Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]([C:10]1[N:11]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:15]=[C:14]([Cl:25])[N:13]=2)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:37](=O)([O-])N.Cl.C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:32])[N:7]([CH:8]([C:10]1[N:11]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[N:15]=[C:14]([Cl:25])[N:13]=2)[CH3:9])[CH3:37])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[O-]
Reactant: CC(NC(=O)OC(C)(C)C)c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC(c1nc2c(N3CCOCC3)nc(Cl)nc2n1C1CCCCO1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of {1-[2-chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethyl}-carbamic acid tert-butyl ester (218 mg, 0.47 mmol) in anhydrous THF (15 mL) was cooled to 0° C. Sodium hydride (60% suspension in oil, 22 mg, 0.56 mmol) was added and the mixture was stirred at 0° C. for 30 min. Iodomethane (10 vol. % solution in THF, 0.35 mL, 0.56 mmol) was added and the mixture was stirred for 16 h at RT. The reaction mixture was combined with another mixture, prepared in a similar manner from 210 mg of the carbamate starting-material, and diluted with water. After adjustment to pH7 by addition of 1M aqueous HCl and aqueous sodium bicarbonate, the mixture was extracted three times with ethyl acetate. The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo, to give a 2:1 mixture of the title compound and carbamate starting-material (0.46 g). This mixture was dissolved in anhydrous THF (20 mL) and treated with sodium hydride (19 mg) and iodomethane (10 vol. % solution in THF, 0.29 mL) as before. After addition of more iodomethane (neat, 0.050 mL) and stirring for another 8 h, the reaction mixture was diluted with water, neutralized and extracted as before. The organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2) gradient 0-20% ethyl acetate in cyclohexane) to give {1-[2-Chloro-6-morpholin-4-yl-9-(tetrahydro-pyran-2-yl)-9H-purin-8-yl]-ethyl}-methyl-carbamic acid tert-butyl ester (316 mg, 72%). LCMS RT=4.48 min, [M+H]+=481/483
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][O:29][C:23]1[CH:22]=[C:21]2[C:26]([CH2:27][CH2:28][CH:19]([N:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:16][CH2:17][CH3:18])[CH2:20]2)=[CH:25][CH:24]=1
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OC)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CC1CCNCC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.3 %

Procedure:
To a solution of 4-{[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (2.4 g, 4.56 mmol) in methylene chloride (30 mL) under a nitrogen atmosphere was added trifluoroacetic acid (10 mL). The reaction was stirred at room temperature for 30 min. and concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and 10% aq. KOH (50 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated to afford (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine (1.62 g).
Reaction SMILES: [C:1]([NH:4][O:5][CH:6]([CH3:29])[C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([C:21]3([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:15]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH2:30](Br)[C:31]#[CH:32]>>[CH2:32]([N:4]([C:1](=[O:3])[CH3:2])[O:5][CH:6]([CH3:29])[C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([C:21]3([O:27][CH3:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[CH:15]=2)=[CH:9][CH:8]=1)[C:31]#[CH:30]
Reactant: C#CCBr
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)ONC(C)=O)cc3)c2)CCOCC1
Product: C#CCN(OC(C)c1ccc(Sc2cc(F)cc(C3(OC)CCOCC3)c2)cc1)C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Using an analogous procedure to that described in Example 7 except that the reaction mixture was stirred at ambient temperature for 2 hours, 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl acetohydroxamate was reacted with 2-propynyl bromide to give 4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]-α-methylbenzyl N-(2-propynyl)acetohydroxamate as a gum (80%).
Reaction SMILES: C[C:2]([O:15][CH3:16])([C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[C:3]([OH:5])=[O:4].O.O.[OH-].[Li+]>CO.O1CCCC1>[CH3:16][O:15][CH:2]([C:6]([CH3:14])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: COC(C)(C(=O)O)C(C)(C)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(C(=O)O)C(C)(C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
According to General Procedure II, methyl 2-methoxy-3-methyl-3-phenylbutanoic acid (0.49 g, 2.2 mmol, from Reference Example 38) is dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). To this solution is added water (5 mL) and lithium hydroxide monohydrate (0.18 g, 4.4 mmol), and the resulting mixture is stirred at 60° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 10% aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a light orange oil, which solidified to a straw colored crystalline solid (0.46 g, 100%). MS (ES−): (M−H)=207.0
Reaction SMILES: P(Cl)(Cl)(Cl)=O.N1C=CN=C1.[C:11]([O:15][C:16](=[O:27])[NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24](=O)[NH2:25])[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1>[C:11]([O:15][C:16](=[O:27])[NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]#[N:25])[CH2:19]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(N)=O)C1
Agent: c1c[nH]cn1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCCC(C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.1 %

Procedure:
To a mixture of phosphorus oxychloride (4.60 g, 30.0 mmol) and imidazole (1.22 g, 18.0 mmol) in pyridine (40 mL) cooled in an ice-methanol bath was slowly added (3-carbamoyl-cyclohexyl)-carbamic acid tert-butyl ester (1.45 g, 6.00 mmol). The reaction was stirred for 3 hours, allowing to warm to room temperature. The suspension was filtered, the filtrate evaporated and the solids combined before partitioning between aq. NH4Cl (30 mL) and EtOAc (3×30 mL). The combined organic layers were dried (MgSO4) and evaporated to give 930 mg (69%) of (3-cyano-cyclohexyl)-carbamic acid tert-butyl ester as a gum, which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ: 4.53-4.29 (m, 1H), 3.50-3.33 (m, 1H), 2.58-2.44 (m, 1H), 2.42-2.33 (m, 1H), 2.09-1.99 (m, 1H), 1.99-1.77 (m, 3 h), 1.44 (s, 9H), 1.39-1.30 (m, 2H), 1.18-1.02 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH2:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:14](OCC)(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].N1CCCCC1>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[C:14](=[O:21])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[CH2:10][CH3:11])=[O:17])[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCc1c(OC)ccc(C=O)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2ccc(OC)c(CC)c2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-3-ethyl-benzaldehyde (3.1 g, 17.2 mmol) in ethanol (93 mL) is added diethyl malonate (2.8 g, 17.2 mmol) and piperidine (1.5 g, 17.2 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then cooled to 0° C. with ice/water bath and the formed precipitate was filtered and washed with ethanol to give 7-methoxy-2-oxo-8-ethyl-2H-chromene-3-carboxylic acid ethyl ester (3.1 g, 65%).
Reaction SMILES: C(CCC=N[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=1)#N>C(Cl)(Cl)Cl>[C:8]([CH2:9][C:10]1[C:9]2[C:8](=[CH:13][CH:12]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:16])=[O:17])[CH:10]=2)[NH:7][CH:11]=1)#[N:7]
Reactant: CNS(=O)(=O)Cc1ccc(NN=CCCC#N)cc1
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 0.33 h

Procedure:
A suspension of the product from stage (a) (0.7 g) in polyphosphate ester (7 g) and chlorform (14 ml) was heated at reflux for 5 min. and then poured onto ice. The resulting suspension was stirred with ice for 20 min., then extracted with chloroform (4×20 ml) and the extract dried. Solvent was then removed and the residue purified by column chromatography (G). The title compound was obtained as a reddish semi-solid (0.38 g) which was impure and was employed directly in the next stage.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>N1C=CC=CC=1>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: NCCCCN
Solvent: c1ccncc1
Product: NCCCCNc1ccccn1
Yield: 67 %

Procedure:
2-Bromopyridine (10 g), 1,4-diaminobutane (35 ml) and pyridine (7 ml) were heated together under reflux for 4 hr. The mixture was stripped to remove the excess of diaminobutane and the residue taken up in water. The solution was extracted with chloroform at pH 7 and 13. After drying (K2CO3) the latter extract was stripped and the residue distilled at reduced pressure to give 2-(4-amino-butylamino) pyridine 7.0 g (67%) bp 136°-38° C., 2 mm Hg. (ii) A mixture of sodium hydride (0.78 g) and 2-(4-aminobutylamino) pyridine (4.9 g) in DMSO (45 ml) was heated slowly to 85° C. under nitrogen. After the evolution of hydrogen had ceased the solution was cooled to room temperature and methyl iodide (2.1 ml) in DMSO (10 ml) added dropwise below 25° C. After a further 1.5 hr the mixture was poured into water (150 l) and extracted with dichloromethane. The volume of the extract was reduced and washed with 2N hydrochloric acid. Partitioning between water, ether and dichloromethane at pH 1 and 13 gave, on stripping the final basic extract, 2-[N-(4-aminobutyl)-N-methylamino]pyridine (3.22 g) as an oil which was used without further purification. (iii) 2-[N-(4-aminobutyl)-N-methylamino]pyridine (0.81 g) and 2-methylthio-5-(4-chlorobenzyl)pyrimid-4-one (1.0 g) were heated together under reflux in pyridine (2.5 ml) for 23 hr. After stripping, the residue was crystallised twice from ethanol/water to give 2-[4-(N-methyl-N-pyrid-2-ylamino)butylamino]-5-(4-chlorobenzyl)pyrimid-4-one 1.5H2O, 0.98 g (62%) mp softens 72-75 melts 133°-35° C.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH2:21])[C:18]([O:22][CH3:23])=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].NC1C(OC)=C2C(C3C=C(C)C=NC=3N2)=C(C2C=C(N[C:53]([CH:55]3[CH2:57][CH2:56]3)=[O:54])C=CC=2)C=1>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([NH:21][C:53]([CH:55]3[CH2:57][CH2:56]3)=[O:54])[C:18]([O:22][CH3:23])=[C:17]3[C:13]=2[C:14]2[CH:27]=[C:26]([CH3:28])[CH:25]=[N:24][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: COc1c(N)cc(-c2cccc(NC(=O)C3CC3)c2)c2c1[nH]c1ncc(C)cc12
Reactant: CCS(=O)(=O)c1cccc(-c2cc(N)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(NC(=O)C3CC3)c(OC)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 239 by using an analogous procedure to that outlined in the preparation of Compound 241. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (br. s., 4H) 1.16 (t, J=7.33 Hz, 3H) 2.17 (m., 1H) 2.25 (s, 3H) 3.95 (s, 3H) 7.44 (br. s., 1H) 7.78 (br. s., 1H) 7.87 (d, J=7.58 Hz, 1H) 7.96 (d, J=3.28 Hz, 1H) 8.01 (d, J=7.33 Hz, 1H) 8.07 (br. s., 1H) 8.23 (br. s., 1H) 9.88 (br. s., 1H) 12.07 (br. s., 1H); [M+H] calc'd for C25H26N3O4S, 464.2; found, 464.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH3:19])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[OH:20].Br[CH2:22][C:23]([OH:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]([C:11]2[N:15]([CH2:16][O:17][CH2:18][CH3:19])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][C:3]=1[O:20][CH2:22][C:23]([OH:25])=[O:24]
Reactant: O=C(O)CBr
Reactant: CCOCn1nccc1C(=O)c1ccc(O)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOCn1nccc1C(=O)c1ccc(OCC(=O)O)c(Cl)c1Cl
Yield: 56.3 %

Procedure:
0.63 g of 2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenol, 0.58 g of bromoacetic acid and 1.11 g of potassium carbonate are added to 40 ml of acetone, and the mixture is refluxed for 48 hours. The reaction mixture is concentrated to remove solvent, and water is added to the residue. The aqueous mixture is washed with ethyl acetate, acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is crystallized with water, and the crystals are separated by filtration, washed successively with water and isopropyl ether, and dried to give 0.42 g of [2,3-dichloro-4-(1-ethoxymethyl-5-pyrazolylcarbonyl)phenoxy]acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[C:14]([O:32]C(=O)C)=[C:15]([CH:29]=[CH:30][CH:31]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[C:14]([OH:32])=[C:15]([CH:29]=[CH:30][CH:31]=2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=2)=[O:17])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2OC(C)=O)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(C(F)(F)F)cc3)c2O)=C(C)C1=O
Yield: 57.9 %

Procedure:
N-[3-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline (0.150 g, 0.290 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was recrystallized from ether to obtain the titled compound (0.080 g, 0.168 mmol, 58%).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:11]([N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NOCc1ccccc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CON(Cc2ccccc2)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 13.04 g of benzyloxyaminehydrochloride, 20.0 ml of benzylbromide, and 32.0 g of sodium carbonate in 85 ml of dimethylformamide is stirred at room temperature for four days. The reaction mixture is worked up as in Example I and the crude product is distilled under reduced pressure to afford the title compound as a clear colorless liquid.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[F:5][C:6]([F:16])([F:15])[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=1[Cl:14])[NH2:10]>O.C(O)(=O)C>[Cl:14][C:13]1[CH:12]=[CH:11][C:9]([NH:10][C:2]([NH2:3])=[O:1])=[CH:8][C:7]=1[C:6]([F:5])([F:15])[F:16]
Reactant: N#C[O-]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Sodium cyanate (1.7 g, 0.02 mol) was dissolved in water (17 ml) at room temperature to obtain a clear solution. This solution was then charged drop wise to the clear solution of 3-trifluoromethyl-4-chloro aniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40° C.-45° C. within 1-2 hours. The reaction mass was then agitated for whole day cooling gradually to room temperature. The obtained solid was then filtered, washed with water and vacuum dried at 50° C. to afford (4.5 g) the desired product, i.e., 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[OH-].[K+].[C:14](Cl)(=[O:18])[CH:15]([CH3:17])[CH3:16]>ClCCl>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16]
Reactant: COc1cc(N)c(Br)cc1C
Reactant: CC(C)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(NC(=O)C(C)C)c(Br)cc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.3 %

Procedure:
To a biphasic mixture of 2-bromo-5-methoxy-4-methyl-aniline (5.6 g, 25.96 mmol), 10% KOH (27 mL) and dichloromethane (30 mL), was added dropwise isobutyryl chloride (3 mL, 28.55 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 48 hrs. The layers were separated. The aqueous layer was further extracted with dichloromethane and the combined organics washed successively with water and brine, dried over MgSO4, filtered and evaporated to give 7.38 g of N-(2-bromo-5-methoxy-4-methyl-phenyl)-isobutyramide (99% yield). 1H NMR (300 MHz; CDCl3): 1.29 (d, J=6.9 Hz, 6 H), 2.14 (s, 3 H), 2.59 (m, 1 H), 3.84 (s, 3 H), 7.24 (s, 1 H), 7.66 (br s, 1 H), 8.07 (s, 1 H).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32]N>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1ccccc1F
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccccc1F

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and 2-fluoro-phenylhydrazine according to the method described for example 91. MS: M=399.1 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1)/[CH:5]=[N:6]/[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1>O1CCCC1.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:10]([CH3:15])([CH3:9])[CH:11]([OH:12])[C:8]3[C:7](=[CH:16][CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=3)[NH:6]2)[CH:17]=[C:18]([N+:20]([O-:22])=[O:21])[CH:19]=1
Reactant: COC(=O)c1ccc(/N=C/c2cc(Cl)cc([N+](=O)[O-])c2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Cl)cc([N+](=O)[O-])c1)N2
Yield: 117.4 %

Procedure:
To a solution of 3-chloro-5-nitrobenzaldehyde (371 mg, 0.1 mmol) in ethanol (6 mL) was added methyl 4-aminobenzoate (302 mg, 2.0 mmol). After a while, solids precipitated from the resulting clear yellow solution. The precipitated solid was filtered and 346 mg of (E)-methyl 4-(3-chloro-5-nitrobenzylideneamino)benzoate as a yellow solid was obtained. Yield=54%. To a solution of (E)-methyl 4-(3-chloro-5-nitrobenzylideneamino)benzoate (346 mg, 1.09 mmol) in dry tetrahydrofuran (4 mL) was added yttrium(III) trifluoromethanesulfonate (34 mg, 0.054 mmol). The mixture was stirred under a nitrogen atmosphere. Then a solution of isobutyl aldehyde (95 mg, 1.30 mmol) in tetrahydrofuran (1 mL) was added via syringe. The mixture was stirred overnight. The reaction mixture was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to afford 250 mg of methyl 2-(3-chloro-5-nitrophenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a crude product. (Yield=59%). MS (ESI+APCI) M+1-water=373.
Reaction SMILES: [C:1]([OH:14])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[N+](=[CH2:17])=[N-].Cl>CO>[C:1]([O:14][CH3:17])(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1
Reactant: C=[N+]=[N-]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: Cl
Solvent: CO
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1

Procedure:
Methyl ferulate was prepared by methylating commercial ferulic acid (made by Tokyo Kasei Kogyo Co. LTD., Japan) with diazomethane or methyl alcohol acidified with hydrochloric acid (Fisher Method).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)O1.Br[C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:28]=1[CH3:35].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:34][O:33][C:31]1[CH:30]=[CH:29][C:28]([CH3:35])=[C:27]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])[N:15]=[CH:16]3)=[CH:11][CH:10]=2)[CH:32]=1
Reactant: COc1ccc(C)c(Br)c1
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)C4CC4)ncc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c1
Temperature: 130 °C
Yield: 21.7 %

Procedure:
To a solution of N-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide (200 mg, 0.59 mmol) in dioxane/water (5.0 ml) were added 2-bromo-4-methoxy-1-methylbenzene (100 mg, 0.50 mmol), cesium carbonate (391 mg, 1.2 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22 mg, 0.03 mmol). It was purged with nitrogen and heated at 130° C. for 30 min under microwave irradiation. The reaction mixture was concentrated, washed with water and extracted with ethyl acetate. It was dried over sodium sulfate, concentrated and purified by pre-HPLC to give the product (36 mg, 18.4%). LCMS (ESI): RT (min)=1.214, M+H+=332.9, method=A; 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.70-7.68 (m, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.91-6.86 (m, 2H), 3.76 (s, 3H), 2.19 (s, 3H), 2.09-2.05 (m, 1H), 0.87-0.81 (m, 4H).
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[O:16]>>[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12)=[O:16]
Reactant: O=Cc1cccs1
Reactant: Ic1ncn2ccsc12
Product: O=C(c1cccs1)c1ncn2ccsc12

Procedure:
7-(Thiophen-2-yl)carbonylimidazo[5,1-b]thiazole (1.37 g) was prepared in the same manner as in step a) of Synthesis Example 3, except that 1.50 g of 7-iodoimidazo[5,1-b]thiazole and 0.561 ml of thiophene-2-aldehyde were used as the starting compounds.