Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:9]1[CH:8]=[CH:7][C:6]2[O:1][CH2:2][C:3](=[O:11])[NH:4][C:5]=2[CH:10]=1)=[O:19]
Reactant: O=C(Cl)CCCCCBr
Reactant: O=C1COc2ccccc2N1
Product: O=C1COc2ccc(C(=O)CCCCCBr)cc2N1
Yield: 45.1 %

Procedure:
Using 2H-1,4-benzoxazin-3(4H)-one (15.0 g) and 6-bromohexanoyl chloride (25.8 g) according to the same method as that of Reference Example 1, the title compound (14.8 g) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([CH2:25][NH:26][C:27](=[O:29])[O-:28])[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:30])=[CH:14][CH:15]=2)[N:10]=1.[ClH:31].[CH3:32][CH2:33][O:34][CH2:35]C>C(Cl)Cl>[ClH:31].[CH3:35][O:34][CH2:33][CH2:32][N:26]([CH2:25][C@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:17]2[C:16]3[C:11](=[CH:12][C:13]([CH3:30])=[CH:14][CH:15]=3)[N:10]=[C:9]([C:3]3[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:18]=2)[CH2:20]1)[C:27](=[O:28])[OH:29]
Reactant: CCOCC
Reactant: Cc1ccc2c(N3CCC[C@@H](CNC(=O)[O-])C3)nc(-c3c(O)cccc3F)nc2c1
Agent: Cl
Solvent: ClCCl
Product: COCCN(C[C@H]1CCCN(c2nc(-c3c(O)cccc3F)nc3cc(C)ccc23)C1)C(=O)O
Reaction time: 0.04 h

Procedure:
To a solution of ((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (352 mg, 0.75 mmol) in CH2Cl2 (3 mL) was added dropwise a 2.0 M HCl solution in ether (0.375 mL, 0.75 mmol) under an N2 atmosphere. It was followed by the addition of 20 mL ether which lead to the precipitation of 2-methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate hydrochloride (350 mg, 92%) which was then filtered and dried. LC/MS: m/z 469.5 (M+H)+ at 2.29 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=7.9 Hz, 1H), 7.63 (s, 1H), 7.45 (m, 3H), 6.89 (d, J=8.3 Hz, 1H), 6.82 (t, J=9.5 Hz, 1H), 4.54 (s, 1H), 4.03 (d, J=2.7 Hz, 2H), 3.47 (t, J=4.6 Hz, 4H), 3.24 (s, 3H), 2.99 (m, 2H), 2.54 (s, 3H), 1.89 (m, 3H), 1.70 (m, 1H), 1.38 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=1[F:31].[CH3:32][Si:33]([CH3:36])([CH3:35])Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][Si:33]([CH3:36])([CH3:35])[CH3:32])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[C:23]=1[F:31]
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reactant: C[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reaction time: 16 h
Yield: 107.7 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 2g (1.31 g, 2.84 mmol) was dissolved in 15 mL pyridine, followed by addition of 4-dimethylamino pyridine (70 mg, 0.57 mmol) and trimethyl-chloro-silane (514 mg, 3.4 mmol). The reaction mixture was stirred for 16 hours and then concentrated under reduced pressure. The resulting residue was dissolved in 150 mL ethyl acetate and washed with pyridine (50 mL×2), water (30 mL) and saturated sodium chloride solution (30 mL) in turn. The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-2-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-methoxy-6-(trimethylsilyloxymethyl)tetrahydropyran-3,4,5-triol 2h (1.63 g, pale yellow solid), yield: 100%.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C([Li])CCC.[CH3:26][CH:27]([CH3:37])[C:28]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)=[O:29].O>O1CCCC1>[OH:29][C:28]([C:2]1[C:3]([CH3:20])=[C:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9])([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)[CH:27]([CH3:37])[CH3:26]
Reactant: Cc1ccc(C(=O)C(C)C)cc1
Reactant: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(NC(=O)OC(C)(C)C)c(C)c1C(O)(c1ccc(C)cc1)C(C)C
Reaction time: 0.33 h
Yield: 75.4 %

Procedure:
To a solution of tert-butyl 3-bromo-4-methoxy-2,5,6-trimethylphenylcarbamate (27.8 g, 80.8 mmol) in tetrahydrofuran (150 ml) was added at -78° C. n-butyllithium (1.6 M, 110 ml, 176 mmol) and the reaction mixture was stirred at the same temperature for 20 minutes. To the reaction solution was added 2-methyl-1-(4-methylphenyl)propan-1-one (13.1 g, 80.7 mmol) and stirred at room temperature for 1 hour. Water (150 ml) was added to the reaction mixture and the product was extracted three times with ethyl acetate. The combined organic layers were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure to obtain 26.0 g of tert-butyl 3-[1-hydroxy-2-methyl-1-(4-methylphenyl)propyl]-4-methoxy-2,5,6-trimethylphenylcarbamate as a crude product. A mixture of this compound and 47% hydrobromic acid (100 ml) was refluxed with heating for 4 hours under argon atmosphere. The reaction mixture was cooled down to room temperature and neutralized with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous, saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, and then concentrated under reduced pressure. The residue was crystallized from isopropyl ether-hexane to obtain 14.8 g (62% yield) of the title compound. Melting point: 114-115° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)[CH2:19][CH3:20].[I-].[K+]>CC(C)=O>[O:17]=[C:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH2:18][CH2:19][CH3:20])[C:11]=2[O:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]1
Reactant: CCOC(=O)c1cc(=O)c2cccc(O)c2o1
Reactant: CCCc1ccccc1OCCCCCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1ccccc1OCCCCCCCOc1cccc2c(=O)cc(C(=O)OCC)oc12

Procedure:
A mixture of 4.84 parts of ethyl 8-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylate, 12.5 parts of 7-bromoheptyl 2-n-propylphenyl ether, 1 part of potassium iodide and 50 parts of anhydrous acetone was refluxed for 76 hours. After filtration the organic layer was concentrated and chromatographed over silica gel. Elution with benzene/chloroform (1:1) furnished 8.9 parts of ethyl 4-oxo-8-[7-(2-n-propylphenoxy)heptyloxy]-4H-1-benzopyran-2-carboxylate as a gum.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH2:24][CH2:25][N:26]4[C:29](=[O:34])[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=3[O:35][CH3:36])[NH:16][C:15]3=[N:37][CH:38]=[CH:39][C:14]=23)[CH:3]=1.[CH3:40]N>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([NH:8][CH3:40])=[O:7])=[C:4]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:28]=[C:27]4[C:23]([CH2:24][CH2:25][N:26]4[C:29](=[O:34])[CH2:30][N:31]([CH3:32])[CH3:33])=[CH:22][C:21]=3[O:35][CH3:36])[NH:16][C:15]3=[N:37][CH:38]=[CH:39][C:14]=23)[CH:3]=1
Reactant: CN
Reactant: COc1cc2c(cc1Nc1nc(Nc3cc(Cl)cc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Solvent: C1CCOC1
Product: CNC(=O)c1c(F)cc(Cl)cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Reaction time: 12 h

Procedure:
The residue obtained from concentration of the filtrates generated from the synthesis of 4-chloro-2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide above were dissolved in tetrahydrofuran (10 mL) and 2.0M methyl amine in THF (5 mL) was added. The resulting solution was stirred for 12 hours and then concentrated to a residue under reduced pressure. The solids were dissolved in 1,4-dioxane (8 mL) and added to a microwave vial with 2.0N sodium hydroxide (8 mL). The mixture was maintained with rapid stirring under microwave irradiation at 120° C. for 8 minutes, cooled, poured into ethyl acetate/tetrahydrofuran/saturated sodium bicarbonate, and the organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2 to afford 4-chloro-2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.078 g); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.31 (s, 1H), 10.53 (s, 1H), 8.62 (d, J=2.57 Hz, 1H), 8.49-8.56 (m, 2H), 7.67 (s, 1H), 7.05 (dd, J=10.26, 1.83 Hz, 1H), 6.96-7.00 (m, 1H), 6.95 (s, 1H), 6.21-6.28 (m, 1H), 4.13 (t, J=8.43 Hz, 2H), 3.76 (s, 3H), 3.13 (s, 2H), 3.09 (t, J=8.62 Hz, 2H), 2.80 (d, J=4.77 Hz, 3H), 2.21 (s, 6H). ESIMS (M+H)+=567.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][C:3]=1[F:14].[CH2:15]([Mg]Br)[CH2:16][CH3:17]>O1CCCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:15][CH2:16][CH3:17])=[CH:4][C:3]=1[F:14]
Reactant: CON(C)C(=O)c1ccc(Br)c(F)c1
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCCC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a stirred solution of 4-Bromo-3-fluoro-N-methoxy-N-methylbenzamide (3.0 g, 12.19 mmol) in tetrahydrofuran (35 ml) was added 2M n-propylmagnesium bromide (12.2 ml, 24.38 mmol) dropwise under nitrogen at 0° C. The reaction mixture was stirred at room temperature for 2 h. This was quenched by sat. ammonium chloride and stirred at rt for 30 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The extracts was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:10) to afford 2.44 g (81.7%) of the titled compound as a slight yellow oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[NH:14]1[CH2:18][CH2:17][C@@H:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([N:14]3[CH2:18][CH2:17][C@@H:16]([N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[CH2:15]3)=[N:6][C:5]=2[CH:7]=1
Reactant: Clc1nc2cc(Br)ccc2s1
Reactant: C1CCN([C@@H]2CCNC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2sc(N3CC[C@@H](N4CCCCC4)C3)nc2c1
Temperature: 100 °C

Procedure:
A stirred mixture of 2-chloro-5-bromobenzothiazole (CAS #824403-26-1, catalog #20284, Daxian Chemical Institute Ltd., #179, 10169 New Hampshire Ave., Silver Spring, Md. 20903, 2.485 g, 0.0100 mole), (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride (Reference Example 5c, 2.73 g, 0.0120 mole), and potassium carbonate (6.00 g, 0.04438 mole) in N,N-dimethylformamide (15 mL) is heated to 100° C. with an oil bath for 15 hours. The reaction mixture is cooled to room temperature then poured into water (300 mL). The resulting precipitate is collected by filtration and the filter cake is rinsed with water (600 mL). The solid is dissolved in dichloromethane and the solution is dried (MgSO4) and filtered. The filtrate is concentrated under reduced pressure to give a solid that is crystallized from hot ethyl acetate to give (R)-5-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C:13](=[O:28])[N:14]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[CH:49]1[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[C:17]([O:19][CH:49]2[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]2)[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13](=[O:28])[N:14]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27]
Reactant: O=C1CCc2c(-c3ccc(F)cc3Cl)cc(O)cc2N1c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(-c3ccccc3Cl)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 55 mg 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-hydroxyquinolin-2(1H)-one (INTERMEDIATE 9), 500 mg of polymer-bound Ph3P, 128 mg of tert-butyl 4-hydroxypiperidine-1-carboxylate, and 122 mg of diethyl azodicarboxylate by a procedure analogous to that described in EXAMPLE 2. Mass spectrum (ESI) 599 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[F:9])([OH:23])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
1-Bromo-2,4-difluoro-benzene (0.67 g, 3.5 mmol) was dissolved in THF (5 mL) and cooled to 0° C. Isopropylmagnesium chloride lithium chloride complex in THF (1.3 M, 2.5 mL, 3.2 mmol) was added. The mixture was stirred for 0.5 hours then added dropwise to a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.5 mmol) in THF (10 mL) that had been cooled to −78° C. The mixture was allowed to warm to room temperature then cooled to −78° C. and a solution of saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 0-50% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.7 g) as a clear, colourless oil. LCMS m/z 314.3 [M+H]+. R.T.=4.65 min (Analytical Method 4).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>CN(C=O)C.[Cl-].[Na+].O>[C:17]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Oc1ccc(CCl)cc1
Reactant: Ic1ccc(Nc2ncccn2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(CN(c2ccc(I)cc2)c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a solution of N-(4-iodophenyl)pyrimidin-2-amine (68 mg) in anhydrous DMF (1.0 ml) was added dropwise to a solution of sodium hydride (116 mg) in anhydrous DMF (1.0 ml), and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 4-acetoxybenzyl chloride (0.04 ml) in anhydrous DMF (0.5 ml) was added, and the resulting mixture was stirred at room temperature overnight. Saturated brine was added to the reaction solution and the resulting mixture was extracted with chloroform. Organic layer was dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:hexane/ethyl acetate=6/1) to obtain (4-acetoxybenzyl)-(4-iodophenyl)pyrimidin-2-ylamine (67 mg). NMR (H1, CDCl3): δ 2.28 (3H, s), 5.22 (2H, s), 6.63 (1H, t, J=4.6 Hz), 6.98-7.02 (4H, m), 7.26 (2H, d, J=8.1 Hz), 7.64-7.67 (2H, m), 8.34 (2H, d, J=4.6 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]=[C:10]=[O:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([NH:12][C:13]2[C:22]([C:23]([OH:32])([C:28]([F:31])([F:29])[F:30])[C:24]([F:25])([F:26])[F:27])=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][N:17]=[CH:18]3)=[O:11])=[CH:6][CH:7]=1
Reactant: Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12
Reactant: O=C=NCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Br)cc1)Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2cnccc12

Procedure:
The title compound was prepared using 1-bromo-4-(isocyanatomethyl)benzene, the product of Example 77A and the procedure described in Example 73B except that THF was used as solvent (white solid, 840 mg, 34%). MS (ESI+) m/z 376 (M+H)+; MS (ESI−) m/z 374 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 4.35 (d, 5.8, 2H), 7.12 (m, 1H), 7.18 (m, 2H), 7.40 (m, 1H), 7.91 (d, J 8.5, 1H), 7.99 (d, J 6.1, 1H), 8.24 (d, J 8.5, 1H), 8.69 (d, J 5.8, 1H), 8.88 (s, 1H), 9.44 (s, 1H); Anal. Calcd for C20H14BrF6N3O2; C, 46.00; H, 3.50; N, 11.23. Found: C, 54.61; H, 3.35; N, 11.14.
Reaction SMILES: Br.[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br.[SH:13][C:14]1[NH:15][C:16]2[C:17](=[CH:19][S:20][CH:21]=2)[N:18]=1.CC(C)=O>CC(N(C)C)=O>[CH3:2][N:3]([CH3:12])[C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][S:13][C:14]1[NH:18][C:17]2=[CH:19][S:20][CH:21]=[C:16]2[N:15]=1
Reactant: Sc1nc2cscc2[nH]1
Reactant: CN(C)c1ccccc1CBr
Agent: Br
Solvent: CC(=O)N(C)C
Solvent: CC(C)=O
Product: CN(C)c1ccccc1CSc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.9 g of 2-dimethylaminobenzyl bromide hydrobromide are added to a solution of 1.56 g of 2-mercaptothieno[3,4-d]imidazole in 20 ml of anhydrous dimethylacetamide. A crystalline precipitate separates out in a weakly exothermic reaction. The mixture is stirred at room temperature for one hour, acetone is added, and the crystals are filtered off and dried in a stream of air. The crystalline solid is then introduced into saturated aqueous NaHCO3 solution, the mixture is heated briefly on a steam bath and, after stirring at room temperature, the crystals are filtered off. Treatment with active charcoal in ethanol and concentration is followed by solution being induced to crystallize with a little acetone.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([NH:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=[CH:19][C:17]=2[N:18]=1)[CH3:12].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:11]([N:13]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=[CH:19][C:17]=2[N:18]=1)[CH:1]=[O:3])[CH3:12]
Reactant: CCNc1nc2ccc(CCc3ccco3)cc2o1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Product: CCN(C=O)c1nc2ccc(CCc3ccco3)cc2o1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A mixture of acetic anhydride (1.13 ml) and formic acid (0.45 ml) was stirred at 50° C. for 40 minutes. Tetrahydrofuran (10 ml) and 2-ethylamino-6-[2-(2-furyl)ethyl]benzoxazole (1.02 g) was added thereto and the mixture was stirred at the same temperature for further 6 hours. After cooling, the mixture was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water dried over magnesium sulfate and evaporated in vacuo to give 2-(N-ethylformamido)-6-[2-(2-furyl)ethyl]benzoxazole (1.18 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH3:25][Si:26]([CH3:32])([CH3:31])[CH2:27][CH2:28][CH:29]=O>C(Cl)Cl.CCOCC>[Br:21][C:20]([Br:24])=[CH:29][CH2:28][CH2:27][Si:26]([CH3:32])([CH3:31])[CH3:25]
Reactant: C[Si](C)(C)CCC=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: C[Si](C)(C)CCC=C(Br)Br
Reaction time: 0.5 h
Yield: 62 %

Procedure:
This known compound was prepared by a modification of the procedure in Piers, E.; Gavai, A. V. J. Org. Chem. 1990, 55, 2374. To a flame dried flask was added dry CH2Cl2 (150 mL) and triphenylphosphine (16 g, 61.2 mmol) The temperature was lowered to 0° C. and CBr4 (10.15 g, 30.6 mmol) was added portionwise. After 30 min, a solution of 3-trimethylsilylpropanal (2.0 g, 15.3 mmol) in dry CH2Cl2 (20 ml) was added. After 1 h at 0° C., the reaction was diluted with ether and filtered through celite. The celite was rinsed with ether (4×50 mL) and the combined ether solution was extracted with H2O (100 mL), saturated NaHCO3 (100 mL), saturated NH4Cl (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered and evaporated to give a crude white solid. The solid residue was washed with pentane. The pentane solution was concentrated and the oily residue was chromatographed on silica gel (pentane 100%) to give (4,4-dibromo-but-3-enyl)trimethylsilane as a clear oil weighing 3.7 g. 1H NMR showed 27% contamination by remaining pentane which gives a corrected yield of 62%: IR (neat, cm−1) 2953, 2922, 2898, 1620, 1443, 1413, 1249, 1176, 1034, 986, 859, 837; 1H NMR (300 MHz, CDCl3) δ0.03 (s, 9 H), 0.62-0.67 (m, 2 H), 2.06-2.14 (m, 2 H), 6.41 (t, J=7 Hz 1 H); 13C NMR (75 MHz, CDCl3) δ−1.9, 15.1, 27.7, 87.5, 141.2.
Reaction SMILES: C(OC([N:8]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2)[CH2:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([N+:17]([O-:19])=[O:18])[C:11]=1[Cl:20])=O)(C)(C)C.C(OCC)(=O)C.[ClH:38]>>[ClH:16].[ClH:38].[Cl:20][C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][NH:8][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[N:29]=[C:28]([CH3:31])[CH:27]=[CH:26]2
Reactant: Cc1ccc2cccc(N(Cc3c(Cl)ccc([N+](=O)[O-])c3Cl)C(=O)OC(C)(C)C)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc2cccc(NCc3c(Cl)ccc([N+](=O)[O-])c3Cl)c2n1

Procedure:
8-[N-tert-Butoxycarbonyl-N-(2,6-dichloro-3-nitrobenzyl)amino]-2-methylquinoline (100 mg) was treated with 4M hydrogen chloride-ethyl acetate (2 ml) at ambient temperature for 40 minutes. The precipitate was collected by vacuum filtration and washed with ethyl acetate to give 8-[(2,6-dichloro-3-nitrobenzyl)amino]-2-methylquinoline dihydrochloride (88 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH2:36][CH3:37])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28](/[CH:34]=[CH:35]\[CH2:36][CH3:37])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CC/C=C\[C@@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC/C=C\[C@@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Reaction time: 21 h
Yield: 71.3 %

Procedure:
To a stirred solution of 34.2 (0.050 g, 0.10 mmol) in THF (2 mL, 0.2 mmol) and EtOH (2 mL, 0.2 mmol) at 23° C. was added a solution of 1 M sodium hydroxide (1.00 mL, 1.0 mmol). The resulting reaction mixture was stirred for 21 hours, and concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted EtOAc, dried over MgSO4, filtered, and concentrated. The resulting product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 34 (35 mg, 71% yield) as a colorless oil. MS ESI (neg.) m/e: 979.5 (2M−H)+, 489.2 (M−H)+.