Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[N:10]=[C:9](Cl)[C:8]([Cl:12])=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[N:10]=[C:9]([O:2][CH3:1])[C:8]([Cl:12])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
Sodium methoxide (295 mg, 5.45 mmol) was taken up in methanol (13.6 mL) and 2,4,5-trichloropyrimidine (500 mg, 2.73 mmol) was added. The mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The resulting residue was diluted with diethyl ether, washed with 1:1 water:saturated aqueous ammonium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by Chromatography on silica gel (0-10% diethyl ether/hexanes) afforded 2,5-dichloro-4-methoxypyrimidine (280 mg, 1.56 mmol, 57%) as a white solid.
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15](OC)[O:16]C)=[CH:11][CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH:15]=[O:16])=[CH:11][CH:10]=[C:9]([N+:20]([O-:22])=[O:21])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cc1c(C(C)(C)C)[nH]c2cc([N+](=O)[O-])ccc12)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1CC=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.6 %

Procedure:
To a solution of 2-tert-butyl-3-(2,2-dimethoxy-ethyl)-6-nitro-1H-indole (0.80 g, 2.6 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (5 mL, 50%) at 0° C. and the resulting solution was stirred at room temperature for 6 h. Saturated sodium bicarbonate was added until pH >7. The aqueous layer was extracted with methylene chloride several times. The combined organic layers were dried over sodium sulfate, filtrated, and concentrated in vacuo. The residue was purified via silica gel column chromatography to give the title compound (0.62 g, 91%). LCMS (m/z): 261.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[C:3]1C(O)=O.N1C2C(=CC=CC=2)C=CC=1>[Cu]=O.Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH:4]=[CH:3]1
Reactant: Cn1c(C(=O)O)cc2cccc(C(=O)O)c21
Agent: O=[Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Cn1ccc2cccc(C(=O)O)c21
Temperature: 180 °C
Yield: 49.5 %

Procedure:
A mixture of 4.60 g (21.0 mmol) of 1-methylindole-2,7-dicarboxylic acid, 0.5 g of copper (II) oxide and 50 ml of quinoline was stirred for an hour with heating at 180° C. After cooling, the reaction mixture was poured onto 200 ml of 2N hydrochloric acid. The mixture was extracted three times with ethyl acetate and the combined extracts were washed with saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was isolated and purified by silica gel column chromatography to give 1.82 g (49.0%) of 1-methyl-7-indolecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O.O>[CH3:1][C:2]1[N:3]([C:7]2[CH:25]=[CH:24][C:10]([CH2:11][O:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc(-n3ccnc3C)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nccn1-c1ccc(COc2ccc(C(=O)O)cc2)cc1

Procedure:
To a solution of ethyl 4-{[4-(2-methyl-1H-imidazol-1-yl)benzyl]oxy}benzoate (Preparation 30, 507 mg, 1.9 mmol) in THF/MeOH/Water (3:3:1, 7 mL) was added lithium hydroxide monohydrate (198 mg, 4.9 mmol) the resulting reaction mixture was heated under reflux for 72 hours. Lithium hydroxide monohydrate (100 mg, 2.5 mmol) was added and the reaction mixture heated at reflux for further 3 hours. The solvent was reduced in vacuo and the residue diluted with water. The resulting aqueous mixture was acidified with 0.2 M aqueous hydrochloric acid to pH 6.5 and the solid precipitate was collected, washed with water and diethyl ether and dried under reduced pressure at 50° C. to yield the title compound as a white solid, which was carried through to the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][N:6]1[C:12](=[O:13])[CH:11]([NH:14]C(=O)OC(C)(C)C)[CH2:10][S:9][CH2:8][CH2:7]1.[ClH:26]>O1CCOCC1>[ClH:26].[NH2:14][CH:11]1[CH2:10][S:9][CH2:8][CH2:7][N:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]([F:25])=[C:2]([F:1])[CH:3]=2)[C:12]1=[O:13]
Reactant: CC(C)(C)OC(=O)NC1CSCCN(Cc2ccc(F)c(F)c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: NC1CSCCN(Cc2ccc(F)c(F)c2)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
460 mg of 30 (1.235 mmol) are taken up in a 25 ml round-bottomed flask and 9.3 ml of a solution of hydrogen chloride in dioxane (4M) are added. The medium is stirred for 4 hours at room temperature under argon. After evaporating off the solvent, 460 mg of amine 31 are obtained in hydrochloride form, which product is used directly in the following step.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].S([O-])([O-])(=O)=O.[Mg+2].[CH3:13][C:14]([CH3:16])=O>>[CH3:13][C:14]1([CH3:16])[O:6][CH:3]([CH2:2][Br:1])[CH2:4][O:5]1
Reactant: OCC(O)CBr
Reactant: CC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC1(C)OCC(CBr)O1

Procedure:
An acetone solution of bromomethyl ethylene glycol is refluxed for 24 hours in the presence of anhydrous magnesium sulfate. The cooled reaction mixture is filtered and the solvent is removed to provide a residual crude product.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4].[Br:22]C1CC(=O)NC1=O>C(#N)C.CCOC(C)=O>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:22])[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: COc1ccc2c(c1)CC(C)N(C(=O)C(F)(F)F)CC2C
Reactant: O=C1CC(Br)C(=O)N1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Reaction time: 8 h

Procedure:
A solution N-trifluoroacetyl-1,4-dimethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.452 g, 1.50 mmol) in acetonitrile (20 mL) was treated with N bromosuccinimide (0.294 g, 1.65 mmol) and stirred overnight at 20 C. The product mixture was diluted with EtOAc (100 mL), washed with sodium bisulfite (50 mL) and brine (50 mL), dried with Na2SO4 and concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) d 7.32 (s, 1 H), 6.62 (m, 1 H), 4.37 (m, 1 H), 3.87 (s, 3 H), 3.81 (m, 1 H), 3.28-3.10 (m, 3 H), 2.73 (m, 1 H), 1.31 (m, 3 H), 1.25 (m, 3H).
Reaction SMILES: CS([O-])(=O)=O.[O:6]([CH:13]1[CH2:16][NH:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:17][N:18]=[C:19]=[O:20]>>[CH3:17][NH:18][C:19]([N:15]1[CH2:16][CH:13]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:20]
Reactant: CN=C=O
Reactant: c1ccc(OC2CNC2)cc1
Agent: CS(=O)(=O)[O-]
Product: CNC(=O)N1CC(Oc2ccccc2)C1

Procedure:
The compound was prepared from the methane sulfonate of 3-phenoxyazetidine and methylisocyanate as described in Example 1 of U.S. Pat. No. 4,226,861, m.p. 139°-141° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:13]=[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.O.[OH-].[Li+]>CO.C1COCC1.O>[C:15]1([NH:14][C:12]2[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH:13]=2)[C:3]([OH:21])=[O:2])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(Nc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)c(Nc2ccccc2)c1
Yield: 96 %

Procedure:
A mixture of compound 1A (4.56 g, 16.0 mmol) and lithium hydroxide monohydrate (2.0 g, 48.0 mmol) in MeOH (32 mL), THF (32 mL) and water (16 mL) was heated to reflux for 0.5 h. HPLC indicated that the reaction was complete. The organic solvents were removed under reduced pressure, and the aqueous residue was diluted with water. The pH was adjusted to 3.0 with 6N aqueous hydrochloric acid. The resulting precipitate was collected by vacuum filtration, rinsed with water and dried under reduced pressure to provide 3.95 g (96%) of 1B as a bright yellow solid. HPLC retention time=2.75 min. (Condition A) and LC/MS M++1=258+.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH2:8]1)C.[OH-].[Na+]>CO>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])[CH2:8]2)[C:4]([OH:24])=[O:3])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(CN1CCC(N(CC)CC)C1)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)C1CCN(CC(C(=O)O)c2ccc(Br)cc2)C1
Reaction time: 2 h

Procedure:
To a solution of 2-(4-bromo-phenyl)-3-(3-diethylamino-pyrrolidin-1-yl)-propionic acid ethyl ester (639 mg, 1.6 mmol) in MeOH (4 mL) was added aq. NaOH (2N, 8 mmol). The solution was stirred at 40 degrees Celsius for 2 h, then concentrated in vacuo. The residue was dissolved in water and neutralized with 2N HCl to pH 5-6 at 0 degrees Celsius. Then the mixture was evaporated to dryness under reduced pressure to obtain a white solid product without further purification. MS: calc'd 369 (MH+), exp 369 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[C:12]1[CH:17]=[CH:16][C:15](OS(C(F)(F)F)(=O)=O)=[CH:14][N:13]=1)[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)=[CH:14][N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH3:2]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(OS(=O)(=O)C(F)(F)F)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccc(F)cc2)cn1
Yield: 22 %

Procedure:
Compound I (13 mg, 0.027 mmol, preparation of which is outlined above in Example 12), Pd(PPh3)4 (3.5 mg, 0.003 mmol), 4-fluorophenylboronic acid (7.6 mg, 0.055 mmol) and potassium carbonate (15 mg, 0.108 mmol) were stirred in toluene (1.5 mL) and water (0.7 mL) at 120° C. under microwave irradiation (300 W) for 20 min. The reaction mixture was then poured onto brine (5 mL) and extracted with EtOAc (3×5 mL). The organic phases were combined then dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 then 85:15) to furnish II as a colourless oil (2.5 mg, 22%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26]CC3C=CC(OC)=CC=3OC)[N:20]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nc(C)cc(NCC3CCN(C(=O)OCc4ccccc4)CC3)n2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 4-{[2-(2,4-dimethoxy-benzylamino)-6-methyl-pyrimidin-4-ylamino)-methyl}-piperidine-1-carboxylic acid benzyl ester from Step 1 above (0.4 g, 0.79 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL). The resulting reaction solution was stirred at rt for 1 h, then concentrated in vacuo. The residue was purified by silica gel chromatography (1–10 (10% NH4OH in MeOH)/99–90 CH2Cl2) to give 4-[(2-amino-6-methyl-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 356.36
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([NH:11][C:4]2[C:5]3[N:10]=[CH:9][S:8][C:6]=3[N:7]=[C:2]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]3)[N:3]=2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: COC(=O)C1CCNCC1
Reactant: COc1ccc(Nc2nc(Cl)nc3scnc23)cc1OC
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)C1CCN(c2nc(Nc3ccc(OC)c(OC)c3)c3ncsc3n2)CC1
Reaction time: 18 h
Yield: 56.3 %

Procedure:
To a mixture of 5-chloro-N-(3,4-dimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (200 mg, 0.62 mmol), methyl piperidine-4-carboxylate (177 mg, 1.24 mmol), Cs2CO3 (404 mg, 1.24 mmol), X-Phos (20 mg, 0.042 mmol), Pd(dba)2 (20 mg, 0.035 mmol) in 30 mL of dioxane were stirred at 100° for 18 hours under N2 atmosphere. The excess of dioxane was removed under reduced pressure and the residue was purified by silica gel chromatography (eluting with a mixture of petroleum ether and ethyl acetate=3:1) to give methyl 1-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)piperidine-4-carboxylate (150 mg, 56%) as a yellow solid. LC-MS: 430 [M+H]+, tR=1.63 min
Reaction SMILES: N#N.C([SiH2][O:8][C:9](C)(C)[C:10]1[O:11][CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[N:14]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[OH:8][CH2:9][C:10]1[O:11][CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[N:14]=1
Reactant: CC(=O)c1coc(C(C)(C)O[SiH2]C(C)(C)C)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1coc(CO)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[2-(tert-butyl-dimethyl-silanyloxymethyl)-oxazol-4-yl]-ethanone (192 mg, 0.75 mmol) in dry THF (5.0 mL) was treated at rt with TBAF (1.1 mL of a 1M solution in THF, 1.10 mmol). The reaction mixture was stirred at rt for 1.5 h. The mixture was then diluted with EA (10 mL), washed with brine (3×10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:1 to 2:1 EA-Hept) gave the title compound as a pale yellow solid. TLC: rf (EA)=0.37. LC-MS-conditions 02: tR=0.34 min, [M+H]+=142.46.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19](O)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH:22]1[CH:23]=[CH:24]C2N(O)N=[N:28][C:26]=2[CH:27]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.N1CCCCC1>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]([N:28]4[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]4)=[O:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(C)N1CCN(c2nc3ccc(C(=O)O)cc3s2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2nc3ccc(C(=O)N4CCCCC4)cc3s2)CC1
Temperature: 45 °C
Reaction time: 12 h
Yield: 21.3 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxylic acid (800 mg, 2.1 mmol) in THF (14 mL) was added HOBt (342 mg, 2.5 mmol), EDAC (807 mg, 4.2 mmol), triethylamine (1.7 g, 17 mmol) and piperidine (718 mg, 8.5 mmol) at room temperature. The reaction mixture was stirred at 40-50° C. for 12 h under a nitrogen atmosphere. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with a gradient of CH2Cl2/MeOH (100:1→50:1) to give the crude product, which was further purified by preparative HPLC to give 167 mg (21%) of [2-(4-isopropylpiperazin-1-yl)benzothiazol-6-yl]piperidin-1-ylmethanone as a trifluoroacetate salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][OH:15])([O-:3])=[O:2].[F:16][C:17]([F:44])([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:16][C:17]([F:44])([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][C:40]([F:42])([F:41])[F:43])=[CH:32][CH:31]=1)[C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:15][CH2:14][CH2:13][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[O:27])=[CH:20][CH:19]=1
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCCc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
2.50 g (11.8 mmol) of 2-(2,4-dinitrophenyl)ethanol, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-di-methylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloro-methane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yields 5.11 g (71%) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7](F)[C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[C:19]([NH:26][CH2:27][CH2:28][NH2:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CC(N(C)C)=O>C(OCC)(=O)C>[C:4]([C:3]1[C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=[CH:8][C:7]=1[NH:29][CH2:28][CH2:27][NH:26][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])(=[O:5])[NH2:6]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: NC(=O)c1c(F)ccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NCCNc1ccc(Cl)c(Cl)c1C(N)=O
Temperature: 140 °C
Yield: 81.8 %

Procedure:
A mixture of 2,3-dichloro-6-fluorobenzamide (4.0 g, 19.32 mmol.), K2CO3 (5.33 g, 38.64 mmol), and N-Boc-ethylenediamine (3.41 g, 21.25 mmol) and dimethylacetamide (50 mL). was heated at 140° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with a solution of aqueous saturated sodium bicarbonate (3×100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to give the title compound (5.50 g, 82% yield) as a brown gum.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[NH2:13])[NH:9][C:8](=[O:14])[CH:7]2[CH:15]([CH3:17])[CH3:16].[CH3:18][O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=O)=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:15]([CH:7]1[C:6]2[C:10](=[CH:11][C:12]3[NH:13][C:24]([C:23]4[CH:27]=[CH:28][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)=[N:3][C:4]=3[CH:5]=2)[NH:9][C:8]1=[O:14])([CH3:17])[CH3:16]
Reactant: CC(C)C1C(=O)Nc2cc(N)c(N)cc21
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)NC(=O)C4C(C)C)cc1
Reaction time: 2 h

Procedure:
2.8 g. (13.6 mmol) 5,6-diamino-3-isopropylindolin-2-one dihydrochloride were suspended in 10 ml. methylene chloride, mixed with 2.55 g. (15 mmol) p-methoxybenzoyl chloride and 4.55 g. (45 mmol) triethylamine added dropwise thereto at 25° C. The reaction mixture was stirred for 2 hours, evaporated and worked up with water. The residue was heated under reflux for about 24 hours in 75 ml. ethanol and 75 ml. concentrated hydrochloric acid, evaporated and rendered neutral with 2N ammonia solution. The residue filtered off with suction was recrystallised from ethyl acetate/methanol. There were obtained 2.1 g. (48.2% of theory) of the title compound; m.p. 326°-328° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](=[NH:7])[NH2:6].[CH:11]1([C:14](=O)[CH2:15][C:16](OCC)=[O:17])[CH2:13][CH2:12]1.C[O-].[Na+].CO>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:6][C:16](=[O:17])[CH:15]=[C:14]([CH:11]3[CH2:13][CH2:12]3)[N:7]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: N=C(N)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(=O)C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=c1cc(C2CC2)nc(-c2cccc(Cl)c2)[nH]1
Temperature: 0 °C
Yield: 33.1 %

Procedure:
A 500-mL round bottomed flask was charged with 3-chlorobenzimidamide (5.75 g, 30.1 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (5.00 g, 32.0 mmol), and ethanol (100 mL) and the mixture cooled to 0° C. To the stirred mixture was added 25% sodium methoxide in methanol (15.0 mL, 64.0 mmol). The resulting mixture was stirred at reflux for 20 h. After cooling to room temperature, the mixture was evaporated under reduced pressure to 25 mL. The residual slurry was cautiously treated with 2N HCl (50 mL) forming a solid. The solid was collected by filtration and washed with water followed by ether to afford the title compound (2.46 g, 31%) as a white solid, which was carried forward into the next step without further purification. MW=246.69. 1H NMR (DMSO-d6, 500 MHz) δ 12.55 (s, 1H), 8.13 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.64-7.60 (m, 1H), 7.54 (t, J=8.0 Hz, 1H), 6.34 (s, 1H), 2.00-1.93 (m, 1H), 1.08-1.02 (m, 2H), 0.99-0.91 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]3[C:20](=[O:30])[NH:19][C:18](=[O:31])[N:17]([CH3:32])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]3[C:20](=[O:30])[N:19]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:18](=[O:31])[N:17]([CH3:32])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2Cc2ccccc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(Benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (182 mg) was dissolved in N,N-dimethylformamide (2 ml), and potassium carbonate (90 mg) and ethyl bromoacetate (0.06 ml) were added thereto. The reaction solution was stirred at room temperature overnight, diluted with ethyl acetate, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound.