Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.BrC1C=CC=CC=1C.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].Cl>O1CCCC1>[C:18]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc(Br)cc1
Agent: Cc1ccccc1Br
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 28.5 g. (1.17 g. atoms) magnesium turnings in 150 ml. tetrahydrofuran under a nitrogen atmosphere there is added 10 ml. of 4-bromo toluene (1.17 mole) in 650 ml. dry tetrahydrofuran; the reaction is started and the remainder of the bromo toluene solution is added dropwise at a rate that maintains a moderate reflux. After the addition is complete, the mixture is refluxed for an additional 11/2 hours. The resulting Grignard solution is added dropwise to a cold solution of 128.0 g. pivaloyl chloride (1.06 mole) in 500 ml. dry tetrahydrofuran at a rate that maintains the temperature at 0° to -5° C. The solution is stirred for an additional 11/2 hours at 0° C. and then at room temperature for 18 hours. The mixture is then cooled to 0° C. and hydrolyzed by the addition of 100 ml. 2N hydrochloric acid. The layers are separated and 200 ml. of ether is added to the organic phases which is then washed respectively with 100 ml. 2N hydrochloric acid, 100 ml. 10% sodium bicarbonate solution, and 100 ml. saturated sodium chloride. The resulting layer is dried over anhydrous sodium sulfate, filtered, and the solvent is removed in vacuo to give p-pivaloyl toluene (b.p. 80° to 84° C./0.7 mm, nC21 1.5108). A mixture of 156.3 g. (0.886 mole) of the resulting p-pivaloyl toluene is then added to 157.8 g. (0.886 mole) N-bromosuccinimide, 4.0 g. (0.016 mole) benzoyl peroxide and 150 ml. carbon tetrachloride and heated at reflux for 18 hours. The mixture is cooled and filtered and the resulting oil is distilled in vacuo to give α-bromo-p-pivaloyl toluene (b.p. 124°-132° C/0.7 mm, nD22 1.5546-V.P.C. 96% monobromo 4%-dibromo).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12](O)=[O:13])[CH:9]=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][N:60]1[CH:64]=[CH:63][C:62]([NH2:65])=[N:61]1>CN(C=O)C.O>[CH2:1]([C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([NH:65][C:62]3[CH:63]=[CH:64][N:60]([CH3:59])[N:61]=3)=[O:13])[CH:9]=[C:8]([O:15][C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=3)[C:6]=2[CH:7]=1)[CH3:2]
Reactant: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)O)cc2o1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1cc2c(Oc3ccc(S(C)(=O)=O)cc3)cc(C(=O)Nc3ccn(C)n3)cc2o1
Reaction time: 8 h
Yield: 22.7 %

Procedure:
A solution of 2-ethyl-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylic acid (400 mg, 1.1 mmol), HATU (635 mg, 1.6 mmol) and DIPEA (214 mg, 1.6 mmol) in DMF (20 mL) was stirred for 1 h. Then, 1-methyl-1H-pyrazol-3-amine (129 mg, 1.3 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 1:1). The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4, concentrated and purified by preparative HPLC to afford the desired product (109.5 mg, 22%) as a yellow solid. 1H NMR (400 MHz, DMSO): δ 10.89 (s, 1H), 8.15 (s, 1H), 7.94 (d, 2H), 7.65 (s, 1H), 7.00 (s, 1H), 7.24 (d, 2H), 6.61 (s, 1H), 6.55 (d, 2H), 3.77 (s, 3H), 3.20 (s, 3H), 2.82 (q, 2H), 1.25 (t, 3H); MS (APCI, pos): 440.3.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:3]([N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:33]([NH:40][C:41](=[O:49])[NH:42][C@H:43]([CH3:48])[CH2:44][C:45](O)=[O:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[CH2:14]([N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:45](=[O:46])[CH2:44][CH:43]([NH:42][C:41]([NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:49])[CH3:48])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[CH:26][CH:27]=1)=[O:4])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(CN(Cc1ccccc1)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: C[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(CN(Cc1ccccc1)C(=O)C(Cc1ccc(OC(C)(C)C)cc1)NC(=O)CC(C)NC(=O)NCc1ccccc1)OCC
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2 (50 ml) was added a solution of (3R)-3-(3-Benzyl-ureido)-butyric acid (1.44 g, 6.1 mmol), EDCI (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mmol) in CH2Cl2 (100 ml) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 661 (M+H), 683 (M+Na)
Reaction SMILES: [OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6](=[O:14])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:22])[C:3]=1[C:23](OCC)=[O:24].[N:28](C1C=CC=CN=1)=C=O.[H-].[Na+].C1(CNC([CH:49](C(OCC)=O)[C:50]([O:52]CC)=[O:51])=O)C=CC=CC=1>O1CCOCC1.ClCCl>[OH:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:6](=[O:14])[N:5]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4](=[O:22])[C:3]=1[C:23]([NH:28][CH2:49][C:50]([OH:52])=[O:51])=[O:24]
Reactant: CCOC(=O)C(C(=O)NCc1ccccc1)C(=O)OCC
Reactant: CCOC(=O)c1c(O)n(-c2ccccn2)c(=O)n(Cc2ccccc2)c1=O
Reactant: O=C=Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CNC(=O)c1c(O)n(-c2ccccn2)c(=O)n(Cc2ccccc2)c1=O
Temperature: 110 °C
Yield: 12 %

Procedure:
Ethyl 6-hydroxy-2,4-dioxo-3-(phenylmethyl)-1-(2-pyridinyl)-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate. 2-Isocyanatopyridine (265 mg, 2.2 mmoles) was added to a suspension of sodium hydride (200 mg, 5 mmoles) and diethyl {[(phenylmethyl)amino]carbonyl}propanedioate (example 1a, 425 mg, 1.45 mmoles) in anhydrous dioxane (10 mL). The mixture was heated in a microwave reactor at 110° C. for 1 hour, cooled, dissolved in dichloromethane, washed with 1 molar hydrochloric acid and purified by flash chromatography (ethyl acetate-10% methanol in ethyl acetate) to give the title compound (90 mg, 12%) 1H NMR (400 MHz, DMSO-d6) δ ppm 8.93 (dd, J=7.20, 1.39 Hz, 1 H), 8.11-8.26 (m, 1 H), 7.19-7.45 (m, 7 H), 4.78-5.01 (m, 2 H), 4.15 (q, J=7.24 Hz, 2 H), 1.24 (t, J=7.07 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[OH:13][C:14]([CH3:20])([CH2:18][CH3:19])[C:15](O)=O.C(O)C.CCOCC.[ClH:29]>>[ClH:29].[CH2:18]([C:14]([CH3:20])([C:15]1[NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[C:10]([N:12]=1)=[CH:9][CH:8]=[CH:7]3)[OH:13])[CH3:19]
Reactant: CCC(C)(O)C(=O)O
Reactant: Nc1cccc2cccc(N)c12
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCC(C)(O)C1=Nc2cccc3cccc(c23)N1

Procedure:
1,8-Diaminonaphthalene (44.5 g, 0.282 mole) is suspended in 400 ml of 4N hydrochloric acid. To this suspension is added 2-hydroxy-2-methyl butyric acid (50 g, 0.423 mole) and the whole is stirred and heated under reflux for 96 hours. Then the reaction mixture is allowed to cool and is filtered, yielding a gray-green solid. The solid is heated and stirred with 1 liter of refluxing ethanol, and is filtered while hot to remove unreacted starting materials. The filtrate is concentrated to dryness and the resulting solid is treated with 500 ml of boiling ethanol. After the insoluble material is removed by filtration, the filtrate was treated with charcoal, yielding a yellow solution. Addition of ether, plus cooling, yields a yellow-brown solid. Recrystallization from ethanol (charcoal) yields the desired product, α-ethyl-α-methyl-2-perimidinemethanol, hydrochloride, m.p. 266°-268° dec.).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[C:9]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[F:17])=[CH:8][CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:6]1[C:24]([O:26]C(C)(C)C)=O)=[N+]=[N-].C1(P([C:44]2[CH:49]=[CH:48]C=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCC(Cl)=O.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[F:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]1[C@H:5]2[N:6]([C:24](=[O:26])[N:1]([CH:48]3[CH2:49][CH2:44]3)[CH2:4]2)[C@H:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:8]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1C(CN=[N+]=[N-])C(c2cc(F)ccc2F)=CC1c1ccccc1
Agent: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1N(C2CC2)C[C@H]2C(c3cc(F)ccc3F)=C[C@@H](c3ccccc3)N12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of the azidocarbamate 2-1a (0.39 g, 0.95 mmol) in THF (10.0 mL) was treated with polystyrene bound triphenylphosphine and heated at 60° C. for 2 h. The reaction was quenched with water and heated at 60° C. for an additional hour. The reaction was diluted with EtOAc and filtered. The filtrate was washed with brine, dried over MgSO4, filtered and concentrated. A solution of this product (0.025 g, 0.07 mmol) in CH2Cl2 (3 mL) was treated with chloroacetyl chloride (0.007 g, 0.07 mmol) and triethylamine (0.007 g, 0.07 mmol) and stirred at rt for 2 h. The reaction was partitioned between dichloromethane and water. The organic solution was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was dissolved in 4M HCl/dioxane and stirred for 1 hr. The reaction was then made basic with 3N aq NaOH and stirred vigorously. After 2 h, the reaction mixture was extracted with EtOAc. The organic solution was washed with brine, dried over MgSO4, filtered and concentrated. The remaining oil was dissolved in CH3CN (0.5 mL) and purified on a Gilson automated system affixed with a YMC J'sphere H80 20×50 mm column (eluting with 5-95% CH3CN +0.1% TFA in water +0.11% TF A over 10 min) to afford pure 5-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][N:2]=1.[CH3:9][O:10][C:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12].O>ClCCl>[CH3:9][O:10][C:11](=[O:12])[CH:13]=[CH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccnnc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)C=Cc1ccnnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.6 %

Procedure:
To a solution of pyridazine-4-carboxaldehyde (3.646 mmol, 1 eq) in dry dichloromethane (25 ml), (methoxycarbonylmethylene)triphenylphosphorane (5,550 mmol, 1.2 eq) was added portionwise. The reaction mixture was stirred at room temperature overnight. Reaction mixture was poured into water (200 ml) and extraction with DCM (3×100 ml) followed. Organic layers were combined, dried over phase separator cartridge to giving crude product which was purified on Biotage SP1 Snap Si 100; 40 ml/min in the gradient of MeOH in DCM: 0-10% in 30 CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 3-pyridazine-4-yl-acrylic acid methyl ester (4.142 mmol, yield=89%, purity=96%). [M+H]+=165.11 1H NMR (300 MHz, CDCl3) δ/ppm 3.82 (s, 3H), 6.64-6.68 (m, 1H), 6.72 (s, 1H), 9.22 (dd, J=5.3, 1.0 Hz, 1H), 9.27 (s, 2H)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)(=O)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:24]1[C:26]2[CH:27]=[CH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:24]([CH:20]3[CH2:21][CH2:22][N:17]([CH2:7][CH:8]=[CH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:18][CH2:19]3)[C:25]=2[CH:27]=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: O=C(C=Cc1ccccc1)N1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C(=Cc1ccccc1)CN1CCC(C2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
0.78 gram (20.6 millimoles) of lithium aluminum hydride was added in small portions under argon atmosphere to a solution of the above prepared cinnamoylpiperidine in 50 milliliters of dry tetrahydrofuran to obtain 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamylpiperidine in the reaction mixture. The latter was recovered in the usual manner, i.e., diluting with tetrahydrofuran, quenching by the "n,n,3n" method, drying the solution over magnesium sulfate, vaporizing the solvent in vacuo from the filtered dried solution thereby obtaining a residue, flash chromatographing the residue on silica gel employing 75/25 ethyl acetate-hexane as eluant to produce 681 grams of a purified 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamylpiperidine base product. The base was dissolved in methanol and a solution of 219 milligrams (1 equivalent) oxalic acid dihydrate in 2 milliliters of methanol added to the solution of the base and the resulting mixture allowed to stand overnight to obtain 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-cinnamylpiperidine hydrogen oxalate product as crystals melting 218°-220° C. The product had elemental analyses as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[CH2:11]([CH:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.[C:21]([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH3:11])=[CH:19][CH:18]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1O
Reactant: O=C([O-])[O-]
Reactant: CCC(Cl)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(COc2ccc(Br)cc2OC)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of 4-bromo-2-methoxyphenol (7.0 g) and ethylbenzyl chloride (5.6 g) in DMF (35 mL) was added K2CO3 (5.7 g). The reaction mixture was stirred at 80° C. for 1 hr. Water was added to the reaction mixture. The precipitated solid was collected on a filter and dried to give the title compound (11 g, 99%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:1]/[C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[S:32][C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/P(=O)(OCC)OCC)cc3OC)c(C)o2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a mixture of ethyl 5-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate (1.50 g), tetraethyl methylenediphosphonate (0.84 g) and N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 0.12 g) at room temperature. The mixture was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 5-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]thiophene-2-carboxylate as colorless crystals (1.20 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (4:1 to 9:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 114-115° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.[H-].[Na+].COC1C=C2C(=CC=1OC)N=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:45]=[CH:44][C:43](NC(NC2CCNCC2)=O)=[CH:42][CH:41]=1.[C:56](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:32][CH2:31][CH2:30][O:39][C:40]2[CH:41]=[CH:42][CH:43]=[C:44]([CH3:56])[CH:45]=2)=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Reactant: O=C([O-])O
Reactant: COc1cc2nccc(Oc3ccc(O)cc3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(OCCCOc4cccc(C)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenol (100 mg) was dissolved in dimethylformamide (2 ml) to prepare a solution. Sodium hydride (16 mg) was then added to the solution, and the mixture was stirred at room temperature for 10 min. A solution of the compound (1) (85 mg) in dimethylformamide was added thereto, and the mixture was further stirred at room temperature for 4 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate, followed by washing three times with saturated brine. The extract was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development to give the title compound (145 mg, yield 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.N1CCOCC1.[CH3:30][N:31]1[C:35]([S:36]([Cl:39])(=[O:38])=[O:37])=[CH:34][N:33]=[C:32]1[CH3:40]>ClCCl>[ClH:39].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][N:22]([CH3:23])[S:36]([C:35]4[N:31]([CH3:30])[C:32]([CH3:40])=[N:33][CH:34]=4)(=[O:38])=[O:37])[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: CNCCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1
Reactant: Cc1ncc(S(=O)(=O)Cl)n1C
Solvent: ClCCl
Solvent: C1COCCN1
Product: Cc1ncc(S(=O)(=O)N(C)CCN2CCN(c3nccnc3-c3ccc(F)cc3)CC2)n1C
Product: Cl
Reaction time: 72 h
Yield: 65.7 %

Procedure:
Dissolve {2-[3′-(4-fluoro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethyl}-methyl-amine (0.111 g, 0.352 mmol) in dichloromethane (4 mL). Add resin-bound morpholine (0.155 g, 0.387 mmol) followed by 1,2-dimethylimidazole-5-sulfonyl chloride (0.075 g, 0.387 mmol) and shake at ambient temperature for 72 hr. Filter, concentrate and purify (SCX chromatography, followed by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, then 10:90 methanol:ethyl acetate, then 20:80 methanol:ethyl acetate) to give the free base of the title compound (118 mg, 71%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[C:17]1([CH2:23][C:24](O)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[C:8]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:24](=[O:25])[CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Product: O=C(Cc1ccccc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Yield: 62 %

Procedure:
Prepared from 2-(2-aminophenyl) indole and phenylacetic acid in 62% yield following procedure 1. The product was crystallized from methanol. 100% Purity by LC/MS (230 DAD), Mass-spec [M+H+]=327, 1H NMR (MeOH-d4): 3.69 s (2H), 6.21 s (1H), 7.03 t, 7 Hz (1H), 7.12 t, 8 Hz (1H), 7.21–7.28 m (6H), 7.33–7.36 m (2H), 7.46 d, 8 Hz (1H), 7.54 dd, 7.1 Hz (1H), 7.89 d, 8 Hz (1H).
Reaction SMILES: FC1C=C2C(C(=O)NC=N2)=CC=1.[F:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[NH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[N+:25]([O-:27])=[O:26].S(Cl)([Cl:30])=O>>[Cl:30][C:18]1[NH:19][CH2:20][N:21]=[C:22]2[C:17]=1[CH:16]=[C:15]([N+:25]([O-:27])=[O:26])[C:14]([F:13])=[CH:23]2
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]cnc2cc(F)c([N+](=O)[O-])cc12
Agent: O=c1[nH]cnc2cc(F)ccc12
Product: O=[N+]([O-])c1cc2c(cc1F)=NCNC=2Cl

Procedure:
4-Chloro-7-fluoro-6-nitroquinazoline (7) can be prepared by methods similar to those described in J. Med. Chem. 1996, 39, 918-928. Generally, 2-amino-4-fluoro-benzoic acid (1) can be reacted with formamidine (2) and acetic acid (3) in the presence of 2-methoxyethanol to provide 7-Fluoro-3H-quinazolin-4-one (4). The 7-fluoro-3H-quinazolin-4-one (4) can then be nitrated to 7-fluoro-6-nitro-3H-quinazolin-4-one (5), which can be treated with thionyl chloride to yield 4-chloro-6-nitro-7-fluoro-3H-quinazoline (6). The 4-chloro-quinazoline compound (6) can be combined with a desirably substituted aniline, represented above by 4-fluoro-3-chloro-aniline, in the presence of a tertiary amine and isopropanol to provide the 4-anilino-6-nitro-7-fluoro-quinazoline (7).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[CH2:32]([C:40]1[CH:41]=[C:42]([NH2:45])[NH:43][N:44]=1)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:7][N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:45][C:42]3[NH:43][N:44]=[C:40]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:41]=3)=[O:20])=[CH:21][CH:22]=2)[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1cc(CCc2ccccc2)n[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3cc(CCc4ccccc4)n[nH]3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
Oxalyl chloride (2M in DCM, 250 μl, 0.50 mmol, 1.1 eq) was added dropwise to a mixture of 4-(4-methylpiperazin-1-yl)benzoic acid (100 mg, 0.45 mmol, 1 eq) in DCM (5 ml, containing a few drops of DMF) and DIPEA (171 μl, 0.95 mmol, 2.1 eq) at 0° C. After stirring for 1 h at 0° C., a solution of 5-phenethyl-2H-pyrazol-3-amine (128 mg, 0.68 mmol, 1.5 eq) in DCM (2 ml) was added dropwise. The mixture was maintained at 0° C. for 2 h, then gradually allowed to warm to room temperature overnight. The mixture was diluted with DCM (50 ml), washed with aq. NaHCO3 solution (50 ml) and the aqueous layer was extracted with DCM (50 ml). The combined organic layers were concentrated. The crude product was purified by reverse-phase prep. HPLC (basic) using a 30-50% gradient of acetonitrile in water (containing 1% ammonium hydroxide) to yield the title compound (8 mg, 3% yield).