Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(=O)([O-])[O-].[K+].[K+].[C:17](Cl)(=O)[C:18]1[C:19]([O:24][CH3:25])=[CH:20][CH:21]=[CH:22][CH:23]=1>CCOCC>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: NC(=O)c1ccccc1N
Reactant: COc1ccccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
In a 2 L three-necked round-bottomed flask equipped with an overhead stirrer and reflux condenser, anthranilamide (20.0 g, 147 mmol) and potassium carbonate (28.4 g, 206 mmol) were suspended in 1 L dry ether and heated to reflux. o-Anisoyl chloride (32.5 g, 191 mmol) was added slowly to the refluxing mixture. After 3 hours at reflux, the reaction mixture was allowed to cool to room temperature, the ether was removed under reduced pressure, and the resulting residue was filtered and washed with water. The resulting solid was then suspended in 600 mL of 5% aq. NaOH solution and boiled for one hour. The reaction was allowed to cool to room temperature, and it was neutralized with acetic acid, upon which 2-(2-methoxyphenyl)quinazolin-4(3H)-one was precipitated. The product was collected by filtration, washed with water, and dried overnight in vacuo to yield 27 g (73%) of pure 2-(2-methoxyphenyl)quinazolin-4(3H)-one. LC/MS: m/z 253.0 (M+H)+ at 3.22 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (DMSO) δ 3.86 (s, 3H), δ 7.09 (t, 1H), δ 7.18 (d, 1H), δ 7.53 (m, 2H), δ 7.70 (m, 2H), δ 7.80 (m, 1H), δ 8.14 (d, 1H), δ 12.11 (s, 1H); 13C NMR (DMSO) δ 55.75, δ 111.86, δ 120.89, δ 120.97, δ 122.74, δ 125.75, δ 126.45, δ 127.26, 8 130.41, δ 132.13, δ 134.32, δ 148.97, δ 152.48, δ 157.12, δ 161.35
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([CH3:17])=[C:9]([C:13]([CH3:16])=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])=[O:4].C(Cl)(=O)[C:21](Cl)=[O:22]>C(Cl)CCl>[F:1][C:2]([F:18])([F:19])[C:3]([NH:5][CH2:6][C:7]1[C:8]([CH3:17])=[C:9]([C:13]([CH3:16])=[CH:14][CH:15]=1)[C:10]([N:12]=[C:21]=[O:22])=[O:11])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(N)=O
Solvent: ClCCCl
Product: Cc1ccc(CNC(=O)C(F)(F)F)c(C)c1C(=O)N=C=O

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 3-((2,2,2-trifluoroacetamido)methyl)-2,6-dimethylbenzamide (1.0 g, 3.6 mmol), oxalyl chloride and EDC (10 mL) to afford 0.900 g of the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12].[Na].[CH2:14]([S:16]([OH:18])=[O:17])[CH3:15]>CS(C)=O>[CH2:14]([S:16]([CH2:2][CH2:3][N:4]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][N:6]=[C:5]1[CH3:12])(=[O:18])=[O:17])[CH3:15]
Reactant: Cc1ncc([N+](=O)[O-])n1CCBr
Reactant: CCS(=O)O
Agent: [Na]
Solvent: CS(C)=O
Product: CCS(=O)(=O)CCn1c([N+](=O)[O-])cnc1C

Procedure:
5.83 g. (25 m moles) of 1-(2'-bromoethyl)-2-methyl-5-nitroimidazole is dissolved in 50 ml. of dimethylsulfoxide and 5.48 g. (30 m mole) of the sodium salt of ethyl sulfinic acid (CH3CH2SO2Na) is added. The reaction mixture is maintained for 21/2 hours at 100°-110° C. thereafter the solvent is removed under vacuum and the solid residue is washed with water and recrystallized from ethanol. The yield is 2.28 (37%) of 1-[2'-(ethylsulfonyl)-ethyl]-2-methyl-5-nitroimidazole, M.P. 124°-126° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C[O:13][P:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([P:14]1(=[O:13])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]2[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=2[O:15]1)=[O:5]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1
Reactant: COP1Oc2ccccc2-c2ccccc21
Product: Cc1ccc(C(=O)P2(=O)Oc3ccccc3-c3ccccc32)c(C)c1
Temperature: 135 °C

Procedure:
33.7 g (0.2 mol) of 2,4-dimethylbenzoyl chloride were warmed to 80° C. under a nitrogen atmosphere. 46 g (0.2 mol) of 6-methoxy-(6H)-dibenz[c,e][1,2]oxaphosphorin were added dropwise with stirring. The batch began to crystallize even during the addition. The temperature when then slowly increased to 135° C. with the proviso that toluene was added as diluent at 90° C. After digestion with toluene, 58 g (83% of theory) of the abovementioned compound of melting point 166° C. were obtained from the crystallizate.
Reaction SMILES: C(=O)([S:3][CH2:4][CH2:5][C:6]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([CH3:8])[CH3:7])C.[OH-].[Na+].O>CO>[SH:3][CH2:4][CH2:5][C:6]([NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:8])[CH3:7]
Reactant: CC(=O)SCCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CCS)NC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of S-3-(benzyloxycarbonylamino)-3-methylbutyl ethanethioate (45.0 g, 152 mmol, prepared as described in WO 2008/083347) in methanol (300 ml) was added 5.0 M NaOH in H2O (60.0 ml, 300 mmol). The solution was stirred for 1 hour, concentrated in vacuo, diluted with saturated NaHSO4 (200 ml), filtered through a coarse glass funnel, and extracted with 5×100 ml ethyl acetate. The organic layers were combined, washed with 100 ml saturated NaCl, dried on MgSO4, and concentrated in vacuo. The residue was used without further purification (24.10 g, 95.1 mmol, 63%).
Reaction SMILES: [ClH:1].[S:2]([O:6][CH2:7][C@H:8]1[O:10][CH2:9]1)([CH3:5])(=[O:4])=[O:3]>>[S:2]([O:6][CH2:7][C@@H:8]([OH:10])[CH2:9][Cl:1])([CH3:5])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OC[C@@H]1CO1
Reactant: Cl
Product: CS(=O)(=O)OC[C@@H](O)CCl
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Concentrated HCl (75 ml) was added to (S)-3-mesyloxy-1,2-epoxypropane (6.8 g, 0.045 m). After stirring for 30 minutes, the water was removed through the addition and subsequent evaporation of ethanol. Finally, the residual ethanol was removed at room temperature and 0.1 mm to give (R)-3-mesyloxy-2-hydroxy-1-chloropropane (7.8 g, 92%). This material was dissolved in ether (50 ml) and methanol (10 ml) in an ice bath and sodium (0.94 g, 0.041 m) was added. After stirring for one hour, the mixture was filtered and concentrated at 30°/25 mm. Added acetone, filtered and reconcentrated at 30°/25 mm. Attempted distillation of the residue led to total decomposition; none of the desired (R)-epichlorohydrin was obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)C.C1(C)C=CC=CC=1>[C:11]1([C:2]2[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#CCc1ncccc1Br
Reactant: OB(O)c1ccccc1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CCc1ncccc1-c1ccccc1
Temperature: 110 °C
Yield: 94.4 %

Procedure:
To a stirred solution of (3-bromo-pyridin-2-yl)-acetonitrile (158) (1 g, 5.07 mmol) and phenyl boronic acid (928 mg g, 7.16 mmol) in a solvent mixture of toluene (25 mL) and ethanol (25 mL) was added K2CO3 (2.1 g, 15.23 mmol). The mixture was degassed by argon, X-Phos (484 mg, 1.01 mmol) and Pd(triphenyl phosphine)4 (586 mg g, 0.51 mmol) were added and the mixture was again degassed. The reaction mixture was refluxed (110° C.) for 4 h. Silica thin layer chromatography was performed (30% ethyl acetate in hexane, Rf=0.45). The catalyst was filtered off through a celite bed, washing with ethyl acetate (3×50 mL) was conducted, the mixture was concentrated, the crude product was purified by a CombiFlash column (eluted at 15% ethyl acetate in hexane) to get (3-phenyl-pyridin-2-yl)-acetonitrile (159) (930 mg, 94.34%) as a light yellow solid.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([NH2:25])[C:16](=[CH:21][C:22]=1[O:23][CH3:24])[C:17](OC)=[O:18].C[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:17](=[O:18])[C:16]2[C:15](=[CH:14][C:13]([O:12][CH3:11])=[C:22]([O:23][CH3:24])[CH:21]=2)[NH:25][C:8]1=[O:9]
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Reactant: Cc1ccccc1N=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2[nH]c(=O)n(-c3ccccc3C)c(=O)c2cc1OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
A solution of o-tolyl isocyanate (13.3 g, 0.10 mol) in toluene (40 ml) is metered at room temperature into a solution of methyl 4,5-dimethoxyanthranilate (21.1 g, 0.10 mol) in toluene (70 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. 1.80 ml of a 30% strength solution of methanolic sodium methoxide (0.010 mol) are metered in and the mixture is stirred at 90° C. for a further 1 hour, methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×30 ml of toluene. The toluene-moist precipitate is treated with dilute sulfuric acid and the residual toluene is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 29.0 g of 3-(2-tolyl)-6,7-dimethoxy-2,4(1H,3H)-quinazolinedione (yield: 92.9% of theory) of melting point 282° to 284° C. are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CC(C)=O>[CH2:38]([O:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4OCc4ccccc4)ncn3)cccc2s1
Temperature: 70 °C
Yield: 12.4 %

Procedure:
To a mixture of N-{4-[6-(2-hydroxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 137), (0.20 g, 0.50 mmol) and potassium carbonate (0.062 g, 0.45 mmol, Aldrich) in anhydrous acetone (2 mL) was added benzyl bromide (0.053 mL, 0.45 mmol, Aldrich) and the reaction mixture was heated at 70° C. for 2 h. The solvent was removed under vacuum and the residue was diluted with water (50 mL) and extracted with ether (2×100 mL). The combined organic extracts were washed with water (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by silica gel chromatography (gradient: 5–60% EtOAc/hexanes) to obtain the title compound (0.030 g, 13%) as a white solid. Mp: 201–203° C. MS (ESI, pos. ion.) m/z: 537 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].BrC[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([O:11][C:16]2[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=2)[CH:8]=[C:7]([O:12][C:16]2[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=2)[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Reactant: N#Cc1cccc(CBr)c1
Product: CCOC(=O)c1cc(Oc2cccc(C#N)c2)cc(Oc2cccc(C#N)c2)c1
Yield: 75.3 %

Procedure:
3,5-Dihydroxy benzoic acid ethyl ester (1.45 g, 7.95 mmol) and 3-bromomethyl-benzonitrile (6.23 g, 31.8 mmol) and other reagents as described in Example 75(a) were used to afford 2.3 g of the required product. 1H NMR (DMSO-d6): 1.15 (3H, t), 4.15 (2H, q), 5.3 (4H, s), 7.0 (1H, s), 7.18 (2H, s), 7.64 (4H, d), 7.86 (4H, d).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].Br[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>CCOCC>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:5][CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COC(CN)OC
Solvent: CCOCC
Product: COC(CNCC(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of aminoacetaldehyde dimethyl acetal (2.2 ml, 0.04 mole) in ether (10 ml) was cooled to 0° C. Benzyl bromoacetate (1.6 ml, 0.02 mole) was added. After stirring at ambient temperature overnight, the solid aminoacetaldehyde dimethyl acetal hydrobromide was filtered and the solution was concentrated to an oil. Flash chromatography on silica (LPS-1) (40:60 ethyl acetate:hexane eluant) gave 2.2 gms of the purified title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:23][CH2:22][CH2:21][C@H:5]1[C:6]([NH:8][C@H:9]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=O)=[O:12])[CH3:10])=[O:7])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:39]([O:41][C:42](=[O:56])[C:43]([C:51](=[O:55])[CH:52]([CH3:54])[OH:53])([CH2:45][C:46](=[O:50])[N:47]([CH3:49])[NH2:48])[OH:44])[CH3:40]>C(#N)C>[CH2:39]([O:41][C:42](=[O:56])[C:43]([C:51](=[O:55])[CH:52]([CH3:54])[OH:53])([CH2:45][C:46](=[O:50])[N:47]([CH3:49])[NH:48][C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:6](=[O:7])[C@@H:5]1[CH2:21][CH2:22][CH2:23][N:4]1[C:1](=[O:3])[CH3:2])[OH:44])[CH3:40]
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(O)(CC(=O)N(C)N)C(=O)C(C)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC#N
Product: CCOC(=O)C(O)(CC(=O)N(C)NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(C)=O)C(=O)C(C)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 0.00185 moles of acetylprolylalanylproline and 0.20 ml of N-methylmorpholine in 20 ml of acetonitrile is cooled to -20° by means of a Dry Ice acetone bath. To this is added 0.28 ml of isobutyl chloroformate. After stirring for 10 minutes at -20° there is added 0.00185 moles of 2-azaalanyllactyllactic acid ethyl ester in 5 ml of acetonitrile. The reaction mixture is allowed to warm to room temperature after which it is stirred for 2 hours and then concentrated in vacuo. The residue is extracted between 50 ml of methylene chloride and 20 ml of cold 0.25 N hydrochloric acid. The acid layer is backwashed 2 times with 25 ml of methylene chloride. The organic extracts are combined, dried over sodium sulfate and concentrated in vacuo to give a glass. This residue is chromatographed on 75 gm of silica gel. Elution with methanol/methylene chloride (1-4%) gives pure acetylprolylalanylprolyl-2-azaalanyllactyllactic acid ethyl ester.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([Cl:18])[C:15]([I:17])=[CH:16][C:11]=3[N:10]=[C:9]2S(C)(=O)=O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:35]([O:37][P:38]([C:43]1[CH:48]=[C:47]([OH:49])[CH:46]=[CH:45][C:44]=1[CH3:50])(=[O:42])[O:39][CH2:40][CH3:41])[CH3:36]>CN(C=O)C>[CH2:40]([O:39][P:38]([C:43]1[CH:48]=[C:47]([O:49][C:9]2[N:8]([CH2:7][C:4]3[CH:5]=[CH:6][C:1]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:2][CH:3]=3)[C:12]3[CH:13]=[C:14]([Cl:18])[C:15]([I:17])=[CH:16][C:11]=3[N:10]=2)[CH:46]=[CH:45][C:44]=1[CH3:50])(=[O:42])[O:37][CH2:35][CH3:36])[CH3:41]
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2n1Cc1ccc(-c2ccccc2)cc1
Reactant: CCOP(=O)(OCC)c1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(Oc2nc3cc(I)c(Cl)cc3n2Cc2ccc(-c3ccccc3)cc2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-biphenyl-4-ylmethyl-6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (1.2 g, 2.3 mmol) in DMF (10 ml) at rt was added K2CO3 (635 mg, 4.6 mmol), followed by (5-hydroxy-2-methyl-phenyl)-phosphonic acid diethyl ester (630 mg, 2.6 mmol). The mixture was stirred overnight at rt. The solvent was then removed on a rotary evaporator. The resulting residue was partitioned between EtOAc and a solution of half-saturated ammonium chloride. The EtOAc layer was washed with H2O, brine, and then dried with MgSO4. After rotary evaporation, the residue was purified by flash chromatography (SiO2, 12 g). The title compound was eluted with a gradient up to 50% EtOAc in Hexane as a mixture of the two protected regioisomers.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C1N2CN3CN(C2)CN1C3.[C:20](O)(=[O:22])C.O>>[OH:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([CH:20]=[O:22])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cccc(C)c1O
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: Cc1cc(C=O)cc(C)c1O
Temperature: 100 °C

Procedure:
2,6-Dimethylphenol (0.34 g/mL) and hexamethylenetetramine (2 eq.) are dissolved in 2:1 acetic acid/water mixture. The whole is heated at 100° C. for 4 hours. The reaction mixture is cooled to room temperature and poured into a water/ice mixture. The precipitate is drained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[C:30]1([C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2CBr)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:12][CH2:13][N:14]([CH2:17][C:43]3[CH:42]=[CH:41][CH:40]=[CH:37][C:36]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:15][CH2:16]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: BrCc1ccccc1-c1ccccc1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3-c3ccccc3)CC1)O2
Yield: 69.7 %

Procedure:
(E)-3-{4-Oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (169 mg, 0.500 mmol, Intermediate 1, hydrochloride salt) was alkylated using 2-phenylbenzyl bromide (0.18 ml, 1.0 mmol) following the procedure described in Example 2, Step A, giving (E)-3-{1′-(biphenyl-2-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (163 mg) as a white solid. The intermediate was hydrolyzed as described in Example 55, Step B, giving (E)-3-{1′-(Biphenyl-2-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (162 mg) as a white solid (hydrochloride salt). The acid was suspended in DCM (5 ml), TEA (0.07 ml, 0.47 mmol) was added, and the clear solution was treated with NH2OTHP following the procedure described in Example 1, Step B, giving (E)-3-{1′-(biphenyl-2-yl-methyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (163 mg) as a light yellow solid. The compound was dissolved in DCM (5 ml) and treated with 4 M HCl in dioxane (0.4 ml, 1.6 mmol) as described in Example 55, Step D, giving a light yellow solid (114 mg, hydrochloride salt).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Mg+2].[Cl-].[Cl-].[F:14][C:15]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:16]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:20]1[CH:16]=[C:15]([F:14])[C:23]([F:24])=[C:22]([F:25])[C:21]=1[F:26])[CH3:9]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium ethyl malonate (3.66 g, 21.5 mmol), MgCl2 (2.44 g, 25.7 mmol) and TEA (2.05 g, 20.3 mmol) were mixed in acetonitrile (70 ml) at 10–15° C. for 2.5 hr. 2,3,4,5-tetrafluorobenzoyl chloride (2.00 g, 10.3 mmol) in acetonitrile (10 ml) was added at 0° C. over 15 min followed by a second addition of TEA (0.23 g, 2.3 mmol). After allowing to warm to RT, the mixture was stirred for 16 hr. After removal of volatiles in vaccuo Toluene (30 ml) was added and removed in vacuo. Following the addition of toluene (60 ml), HCl 1.5 M (40 ml) was added cautiously, ensuring the temperature did not exceed 25° C. The organic fraction was washed with HCl 1.5 M (2×25 ml) and water (2×25 ml), dried over MgSO4 and reduced to a light orange oil in vacuo ([M+1]+ 265, 98%).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].N[C:9]1[CH:13]=[CH:12][NH:11][C:10]=1[C:14](OCC)=[O:15]>C(O)C>[N:6]1[C:9]2[CH:13]=[CH:12][NH:11][C:10]=2[C:14](=[O:15])[NH:7][CH:5]=1
Reactant: N=CN
Reactant: CCOC(=O)c1[nH]ccc1N
Solvent: CCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc[nH]c12
Yield: 85.2 %

Procedure:
Formamidine acetate (20 g, 0.19 mol.) was added to a solution of crude 2-ethoxycarbonyl-3-aminopyrrole (14) (15.3 g, 0.1 mol.) in ethanol (150 ml) and the solution was heated under reflux for 16 h and then cooled. The solid formed was filtered, washed with ethanol and dried to give 3H,5H-pyrrolo[3,2-d]pyrimidin-4-one (1) (11.5 g, 85.2 mmol.). Recrystallized from water it had mp >300° C. 1H NMR (d6-DMSO) was as reported3. 13C NMR δ 154.0, 145.0, 141.8, 127.7, 118.2, 103.3.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Br[CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22](=[O:27])[CH2:21][N:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H]1CCC2(CCN(CC(=O)C(C)(C)C)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of the piperidine (B5) (24 mg, 0.09 mmol), 1-bromo -3,3-dimethylbutan-2-one (13.5 mg, 0.08 mmol) and sodium carbonate (32 mg, 0.3 mmol) in DMF (1 ml) was stirred at 50° C. in a sealed vial for 16 hours. The mixture was cooled and carefully neutralized with TFA and purified by reverse phase HPLC to give the title compound no. 19 as a TFA salt. LC-MS: m/e=357.30 (M+H). Rt=1.61 min. 1H-NMR (500 MHz, DMSO-d6): 9.60 (br. s, 1H), 8.21 (d, 1H), 7.44 (d, 1H), 7.32 (t, 1H), 7.20 (t, 1H), 7.16 (d, 1H), 4.92 (q, 1H), 4.60 (d, 2H), 3.26 (m, 4H), 2.35 (m, 2H), 2.04 (dd, 1H), 1.87 (s, 3H), 1.80 (m, 3H), 1.71 (d, 1H), 1.63 (m, 1H), 1.16 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[CH2:4][O:3]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32])/[C:23](=[N:25]/O)/[NH2:24]>N1C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[C:22]([C:23]2[N:25]=[C:13]([C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:7][CH:5]4[CH2:4][O:3][C:2]([CH3:18])([CH3:1])[O:6]4)=[CH:10][CH:11]=3)[O:14][N:24]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)Oc1ccc(/C(N)=N/O)cc1Cl
Reactant: CC1(C)OCC(COc2ccc(C(=O)Cl)cc2)O1
Solvent: c1ccncc1
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OCC4COC(C)(C)O4)cc3)n2)cc1Cl
Temperature: 200 °C
Yield: 56.7 %

Procedure:
In a 25 mL microwave tube 4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)benzoyl chloride (0.483 g, 1.784 mmol) and (Z)-3-chloro-N′-hydroxy-4-isopropoxybenzimidamide (0.272 g, 1.189 mmol) in pyridine (15 mL) were combined to give an orange solution. The vessel was capped and the reaction heated at 200° C. for 20 min under microwave irradiation (Biotage Optimizer, 300 W). The mixture was cooled, the solvent was removed to afford a yellow solid, which was partitioned between water (100 mL) and EtOAc (50 mL), extracted by EtOAc (2×30 mL), the combined EtOAC layer was washed by water (2×30 mL), and concentrated to afford a yellow solid, which was purified via silica gel chromatography (40 g, 30% EtOAc:Heptane) to afford 3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.3 g, 0.674 mmol, 56.7% yield) as white solid. LC/MS (30—95 NH4OAc 4m GC8.olp) Rt=3.22 min.; MS m/z: 445.31 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSOδ ppm 8.17-8.09 (m, 2H), 8.05 (d, J=2.13 Hz, 1H), 7.99 (dd, J=8.64, 2.15 Hz, 1H), 7.38 (d, J=9.01 Hz, 1H), 7.26-7.19 (m, 2H), 4.88-4.77 (m, 1H), 4.45 (s, 1H), 4.23-4.07 (m, 3H), 3.79 (dd, J=8.42, 6.29 Hz, 1H), 1.35 (m, 12H).