Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[C:15](=[O:27])[O:14][N:13]=2)=[N:9][O:10][N:11]=1)=[N+]=[N-].[I-:28].[Na+].Cl[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>CO.O>[IH:28].[NH2:1][CH2:4][CH2:5][NH:6][C:7]1[C:8]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=3)[C:15](=[O:27])[O:14][N:13]=2)=[N:9][O:10][N:11]=1
Reactant: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: [I-]
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: O
Product: I
Product: NCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-{4-[(2-azidoethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one (1.05 g, 2.8 mmol) in methanol (12 mL) was added sodium iodide (2.5 g, 17 mmol). After stirring for 10 minutes, a solution of chlorotrimethylsilane (2.1 mL, 17 mmol) in methanol (1.41 mL) was added dropwise over 15 minutes. The reaction continued to stir for 40 minutes and then a solution of sodium thiosulfate (2.7 g, 17 mmol) in water (12.5 mL) was added in one portion. A beige solid precipitated upon addition of the sodium thiosulfate solution and it was collected by vacuum filtration. The solid was rinsed with water (2×10 mL) and was dried under vacuum overnight to give the desired product. A solid had also precipitated from the filtrate and it was collected by vacuum filtration. After washing with water (3×10 mL) in the funnel, the product was dried overnight under vacuum. The solid was slurry washed with ethyl acetate (3.8 mL) for 1 hour and recollected by filtration. After rinsing with ethyl acetate (2×2 mL) and drying overnight, additional product was obtained. In total, 760 mg of desired product (57%) was obtained as the hydroiodide salt. LCMS calculated for C13H12F3N6O3 (M+H)+: m/z=357.1. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.95 (m, 2H), 7.81 (t, J=8.1 Hz, 1H), 7.68 (br s, 2H), 6.74 (t, J=6.7 Hz, 1H), 3.49 (m, 2H), 3.03 (t, J=6.7 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:19](O)[CH3:20].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([O:6][CH2:19][CH3:20])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First, 50 g (0.29 mol) of 2-chloro-4-fluorobenzoic acid was dissolved in 150 ml of hydrochloric acid at room temperature, to which a mixed acid of 28 ml (0.31 mol) of fuming nitric acid and 56 ml of concentrated sulfuric acid was added dropwise at 35′ to 45° C. Then, the solution was stirred at 40° C. for 1 hour and poured into 250 ml of ice-water. The precipitated crystals were collected by filtration and recrystallized from a mixed solution of hexane and ethyl acetate, which afforded 55 g (025 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid. Then, 55 g (0.25 mol) of 2-chloro-4-fluoro-5-nitrobenzoic acid was dissolved in 50 ml of ethyl acetate, to which 33 g (0.28 mol) of thionyl chloride was added, and the mixture was heated under reflux for 3 hours and then allowed to stand for cooling to room temperature. Then, 20 ml of ethanol and 30 g of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled out, and the residue was purified by silica gel chromatography, which afforded 57 g (0.23 mol) of ethyl 2-chloro-4-fluoro-5-nitrobenzoate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([F:11])[C:3]=1[F:12].NC1C(F)=CC([OH:21])=CC=1F>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:21])=[C:3]([F:12])[C:4]=1[F:11]
Reactant: Nc1c(F)cc(O)cc1F
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Product: Nc1ccc(O)c(F)c1F
Yield: 84 %

Procedure:
This compound was prepared from 1,2,3-trifluoro-4-nitrobenzene (5.0 g, 28 mmol) in the manner described for 4-amino-3,5-difluorophenol, affording 0.60 g (84%) of 4-amino-2,3-difluorophenol. 1H-NMR (DMSO-d6) δ 9.19 (s, 1H), 6.59 to 6.53 (m, 1H), 6.48 to 6.41 (m, 1H), 4.85 (s, 2H); TLC (12% DCM/Hex), Rf=0.08.
Reaction SMILES: C(O[CH:5]([C:28]1[N:44]=[C:31]2[N:32]=[CH:33][C:34]3[CH2:35][C:36]4([O:43][CH2:42][CH2:41][O:40]4)[CH2:37][CH2:38][C:39]=3[N:30]2[N:29]=1)[C:6]1(Br)[C:12](=[O:13])[N:11]2[C@@H:7]1[S:8][CH:9]=[C:10]2[C:14]([O:16]CC1C=CC([N+]([O-])=O)=CC=1)=[O:15])(=O)C.C(#N)C>C1COCC1.[Pd]>[N:29]1[N:30]2[C:39]3[CH2:38][CH2:37][C:36]4([O:43][CH2:42][CH2:41][O:40]4)[CH2:35][C:34]=3[CH:33]=[N:32][C:31]2=[N:44][C:28]=1/[CH:5]=[C:6]1\[C@@H:7]2[N:11]([C:12]\1=[O:13])[C:10]([C:14]([OH:16])=[O:15])=[CH:9][S:8]2
Reactant: CC(=O)OC(c1nc2ncc3c(n2n1)CCC1(C3)OCCO1)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CS[C@@H]21
Agent: [Pd]
Solvent: CC#N
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C\c3nc4ncc5c(n4n3)CCC3(C5)OCCO3)C(=O)N12
Temperature: 3 °C

Procedure:
4-nitrobenzyl (5R)-6-[(acetyloxy)(8′,9′-dihydro-6′H-spiro[1,3-dioxolane-2,7′-[1,2,4]triazolo[1,5-a]quinazolin]-2′-yl)methyl]-6-bromo-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (300 mg, 0.43 mmol) was dissolved in THF (20 mL) and acetonitrile (20 mL) and phophate buffer (6.5 pH) (20 ml) and hydrogenated over Pd/C (10%) (200 mg) under 40 psi pressure. At the end, reaction mixture was filtered, cooled to 3° C., and 0.1 N NaOH was added to adjust the pH to 8.5. The filtrate was washed with ethyl acetate and the aqueous layer was separated. The aqueous layer was concentrated under high vacuum at 35° C. to give a yellow precipitate. The product was purified by HP21 resin reverse phase column chromatography. Initially the column was eluted with deionized water (2 L) and latter with 10% acetonitrile:water. The fractions containing the product were collected and concentrated under reduced pressure at room temperature. The yellow solid was washed with acetone, filtered and dried. Yield: 15 mg, 9%; Yellow crystals; mp>250° C. (Dec); (M+H+Na) 435.9. 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 6.97(s, 1H), 6.85(s, 1H), 6.38(s, 1H), 4.05 (s, 4H, OCH2CH2O), 3.28(m, 2H), 3.07 (s, 2H), 2.13(t, 3H, CH3, J=4.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([CH3:30])[CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([CH3:30])[CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)cc(C)n1
Yield: 47.2 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (95 mg, 47%). MS (ISP) 403.2 [(M+H)+]; mp 256° C.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CI.[C:17]([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:17][O:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CS(C)=O
Product: COC(=O)c1sc(C(F)(F)F)cc1OC
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 20 g (88 mmole) of methyl 3-hydroxy-5-trifluoromethyl-2-thiophenecarboxylate in 200 mL of DMSO was added 37 g (260 mmole) of methyl iodide and 25 g (181 mmole) of powdered K2CO3. After 2 hr of stirring, the reaction mixture was poured into water and extracted with ether. The organic phase was separated, washed with water several times, dried over MgSO4, filtered and concentrated to give 20 g of a nearly colorless solid. This solid was further purified by recrystallization from 12:1 hexane:ethyl acetate to give 10.5 g of colorless crystals. The mother liquor was concentrated and purified by column chromatography to give another 8 g (87% yield). mp 78-79° C. 1H NMR (300 MHz, CDCl3): δ 7.2 (s, 1H); 4.0 (s, 3H),; 3.9 (s, 3H). Anal. Calc'd for C8H7F3O3S: C, 40.00; H, 2.94; S, 13.35. Found: C, 39.87; H, 2.94; S, 13.47.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].CC1C=CC(S(O[C@@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][N:10]1[CH:11]=[CH:12][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([O:1][C@H:36]3[CH2:40][CH2:39][O:38][CH2:37]3)[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)=[N:9]1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A suspension of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a Smith Creator microwave at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow foam which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in iso-hexane, to give the title compound as a white foam (452 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=2)[N:3]=1.S(Cl)([Cl:25])=O>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:25][CH2:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:4]2[C:5]([CH3:13])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]([CH3:1])=[N:3]2)=[CH:15][CH:16]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1nn(-c2ccc(CCCl)cc2)c(C)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethanol (step 1 of Example 2, 100 mg, 0.34 mmol) in toluene (3 mL) and chloroform (1 mL) was added thionyl chloride (50 μL, 0.68 mmol), and the resulting mixture was stirred at 80° C. for 3h. The reaction mixture was quenched by 2 M NaOH aq. and extracted with dichloromethane. Organic layer was dried (Na2SO4) and the solvent was evaporated to give the title compound as brown solids (quant.): MS (ESI) m/z 311 [M+H]+, 1H-NMR (CDCl3) δ 7.46-7.31 (9H, m), 3.74 (2H, t, J=7.3 Hz), 3.12 (2H, t, J=7.3 Hz), 2.34 (3H, s), 2.30 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C[Si]([N-][Si](C)(C)C)(C)C.NC1N=CC(C2C=CN=C(C3(C#N)CCOCC3)C=2)=NC=1C1ON=C(C2C=CC(CNC)=CC=2)C=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:10]([CH3:12])([CH3:11])[C:9]#[N:13])[CH:7]=1
Reactant: Clc1cc(I)ccn1
Reactant: CC(C)C#N
Agent: CNCc1ccc(-c2cc(-c3nc(-c4ccnc(C5(C#N)CCOCC5)c4)cnc3N)on2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cc(I)ccn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
An oven-dried flask was evacuated and back-filled with nitrogen three times. The flask was charged with 2-chloro-4-iodo-pyridine (3 g, 12.53 mmol) and isobutyronitrile (865.9 mg, 1.125 mL, 12.53 mmol) in anhydrous toluene (30.00 mL). The reaction mixture was cooled to 0° C. and treated with bis(trimethylsilyl)azanide in tetrahydrofuran (sodium ion (1)) (12.53 mL of 1 M, 12.53 mmol) over a period of 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred at this temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with 1 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (×3) and the combined organic extracts dried MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 80 g column) loaded with dichloromethane and eluted with 0 to 30% ethyl acetate/petroleum ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as an off-white solid (2.22 g, 65% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.70 (s, 6H), 7.84 (dd, 1H), 7.98 (d, 1H) and 8.31 (d, 1H) ppm; LC/MS m/z 273.0 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[N:3]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:28]2[CH2:27][CH2:26][CH2:25][C:24]=2[C:23]=1[S:31]([NH2:34])(=[O:33])=[O:32].Cl>C(O)(C)C>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:30]=[CH:29][C:28]4[CH2:27][CH2:26][CH2:25][C:24]=4[C:23]=3[S:31]([NH2:34])(=[O:32])=[O:33])[CH:7]=[CH:6][N:5]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(Nc2nccc(Cl)n2)cc(OC)c1OC
Reactant: Nc1ccc2c(c1S(N)(=O)=O)CCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(Nc2nccc(Nc3ccc4c(c3S(N)(=O)=O)CCC4)n2)cc(OC)c1OC

Procedure:
(4-Chloro-pyrimidin-2-yl)-(3,4,5-trimethoxy-phenyl)-amine (240 mg, 0.81 mmol) and 5-amino-indan-4-sulfonic acid amide (190 mg, 0.89 mmol) are suspended in isopropanol (15 ml). Conc. HCl (1.5 ml) is added. The mixture is heated to reflux for 1 h. The reaction mixture is separated between ethyl acetate (300 ml) and water (100 ml). NaHCO3 is added to achieve basic pH. The layers are separated. The organic layer is dried with Na2SO4 and evaporated. The residue is crystallized from ethyl acetate to give 5-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-ylamino]-indan-4-sulfonic acid amide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22]CC)=[CH2:21])CCC.[Li+].[Cl-]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:20](=[O:22])[CH3:21])=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cc1C(F)(F)F
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CC(=O)c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
A mixture of 4-bromo-1-nitro-2-(trifluoromethyl)benzene (1.87 g, 6.93 mmol), tributyl(1-ethoxyvinyl)tin (3.00 g, 8.31 mmol), Pd(PPh3)4 (801 mg, 0.693 mmol), and LiCl (734 mg, 17.3 mmol) in 1,4-dioxane (50 ml) was heated to reflux for 7 hours. The mixture was filtered through a pad of Celite with ethyl acetate. The filtrate was washed with water (100 ml) and brine (100 ml), dried over MgSO4, and evaporated in vacuo. To the obtained residue were added 2N HCl (20 ml) and THF (60 ml). The mixture was stirred at room temperature for 1.5 hours. Saturated aqueous NaHCO3 (60 ml) was added and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layer was dried over MgSO4, and evaporated in vacuo. The resulting residue was chromatographed over silica gel with hexane/ethyl acetate (3:1) to give 1.51 g (94%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O-])(=[O:3])[CH3:2].[Na+].BrCCO.[CH2:10]1[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[O:11]1.O>C(O)C>[CH2:10]1[O:19][C:18]2[CH:17]=[CH:16][C:14]([NH:15][CH2:2][CH2:1][OH:3])=[CH:13][C:12]=2[O:11]1
Reactant: CC(=O)[O-]
Reactant: Nc1ccc2c(c1)OCO2
Agent: OCCBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCCNc1ccc2c(c1)OCO2

Procedure:
27 mmol of sodium acetate and 15 mmol of 2-bromoethanol are added to 10 mmol of 3,4-methylenedioxyaniline dissolved in ethanol. After 24 hours of heating at reflux, the reaction mixture is brought to ambient temperature, water is added, and then the aqueous phase is extracted with dichloromethane. The organic phases are combined, the solvent is evaporated off and the crude residue is purified by chromatography on silica, using a 10:90 dichloromethane/ethyl acetate mixture as eluant, to yield the expected product in the form of an oil.
Reaction SMILES: O=[C:2]([CH2:7][CH2:8][CH3:9])[C:3]([O:5]C)=O.[F:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=N[CH:22]=[C:17]2[C:16]([C:23](=[NH:26])[NH:24][NH2:25])=[N:15]1.[CH2:31](O)C>>[F:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:31][CH:22]=[C:17]2[C:16]([C:23]2[N:24]=[N:25][C:2]([CH2:7][CH2:8][CH3:9])=[C:3]([OH:5])[N:26]=2)=[N:15]1
Reactant: CCCC(=O)C(=O)OC
Reactant: CCO
Reactant: N=C(NN)c1nn(Cc2ccccc2F)c2ncncc12
Product: CCCc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O

Procedure:
0.916 g (7.035 mmol) of methyl 2-oxopentanoate in 15 ml of ethanol were initially introduced and heated to reflux. Then, 2.000 g (7.035 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidohydrazide suspended in 20 ml of ethanol were added and the mixture was heated under reflux overnight. After cooling, the mixture was filtered off with suction, and the filtercake was washed with a little ethanol and dried under high vacuum. This gave 1.75 g of the target compound (purity 92%; 63% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:20]([C:22]4([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]4)=[O:21])=[N:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CS(O[CH2:39][CH2:40][CH2:41][C:42]1([OH:45])[CH2:44][CH2:43]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:45][C:42]1([CH2:41][CH2:40][CH2:39][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:20]([C:22]5([C:25]([NH2:27])=[O:26])[CH2:24][CH2:23]5)=[O:21])=[N:17][CH:18]=4)=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:44][CH2:43]1
Reactant: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(O)ccc34)cn2)CC1
Reactant: CS(=O)(=O)OCCCC1(O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: NC(=O)C1(C(=O)N(c2ccccc2)c2ccc(Oc3ccnc4cc(OCCCC5(O)CC5)ccc34)cn2)CC1
Yield: 64.9 %

Procedure:
The title compound was prepared according to the procedure described in Example 9 by using N-(5-(7-hydroxyquinolin-4-yloxy)pyridin-2-yl)-N-phenyl-cyclopropane-1,1-dicarboxamide (300 mg, 0.682 mmol), 3-(1-hydroxycyclopropyl)-propyl methanesulfonate (155 mg, 0.80 mmol), and Cs2CO3 (668 mg, 2.05 mmol) in 3 mL of DMA. The residue was purified by a silical gel column chromatography (3:1 (v/v) EtOAc/n-hexane) to give the title compound as a white solid (238.5 mg, 65%).
Reaction SMILES: COC1C=CC(CN2C(C(OCC)=O)=NN=N2)=CC=1.[CH3:20][O:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][N:27]2[N:31]=[N:30][C:29]([C:32]([O:34]CC)=[O:33])=[N:28]2)=[CH:24][CH:23]=1.S1(CCCC1)(=O)=O.[OH-].[K+:47]>C(O)C.O>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:27]2[N:31]=[N:30][C:29]([C:32]([O-:34])=[O:33])=[N:28]2)=[CH:37][CH:38]=1.[K+:47]
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)n1
Agent: CCOC(=O)c1nnnn1Cc1ccc(OC)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2nnc(C(=O)[O-])n2)cc1
Yield: 35.4 %

Procedure:
A mixture of ethyl 1-(4-methoxybenzyl)-1H-tetrazole-5-carboxylate and ethyl 2-(4-methoxybenzyl)-2H-tetrazole-5-carboxylate (11.7 g) (prepared as described below and still containing a little sulpholane) was dissolved in hot ethanol (165 ml) and the solution was treated with a solution of potassium hydroxide (4.5 g) in water (13.5 ml). The mixture was cooled and the white crystalline solid which separated was filtered off to give potassium 2-(4-methoxybenzyl)-2H-tetrazole-5-carboxylate (4.3 g), m.p. 271°-273° C. (with decomposition). [The pure salt, obtained as a hemihydrate after recrystallisation from water, had a melting point of 273°-274° C. (with decomposition)].
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A 500-mL round-bottomed flask was purged with nitrogen and charged with 339a (3.1 g, 10 mmol), 10% palladium on carbon (50% wet, 1.0 g), and ethanol (100 mL). It was evacuated, charged with hydrogen gas via a balloon, and stirred at room temperature for 16 h. The hydrogen was then evacuated and nitrogen was charged into the flask. The catalyst was removed by filtration through a pad of CELITE® and the filtrate was concentrated under reduced pressure to afford 339b (2.7 g, 97%). MS-ESI: [M+H]+ 279
Reaction SMILES: [CH2:1]([NH:3][C:4]1([C:8]([NH2:10])=[O:9])[CH2:7][NH:6][CH2:5]1)[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:21]1[N:26]2[C:27](=[O:30])[NH:28][N:29]=[C:25]2[C:24]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[C:23]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[N:22]=1>CCO>[Cl:44][C:41]1[CH:42]=[CH:43][C:38]([C:23]2[N:22]=[C:21]([N:6]3[CH2:7][C:4]([NH:3][CH2:1][CH3:2])([C:8]([NH2:10])=[O:9])[CH2:5]3)[N:26]3[C:27](=[O:30])[NH:28][N:29]=[C:25]3[C:24]=2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[CH:39][CH:40]=1
Reactant: CCNC1(C(N)=O)CNC1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)nc(Cl)n12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3n[nH]c(=O)n23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a stirred suspension of 3-(ethylamino)azetidine-3-carboxamide (25 mg, 0.17 mmol) in EtOH (1.0 mL) at room temperature under argon was added N,N-diisopropylethylamine (60 mg, 0.46 mmol). The reaction mixture was stirred at room temperature for 10 min to obtain a clear solution to which was added 5-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (60 mg, 0.15 mmol). The reaction mixture was stirred at 60° C. in a pre-heated oil bath for 5 min. The reaction mixture was then concentrated under reduced pressure, and the residue was dissolved in CH2Cl2 (5 mL). The resulting mixture was washed with water (2 mL×2), dried (MgSO4), and concentrated under reduced pressure to obtain the crude product. This crude product was purified by preparative reverse phase HPLC (without TFA) to obtain 35 mg of the title compound as a pale yellow solid. HPLC/MS: retention time=3.306 min, [M+H]30 =498.