Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=[C:5]([CH:9](C)[CH2:10][CH2:11][C:12](=[O:15])C=C)[CH:6]=[CH:7]C=1.C(N(CC)CCC(=O)CCC(C1C=CC=C([O:33]C)C=1)C)C>[OH-].[K+]>[CH2:6]([CH:5]1[C:9](=[O:33])[CH2:10][CH2:11][C:12]1=[O:15])[CH3:7]
Reactant: C=CC(=O)CCC(C)c1cccc(OC)c1
Reactant: CCN(CC)CCC(=O)CCC(C)c1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux a mixture of 6-(m-methoxyphenyl)hept-1-en-3-one and 1-diethylamino-6-(m-methoxyphenyl)heptan-3-one (10 g, obtained by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (7 g) in 0.12% methanolic potassium hydroxide solution (40 cc) for 15 hours. Remove most of the methanol under reduced pressure and add a mixture of equal volumes of ether and benzene (50 cc). Wash the solution with 5% aqueous sodium hydroxide, water, 10% hydrochloric acid, and brine, and dry. Evaporate the solvent to leave as residue the triketone adduct 2-(6-m-methoxyphenyl-3-oxoheptyl)-2-ethylcyclopentane-1,3-dione (14 g); infrared absorption peak at 5.80 μ.
Reaction SMILES: ClC1C(C(C2C=C3C(C=CC=N3)=CC=2)N2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=NC=CN=1.[NH2:30][NH2:31].C(Cl)Cl.CC[OH:37]>>[C:17]([NH:30][NH2:31])(=[O:18])[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:10]([OH:19])=[O:37]
Reactant: NN
Reactant: CCO
Reactant: O=C1c2ccccc2C(=O)N1C(c1ccc2cccnc2c1)c1nccnc1Cl
Solvent: ClCCl
Product: NNC(=O)c1ccccc1C(=O)O
Reaction time: 48 h

Procedure:
A solution of 2-[(3-chloropyrazin-2-yl)-quinolin-7-ylmethyl]-isoindole-1,3-dione (789 mg, 1.97 mmol) and anhydrous hydrazine (63 μL, 64 mg, 2.0 mmol) in EtOH (4 mL)/CH2Cl2 (2 mL) was stirred at ambient temperature for 1 d. More hydrazine (93 μL, 95 mg, 3.0 mmol) was added, and stirring was continued for 2 d. The solid formed (phthalic hydrazide) was filtered off and washed with EtOH, and the combined filtrate and washings were dried to yield a red, sticky solid. This solid was suspended in CH2Cl2 and filtered, and the filtrate was concentrated to give the title compound as an orange gum; 1H NMR (CDCl3, 400 MHz) δ 2.4 (brs, 2H), 5.79 (s, 1H), 7.39 (dd, J=4.2, 8.2 Hz, 1H), 7.64 (dd, J=1.8, 8.6 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 8.13 (dd, J=0.8, 8.0 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.90 (dd, J=1.6, 4.4 Hz, 1H); MS (ES+): m/z 271.0/273.0 (30/10) [MH+], 254.1/256.1 (30/10) [MH+-NH3].
Reaction SMILES: [CH2:1]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[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][CH3:16].[OH:34]O>C(O)C>[CH2:18]([N:17]([CH2:1][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][CH3:16])[OH:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: OO
Reactant: CCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCC
Solvent: CCO
Product: CCCCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCCCC
Reaction time: 48 h

Procedure:
The general procedure of Example 3 is followed using 100 grams (0.19 mol) of di(hexadecyl)amine (451 eq. wt., 88% secondary amine), 30.2 grams (0.44 mol) of 50% aqueous hydrogen peroxide solution and 400 ml of ethanol. After stirring for 48 hours, the reaction mixture is filtered to give the above-named product which is twice recrystallized from 500 ml of chloroform. The desired product is obtained in a yield of 29.4 grams (32%) as white needles melting at 97-99° C.
Reaction SMILES: [OH:1][O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH:20]1[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:30][CH2:31][S:32][CH3:33])[C:21]1=[O:34])=[O:18])=[CH:11]2.[CH3:35]O>O.CCOC(C)=O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH:20]1[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:30][CH2:31][S:32]([CH3:33])=[O:1])[C:21]1=[O:34])=[O:18])=[CH:11]2.[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][CH:20]1[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH2:30][CH2:31][S:3]([CH3:35])(=[O:5])=[O:2])[C:21]1=[O:34])=[O:18])=[CH:11]2
Reactant: CO
Reactant: CSCCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)CCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Product: CS(=O)CCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 18 h
Yield: 25 %
Yield: 34 %

Procedure:
Oxone (701 mg, 1.14 mmol) in H2O (12 mL) was added to 5-chloro-N-{1-[2-(methylthio)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-1H-indole-2-carboxamide (Example 5; 355 mg, 0.86 mmol) in MeOH (12 mL) and stirred for 18 hours. The mixture was diluted with EtOAc (100 mL) washed with saturated NaHCO3 (20 mL), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:THF (3:2) then DCM:MeOH (4:1)) to give 2 yellow solids. Each solid was triturated with refluxing Et2O (25 mL) and the solids filtered, washed with Et2O (25 mL) then hexane (25 mL) to afford 5-chloro-N-{1-[2-(methylsulphinyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-1H-indole-2-carboxamide (125 mg, 34%) and 5-chloro-N-{1-[2-(methylsulphonyl)ethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl}-1H-indole-2-carboxamide (95 mg, 25%) as white solids.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.[ClH:10].[CH2:11]([OH:13])[CH3:12]>>[ClH:10].[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([C:7](=[NH:8])[O:13][CH2:11][CH3:12])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: Cc1ccc(C#N)cc1
Agent: Cl
Product: CCOC(=N)c1ccc(C)cc1

Procedure:
Ethyl 4-methylbenzimidate hydrochloride was synthesized in the same manner as in Reference Example 2. That is, p-tolunitrile (25.6 g, 0.219 mol) was treated with hydrogen chloride in ethanol (250 mL) to give 42.3 g (97%) of the target compound as colorless crystals.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)O.C(OC[CH2:13][CH2:14][NH2:15])=C.C=O.C1(C)C=CC=CC=1>O>[O:5]1[C:4]2[CH:3]=[CH:1][CH:8]=[CH:7][C:6]=2[CH:13]=[CH:14][NH:15]1
Reactant: Oc1cccc(O)c1
Reactant: C=COCCCN
Agent: C=O
Solvent: Cc1ccccc1
Solvent: O
Product: C1=Cc2ccccc2ON1
Temperature: 25 °C
Yield: 125.2 %

Procedure:
A 500 mL flask was charged with resorcinol (33 g, 300 mmol), 3-amino-1-propanol vinyl ether (61 g, 600 mmol), and paraformaldehyde (38 g, 1260 mmol). Approximately 200 g of toluene was added and the mixture was heated to reflux. Reflux continued until water ceased to collect in the trap (about one hour). The reaction mixture was then cooled to room temperature. A large volume of solid byproduct formed in the reaction vessel. The toluene solution was decanted from the solid, and the remaining solid was washed with extra toluene. All of the toluene fractions were combined in a separatory funnel. The toluene solution was washed with a 5% NaOH solution, followed by a saturated NaCl solution. The toluene solution was dried with magnesium sulfate, and filtered over a small bed of neutral alumina. Removal of the solvent under reduced pressure produced about 50 g of an orange colored liquid (46% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([O:29]C)=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]4[CH3:26])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:27]([OH:29])=[O:28])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N3CCCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: C[C@H]1CCCCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a solution of (S)-methyl 2-(1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylate (79 mg, 0.20 mmol) in methanol (15 mL) and CHCl3 (5 mL) was added NaOH (24 mg, 0.60 mmol) and water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (15 mL) and adjusted to pH 5 with hydrochloric acid (1N). The solids were collected by filtration to afford (S)-2-(1H-indol-5-yl)-3-(2-methylpiperidin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (70 mg, 92%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](COC)[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([CH:21]3[CH2:23][CH2:22]3)[CH:17]=2)[N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1.Cl.[O:32]1[CH2:37]COC[CH2:33]1>CN1C(=O)CCC1>[CH:21]1([C:18]2[CH:17]=[C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:4]3[N:5]=[C:6]([NH:24][C:25]4[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=4)[C:7]([CH2:33][O:32][CH3:37])=[CH:2][N:3]=3)[O:20][N:19]=2)[CH2:22][CH2:23]1
Reactant: Cc1cc(N)n[nH]1
Reactant: C1COCCO1
Reactant: COCc1cc(Cl)nc(N2CCCC2c2cc(C3CC3)no2)n1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COCc1cnc(N2CCCC2c2cc(C3CC3)no2)nc1Nc1cc(C)[nH]n1
Temperature: 120 °C
Yield: 34 %

Procedure:
A mixture of 4-chloro-2-[2-(3-cyclopropylisoxazol-5-yl]pyrrolidin-1-yl]-6-methoxymethylpyrimidine (Method 19) (250 mg, 0.746 mmol), 3-amino-5-methyl-1H-pyrazole (109 mg, 1.2 mmol) and hydrogen chloride (0.56 ml of a 4M solution in dioxane, 2.24 mmol) in NMP (5 ml) was heated at 120° C. for 18 hours. The mixture was allowed to cool then directly applied to an isolute SCX2 ion exchange column. The column was eluted with DCM/methanol (4:1) to remove neutrals and then with 7M methanolic ammonia to elute the product. The partially purified product was then purified by chromatography on silica gel eluting with DCM/methanol (100:0 increasing in polarity to 95:5). The product was triturated with diethyl ether/DCM and the solid product collected by filtration to give the title compound (100 mg, 34%) as a white solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[O:4][CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][OH:15].CCN(C(C)C)C(C)C.[C:25](OCC)(=[O:27])[CH3:26]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]([CH2:26][CH2:25][OH:27])[CH2:13][CH2:14][OH:15])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1cccc2c1OCCO2
Reactant: CCOC(C)=O
Reactant: OCCCl
Solvent: CCN(C(C)C)C(C)C
Product: OCCN(CCO)c1cccc2c1OCCO2
Temperature: 120 °C
Reaction time: 12.5 h
Yield: 80 %

Procedure:
2,3-Dihydro-benzo[1,4]dioxin-5-ylamine (31.1 g, 0.2 mol) is mixed with 2-chloroethanol (210 mL, 3.1 mol) and Hunigs base (105 mL, 0.6 mol). The resulting dark solution is heated to 120° C. and stirred at this temperature with continuous monitoring by HPLC. After 12.5 h, the reaction is stopped. Ethyl acetate (300 mL) is added and the solution is washed with diluted brine (1×250 mL) followed by brine (2×75 mL). All aqueous layers are combined, the pH adjusted to 7 with K2CO3, and solution is back-washed with ethyl acetate (2×100 mL). All organic layers are then combined and extracted with 2N HCl (3×150 mL). The resulting aqueous solution is neutralized with solid K2CO3 to pH 7 and extracted with ethyl acetate (3×100 mL). The organic phase is dried with MgSO4, concentrated and chased with toluene (2×50 mL) to remove residual chloroethanol. 39.6 g (80%) of crude product is obtained as a dark oil of 94 area % (LC-MS) purity. 1H NMR (CDCl3) δ6.88-6.70 (m, 3H), 4.34-4.22 (m, 4H), 3.54 (t, J=7.5 Hz, 4H), 3.18 (t, J=7.5 Hz, 4H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][CH:8]=[CH:7]2.[CH3:14][C@@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[N:9]([CH2:14][C@H:15]([OH:16])[CH3:17])[CH:8]=[CH:7]2
Reactant: C[C@@H]1CO1
Reactant: Fc1cc2[nH]ccc2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)Cn1ccc2cc(Cl)c(F)cc21
Reaction time: 1 h
Yield: 77 %

Procedure:
A suspension of 128 mg of sodium hydride dispersion in 8 ml of tetrahydrofuran was treated with 0.5 7 g of 5-chloro-6-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.48 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removing the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.59 g (77%) of (R)-1-(5-chloro-6-fluoro-indol-1-yl)-propan-2-ol as beige crystals with m.p. 108°-110°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:12]1(C(OC(C)(C)C)=O)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:1].[ClH:1].[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: FC(F)(F)c1cccnc1N1CCNCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
2-Chloro-3-(trifluoromethyl)pyridine (1.07 g) and tert-butyl piperazine-1-carboxylate (1.0 g) was dissolved in DMF (10 ml), and K2CO3 (3.0 g) was added thereto, followed by stirring at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, and then a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The product was dissolved in MeOH (16 ml), and 4 M hydrogen chloride/EtOAc (8 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, then EtOAc was added thereto, and the solid was collected by filtration to obtain 1-[3-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (858 mg).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[N:1]1[N:2]([C:10]2[C:11]([OH:19])=[C:12]([CH:13]=[C:14]([CH3:16])[CH:15]=2)[CH2:17][O:25][C:23](=[O:24])[CH:22]([CH2:20][CH3:21])[CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: CCCCC(CC)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)OCc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (10.0 g, 33 mmol) is suspended in a mixture of 2-ethylhexanoic acid (11.9 g, 82 mmol) and tetrahydrofuran (75 g) and stirred at 70° C. for 30 minutes. Sodium carbonate (10.5 g, 99 mmol) is added. The slightly yellow reaction mixture is stirred at 60° C. for 15 minutes and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with an aqueous potassium carbonate solution (10%) and brine. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 11.2 g of 2-Ethyl-hexanoic acid 3-(2H-benzotriazol-2-yl)-2-hydroxy-5-methyl-benzyl ester.
Reaction SMILES: C([Li])CCC.[CH:6]1([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[O:15][CH:16]=2)=[O:11])[CH2:8][CH2:7]1.[C:20](=[O:22])=[O:21]>CCCCCC.O1CCCC1>[CH:6]1([NH:9][C:10]([C:12]2[N:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[O:15][C:16]=2[C:20]([OH:22])=[O:21])=[O:11])[CH2:7][CH2:8]1
Reactant: O=C=O
Reactant: CC(C)c1nc(C(=O)NC2CC2)co1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)c1nc(C(=O)NC2CC2)c(C(=O)O)o1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
At -70° C. and under a nitrogen blanket, 0.12 mol of n-butyllithium (80.0 ml of a 1.5 molar solution in hexane) was dripped into a solution of 10.4 g (0.054 mol) of 2-isopropyloxazole-4-carboxylic acid-cyclopropylamide in 250 ml of tetrahydrofuran, and the mixture was stirred for 30 minutes at this temperature. The reaction mixture was then poured onto 500 g of solid CO2 and allowed to stand overnight. The residue remaining after evaporating down was taken up in 200 ml of water and 30 ml of 2N NaOH, the solution was extracted twice, each time with 100 ml of diethyl ether, the aqueous phase was acidified to a pH of 2 with concentrated hydrochloric acid and the solution extracted three times, each time with 200 ml of ethyl acetate. Drying over magnesium sulfate and removal of the solvent under reduced pressure gave 10.4 g (81%) of 4-cyclopropylaminocarbonyl-2-isopropyloxazole-5-carboxylic acid as a white powder of m.p. 109°-112° C. (active ingredient no. 3.007).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:22]([F:25])([F:24])[F:23])([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[O:55]1[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[CH2:57][CH:56]1[CH2:64][N:65]1[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]1>ClCCl>[O:55]1[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[CH2:57][CH:56]1[CH2:64][N:65]1[CH2:70][CH2:69][N:68]([C:19](=[O:21])[CH2:18][O:17][CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:6]=3)[CH2:12][CH2:13]2)[CH2:67][CH2:66]1
Reactant: c1ccc2c(c1)CC(CN1CCNCC1)O2
Reactant: O=C(O)COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COC1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(CC2Cc3ccccc3O2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
To a solution of 2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid (900 mg, 2.48 mmol) in dichloromethane (50 ml) was added EDAC.HCl (661 mg, 3.45 mmol), HOBt (464 mg, 3.43 mmol), triethylamine (463 mg, 4.58 mmol) and 1-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazine (500 mg, 2.29 mmol) in dichloromethane (1 ml) with stirring for overnight at room temperature. Then the mixture was diluted with dichloromethane (300 ml) and washed with water (100 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 0.5%-3% methanol in dichloromethane to afford 1-[4-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one as a yellow solid (462.4 mg, 36%); (ES, m/z): [M+H]+ 563.00; 1H NMR (300 MHz, CDCl3): δ 8.00 (d, J=8.7 Hz, 1H), 7.09-7.18 (m, 2H), 6.77-6.88 (m, 3H), 6.61 (dd, J=2.1 Hz, 8.7 Hz, 1H), 5.03 (broad s, 1H), 4.45 (d, J=6.9 Hz, 1H), 4.20 (s, 2H), 3.67-3.78 (m, 3H), 3.40-3.49 (m, 3H), 2.66-2.99 (m. 6H), 2.13-2.23 (m, 4H), 1.41-1.63 (m, 3H), 1.21-1.34 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH2:18][CH2:19][Cl:20].[OH2:21]>CS(C)=O>[Cl:20][CH2:19][CH2:18][CH2:17][CH2:16][N:5]1[CH:6]=[C:7]([CH3:8])[C:2]([OH:1])=[N:3][C:4]1=[O:21]
Reactant: O
Reactant: ClCCCCBr
Reactant: Cc1cncnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn(CCCCCl)c(=O)nc1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.1 g (80.0 mmol) of 4-hydroxy-5-methylpyrimidin-2(1H-one (thymine) in 300 ml of dimethyl sulfoxide (DMSO) and 11.1 g (80.0 mmol) of K2CO3 were stirred at room temperature for 1 hour. Then 13.7 g (80.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to the mixture, and the reaction mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The aqueous phase was then neutralized and extracted with methylene chloride. Drying of the organic phase, removal of the desiccant by filtration and evaporation of the solvent to dryness in vacuo resulted in 7.1 g of 1-(4-chlorobutyl)-4-hydroxy-5-methylpyrimidin-2(1H)-one.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[NH:20][N:19]=[N:18][N:17]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[N:17]=[N:18][N:19]([CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22])[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: C=CCCCBr
Reactant: CCCCc1nc(=O)c2cc(-c3nnn[nH]3)ccc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCn1nnc(-c2ccc3[nH]c(CCCC)nc(=O)c3c2)n1
Yield: 53.2 %

Procedure:
A mixture of 3.0 g of 2-butyl-6-(1H-tetrazol-5-yl)-4(1H)-quinazolinone, 2.2 g of 5-bromo-1-pentene and 2 ml of N,N-diisopropylethylamine in 50 ml of tetrahydrofuran is refluxed for 24 hours. The volatiles are evaporated in vacuo to a residue which is partitioned between chloroform and water. The organic layer is dried over MgSO4, filtered and evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 3:2 ethyl acetate-hexanes to give a residue which crystallizes from ethyl acetate-hexanes to give 2.0 g of the desired product as a solid, m.p. 130° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.OB(O)[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.CN(C=O)C>[NH:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Brc1ccc2cc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 6-bromoindole (480 mg, 2.45 mmol), 4-(dihydroxyboryl)benzoic acid (406 mg, 2.45 mmol), Pd(dppf)Cl2CH2Cl2 (10 mg, 0.01 mmol), and 2M Na2CO3 (5.6 mL, 11.2 mmol) in a mixture of ethanol (4 mL) and DMF (7 mL) was heated to 100° C., stirred for 16 hours, filtered, and concentrated The concentrate was dissolved in ethyl acetate, washed sequentially with 1M H3PO4, water, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5% methanol/dichloromethane to provide the desired product. MS (ESI(−)) m/e 236 (M−H)−.