Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+]>CO>[C:10]([C:7]1[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccccc2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(C(=O)c2ccccc2)o1

Procedure:
The crude ester (8) (80 mg, 0.35 mmol) was hydrolysed using Method C, except that MeOH (0.8 mL) and 1 M NaOH (0.8 mL) were used. After the reaction, the solvent was removed under a stream of nitrogen gas, acidified using 1N HCl, extracted with EtOAc, dried (MgSO4), filtered and the solvent concentrated in vacuo to give the crude title compound. Yield: 48 mg; HPLC Purity: >66%; LC tr 0.09 min
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20](=[O:26])[C:21]2[S:25][CH:24]=[CH:23][CH:22]=2)[C:3]1=[O:27].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1>O1CCCC1>[O:27]=[C:3]1[CH:2]([NH:1][C:35]([NH:34][C:30]2[CH:29]=[C:28]([CH3:37])[CH:33]=[CH:32][CH:31]=2)=[O:36])[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]1[CH2:19][C:20](=[O:26])[C:21]1[S:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2cccs2)C1=O
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)c3cccs3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
A mixture of 0.26 g 3-amino-1,3-dihydro-5-phenyl-1-(2-thenoyl)methyl-2H-1,4-benzodiazepin-2-one, 95 mg 3-tolylisocyanate and 5 ml tetrahydrofuran was stirred at room temperature for two hours. The solvent was distilled off from the reaction mixture under reduced pressure, a 1:1 mixture of toluene and diethyl ether (5 ml) was added to the residue, and the crystals were collected by filtration, thus giving 0.2 g of 1-[2,3-dihydro-2-oxo-5-phenyl-1-(2-thenoyl)methyl-1H-1,4-benzodiazepin-3-yl]-3-(3-tolyl)urea.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[C:19](=[O:24])[O:20][C@@H:21]([CH2:22][OH:23])[C@H:14]1[CH2:13][CH2:12]2)C1C=CC=CC=1.O>C(O)C.O1CCCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]1[C:19](=[O:24])[O:20][C@@H:21]([CH2:22][OH:23])[C@H:14]1[CH2:13][CH2:12]2
Reactant: O=C1O[C@@H](CO)[C@H]2CCc3cc(OCc4ccccc4)ccc3N12
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: O=C1O[C@@H](CO)[C@H]2CCc3cc(O)ccc3N12
Yield: 50.8 %

Procedure:
3.0 g (9.2 mmol) of trans-7-benzyloxy-3-hydroxymethyl-3,3a,4,5-tetrahydro-1H-oxazolo[3,4-a]quinolin-1-one, dissolved in 20 ml of ethanol and 40 ml of tetrahydrofuran, are hydrogenated for 1 h in the presence of 1 g of 10% palladium-on-charcoal containing 50% of water. The mixture is then filtered on silica and the solvent is evaporated off under reduced pressure. 1.1 g of product are obtained.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3](=O)/[CH:4]=[CH:5]/OCC.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]1[CH:4]=[CH:5][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]=1
Reactant: CCO/C=C/C(=O)C(Cl)(Cl)Cl
Reactant: Nc1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: ClC(Cl)(Cl)c1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Yield: 100.4 %

Procedure:
(E)-1,1,1-trichloro-4-ethoxybut-3-en-2-one (6.1 g, 28.0 mmol) was added to a solution containing 1H-benzo[d]imidazol-2-amine (3.73 g, 28.0 mmol) and Triethylamine (3.91 mL, 28.0 mmol) in Toluene (Volume: 100 mL). Heated the reaction to 120° C. for 2 hours. Let the reaction cool to room temperature and concentrated under vacuum. Diluted with water and filtered. Collected solid and dried under vacuum to afford crude 2-(trichloromethyl)benzo[4,5]imidazo[1,2-a]pyrimidine (8.04 g, 28.1 mmol, 100% yield).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:48](Cl)(=[O:51])[CH2:49][CH3:50]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:47]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38](=[O:46])[CH2:39][CH:40]1[CH2:45][CH2:44][N:43]([C:48](=[O:51])[CH2:49][CH3:50])[CH2:42][CH2:41]1
Reactant: CCC(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 31 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide bis(trifluoroacetate) and propanoyl chloride as starting materials in 31% yield. LCMS for C28H32ClN6O2 (M+H)+: m/z=519.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:17])[N:10]=[C:9](Cl)[N:8]=1.[OH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([Cl:17])[N:10]=[C:9]([N:28]2[CH2:29][CH2:30][CH:25]([OH:24])[CH2:26][CH2:27]2)[N:8]=1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Reactant: OC1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)nc(N2CCC(O)CC2)nc1NCc1ccc(OC)c(Cl)c1
Reaction time: 0.25 h

Procedure:
To a solution of 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-2,6-dichloropyrimidine (prepared in the above (2)) 1.01 g in dimethylformamide 10 ml are added 4-hydroxypiperidine 338 mg and triethylamine 411 mg at room temperature, and the mixture is stirred for 15 minutes. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give a slightly yellow oil. The oil is separated with silica gel chromatography (solvent; chloroform:ethyl acetate=8:1→5:1), and further separated with silica gel chromatography (solvent; hexane:ethyl acetate=1:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-chloro-2-(4-hydroxypiperidin-1-yl)pyrimidine as colorless crystals 540 mg (mp 138-139° C.) and 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-chloropyrimidine as a colorless foam, 617 mg.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][CH:12](OCC)OCC.[OH-].[Na+]>C1COCC1.O>[C:2]1([C:1]2[S:8][CH:11]=[CH:12][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(CBr)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 34 %

Procedure:
To a solution of thiobenzamide (1 g, 7.3 mmol) in THF (10 ml) was added a solution of 2-bromo-1,1-diethoxy-ethane (1.4 g, 7.3 mmol) in THF (5 ml) and the reaction was heated at reflux overnight. The reaction mixture was cooled to room temperature and diluted with water (50 ml). The solution was basified with dilute sodium hydroxide and extracted with ethyl acetate: pet ether (1:4). The organic layer was then washed with water, brine and dried. Evaporation gave a residue which was purified by column chromatography over silica gel using EtOAc/pet ether as eluent to give 2-phenyl thiazole (400 mg, 34%) as solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc(C#Cc2ccc(-c3ccccc3C)nc2)cs1
Temperature: 80 °C

Procedure:
2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (1.0 mmol, 234 mg), 2-methylphenylboronic acid (2.0 mmol, 272 mg), dichlorobis(triphenylphosphine)palladium(II) (0.05 mmol, 35 mg), and potassium carbonate (3.5 mmol, 500 mg) were added to deoxygenated DME:water (1:1, 5 mL) at room temperature. The reaction was heated for 18 h at 80° C., then partitioned in a separatory funnel with EtOAc (100 mL) and water (30 mL). The organic layer was washed with one additional portion of water (20 mL) and the combined aqueous layers back extracted with EtOAc (50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with a 0% to 60% EtOAc gradient in hexanes, to afford the title compound as a tan solid, which was dissolved in ether and precipitated as the hydrochloride salt with 1M HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 9.14 (s, 1H), 8.76 (d, 1H), 8.18 (d, 1H), 8.03 (s, 1H), 7.44-7.61 (m, 4H), 2.76 (s, 3H), 2.26 (s, 3H). MS (ESI) 291.2 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH3:21])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[CH3:21][C@@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CNCCN1C(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl 4-benzyl-(2R)-methyl-1-piperazinecarboxylate (XXII, 5.40 g), ethanol (200 ml) and Pearlman's catalyst (1.36 g) is hydrogenated (36 psi) for 16 hr at 20-25° in a Parr flask. The mixture is filtered and the solids washed successively with ethanol, methylene chloride and methanol. The combined filtrates are concentrated, diluted with methylene chloride, filtered, and concentrated to give the title compound which solidified upon standing, mp 33-36°; [α]25D -59° (CHCl3); IR (mineral oil) 1695, 1408, 1363, 1301, 1226, 1173 and 1095 cm-1 ; NMR (CDCl3) 4.1-4.3, 3.7-3.85, 2.6-3.05, 1.84, 1.46 and 1.22 δ; MS (EI) 200, 144, 127, 99, 70 and 57.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([S:50](Cl)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>N1C=CC=CC=1.ClCCl.C(Cl)(Cl)Cl>[CH2:1]([O:19][CH2:20][CH:21]([CH2:23][O:24][C:25]([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:22][S:50]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:52])=[O:51])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
To a stirred solution of (rac)-1-O-octadecyl-3-O-trityl-glycerol (30.52 g) in a mixture of pyridine (41.08 g) and dichloromethane (250 ml) was dropwise added a solution of benzenesulfonyl chloride (18.36 g) in chloroform (50 ml) during a period of 10 minutes below 10° C. After stirring for 2 days at ambient temperature, the reaction mixture was refluxed for 8 hours. To the reaction mixture, were dropwise added pyridine (12.75 g) and benzenesulfonylchloride (5.7 g) successively. After stirring for 2 hours at room temperature, the reaction mixture was allowed to stand for 2 days. The reaction mixture was washed with water, 0.5N aqueous sulfuric acid, water, aqueous sodium bicarbonate and water, successively. The solution was dried over magnesium sulfate and evaporated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (450 g, elution by benzene) to give 37.4 g of (rac)-1-O-octadecyl-2-O-benzenesulfonyl-3-O-trityl-glycerol as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[S:8][CH:9]=[N:10][C:4]=2[CH2:3]1.CCCCCC.C([Li:21])CCC.[C:22](=[O:24])=[O:23]>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[S:8][C:9]([C:22]([O-:24])=[O:23])=[N:10][C:4]=2[CH2:3]1.[Li+:21]
Reactant: O=C=O
Reactant: CN1CCc2scnc2C1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCc2sc(C(=O)[O-])nc2C1
Product: [Li+]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In anhydrous tetrahydrofuran (10 ml) was dissolved 5-methyl-4,5,6,7-tetrahydrothiazolo[4,5-c]pyridine (583 mg), followed by the dropwise addition of a hexane solution (1.54M, 2.70 ml) of n-butyl lithium at −78° C. After stirring for 10 minutes, the reaction mixture was warmed up to 0° C. and stirring was conducted for 30 minutes. The reaction mixture was cooled to −78° C. A carbon dioxide gas was blown into the reaction mixture for 15 minutes, followed by warming up to room temperature. The reaction mixture was concentrated under reduced pressure, whereby the title compound (820 mg) was obtained as a pale brown foamy solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]([OH:9])=[O:8])=[N:4][O:5][N:6]=1.O=S(Cl)Cl.[CH3:14][CH2:15]O>>[NH2:1][C:2]1[C:3]([C:7]([O:9][CH2:14][CH3:15])=[O:8])=[N:4][O:5][N:6]=1
Reactant: CCO
Reactant: Nc1nonc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nonc1N
Yield: 50 %

Procedure:
To a solution of 4-amino-1,2,5-oxadiazole-3-carboxylic acid (0.25 g, 1.9 mmol) in 2 mL of EtOH was added SOCl2 (0.2 mL) dropwise, under cooling with an ice-bath. The resulting mixture was refluxed for 4 hours and then concentrated. The oil was diluted with 50 mL of H2O and extracted with diethyl ether (3×100 mL). The combined organic layer was dried over MgSO4 and concentrated to give a white solid (0.15 g, 50%). 1H NMR (DMSO, 500 MHz) δ 6.39 (s, 2H), 4.39 (q, 2H), 1.35 (t, 3H). Mass Spec. FIA MS 158.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][NH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1.[H-].[Na+].I[CH:30]([CH3:32])[CH3:31].O>CN(C)C=O>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:26]=[CH:25][N:24]([CH:30]([CH3:32])[CH3:31])[N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:3]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4nc[nH]n4)nn23)no1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C(C)C)n4)nn23)no1
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
To a stirred solution of 3-(5-methylisoxazol-3-yl)-6-(1,2,4-triazol-3-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine (100 mg, 0.29 mmol) in N,N-dimethylformamide (6 ml) at room temperature under nitrogen was added sodium hydride (17 mg, 0.41 mmol). The mixture was cooled to 0° C. and 2-iodopropane (0.04 ml, 0.36 mmol) added after 0.25 h. The mixture was left to stir at room temperature overnight, water was added and the precipitate filtered off. The crude product was flash chromatographed on silica gel, eluting with ethyl acetate→4% methanol/ethyl acetate, to give the title-product (25 mg, 22%), mp 179-181° C.; 1H NMR (360 MHz, CDCl3) δ 1.58 (6H, d, J=6.7 Hz, 2 of CH3), 2.59 (3H, s, CH3), 4.58 (1H, septet, J=6.7 Hz, CH), 5.72 (2H, s, CH2), 7.01 (1H, s, Ar—H), 7.78 (1H, t, J=7.2 Hz, Ar—H), 7.94 (1H, t, J=7.6 Hz, Ar—H), 8.13 (1H, s, Ar—H), 8.28 (1H, d, J=7.9 Hz, Ar—H), 8.80 (1H, d, J=7.4 Hz, Ar—H); MS (ES30) m/e 391 [MH]+; Anal. Found. C, 56.81; H, 4.68; N, 27.89; C19H18N8O2.0.7H2O requires C, 56.62; H, 4.85; N, 27.80%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N2CCOCC2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 120 °C
Yield: 33.1 %

Procedure:
To a 5 mL Wheaton vial was added was added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (100 mg, 0.41 mmol) and morpholine (Aldrich Chemical Company) (0.18 mL, 2.1 mmol). A solution of K2CO3 (0.37 g, 2.7 mmol) in H2O (2.5 mL) was added, the vial was securely capped, and the reaction mixture was heated at 120° C. for 2 h. The reaction mixture was allowed to cool to room temperature and the resulting light-pink precipitate was collected by filtration, recrystallized from EtOAc and dried overnight in a 60° C. vacuum oven to give 0.04 g (33%) of the title compound as a white solid. Mp: 276° C. (dec.) 1H NMR (CDCl3; 500 MHz): δ 2.62 (s, 3), 3.87 (s, 4), 3.90 (s, 4), 6.79 (s, 1), 7.41 (t, 1, J=6.8), 7.48 (t, 2, J=7.4), 7.67 (d, 2, J=6.8), 8.17 (br s, 1). MS m/z: 295 (M+1). Anal. Calcd for C17H18N4O.0.25 H2O: C 68.32, H 6.24, N 18.75. Found: C 67.90, H 6.02, N 18.64.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=O)[O:28]C(C)(C)C)[CH3:25])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:34])[CH2:3][CH2:2]1.Cl.[C:36](OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([F:34])=[CH:8][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([O:22][CH2:23][C@@H:24]([NH:26][C:27](=[O:28])[CH3:36])[CH3:25])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:10][C:11]=2[F:12])[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl ((2S)-1-((2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)carbamate (2.60 g) was added 4 M hydrogen chloride/ethyl acetate (10 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (10 mL) and acetic anhydride (10 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/methanol, and the solution was subjected to silica gel column chromatography (NH, ethyl acetate). The solvent was evaporated, and the obtained solid was washed with diethyl ether to give the title compound (1.39 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:39]3[CH:40]=[CH:41][C:36]([C:33]4[CH:34]=[CH:35][CH:30]=[CH:31][CH:32]=4)=[CH:37][CH:38]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Sc2c(C)n(-c3ccc(-c4ccccc4)cc3)c3cc(Cl)ccc23)c1
Temperature: 170 °C

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.100 g, 0.3 mmol) was combined with CuO (0.0024 g, 0.03 mmol), potassium carbonate (0.041 g, 0.3 mmol) and 4-bromobiphenyl (0.0699 g, 0.3 mmol) in DMF (150 μL) and the reaction was heated to 170° C. overnight. After cooling the reaction was submitted to standard aqueous workup to give the title compound as a crude mixture that was taken directly to the next step without purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2N=N[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:11][C:10]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1.[CH:28](N1CCCC1)=[CH2:29]>C(Cl)(Cl)Cl>[C:20]1([C:10]2[N:11]=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:29]=[CH:28][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1nnc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1
Reactant: C=CN1CCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)c(-c2ccccc2)n1

Procedure:
Following General Procedure D, ethyl 6-(4-trifluoromethylphenyl)-5-phenyl-1,2,4-triazine-3-carboxylate (Compound 15), (378 mg, 1.01 mmol) and crude 1-vinylpyrrolidine (Compound 38, 780 mg) in CHCl3 (10 ml) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:25][C:26]1[NH:27][CH:28]=[CH:29][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:27]3[CH:28]=[CH:29][N:30]=[C:26]3[CH3:25])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[CH:8][CH:9]=1
Reactant: Cc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 125 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methylphenoxy)propyl]oxazole (30.0 g), 2-methylimidazole (20.6 g), potassium carbonate (34.6 g), and N,N-dimethylformamide (50 ml) was stirred at 125° C. for 1 hour. The reaction mixture was poured into ice water (500 ml). The precipitated crystals were filtered, washed in sequence with water and isopropyl ether, and air-dried to give crude crystals of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole (34.5 g).
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[CH:14][C:13]=1[C:22]1[C:23](=[O:37])[O:24][C:25]2[C:30]([C:31]=1[CH3:32])=[CH:29][CH:28]=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=2.[CH:38](OC1C=CC=CC=1)=[O:39]>C1COCC1>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][O:20][CH3:21])[CH:15]=[CH:14][C:13]=1[C:22]1[C:23](=[O:37])[O:24][C:25]2[C:30]([C:31]=1[CH2:32][CH:38]=[O:39])=[CH:29][CH:28]=[C:27]([O:33][CH2:34][O:35][CH3:36])[CH:26]=2
Reactant: O=COc1ccccc1
Reactant: COCOc1ccc(-c2c(C)c3ccc(OCOC)cc3oc2=O)c(OCOC)c1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1ccc(-c2c(CC=O)c3ccc(OCOC)cc3oc2=O)c(OCOC)c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a clean dry 200 ml flask purged with nitrogen was added diisopropylamine (2.7 ml, 19.5 mmol, 3 eq), dry THF (50 mL) and 3-(2,4-Bis-methoxymethoxy-phenyl)-7-methoxymethoxy-4-methyl-chromen-2-one (8.1 mL, 16.25 mmol, 2.5 eq.) at −78° C. After 30 minutes, to this solution was added drop-wise, a solution of 3-(2,4-bis-methoxymethoxy-phenyl)-7-methoxymethoxy-4-methyl-chromen-2-one (2.7 g, 6.5 mmol, 1 eq.) in dry THF (13 mL). The solution was warmed to −10° C. and stirred at this temperature for 30 minutes. Phenyl formate (3.6 ml, 33 mmol, 5 eq) was then added slowly into the reaction mixture. The reaction mixture was then stirred for 30 mins, quenched with saturated aqueous NH4Cl, extracted with ethyl acetate and then concentrated to yield th title product as a crude solid which was purified by flash chromatography eluting with 30% ethyl acetate in hexane to yield the title product as a solid.