Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]([CH2:9][CH2:10][NH2:11])=[CH:7][O:8][C:4]=2[CH:3]=1.CO.[CH3:16][C:17]([CH3:19])=O>>[I:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6]3[CH2:9][CH2:10][NH:11][C:17]([CH3:19])([CH3:16])[C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: NCCc1coc2cc(I)ccc12
Reactant: CC(C)=O
Solvent: CO
Product: CC1(C)NCCc2c1oc1cc(I)ccc21
Temperature: 25 °C

Procedure:
To a solution of 2-(6-iodo-benzofuran-3-yl)-ethylamine (4.20 g, 14.63 mmol) in methanol (60.0 mL, 1.48 mol) was added acetone (1.63 mL) and the reaction mixture was stirred at rt. After 2 days the solvent was evaporated. The residue was dissolved in a mixture of TFA (7.0 mL) and DCE (70.0 mL) and heated to reflux. After 20 h the reaction mixture was cooled down and basified with 5M aq. NaOH. The layers were separated and the aqueous phase extracted with DCM. The combined organic layers was dried (Na2SO4) and the solvent was evaporated. The residue was purified on a silica gel column eluting with DCM-MeOH—NH4OH to afford 7-iodo-1,1-dimethyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine as an off-white solid. mp 97-98° C.; MS m/z 328 [M+H]+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.[NH:11]1[C:20](=O)[C:19]2[NH:18][CH:17]=[N:16][C:15]=2[N:14]=[C:12]1[NH2:13]>O>[NH2:13][C:12]1[N:14]=[C:15]2[C:19]([NH:18][CH:17]=[N:16]2)=[C:20]([Cl:3])[N:11]=1
Reactant: Nc1nc2nc[nH]c2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2[nH]cnc2n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
46.0 g (0.3 mol) of phosphorus oxychloride was added to 73.1 g (1.0 mol) of N,N-dimethylformamide, and 15.1 g (0.1 mol) of guanine (manufactured by Sumika Fine Chemicals Co., Ltd. ) was then added, followed by stirring at 100° C. for 4 hours. After cooling, 100 ml of water was carefully added at 20° C. After stirring at room temperature for 24 hours, the precipitating crystal was collected by filtration and dissolved in 100 ml of 25% aqueous ammonia with heating, and the insoluble substances were filtered out. The mother liquor was concentrated under reduced pressure, and the precipitating crystal was collected by filtration to yield 9.3 g (0.055 mol) of a white crystal of 2-amino-6-chloropurine (yield 55%).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=1)#[CH:23]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:21][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:23]#[C:22][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH3:33])=[CH:26][CH:25]=2)=[CH:9][CH:8]=1
Reactant: C#Cc1ccc(OCCC)cc1
Reactant: CC(=O)NC(C)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCOc1ccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To 0.33 g (1.00 mmol) trifluoromethanesulfonic acid 4-(2-acetylamino-propyl)-phenyl ester (I53.2) and 0.18 g (1.10 mmol) 1-ethynyl-4-propoxybenzene in 3 mL DMF and 0.60 mL (4.50 mmol) TEA are added 0.04 g (0.06 mmol) bis-(triphenylphosphin)-palladiumdichlorid. The mixture is stirred in a sealed tube at 80° C. for 24 h. The reaction mixture is partitioned between EtOAc and water, the organic layer is dried with Na2SO4 and the solvent is removed in vacuo. The residue is purified by column chromatographie (silica gel, DCM/EtOAc 1/1). The resulting product is triturated with diethylether and dried at 80° C. in vacuo.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12](F)=[C:11]([F:16])[CH:10]=1.[CH2:18]([OH:21])[C:19]#[CH:20].[H-].[Na+].Cl>CN(C=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:21][CH2:18][C:19]#[CH:20])=[C:11]([F:16])[CH:10]=1
Reactant: C#CCO
Reactant: CC1CCCC1NC(=O)c1ccc(F)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C(=O)NC2CCCC2C)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.6 %

Procedure:
To 2 ml of DMF were added 0.23 g of N-(2-methylcyclopentyl)-3,4-difluorobenzamide and 0.11 g of propargyl alcohol. To the mixture obtained was added 60 mg of 60% sodium hydride (oily) at 0° C. The mixture was stirred at room temperature for 2 hours. Then, dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried on magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.11 g of N-(2-methylcyclopentyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 69 of the present invention) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:20]([O-])=O)[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[H][H].C([O-])(O)=O.[Na+]>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:20])[C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: O=[N+]([O-])c1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1c(OCC2CC2)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
6-chloro-7-cyclopropylmethoxy-8-nitro-9H-β-carboline (510 mg, 1.61 mmol) was suspended in 12 ml of methanol and 100 mg of Pd/C (10%) was added. The flask was fitted with a balloon of hydrogen and the reaction mixture was stirred overnight at RT. Upon filtration through a pad of celite and evaporation of the methanol, a dark brown solid was obtained. This residue was suspended in methanol (10 ml) and added, with vigorous stirring, to a solution of saturated NaHCO3 (100 ml). The light brown solid that precipitated out was collected by filtration and dried thoroughly in vacuo to give the desired 6-chloro-7-cyclopropylmethoxy-9H-β-carbolin-8-ylamine (371 mgs, 80% yield). 1H-NMR (300 MHz, methanol-d4): δ 0.36 (m, 2H), 0.61 (m, 2H), 1.37 (m, 1H), 3.88 (d, 2H), 7.58 (s, 1H), 7.96(d, 1H), 8.23 (d, 1H), 8.76 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 2.28 min. MS (M+H+): 288.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH:20]([CH3:22])[CH3:21]>CN(C=O)C.CCOCC>[CH:20]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:12])([CH3:22])[CH3:21]
Reactant: CC(C)I
Reactant: COC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(OC(C)C)c(C)c1
Temperature: 60 °C
Yield: 89.9 %

Procedure:
To methyl 4-hydroxy-3-methyl-benzoate (1.0 g, 59.8 mmol) in dry DMF (62 mL) was added finely ground potassium carbonate (33.1 g, 239.3 mmol) followed by 2-iodopropane (20.3 g, 12.0 mL, 119.6 mmol). The reaction mixture was heated at 60° C. for 2 hours. The reaction mixture was cooled and diluted with ether (350 mL), and filtered over celite. The filtrate was washed with water (3×100 mL) and brine (100 mL) solution. The layers were separated and organics were dried over MgSO4. The solvent was evaporated and resulting residue was purified by silica gel using 0-30% EtOAc/hexanes mixtures as eluent to give methyl 4-isopropoxy-3-methylbenzoate as a colorless oil (11.2 g, 89%). ESI-MS m/z calc. 208.25. found 209.2 (M+1)+; Retention time: 1.93 minutes (3 min run). Lithium hydroxide (4.4 g, 181.6 mmol) was added to a solution of methyl 4-isopropoxy-3-methylbenzoate (11.2 g, 53.8 mmol) in tetrahydrofuran (31 mL) and water (31 mL). The mixture was rapidly stirred and heated at 65° C. for 6 hours. The reaction mixture was cooled, diluted with water (75 mL) and extracted with ether (2×50 mL). The aqueous layer was acidified to pH 2 with 6N aq. HCl and extracted with ethyl acetate (4×75 mL). The combined organics were washed with water (75 mL) and brine solution (75 mL) and layers were separated. The organics were dried over MgSO4 and concentrated in vacuo to give 4-isopropoxy-3-methyl-benzoic acid (9.5 g, 82%) as colorless crystals. ESI-MS m/z calc. 194.2. found 195.3 (M+1)+; Retention time: 1.53 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.78-7.71 (m, 2H), 7.02 (d, J=8.6 Hz, 1H), 4.70 (dt, J=12.1, 6.0 Hz, 1H), 2.15 (s, 3H), 1.30 (d, J=6.0 Hz, 6H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].I[CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:36][C:37]([CH3:40])([CH3:39])[CH2:38][O:34][C:31]1[CH:32]=[CH:33][C:28]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:29][CH:30]=1
Reactant: CC(C)(C)CI
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 86.5 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.4 g) in N,N-dimethylacetamide (10 mL) were added 1-iodo-2,2-dimethylpropane (0.26 g) and cesium carbonate (0.44 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature and the insoluble material was filtered off. The filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound as a pale-yellow solid (0.40 g, 87%).
Reaction SMILES: O[C:2]1[C:10]([C:11](=[O:25])[CH2:12][C:13](=[O:24])[C:14]2[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].Cl.[C:27](O)(=O)C>>[O:25]=[C:11]1[C:10]2[C:2](=[C:3]([C:4]([O:6][CH3:27])=[O:5])[CH:7]=[CH:8][CH:9]=2)[O:24][C:13]([C:14]2[C:15]([C:20]([F:23])([F:21])[F:22])=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:12]1
Reactant: O=C(CC(=O)c1cccc(C(=O)[O-])c1O)c1cccnc1C(F)(F)F
Reactant: CC(=O)O
Agent: Cl
Product: COC(=O)c1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Yield: 23 %

Procedure:
A mixture of 2-hydroxy-3-(3-oxo-3-(2-(trifluoromethyl)pyridin-3-yl)propanoyl)benzoate 39 (600 mg, 1.46 mmol) and con. HCl (1 mL) in acetic acid (5 mL) was heated at 100° C. for 4 hours. The reaction mixture was concentrated and sat. aq NaHCO3 was added. The mixture was extracted with ethyl acetate and the combined organics were washed with brine, dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography to give 40 (120 mg, 23% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH:9]2[CH2:10][CH:5]([C:6]([CH3:11])=[CH:7][CH2:8]2)[CH:4]([OH:12])[CH2:3]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>O1CCCC1>[C:13]([O:12][CH:4]1[CH2:3][CH:2]([CH3:1])[CH:9]2[CH2:10][CH:5]1[C:6]([CH3:11])=[CH:7][CH2:8]2)(=[O:15])[CH3:14]
Reactant: CC1=CCC2CC1C(O)CC2C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OC1CC(C)C2CC=C(C)C1C2
Yield: 86.9 %

Procedure:
To a solution of 10 g (60.2 mmol) of 4,8-dimethylbicyclo[3.3.1]nona-7-en-2-ol [IA] in 40 ml of tetrahydrofuran were added 6.8 g (66.6 mmol) of acetic anhydride and 5.2 g (65.7 mmol) of pyridine and the resulting mixture was heated under reflux for 5 hours. After cooling, the tetrahydrofuran was distilled off, the residue was subjected to column chromatography and eluate with toluene gave 10.9 g of the title compound, which had a woody-like smell.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CO.O>[Cl:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][N:6]=1
Reactant: CC(=O)CCl
Reactant: Nc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cn2ccnc(Cl)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
A solution of 2-amino-3-chloropyrazine (10 g, 77.5 mmol), chloroacetone (30 mL, 387 mmol) in MeOH (25 mL) is refluxed overnight at 88° C. It is then stirred for 1 h at 0° C. and any solid that forms, is filtered off and washed twice with MeOH (5 mL). The mother liq. are evaporated, diluted with EtOAc, and washed with HCl 2N, water and brine. The water and HCl mother liq. are evaporated to give a yellow solid that is neutralized with a saturated solution of K2CO3 in water, extracted with DCM, dried with MgSO4 anh. filtered and concentrated. The crude material is purified by column chromatography using a gradient of (DCM/MeOH: 1/0 to 99/1) to give 8-Chloro-2-methyl-imidazo[1,2-a]pyrazine as an orange solid (1.02 g, 7.7%).
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[C:14]([CH2:17][CH2:18][N:19](C)[CH:20]=O)([CH3:16])[CH2:13][CH2:12][CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]>[OH-].[K+]>[CH2:1]([N:3]1[C:15]2[C:14]([CH3:16])([CH2:17][CH2:18][NH:19][CH3:20])[CH2:13][CH2:12][CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2c(c3ccccc31)CCCC2(C)CCN(C)C=O
Agent: [K+]
Agent: [OH-]
Product: CCn1c2c(c3ccccc31)CCCC2(C)CCNC

Procedure:
N-[2-(9-ethyl-1,2,3,4-tetrahydro-1-methylcarbazol-1-yl)ethyl]-N-methylformamide (2.1 g), described in Example 225, is heated at reflux in a solution of 10% KOH (50 ml) for 48 hr. After cooling the solution is rendered acidic and extracted with ether. The aqueous phase is then rendered alkaline and extracted with ether. The latter extract is dried (MgSO4) and conc. to yield the title compound, nmr (CDCl3) δ 1.4 (m, 6H), 2.37 (s, 3H), 4.3 (q, J = 7, 2H), 7.25 (m, 4H); the corresponding hydrochloric acid addition salt has mp 213°-216° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13]([OH:15])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:13]([Cl:17])=[O:15]
Reactant: Cc1cc(C(=O)O)c2cc(F)ccc2n1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)c2cc(F)ccc2n1

Procedure:
A solution of 6-fluoro-2-methylquinoline-4-carboxylic acid (500 mg) and PCl5 (500 mg) in dichloromethane (10 mL) was refluxed for half an hour. Then dichloromethane and POCl3 were removed under reduced pressure to give 6-fluoro-2-methylquinoline-4-carbonyl chloride.
Reaction SMILES: [C:1](=[O:26])([O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=2)[CH2:15][CH2:14]1)OC1C=CC([N+]([O-])=O)=CC=1.[CH:27]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([N:31]2[CH2:36][CH2:35][N:34]([C:1]([O:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=4)[CH2:17][CH2:18]3)=[O:26])[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28]1
Reactant: C1CC(N2CCNCC2)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2ccc(=O)[nH]n2)CC1
Solvent: ClCCl
Product: O=C(OC1CCN(c2ccc(=O)[nH]n2)CC1)N1CCN(C2CCC2)CC1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl 1-(6-oxo-1,6-dihydropyridazin-3-yl)piperidin-4-yl carbonate (440 mg, 1.22 mmol) in DCM (20 mL) was added TEA (616 mg, 6.1 mmol) and 1-cyclobutylpiperazine (388 mg, 1.83 mmol). The resulting mixture was stirred at 30° C. for 2 h before it was concentrated to dryness. The title compound was obtained as a white solid after silica gel chromatography (DCM/MeOH=50/1 to 5/1) (410 mg, 93%). [1H NMR (400 MHz, CDCl3) (δ 11.20 (s, 1H), 7.20 (d, J=10 Hz, 1H), 6.87 (d, J=10 Hz, 1H), 4.87˜4.92 (m, 1H), 3.45˜3.50 (m, 6H), 3.16˜3.23 (m, 2H), 2.68˜2.76 (m, 1H), 2.29 (br, 4H), 1.72˜2.07 (m, 10H); LCMS: Rt=1.36 min, m/z 362.3 (M+H)+].
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([Cl:15])[C:9]([F:16])=[CH:8][C:4]=1[C:5](Cl)=[O:6]>C1COCC1>[Cl:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([Cl:15])[C:9]([F:16])=[CH:8][C:4]=1[C:5]([NH2:1])=[O:6]
Reactant: N
Reactant: O=C(Cl)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 0.33 h

Procedure:
32%-aq. NH3-solution (250 mL) is dropped to 2,4-dichloro-5-fluoro-3 nitro-benzoic acid chloride (16.0 g, 59 mmol) in 100 mL THF and it is stirred for 20 min. Then the mixture is concentrated and the resulting precipitate is collected and dried.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:19]=3)=[C:13]([CH3:30])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([O-])([O-])=O.[Cs+].[Cs+].IC>CC(C)=O>[C:1]([C:5]1[N:9]([CH3:31])[C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:19]=3)=[C:13]([CH3:30])[N:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc(-n2nc(C(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1nc(-n2nc(C(C)(C)C)n(C)c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.7 %

Procedure:
A suspension of Example 7 (0.050 g, 0.12 mmol) in acetone (2.5 mL) was treated with Cs2CO3 (0.080 g, 0.25 mmol) and iodomethane (0.02 mL, 0.32 mmol) and the mixture was stirred at RT for 12 h. The solvent was removed in vacuo and the residue was dissolved in DCM (3 mL) and washed with water (3 mL). The aqueous phase was extracted with DCM (4×5 mL) and the combined organics were dried (MgSO4) and concentrated in in vacuo. The residue was triturated with Et2O (2 mL) and sonicated for 5 min, which lead to the precipitation of an off white solid. Solid was isolated by filtration and washed with Et2O (3×1 mL). The solid was dried under high vacuum for 3 h, and was then dissolved in MeCN and water, frozen to −78° C., and lyophilized to afford 3-(tert-butyl)-4-methyl-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.024 g, 46.4%) as an off white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.72 (d, J=8.7 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.39 (s, 3H), 2.34 (s, 3H), 1.37 (s, 9H); MS (ESI) m/z: 420.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:13][C:14]2[NH:15][C:16](=[O:24])[C:17]3[CH2:23][O:22][CH2:21][CH2:20][C:18]=3[N:19]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(OCC)C>Cl.O1CCOCC1>[CH:1]1([CH2:4][NH:5][CH2:13][C:14]2[NH:15][C:16](=[O:24])[C:17]3[CH2:23][O:22][CH2:21][CH2:20][C:18]=3[N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1nc2c(c(=O)[nH]1)COCC2)CC1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 121.8 %

Procedure:
tert-butyl cyclopropylmethyl((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)carbamate (5.639 g, 16.81 mmol) was dissolved in 4 N HCl in dioxane (40 mL) and stirred at room temperature after approximately 5 min a white suspension formed and the reaction was allowed to stir overnight. 100 mL diethyl ether was added and the reaction mixture was filtered, washed with diethyl ether (2×25 mL) and dried in vacuo to yield the title compound as a white solid (4.819 g).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16][N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27].C(N(CC)CC)C>C(O)C>[C:18]1(=[O:27])[N:17]([CH2:16][CH2:15][O:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CCOCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCOCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (3.00 g, 20 mmoles) and N-[2-[2-(bromo)ethyloxy]ethyl]phthalimide (5.96 g, 20 mmoles) in ethanol (200 ml) was added triethylamine (4.2 ml, 30 mmoles) and the mixture was stirred at room temperature for 12 hours and heated at reflux for 3 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 4.00 g of the desired product (54.5%, light tan solid).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[N:28]1([CH2:27][CH2:26][NH:25][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: NCCN1CCOCC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCN1CCOCC1)c1n[nH]c2ccccc12
Yield: 24.3 %

Procedure:
Same procedure followed as described in Example 1. The following amounts were used: 1H-indazole-3-carboxylic acid (0.65 g, 4 mmol), 1,1'-carbonyldiimidazole (0.65 g, 4 mmol) and 4-(2-aminoethyl)morpholine (0.52 mL, 4 mmol). The ethyl acetate extracts were evaporated to 0.468 g solid. Crystallization from ethyl acetate provided 0.267 g colorless crystals. Mass spectrum, m+ =274.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)[CH3:2].[NH3:16].C(O)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[C:8]([NH2:16])=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)CSc1cnc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCOC(=O)CSc1cnc(Cl)nc1N
Temperature: 25 °C

Procedure:
A solution of ethyl[(2,4-dichloro-5-pyrimidinyl)thio]acetate (2.0 g, 7.49 mmol) in DMF (75 ml) was treated with ammonia in isopropanol (7.49 ml, 14.97 mmol) in a pressure tube. The tube was capped, and the reaction was stirred at ambient temperature. Upon completion, the solution was concentrated under reduced pressure and pumped on to remove any residual DMF. The crude material was chromatographed using a gradient of 0-10% acetone/chloroform. The product contained a small amount of cyclized material (which is the product of the next step). The product was isolated as a light yellow solid.
Reaction SMILES: CO[C:3](=[O:15])[NH:4][C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=2[N:6]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>CN1CCCC1=O>[CH:16]1([NH:19][C:3]([NH:4][C:5]2[NH:9][C:8]3[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:7]=3[N:6]=2)=[O:15])[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: COC(=O)Nc1nc2cc(O)ccc2[nH]1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2cc(O)ccc2[nH]1)NC1CC1
Reaction time: 0.42 h
Yield: 8.9 %

Procedure:
3 g of methyl(5-hydroxy-1H-benzimidazol-2-yl)carbamate are placed in 15 cm3 of 1-methyl-2-pyrrolidinone and 4.19 g of cyclopropylamine in a 20 cm3 microwave reactor. After the reaction has been hermetically closed, it is placed in the microwave cavity at 130° C. for 25 minutes. The reaction medium is evaporated to dryness under reduced pressure (0.2 to 0.4 kPa) with a bath temperature of 85° C. The residue is taken up in 100 cm3 of water, solidified, filtered off by suction and washed with three times 80 cm3 of water. The cake is taken up in 30 cm3 of a dichloromethane/methanol mixture (90/10 by volume) and the insoluble material is filtered off. This operation is repeated ten times. The filtrates are evaporated to dryness under reduced pressure (2 kPa) at a bath temperature of 50° C. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (90/10 by volume)], 300 mg of 1-cyclopropyl-3-(5-hydroxy-1H-benzimidazol-2-yl)urea are obtained in the form of cream-coloured crystals, the characteristics of which are as follows: