1
Reactant: COC(CBr)OC
Agent: c1ccc(Nc2ccccn2)nc1
Product: COC(CC(c1ccccn1)c1ccccn1)OC
Yield: 77 %

Procedure:
This product was prepared as described above, (in Example 5), with the exception that bis-(2-pyridyl)amine was replaced by bis-(2-pyridyl)methane (prepared as described in Heterocycles 1995, 40, 757-776) and substituting 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine with 2-bromoacetaldehyde dimethyl acetal. After 12.5 h at reflux the reaction mixture was worked-up as described above. The crude residue was purified by flash chromatography (ethyl acetate-petroleum ether-2.2 N methanolic ammonia 6:4:0.6) affording the title product (77%).
Reaction SMILES: N1C(C)=CC=CC=1C.[Cl:9][C:10]1[C:19]2[C:14](=[C:15]([OH:21])[CH:16]=[CH:17][C:18]=2[Cl:20])[N:13]=[CH:12][N:11]=1.[Br:22]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:22][C:16]1[C:15]([OH:21])=[C:14]2[C:19]([C:10]([Cl:9])=[N:11][CH:12]=[N:13]2)=[C:18]([Cl:20])[CH:17]=1
Reactant: BrBr
Reactant: Oc1ccc(Cl)c2c(Cl)ncnc12
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: Oc1c(Br)cc(Cl)c2c(Cl)ncnc12

Procedure:
2,6-Lutidine (0.27 mL, 0.248 g, 2.32 mmol) is added to a solution of 4,5-dichloro-8-quinazolinol (0.5 g, 2.33 mmol) in chloroform at ice bath temperature. A solution of bromine in carbontetrachloride (2.4 mL, 1.0 molar) is then added dropwise to the reaction mixture and a precipitate forms. The reaction mixture is diluted with chloroform, washed sequentially with water and saturated NaHCO3 solution, dried over MgSO4 and concentrated in vacuo to give the title product as a yellow solid, 0.7 g, mp 156.5° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([I:22])[CH:18]=3)[N:13](C)[C:12]2=O)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.C1(CC#C)C=CC=CC=1.O>CN(C=O)C.[Cu]I>[I:22][C:17]1[CH:16]=[CH:15][C:14]([NH:13][CH3:12])=[C:19]([CH:18]=1)[C:20]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:25])=[CH:5][CH:6]=1)=[O:21]
Reactant: COC(=O)c1ccc(Cn2c(=O)c3cc(I)ccc3n(C)c2=O)cc1
Agent: [Cu]I
Agent: C#CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ccc(I)cc1C(=O)NCc1ccc(C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To 19.6 g (44.9 mmol) 4-(6-Iodo-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid methyl ester and 23.2 g (179.6 mmol) di-isopropyl ethylamine in 200 ml DMF is added bis-triphenylphosphine palladium di-chloride (1.0 g, catalytic) followed by CuI (0.4 g, catalytic). 7.3 g (62.9 mmol) 3-phenyl-propyne is added and the mixture is heated to 70° C. for 6 hrs. The mixture is allowed to cool to room temperature and stir overnight. Water is added and the mixture stirred 30 minutes. Filter and dry under reduced pressure. Solid from EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2.[N+:15]([O-])([OH:17])=[O:16]>>[F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2
Reactant: O=C1Cc2cccc(F)c2N1CCF
Reactant: O=[N+]([O-])O
Product: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1CCF
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7-Fluoro-1-(2-fluoro-ethyl)-1,3-dihydro-indol-2-one (0.880 g, 0.0119 mol) is added portionwise to 70% nitric acid (8 ml) at −10° C. After the addition is complete, the reaction is allowed to warm to room temperature and then stirred for 24 hours. The mixture is diluted with ice water and the resulting precipitate filtered, washed with water, and dried under vacuum to give the title compound as a light brown solid. HPLC r.t. 4.65 min; MS for C10H8F2N2O3 m/z 243.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[C:11]#[N:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:17][Mg+].[Br-]>C1COCC1>[CH:14]1([CH2:13][CH:10]([C:7]2[CH:8]=[N:9][C:4]([C:1]([OH:3])([CH3:17])[CH3:2])=[CH:5][CH:6]=2)[C:11]#[N:12])[CH2:16][CH2:15]1
Reactant: CC(=O)c1ccc(C(C#N)CC2CC2)cn1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(C#N)CC2CC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.7 %

Procedure:
A solution of 2-(6-acetylpyridin-3-yl)-3-cyclopropylpropanenitrile (520 mg, 2.43 mmol) in THF (6 mL) was added MeMgBr (0.89 mL, 2.67 mmol, 3M in Et2O) at 0° C. under N2 and stirred at room temperature for 2 h. The solution was quenched with water and extracted with EtOAc (3×20 mL). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography on silica gel (EtOAc: Petroleum ether=1:10) to give 3-cyclopropyl-2-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)propanenitrile (200 mg, yield: 35.6%). 1H NMR (CDCl3 varian 400): δ8.41 (d, J=2.4 Hz, 1H), 7.67 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.36 (dd, J=8.4 Hz, 0.8 Hz,
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[NH:10][C:9]=2[C:8]([OH:21])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:21])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O (2:1) was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]([C:15]2[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[BrH:24]>CC(O)=O>[Br:24][C:17]1[CH:16]=[C:15]([C:12]2[N:11]([CH3:22])[C:10](=[O:23])[C:9]([OH:8])=[CH:14][N:13]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Br
Reactant: Cn1c(-c2ccnc(Cl)c2)ncc(OCc2ccccc2)c1=O
Solvent: CC(=O)O
Product: Cn1c(-c2ccnc(Br)c2)ncc(O)c1=O
Temperature: 100 °C
Yield: 62.3 %

Procedure:
A mixture of 5-(benzyloxy)-2-(2-chloropyridin-4-yl)-3-methylpyrimidin-4(3H)-one (3.5 g, 10.7 mmol), conc. aq. HBr (10 mL), and HOAc (50 mL) was heated at 100° C. for 2 h with stirring. After cooled to rt, the solid was filtered, washed with EtOAc several times, dried to give 5 g of crude compound, which was purified by prep-HPLC to give pure 2-(2-bromopyridin-4-yl)-5-hydroxy-3-methylpyrimidin-4(3H)-one (1.9 g, 62.3%). 1H-NMR δ (400 MHz, d6-DMSO): 9.88 (s, 1H), 8.52 (dd, J=5.6, 0.4 Hz, 1H), 7.86 (dd, J=5.2, 0.4 Hz, 1H), 7.65 (dd, J=5.2, 1.6 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 3.33 (s, 3H); MS (ESI) m/z (M+H)+ 282.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.IC>C(O)(C)(C)C.O>[CH3:1][C:13]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:17][CH2:16][CH2:15][C:14]1=[O:18]
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCCC1c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CC(C)(C)O
Product: CC1(c2ccccc2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.9 %

Procedure:
2-Methyl-2-phenyl-cyclopentanone was prepared using the technique described by Ireland et al., J Org. Chem., 31, 2543 (1966). Potassium tert-butoxide (6.2 g, 55 mmol) was added to a solution of 2-phenylcyclopentanone (8.4 g, 53 mmol) in 100 mL of tert-butanol and the solution was stirred at room temperature for 45 min. Iodomethane (6 mL, 100 mmol) was added and after 2 hours the mixture was diluted with water and extracted twice with ether. The ether extract was washed with water and brine, dried (sodium sulfate) and evaporated. Purification of the residue by flash chromatography (5% ethyl acetate-hexane) afforded 8.3 g of 2-methyl-2-phenyl-cyclopentanone as an oil.
Reaction SMILES: N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](N4N=NC(CC)=N4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[ClH:45].[C:46]1([CH:52]([C:95]2[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70](NC4C=NC(OC)=CC=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:81]2[CH2:85][C@H:84]([N:86]3[N:90]=[N:89][C:88]([CH2:91][CH3:92])=[N:87]3)[C@@H:83]([OH:93])[C@H:82]2[OH:94])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[NH:101]1[C:105]([C:106]2[CH:107]=[C:108]([NH2:112])[CH:109]=[CH:110][CH:111]=2)=[N:104][N:103]=[N:102]1>>[ClH:45].[C:95]1([CH:52]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:53][NH:54][C:55]2[N:63]=[C:62]([N:64]3[CH2:68][CH2:67][C@@H:66]([NH:69][C:70]([NH:112][C:108]4[CH:109]=[CH:110][CH:111]=[C:106]([C:105]5[NH:101][N:102]=[N:103][N:104]=5)[CH:107]=4)=[O:71])[CH2:65]3)[N:61]=[C:60]3[C:56]=2[N:57]=[CH:58][N:59]3[C@@H:81]2[CH2:85][C@H:84]([N:86]3[N:90]=[N:89][C:88]([CH2:91][CH3:92])=[N:87]3)[C@@H:83]([OH:93])[C@H:82]2[OH:94])[CH:100]=[CH:99][CH:98]=[CH:97][CH:96]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6ccc(OC)nc6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)Nc6cccc(-c7nnn[nH]7)c6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from ((1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (Example 48) using a procedure analogous to that of 1-((R)-1-{6-(2,2-Diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-(6-methoxy-pyridin-3-yl)-urea hydrochloride (Example 156) by replacing (6-Methoxy-pyridin-3-yl)-carbamic acid phenyl ester with 3-(1H-tetrazol-5-yl)-phenylamine (first step a).