Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][C:11](=[O:14])[CH:10]([OH:15])[C:9]=2[CH:8]=[C:7]([CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:24]([C:28]1[CH:29]=[C:30]([CH2:39][CH2:40][C:41](Cl)=[O:42])[CH:31]=[C:32]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:33]=1[OH:34])([CH3:27])([CH3:26])[CH3:25].C(C1C=C(CCC(O)=O)C=C(C(C)(C)C)C=1O)(C)(C)C>ClCCl>[C:35]([C:32]1[CH:31]=[C:30]([CH2:39][CH2:40][C:41]([O:15][CH:10]2[C:9]3[CH:8]=[C:7]([CH3:16])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]=3[O:12][C:11]2=[O:14])=[O:42])[CH:29]=[C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:33]=1[OH:34])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)c1cc(CCC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc2c(c(C(C)(C)C)c1)OC(=O)C2OC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A solution of 5.5 g (25.0 mmol) of 7-tert-butyl-3-hydroxy-5-methyl-3H-benzofuran-2-one (compound (102), Example 2), and 3.9 ml (28.0 mmol) of triethylamine in 30 ml of dichloromethane is added dropwise to a solution of 8.32 g (28.0 mmol) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl chloride (prepared from 7.8 g (28.0 mmol) of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid and thionyl chloride) in 10 ml of dichloromethane. The reaction mixture is then refluxed for 1 hour, then cooled and washed with water and 5% aqueous sodium hydrogencarbonate solution. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator. Three crystallisations of the residue from acetonitrile yield 4.6 g (38%) of 3-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyloxy]-7-tert-butyl-5-methyl-3H-benzofuran-2-one, m.p. 151°-154° C. (compound (113), Table 1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:16]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:20]([CH3:30])[N:19]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:17]=1>O1CCCC1.C(=O)([O-])O.[Na+]>[CH3:30][C:20]1[C:21]([CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[C:16]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:17]=[C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:19]=1
Reactant: CN1CCNCC1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCN(C)CC1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
1-methylpiperazine (0.111 mL, 1.00 mmol) and triethylamine (0.277 mL; 2.00 mmol) were added to a solution of methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.159 g; 0.5 mmol) in tetrahydrofuran (1.5 mL). the reaction vessel was heated at 100° C. for 18 h. The mixture was diluted with a saturated solution of sodium hydrogen carbonate and was extracted with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (60-100%) in heptane furnished 0.120 g (63%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7](Cl)[CH:6]=[N:5][CH:4]=1)#[N:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:18]1(B(O)O)[CH2:20][CH2:19]1>O1CCCC1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:18]1([C:7]2[N:8]=[C:3]([C:1]#[N:2])[CH:4]=[N:5][CH:6]=2)[CH2:20][CH2:19]1
Reactant: N#Cc1cncc(Cl)n1
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: N#Cc1cncc(C2CC2)n1
Yield: 82 %

Procedure:
A suspension of 6-cyano-2-chloropyrazine (0.3 g, 2.1 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium (II) (153.6 mg, 0.21 mmol), potassium phosphate (1.3 g, 6.30 mmol) and cyclopropylboronic acid (0.184 mg, 2.1 mmol) in tetrahydrofuran (25 mL, nitrogen bubbled) was degassed for 15 min. using nitrogen. The reaction mixture was refluxed for 16 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 5-20% ethyl acetate in petroleum ether) to afford 6-cyclopropylpyrazine-2-carbonitrile (250 mg, 50%).
Reaction SMILES: [C:1]([C@:3]1([CH2:17][O:18]C(=O)C)[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][CH2:4]1)#[N:2]>[NH4+].[OH-]>[C:1]([C@:3]1([CH2:17][OH:18])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(=O)OC[C@]1(C#N)CC[C@H](n2cc(C)c(=O)[nH]c2=O)O1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cn([C@H]2CC[C@@](C#N)(CO)O2)c(=O)[nH]c1=O
Temperature: 24 °C
Reaction time: 2 h

Procedure:
The 4'-α and 4'-β isomers of 3'-deoxy-4'-cyano-5'-O-acetylthymidine (Formula 30) (26 mg, 0.09 mM) is dissolved in 0.2 ml NH4OH/0.2 ml CH3OH and stirred at 24° C. for 2 hours. The solvent is removed by evaporation and the residue chromatographed on silica gel (Preparative TLC, 2 plates, 1000 microns) using 1% CH3OH/EtOAc with 0.8% NH4OH, affording the 4'-α and 4'-β isomers of 3'-deoxy-4'-cyanothymidine, 6 mg, 0.024 mM, MS 251 (M+); and 11 mg, 0.044 mM, MS 251(M+), respectively.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>C1COCC1>[C:18]([C:17]1[CH:16]=[C:15]([O:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:22]=[CH:21][CH:20]=1)#[N:19]
Reactant: N#Cc1cccc(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 101.6 %

Procedure:
Ethyl bromoacetate (14.7 g, 88.1 mmol) was added dropwise to a suspension of potassium carbonate (12.8 g, 92.3 mmol) and 3-hydroxybenzonitrile (10.0 g, 83.9 mmol) in THF (50 mL) at room temperature, and the mixture was stirred at 50° C. for 24 hr. The mixture was extracted with ethyl acetate and saturated aqueous ammonium chloride solution, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as a pale-yellow powder (17.5 g, 99%).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)=[CH:3][CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[O:44][C:45]1[CH:46]=[C:47]([CH:49]=[CH:50][CH:51]=1)[NH2:48]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][O:42][CH3:43])[N:35]=[CH:34][N:33]=[C:32]2[O:44][C:45]1[CH:46]=[C:47]([NH:48][C:13]([NH:12][C:11]2[N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)[N:8]=[C:9]([C:22]([F:23])([F:25])[F:24])[CH:10]=2)=[O:21])[CH:49]=[CH:50][CH:51]=1
Reactant: Cc1ccc(-n2nc(C(F)(F)F)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccc(C)cc4)c3)c2cc1OC
Yield: 78 %

Procedure:
Using the procedure described in Example 162B, phenyl 1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate described in Example 172B (0.145 g, 0.4 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and 4-(dimethylamino)pyridine (0.025 g) in THF (6 mL), to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-p-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.190 g, 78%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 7.55 (m, 2H), 7.36 (m, 6H), 7.19 (d, 1H), 6.95 (d, 1H), 6.84 (s, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.35 (s, 3H), 2.41 (s, 3H); LC-MS (ESI) m/z 609 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]#[CH:16])[C:8]=2[CH:17]=1)([O-])=O>C(O)(=O)C.CCOC(C)=O.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:14][C:15]#[CH:16])[C:8]=2[CH:17]=1
Reactant: C#CCN1C(=O)COc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: C#CCN1C(=O)COc2ccc(N)cc21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a slurry of 5.1 g (91 mmol) of iron powder in 42.5 ml of 5% aqueous acetic acid was added dropwise a solution of 4 g (17 mmol) of 6-nitro-4-propargyl-2H-1,4-benzoxazin-3(4H)-one dissolved in 42.5 ml of glacial acetic acid and 42.5 ml of EtOAc. The reaction mixture was heated to gentle reflux for 1 hour then cooled to room temperature. The iron was removed by suction filtration. EtOAc (50 ml) was added to the filtrate and the layers were separated. The aqueous phase was extracted with EtOAc (2×50 ml) and the organic layers were combined, washed with saturated aqueous sodium bicarbonate solution (100), and dried (MgSO4). The solvent was removed in vacuo to yield a thin brown oil which was taken up in 50 ml of water and reextracted with EtOAc (3×50 ml). The organic layers were combined, washed with water (2×50 ml) and then dried (MgSO4). The solvent was removed in vacuo to yield 2.55 g (75% yield) of 6-amino-4-propargyl-2H-1,4-benzoxazin-3(4H)-one, a dark brown solid, m.p. 136°-140° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=O.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[CH-:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:18].P(OP(O)(O)=O)(O)(O)=O.C(OCCCC)CCC.[OH-].[Na+]>O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([C-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)=[O:7].[CH-:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.[Fe+2:18]
Reactant: O=C(O)CCCBr
Agent: [Fe+2]
Agent: O=P(O)(O)OP(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCCCOCCCC
Product: O=C(CCCBr)[c-]1cccc1
Yield: 82.1 %

Procedure:
6.68 g of 4-bromobutyric acid, 1.86 g of ferrocene, 20 g of pyrophosphoric acid, 20 g of polyphosphoric acid, and 20 ml of di n-butylether were added and stirred while heating at 50° to 60° C. for 3 hours, then poured into water, made to be basic with sodium hydroxide, extracted with methylene chloride, and dried. The unreacted-ferrocene was removed with column chromatography, to obtain 2.75 g of 3-bromopropylferrocenyl ketone presented by the formula (D), in a yield of 82.0%. The proton nuclear magnetic resonance (1H--NMR) spectrum of the product is shown in FIG. 4. The result showed that the resulting product was the desired product (3-bromopropylferrocenyl ketone). ##STR11##
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([O:11][C:12](=[O:24])[CH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16](Br)[CH:15]=1)[CH3:10].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Na+].[Cl-]>COCCOC.CCOC(C)=O.O.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].C(P([C-]1C=CC=C1)C(C)(C)C)(C)(C)C.C1(C2[C-](C3C=CC=CC=3)C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C=2C2C=CC=CC=2)C=CC=CC=1.[Fe+2]>[CH2:9]([O:11][C:12](=[O:24])[CH2:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]([N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)[CH:15]=1)[CH3:10]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cc1cc(Br)ncc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(N2CCN(C)CC2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium phosphate (2.48 g, 11.67 mmol) is dried at 120° C. under high vacuum for 45 minutes. After cooling to RT and venting with dry argon, palladium dibenzylideneacetone (Pd2(dba)3, 24 mg, 0.026 mmol) and di-tert-butylphosphino pentaphenylferrocene (37 mg, 0.052 mmol) are added. (2-Bromo-5-nitro-pyridin-4-yl)-acetic acid ethyl ester (750 mg, 2.59 mmol), dissolved in 1,2-dimethoxyethane (10 ml, dried by passing through a column of basic aluminium oxide), and 1-methyl piperazine (780 mg, 7.78 mmol) are added. The reaction mixture is stirred at RT for 10 minutes, after which TLC and MS analysis indicated complete conversion of the starting material. The reaction mixture is diluted with EtOAc and poured into a saturated solution of NaCl in water. The organic layer is separated, dried over Na2SO4, and the solvent is evaporated. Purification of the residue by FCC (hexane/EtOAc, gradient from 95:5 to 90:10) affords the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=7 Hz, 3H), 2.35 (s, 3H), 2.50 (m, 4H), 3.76 (m, 4H), 3.94 (s, 2H), 4.18 (q, J=7 Hz, 2H), 6.36 (s, 1H), 9.05 (s, 1H). ES+−MS: 309.3 [M+H]+, ES−−MS: 307.3 [M−H]−.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[N:12]=1)C(OCC)=O)C.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>O>[Br:17][C:13]1[N:12]=[C:11]([CH2:5][C:4]([OH:18])=[O:3])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1cccc(Br)n1
Temperature: 100 °C

Procedure:
2-(6-Bromo-pyridin-2-yl)-malonic acid diethyl ester (64.0 g, 202.4 mmol) was added to a solution of potassium carbonate (279.8 g, 2024 mmol) in water (400 ml) at rt and the reaction mixture was heated to reflux at 100° C. for 36 h. The reaction mixture was treated with sat. ammonium chloride solution and the product formed was extracted with ethyl acetate (3×800 ml), washed with brine (10 ml). Organic layer was concentrated under reduced pressure to obtain title compound as a pale brown solid. Yield=34.0 g (77.7%). TLC (50% ethyl acetate in hexane) Rf=0.11; LCMS: RtH8=0.45; [M+1]=216.0 and 218.0.
Reaction SMILES: C([O:8][C:9]([C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.C(Cl)(Cl)Cl.CO.[NH4+:26].[OH-]>>[C:9]([C:11]1[N:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[CH:13][CH:12]=1)(=[O:8])[NH2:26]
Reactant: [NH4+]
Reactant: O=C(O)c1cccc(C(=O)OCc2ccccc2)n1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: NC(=O)c1cccc(C(=O)O)n1
Yield: 94 %

Procedure:
A solution of 6-((benzyloxy)carbonyl)picolinic acid (3.0 g, 11.7 mmol) in saturated NH4OH (100 mL) was heated in a sealed tube at 90° C. for 6 h and monitored by TLC (CHCl3/MeOH 8:2 v/v). The reaction mixture was evaporated to dryness to get the 6-carbamoylpicolinic acid (1.8 g, yield 94%) as a white solid, which was carried through without further purification. MS (ESI) m/z: Calculated for C7H6N2O3: 166.04. found: 167.0 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]2[C@@H:6]([CH2:7][C:8]3[C:15]([O:16]C)=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)[CH2:5][CH2:4][CH2:3]1.Cl>>[CH3:1][N:2]1[C@@H:11]2[C@@H:6]([CH2:7][C:8]3[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:9]=3[CH2:10]2)[CH2:5][CH2:4][CH2:3]1
Reactant: COc1cccc2c1C[C@H]1CCCN(C)[C@H]1C2
Agent: Cl
Product: CN1CCC[C@@H]2Cc3c(O)cccc3C[C@@H]21

Procedure:
This compound is obtained from the title compound of Example 7, analogously to Example 5 and 3. M.p. 256°-258° (Hydrochloride).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(F)cc3)c2c1Cl
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc(F)cc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]([O:27]C)=O)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][CH2:30][Mg+].[Br-]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:1]([N:20]1[CH:24]=[C:23]([C:25]2([OH:27])[CH2:30][CH2:29]2)[N:22]=[CH:21]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC[Mg+]
Reactant: COC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: OC1(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4 %

Procedure:
A solution of methyl 1-trityl-1H-imidazole-4-carboxylate (11.0 g, 29.9 mmol) and Ti(OiPr)4 (12.37 mL, 41.8 mmol) in THF (3 mL) was treated dropwise with a 1M solution of EtMgBr (76 mL, 76 mmol) to maintain the temperature below 35° C. The mixture was then stirred at RT for 4 h, and then poured onto H2O. The precipitate was filtered off, and the filtrate was extracted with AcOEt. The combined org. layers were dried over Na2O4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, AcOEt/heptane 30:70 to 100:0) gave the title compound (440 mg). UPLC-MS: MS 367.3 (M+H+); UPLC rt 1.01 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH2:14]([O:21][C:22]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52]Br)=[CH:46][C:23]=1[C:24]([NH:26][C:27]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[CH2:14]([O:21][C:22]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH2:52][N:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)=[CH:46][C:23]=1[C:24]([NH:26][C:27]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN1CCN(CCOc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C

Procedure:
Potassium carbonate (1.0 g) and 1-methylpiperazine (0.83 mL) were added to an acetone (7.5 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (1.5 g), followed by heating to reflux for 2 hours. The reaction mixture was cooled to room temperature, and potassium carbonate (0.34 g) and 1-methylpiperazine (0.28 mL) were added thereto, followed by heating to reflux for 2 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water and chloroform were added to the residue. The organic layer was separated, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-95% chloroform/methanol] to obtain tert-butyl 2-(2-(benzyloxy)-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]/[N:16]=[C:17](/[C:19]1[CH:33]=[CH:32][C:22]([CH2:23][N:24]2[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]2)=[CH:21][CH:20]=1)\[NH2:18])=O.C([O-])(=O)C.[Na+]>CCO.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]1[O:15][N:16]=[C:17]([C:19]2[CH:33]=[CH:32][C:22]([CH2:23][N:24]3[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]3)=[CH:21][CH:20]=2)[N:18]=1
Reactant: COC(=O)C1CN(Cc2ccc(/C(N)=N/OC(=O)c3cnn(-c4ccccc4)c3N)cc2)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccc5)c4N)n3)cc2)C1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
To a suspension of (Z)-methyl 1-(4-(N′-(5-amino-1-phenyl-1H-pyrazole-4-carbonyloxy)carbamimidoyl)benzyl)azetidine-3-carboxylate (102 mg, 0.227 mmol) in EtOH (3 mL) was added sodium acetate (37.3 mg, 0.455 mmol) as a solution in water (1 mL). The mixture was heated to 90° C. for 3 hr. The reaction mixture was transferred to a microwave vial and was then heated to 120° C. for 30 minutes. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (15 mL) and the combined organic layers were dried (MgSO4) and concentrated to afford an oil that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/hexane gradient. The pure fractions were concentrated to afford methyl 1-(4-(5-(5-amino-1-phenyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (70 mg, 0.163 mmol) as a colorless oil. HPLC retention time=1.35 (ethyl ester-1.42) minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS:(M+H)=431.23 (ethyl ester-445.25). (The product is a mixture of methyl ester and ethyl ester due to partial transesterification during the reaction. The mixture was carried on through the sequence.)
Reaction SMILES: COC(=O)[CH:4]([CH3:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].[C:14](Cl)(=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[O:11][CH:12]=[CH:4][C:5]=2[CH:10]=1)(=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCC(=O)Cl
Reactant: COC(=O)C(C)c1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCCCCC(=O)c1ccc2occc2c1
Yield: 9.3 %

Procedure:
To a solution of methyl 2-hydroxyphenylacetic acid methyl ester (1000 mg, 6.02 mmol) in nitrobenzene (10 ml) was added heptanoyl chloride (900 mg, 6.02 mmol), followed by aluminium chloride (1.6 g, 12.0 mmol, 2 equiv). The solution was heated to 60 C for 18 h, then cooled on ice before quenching with aqueous hydrochloric acid (1 M, 50 ml). The mixture was extracted with dichloromethane. (3×50 ml) and concentrated. Chromatography on silica gel using ethyl acetate/petroleum spirits (20:80) as eluant gave a semi-solid yellow residue. Recrystallization from dichloromethane/petroleum spirits at −15 C gave the title compound as a pale yellow solid (129 mg). Mp 64-67° C.;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C:12]([C:18]([OH:21])([CH3:20])[CH3:19])([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C:12]([C:18]([OH:21])([CH3:20])[CH3:19])([C:14]([O:16][CH3:17])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(C(C)(C)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: CCO
Product: COC(=O)C1(C(C)(C)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
Methyl (4S)-4-[(tert-butoxycarbonyl)amino]-1-(1-hydroxy-1-methylethyl)cyclopent-2-ene-1-carboxylate (1.4 g, 4.7 mmol) was dissolved in ethanol (30 mL) in a Parr flask and purged with N2. 10% Palladium on carbon (0.14 g) was added and the mixture was shaken overnight under nitrogen at 50 psi. The mixture was filtered through celite, washed with methylene chloride and concentrated to give the desired product (1.06 g, 86%).