Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[S:25])=[CH:19][CH:18]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)=[S:25])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1

Procedure:
A stirring mixture of 2-amino-3-benzyloxy pyridine (5.37 g, 0.0268 mol) and 4-chlorophenylisothiocyanate (5 g, 0.0295 mol) in toluene (20 ml) was heated under reflux for 2 h. After allowing to cool, the solution was treated with ether, and the resulting solid filtered off, washed and dried. Yield 8.33 g (84%), m.p. 140°-143 ° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9](Cl)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1Cl
Temperature: 95 °C
Reaction time: 18 h
Yield: 29.1 %

Procedure:
A mixture of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid ethyl ester (29.7 g, 127 mmol), potassium carbonate (26.3 g, 190 mmol), and morpholine (13.3 g, 152 mmol) in dimethylformamide (350 ml) is stirred for 18 h at 95° C. After completion of the reaction, water is added and the mixture is extracted with diethyl ether (3×). The combined organic layers are washed with water (2×) and brine (1×), dried over magnesium sulphate and evaporated to dryness. The crude product is purified by flash chromatography (silica gel, 25% ethyl acetate/cyclohexane) to yield 2-chloro-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (10.5 g, 36.9 mmol, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([OH:17])=[O:16]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([C:15]([OH:17])=[O:16])[N:11]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)Nc1ccc(Cl)cc1
Solvent: CO
Product: O=C(O)c1csc(Nc2ccc(Cl)cc2)n1
Yield: 94.6 %

Procedure:
2-(4-Chloro-phenylamino)-thiazole-4-carboxylic acid (240 mg) was prepared according to General Procedure B using (4-chloro-phenyl)-thiourea (186 mg) and 3-bromo-2-oxo-propionic acid (200 mg) in methanol (2 mL). The crude product was used in a subsequent step without further purification.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N:14]([CH2:17][C:18]([O:20][CH2:21]C)=[O:19])=[N+:15]=[N-:16].C[O-].[Na+]>CO.[Cl-].[Na+].O>[N:14]([C:17](=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:7][CH:8]=1)[C:18]([O:20][CH3:21])=[O:19])=[N+:15]=[N-:16]
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C(=Cc1ccc(-n2ccnc2)cc1)N=[N+]=[N-]
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of 4-(1-imidazolyl)benzaldehyde (1.41 g, 8.16 mol) and ethyl azidoacetate (10.6 g, 81.7 mmol) in MeOH (50 ml) under nitrogen atmosphere is added sodium methoxide (28 wt. % solution in MeOH, 13,2 ml, 65 mmol) dropwise. Stirring is continued for 1.5 h. Then, the reaction mixture is diluted with brine (100 ml) and extracted with three portions of ether. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give methyl 2-azido-3-[4-(1-imidazolyl)phenyl]-2-propenate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][C@H:6]([OH:8])[CH2:5][N:4]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:9]([N:4]1[CH2:5][C@H:6]([O:8][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:7][C@H:3]1[CH2:2][O:1][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](O)C[C@@H]1CO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
To an ice-cold solution of 150 g (596.9 mmol) of (2R,4S)-2-hydroxymethyl-4-hydroxy-N-(carbobenzyloxy)pyrrolidine in 0.5 1 of pyridine was added 250 g (1.32 mol) of 4-toluenesulfonyl chloride in 3 portions to keep the temperature of the reaction below 15° C. for 1 hour and then warmed to room temperature. After 12 hours, an additional 125 g (656 mmol) of p-toluenesulfonyl chloride was added and the mixture was allowed to stir at room temperature for 16 additional hours. The mixture was then cooled with an ice bath and 3 1 of 10% aqueous HC1 solution was carefully added. The mixture was extracted with 2 x 250 ml of methylene chloride and dried over MgSO4. Evaporation of the solvent provided 274 g of the product as an oil (82% yield). NMR(CDC13): 7.70 & 7.40 (m,9H, aromatic), 5.0 (m,3H), 4.43 (dd,1H), 4.12 (m,1H), 4.02 (m,H), 3.70 (m,1H), 3.88 (m,1H), 2.42 (m,6H), 2.15 (m,2H).
Reaction SMILES: [OH:1][C:2]([C:5]([OH:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:14]([B:16](O)O)[CH:15]=1>C(OCC)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:14]([B:16]2[O:8][C:5]([CH3:7])([CH3:6])[C:2]([CH3:4])([CH3:3])[O:1]2)[CH:15]=1
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: CC(C)(O)C(C)(C)O
Solvent: CCOCC
Product: CC1(C)OB(c2cc(Cl)ccc2OCc2ccccc2)OC1(C)C
Reaction time: 24 h

Procedure:
Pinacol (3.24 g) was added to a solution of [5-chloro-2-(phenylmethoxy)phenyl]-boronic acid (6 g) in diethyl ether, and stirred for 24 h. 4A molecular sieves and pinacol (1.5 g) were added, stirred for a further 24 h. The sieves were filtered and the filtrate was washed with water and brine, then dried (MgSO4) and concentrated in vacuo. Yield 6.8 g.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[Br:35]Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([OH:30])=[C:28]([Br:35])[CH:29]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(O)c(Br)c1

Procedure:
To a mixture of 6-bromo-2-(4-hydroxybenzyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (290 mg), aluminum chloride (82 mg) and dichloromethane (5.7 ml) was added bromine (39 μl) at 0° C. with stirring, and the mixture was stirred for 1 hr. After the completion of the reaction, the reaction mixture was washed with water, dried and concentrated. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=4/1-1/1) to give the title compound (180 mg) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([I:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(OCC)(=O)C>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=3[I:12])=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2c(I)cccc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cccc2c1O
Temperature: 25 °C

Procedure:
A portion of the resulting ethyl 4-hydroxy-8-iodo-3-quinolinecarboxylate (4.01 g) and 4-chlorobenzylamine (20.00 mL) are heated at 180° C. for 1.5 h. The reaction is cooled to room temperature. Ethyl acetate is added, followed by hexanes, and the solid is filtered, washed with hexanes, and dried to give N-(4-chlorobenzyl)-4-hydroxy-8-iodo-3-quinolinecarboxamide (3.98 g).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27](O)=[O:28])[C:10]=2[C:30](O)=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][C:36](=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)[CH3:34].O>C(O)(=O)C>[CH2:33]([O:35][C:36](=[O:45])[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([N:44]2[C:27](=[O:28])[C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]4=[C:9]([O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:10]=3[C:30]2=[O:31])=[CH:42][CH:43]=1)[CH3:34]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)c1c(C(=O)O)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCc3ccccc3)C2=O)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 1,4-bis[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (2.0 g, 4.67 mmol) and ethyl(4-aminophenyl)acetate (1.67 g, 9.35 mmol) were heated to 120° C. in acetic acid (30 ml) for 2 hours. The mixture solidified on standing at room temperature overnight. Water was added and the solid collected by filtration and washed with water. This was dried under vacuum to give the title compound (2.65 g, 4.64 mmol). LC/MS: Rt=4.24, [MH]+ 572.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:8]([CH:11]=[C:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[CH2:28]([Li])CCC>CO.[Pt]=O>[ClH:27].[CH2:2]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:8]([CH2:11][CH:12]([CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([O:15][CH3:28])=[O:14])=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=Cc1cnc(CCCC)n1Cc1ccccc1Cl)C(=O)O
Reactant: [Li]CCCC
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CCCCc1ncc(CC(CCCC)C(=O)OC)n1Cc1ccccc1Cl
Yield: 74 %

Procedure:
A mixture of methyl (E and Z)-3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butyl-propenoate hydrochloride salt (prepared by the method in Example 6, replacing methyl lithium with butyl lithium) (245 mg, 0.578 mmol) in methanol (15 mL) and platinum oxide (30 mg) was stirred under an atmosphere of hydrogen for 0.5 hours. The catalyst was filtered, the filtrate was concentrated, and the residue was triturated with diethyl ether to afford 181 mg (74%) of methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-n-butylpropanoate hydrochloride; mp 123°-125° C.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN(C)C=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:12][CH2:11][CH2:10][CH2:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: OCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
Sodium hydride (99 mg, 4.14 mmol) was added to a solution of 3-phenyl-1-propanol (564 μL, 4.14 mmol) in N,N-dimethylformamide (15 mL) while cooling in ice, and the mixture was stirred for 30 min while cooling in ice. A solution of 2-fluoro-5-nitropyridine (500 mg, 3.45 mmol) in N,N-dimethylformamide (5 mL) was added thereto. The mixture was warmed to room temperature and stirred for 19 hr. Subsequently, sodium hydride (99 mg, 4.14 mmol) was added thereto and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was heated to 85° C., stirred for 1.5 hr, and further stirred at room temperature for 2 hr. Water was added to the reaction mixture while cooling in ice, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and dried over anhydrous magnesium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to afford 5-nitro-2-(3-phenylpropoxy)pyridine as a brown solid (440 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([F:22])[C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:23])[CH2:3][CH2:2]1.O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[CH:20]=[C:19]([O:21][CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:25])[CH:18]=[C:17]([F:22])[C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:23])[CH2:2][CH2:3]1
Reactant: Oc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1cc(F)c2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-4-fluoro-1,3-benzoxazol-6-ol (110 mg), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (91.0 mg) and triphenylphosphine (136 mg) in THF (5 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 0.274 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (159 mg).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1
Reactant: BrP(Br)Br
Reactant: OCC1CCc2ccccc2C1
Solvent: ClCCl
Product: BrCC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 124.9 %

Procedure:
A solution of 2-hydroxymethyl-1,2,3,4-tetrahydronaphthalene (2.28 g, 14.0 mmol) in 100 ml of CH2Cl2 was treated with PBr3 (1.28 g, 4.73 mmol) at 0° C. The mixture was stirred at room temperature for 72 hours then poured onto 100 g of ice. The organic layer was isolated, washed with 10% K2CO4 aqueous solution, H2O, sat'd brine, and then dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, F. tOAc:hexane, 1:10) to give a colorless oil (1.33 g, 41.6%); 1H NMR (CDCl3, 300 g MHz)δ 1.55 (m, 1H) , 2.11 (m, 1H) , 2.11 (m, 2H) , 2.58 (dd, J1 =16.2 Hz, J2 =10.2 Hz, 1H) , 2.80-3.10 (m, 3H) , 3.45 (d, J=6.3 Hz, 2H), 7.10 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2ccc(C)cc2C(=O)O)nc1
Product: Cc1ccc(-c2ccc(C)cc2C(=O)N2CCC[C@@H](C)[C@H]2CN)nc1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, starting with 5-methyl-2-(5-methylpyridin-2-yl)benzoic acid. ESI-MS (m/z): 338 [M+1]+.
Reaction SMILES: [CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:17][CH2:18][OH:19])[C:11]([CH3:21])([CH3:20])[CH2:10]1)C(=O)C)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>Cl>[CH2:1]([NH:5][CH:9]1[CH2:10][C:11]([CH3:20])([CH3:21])[N:12]([CH2:17][CH2:18][OH:19])[C:13]([CH3:15])([CH3:16])[CH2:14]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(C)=O)C1CC(C)(C)N(CCO)C(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCNC1CC(C)(C)N(CCO)C(C)(C)C1
Yield: 74.9 %

Procedure:
A solution of 12.6 g (42.2 mmol) of N-n-butyl-N-[1-(2-hydroxyethyl)-2,2,6,6-tetramethylpiperidin-4-yl]acetamide [Example 1bη2] in 180 ml of 2N hydrochloric acid is refluxed for 48 hours. The reaction mixture is then cooled 0°-5° C. and, after addition of 40 ml of 30% sodium hydroxide solution, extracted twice with toluene. The organic phases are washed with water, combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Chromatography of the residue over silica gel with the solvent system ethyl acetate/ethanol/triethylamine=50:2:1 gives 8.1 g (68%) of 2-(4-n-butylamino-2,2,6,6-tetramethylpiperidin-1-yl) ethanol (208) in the form of a white powder, m.p. 106°-111° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: Cc1cc2c(NCc3ccccc3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17]OS(C)(=O)=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[I-:23].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][I:23])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: [I-]
Reactant: CS(=O)(=O)OCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CI)CC3
Temperature: 60 °C
Yield: 78.4 %

Procedure:
A mixture of 9-bromo-5-methylsulfonyloxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (2.3 g, 5.91 mmol) and sodium iodide (7.9 g, 52.7 mmol) in DMF (30 mL) was heated at 60° C. for 22 h and poured into water (400 mL). The precipitates formed was collected by filtration, washed with water, and dried in vacuo to give 1.95 g of the title compound (78%): mp 260°~270.5° C.; 1H NMR (270 MHz, CD3OD) δ7.22 (s, 1H), 7.19 (s, 1H), 4.95~5.07 (m, 1H), 3.50 (dd, 1H, J=10.2, 4 Hz), 3.24 (d, 1H, J=10.2 Hz), 2.97 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz), 2.70 (dm, 1H, J=13.5 Hz), 1.90~2.07 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[C:8]([F:9])=[C:7]([CH2:10][OH:11])[C:6]([F:12])=[C:5]([F:13])[N:4]=1.[Cl:15][C:16]([C:26]([F:29])([F:28])[F:27])=[CH:17][C@@H:18]1[C@H:20]([C:21](Cl)=[O:22])[C:19]1([CH3:25])[CH3:24]>>[Cl:15][C:16]([C:26]([F:27])([F:28])[F:29])=[CH:17][C@@H:18]1[C@H:20]([C:21]([O:11][CH2:10][C:7]2[C:6]([F:12])=[C:5]([F:13])[N:4]=[C:3]([N:2]([CH3:14])[CH3:1])[C:8]=2[F:9])=[O:22])[C:19]1([CH3:25])[CH3:24]
Reactant: CN(C)c1nc(F)c(F)c(CO)c1F
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Product: CN(C)c1nc(F)c(F)c(COC(=O)[C@H]2[C@@H](C=C(Cl)C(F)(F)F)C2(C)C)c1F

Procedure:
By the method of Example 2, 0.5 g (0.002 mole) of 2-dimethylamino-4-hydroxymethyl-3,5,6-trifluoropyridine (from Example 13) was reacted with 0.6 g (0.002 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride to produce, after purification through a short silica gel column and the Chromatotron, 0.45 g of (2-methoxy-3,5,6-trifluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as an oil, Compound No. 20 of the tables below.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: C1COCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCOCC1
Temperature: 60 °C
Yield: 20.6 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was added morpholine (114.86 mg, 1.318 mmol) followed by diisopropylethylamine (0.229 mL, 1.318 mmol) and tetrabutylammonium iodide (162.3 mg, 0.439 mmol). The reaction mixture was heated at 60° C. for 3 days. Formation of product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-morpholinoethoxy)quinazolin-4-yloxy)phenyl)urea (51 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.60-7.35 (m, 4H), 7.25 (m, 1H), 6.95 (m, 1H), 6.45 (s, 1H), 4.32 (m, 2H), 3.95 (s, 3H), 3.62 (m, 4H), 2.85 (m, 2H), 2.65-2.45 (m, 4H), 1.28 (s, 9H); LC-MS (ESI) m/z 563 (M+H)+.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:10]=[C:9]([C@:11]2([O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]2[O:14]C(=O)C)[OH:12])[CH:8]=[C:7]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][CH:37]=2)[C:6]=1[CH3:44])#[N:4].Cl>CO.C1COCC1>[C:3]([C:5]1[CH:10]=[C:9]([C@:11]2([O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]2[OH:14])[OH:12])[CH:8]=[C:7]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([CH2:42][CH3:43])=[CH:40][CH:41]=2)[C:6]=1[CH3:44])#[N:4]
Reactant: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(C#N)c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(C#N)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide solution (1.7 mL, 4 mol/L) is added to 1-cyano-3-(4-ethylbenzyl)-2-methyl-5-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-benzene (0.85 g) dissolved in methanol (6 mL) and THF (3 mL). The solution is stirred at room temperature for 1 h and then neutralized with hydrochloric acid (1 mol/L). After removal of the organic solvents, the residue is diluted with aqueous sodium bicarbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (dichloromethane/methanol 1:0->8:1).