Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21][CH3:22])[C:17]([CH:23]=[N:24][OH:25])=[N:16]1>FC(F)(F)C(O)=O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:7]=[C:6]([Cl:14])[C:5]=1[N:15]1[C:19]([CH3:20])=[C:18]([S:21]([CH3:22])=[O:1])[C:17]([CH:23]=[N:24][OH:25])=[N:16]1
Reactant: OO
Reactant: CSc1c(C=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(S(C)=O)c(C=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
30% Hydrogen peroxide solution (0.32 ml) was added to a solution of 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylthio-1H-pyrazole-3-carboxaldehyde oxime (0.8 g) in trifluoroacetic acid at 20° C. The reaction solution was partitioned between water and dichloromethane and the organic layer dried (magnesium sulfate), evaporated and flash-chromatographed on silica gel, eluting with dichloromethane/ethyl acetate (3:1) to give 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylsulfinyl-1H-pyrazole-3-carboxaldehyde oxime (0.29 g), m.p. 210-214° C. Compound 30 and 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-methyl-4-methylsulfonyl-1H-pyrazole-3-carboxaldehyde oxime (0.2 g), m.p. 211-2120° C. Compound 31.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=3)[CH:19]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: OB(O)c1cccnc1
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3cccnc3)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-3-yl-7-methoxy-isoquinolin-3-yl)-amine. LC-MS m/e 332(MH+).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(CC(C)(Oc2ccccc2F)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(2-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure of Example 26. 1H NMR (400 MHz, CDCl3) δ 7.58 (dd, 1H, J=3.52 Hz, 1.17 Hz), 7.36 (dd, 1H, J=5.08 Hz, 1.17 Hz), 7.21 (d, 3H, J=8.60 Hz), 7.12-6.95 (m, 3H), 6.83 (d, 3H, J=8.60 Hz), 4.19 (t, 2H, J=6.65 Hz), 3.27 (d, 1H, J=14.08 Hz), 3.17 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.65 Hz), 2.35 (s, 3H), 1.41 (s, 3H). HRMS (ES+) m/z exact mass calcd for C26H25FNO5S 482.1437, found 482.1454.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].C(N(CC)CC)C.[CH3:12][NH:13][C:14]([NH:16][CH3:17])=[O:15]>O>[CH3:12][N:13]1[CH2:3][C:1](=[O:2])[N:16]([CH3:17])[C:14]1=[O:15]
Reactant: O=CC=O
Reactant: CNC(=O)NC
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CC(=O)N(C)C1=O
Temperature: 30 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
In a 1000 ml glass vessel equipped with a stirrer, thermometer, a dropping funnel and a distillation unit was charged 290 g (2.0 mol) of 40 wt % aqueous glyoxal solution. And then, triethylamine is added thereto to prepare a basic mixed solution (At this time, the solution had a pH of 9). To the mixed solution was gradually added dropwise a solution comprising 176 g (2.0 mol) of 1,3-dimethylurea and 176 ml of water while maintaining a liquid temperature to 25 to 35° C. After stirring the solution at room temperature for 3 hours, the mixture was reacted by elevating the temperature to 200° C. over 2 hours while removing triethylamine and water under normal pressure by distillation. After completion of the reaction, the obtained reaction mixture was distilled under reduced pressure (105 to 107° C./0.67 to 1.33 kPa) to obtain 217 g (Isolation yield; 85%) of 1,3-dimethylimidazolidin-2,4-dione as a pale yellowish liquid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.CCN(CC)CC.[C:20](Cl)(=[O:22])[CH3:21]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:20](=[O:22])[CH3:21])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: NC1CCCc2c(Br)cncc21
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1CCCc2c(Br)cncc21
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (intermediate B-12 [A], 318 mg, 1.4 mmol) and Et3N (3.0 mL) in DCM (10 mL) was added acetyl chloride (0.106 mL, 1.4 mmol) at 0° C. and stirring was continued at 0° C. for 1 hour. The resulting mixture was extracted with EtOAc (2×100 mL). The combined organics were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to afford a crude product which was purified by silica gel flash chromatography eluting with a 0 to 50% EtOAc-heptane gradient to give the title compound (346 mg, 92%) as light yellow solid. MS: 269.1 & 271.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][C:14]1([CH3:29])[CH2:19][CH2:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH2:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:13][C:14]1([CH3:29])[CH2:19][CH2:18][C:17]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])=[CH:16][CH2:15]1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COc1ccc(C2=CCC(C)(C)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a mixture of 4-bromo-3-nitroanisole (3.3 g, 14.1 mmol), 2-(4,4-dimethylcyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4.0 g, 16.9 mmol) prepared in Example (1b), tripotassium phosphate (4.5 g, 21.3 mmol) and 1,2-dimethoxyethane (30 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.82 g, 0.71 mmol) with stirring at room temperature under a nitrogen atmosphere. The mixture was then stirred at an external temperature of 80° C. for 24 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]=[C:8]1[C:12]2=[CH:13][C:14]3[CH:15]=[C:16]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:17]=[CH:18][C:19]=3[N:11]2[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C1COCC1.[Pd]>[CH2:21]([O:20][C:16]1[CH:17]=[CH:18][C:19]2[N:11]3[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[C:12]3=[CH:13][C:14]=2[CH:15]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C=C1CCn2c1cc1cc(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccccc3)ccc12

Procedure:
tert-Butyl-2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ylidene)acetate (1.391 g, 3.70 mmol) was dissolved in THF (25 mL) and 10% palladium on carbon (50% in water, 217 mg) was added. The reaction mixture was placed under 225 psi of hydrogen in a hydrogenation reactor for 24 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to provide tert-butyl 2-(7-(benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The above material was taken up in a mixture of THF (20 mL) and EtOH (20 mL) and Pd(OH)2/C (250 mg) was added. The reaction mixture was placed under 200 psi of hydrogen in a hydrogenation reactor for 2 days. Additional Pd(OH)2/C (250 mg) was added and the reaction mixture was placed under 300 psi of hydrogen in a hydrogenation reactor for 24 h. Pd(OH)2/C (250 mg) was again added and the vessel placed under 500 psi of hydrogen in a hydrogenation reactor for 24 h. The hydrogenation reactor was warmed to 50° C. for 8 h. The reaction mixture was cooled to room temperature and AcOH (5 mL) was added. The reaction mixture was placed under 500 psi of hydrogen for 16 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure to provide a mixture of the title compound and tert-butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate. The title compound (150 mg) was isolated by silica gel column chromatography. tert-Butyl 2-(7-hydroxy-2,3,9,9a-tetrahydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (600 mg) was dissolved in toluene (100 mL) and Pd/C (1.0 g) was added. The reaction mixture was warmed to 80° C. and stirred for 2 days. The reaction mixture was filtered through Celite® and the title compound (250 mg) was isolated as a white solid resulting from precipitation during concentration of the filtrate. LCMS m/z=288.3 [M+H]+.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:21]([C:23]3[O:24][C:25](=[O:43])[C:26]4[C:31]([C:32]=3[C:33]3[CH2:34][CH2:35][N:36]([CH:39]5[CH2:42][NH:41][CH2:40]5)[CH2:37][CH:38]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:22])[N:11]=[C:12]([C:13]3[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[C:5]=12.[CH:44]1([CH:47]=O)[CH2:46][CH2:45]1>>[ClH:1].[ClH:1].[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:21]([C:23]3[O:24][C:25](=[O:43])[C:26]4[C:31]([C:32]=3[C:33]3[CH2:34][CH2:35][N:36]([CH:39]5[CH2:42][N:41]([CH2:47][CH:44]6[CH2:46][CH2:45]6)[CH2:40]5)[CH2:37][CH:38]=3)=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:22])[N:11]=[C:12]([C:13]3[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[C:5]=12
Reactant: O=CC1CC1
Reactant: CC(c1oc(=O)c2ccccc2c1C1=CCN(C2CNC2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21
Agent: Cl
Product: CC(c1oc(=O)c2ccccc2c1C1=CCN(C2CN(CC3CC3)C2)CC1)n1nc(-c2cc(O)cc(F)c2)c2c(N)ncnc21

Procedure:
Title compound was prepared following the procedure described for the synthesis of Intermediate D24, from 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1-(azetidin-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one dihydrochloride (Example 156, 35 mg, 0.059 mmol) and cyclopropanecarbaldehyde (10.19 μl 0.136 mmol) to give the compound (33.8 mg, 0.050 mmol, 84% yield) as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([C:9]2([CH2:15][C:16]([OH:18])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[N+:21]([O-:23])=[O:22].[CH3:24]O>O1CCCC1>[CH3:24][O:17][C:16](=[O:18])[CH2:15][C:9]1([C:7](=[O:8])[C:6]2[CH:19]=[CH:20][C:3]([NH:2][CH3:1])=[C:4]([N+:21]([O-:23])=[O:22])[CH:5]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CNc1ccc(C(=O)C2(CC(=O)O)CCCCC2)cc1[N+](=O)[O-]
Reactant: CO
Solvent: C1CCOC1
Product: CNc1ccc(C(=O)C2(CC(=O)OC)CCCCC2)cc1[N+](=O)[O-]

Procedure:
4.9 g (0.015 mol) of [1-(4-methylamino-3-nitro-benzoyl)-cyclohexyl]-acetic acid are dissolved in 100 ml tetrahydrofuran and after the addition of 2.4 g (0.015 mol) of N,N'-carbonyldiimidazole the mixture is refluxed for 15 minutes. After concentration of the solution and addition of 30 ml methanol the mixture is refluxed for 3 hours. The solvent is distilled off, the residue chromatographed on silica gel and eluted with methylene chloride+methanol (1-5%). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:23]([OH:31])(=[O:30])[C:24]([CH2:26][C:27](O)=[O:28])=[CH2:25]>C(OCC)(=O)C>[CH2:1]([NH:11][C:12](=[O:22])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:23]([OH:31])=[O:30])[CH2:26][C:27]2=[O:28])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N)c1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Temperature: 25 °C

Procedure:
A mixture of 9.0 g. of N-decyl-3-(3-aminophenyl)-propenamide and 3.9 g. of itaconic acid was heated as a melt at 140°-145° C. for 1 hour, and then ca. 70 ml. of ethyl acetate was added to the hot mass. The resulting mixture was stirred and a solid appeared. The mixture was cooled to room temperature, and the solid was recovered by filtration to give 9.5 g. of the title compound. This produce was recrystallized from acetonitrile to give 8.4 g. (69% yield) of product having a melting point of 152.5°-153.5° C.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=3)=[CH:14][C:6]1=2.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:21])=[CH:22][CH:23]=3)=[CH:14][C:6]1=2
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(F)ccc2F)CCN3)cc1
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)N(Cc3cc(F)ccc3F)CCN4)cc2)CC1
Yield: 25 %

Procedure:
4-[1-(2,5-Difluorobenzyl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl]benzoic acid (34 mg) was reacted with 1-methylpiperazine as in General Procedure 8 to give the title compound as a pale yellow solid (25% yield). M.p. 180° C., LCMS: m/z=464.10 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.32 (s, 3H), 2.30-2.49 (m, 4H), 3.46 (t, J=5.0 Hz, 2H), 3.50-3.55 (m, 2H), 3.62-3.66 (m, 2H), 3.67-3.83 (m, 2H), 4.50 (s, 2H), 5.02 (bs, 1H), 6.75 (s, 1H), 6.86-7.08 (m, 3H), 7.40 (dd, J=8.3 Hz, 4H), 7.72 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:23]=O)[CH2:18][CH2:17][CH2:16][CH2:15]1>C1COCC1.CCOCC>[CH:14]1([O:19][C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH:23]=[CH:5][C:3]#[N:4])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C=CC#N)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a slurry of NaH (1.1 g, 27.5 mmol) in 80 mL of THF at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.42 g, 24.9 mmol) in 20 mL of THF. The mixture was stirred for 30 min, and a solution of 3-cyclopentoxy-4-methoxybenzaldehyde (5.0 g, 22.7 mmol) in 20 mL of THF was then added dropwise. The mixture was for 2 hr and then diluted with ether. The mixture was washed with 1M H3PO4, H2O, and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to yield 3-cyclopentoxy-4-methoxycinnamonitrile (4.8 g, 87%) as a yellow oil, which was carried on without further purification. 1H-NMR (300 MHz): δ 3.89 (s, 3), 5.69 (d, 1, J=16.6).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].[Br-].[Li+].P(Br)(Br)[Br:23]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:23])=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COC(=O)c1ccc(CO)cc1-c1ccccc1C
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CBr)cc1-c1ccccc1C
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a stirred solution of 4-hydroxymethyl-2-(2-methylphenyl)benzoic acid methyl ester prepared in Example 331A (10.85 g, 42.2 mmol) in dry DMF (40 mL) at 0° C. was added successively lithium bromide (4.00 g, 46.6 mmol, 1.1 eq) and phosphorus tribromide (4.18 mL, 44.5 mmol, 1.05 eq) at a rate such that the temperature did not exceed 5° C. On completion of the addition the mixture was warmed to ambient temperature, and quenched by the addition of ice. The resultant solution was partitioned between water and ether; the ethereal solution was dried (Na2SO4), filtered and the solvent removed under reduced pressure to afford the title compound (13 g, 96%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44](O)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([O:14][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([Cl:1])=[N:3][CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Cl)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A suspension of 4-chloro-7-hydroxy-6-methoxyquinazoline (11.5 g), prepared as described in Example 1, in dichloromethane (250 ml) was treated with triphenylphosphine (21.5 g), 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (13.2 g) and di-tert-butyl azodicarboxylate (19 g) and the mixture stirred at ambient temperature overnight. The crude reaction mixture was concentrated to a third and loaded onto a silica column and eluted using ethyl acetate/petroleum ether (35/65) as solvent. The relevant fractions were combined and evaporated under vacuum to give 7-{[1-(tert-butoxycarbonyl)-piperidin-4-yl]oxy}-4-chloro-6-methoxyquinazoline as a white solid (20 g).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)c2nc[nH]c2c1
Reactant: Cc1c(Cl)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
Into a 250 mL round bottomed flask charged with 4-bromo-6-nitro-1H-benzo[d]imidazole (5 g, 20.66 mmol) in N,N-Dimethylformamide (DMF) (100 mL) was added 1-(bromomethyl)-3-chloro-2-methylbenzene (6.80 g, 31.0 mmol) and potassium carbonate (8.57 g, 62.0 mmol The resulting reaction mixture was stirred 1 h at 60° C., cooled to room temperature and poured into water, extracted with ethyl acetate, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified on a silica gel cartridge and eluted with a gradient of 0% ethyl acetate/hexanes to 80% over 10 column volumes. The expected compound was collected and evaporated to yield 4-bromo-1-(3-chloro-2-methylbenzyl)-6-nitro-1H-benzo[d]imidazole (3.05 g, 8.01 mmol, 38.8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.40 (s, 3H) 5.79 (s, 2H) 6.61 (d, J=7.58 Hz, 1H) 7.16 (t, J=7.83 Hz, 1H) 7.42 (d, J=7.58 Hz, 1H) 8.34 (d, J=2.02 Hz, 1H) 8.65 (d, J=2.02 Hz, 1H) 8.73 (s, 1H); LC/MS: MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=O)[NH:8][CH:7]=[CH:6]2.[N+:16]([O-])([OH:18])=[O:17].OS(O)(=O)=O>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:16]([O-:18])=[O:17])[C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2cc[nH]c(=O)c2cc1OC
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COc1cc2ccncc2c([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6,7-Dimethoxy-isoquinolinone (2.88 g) in sulphuric acid (20 ml) at 5-10° C. was added 2 M HNO3—H2SO4-solution (8 ml) and the reaction mixture stirred overnight at ambient temperature. The reaction mixture was poured into ice water, pH adjusted to 12 and the product extracted in methylene chloride. The methylene chloride phase was extracted with 1 M HCl , the pH of the aqueous phase adjusted to 12 and extracted into methylene chloride, dried and evaporated. Yield: 2.5 g.
Reaction SMILES: N1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[S:21](Cl)(=[O:23])=[O:22].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1>C(#N)C>[Br:7][C:8]1[CH:13]=[C:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[S:21](=[O:23])(=[O:22])[NH:25][C:26]1[CH:27]=[CH:28][C:29]2[CH2:33][O:32][B:31]([OH:34])[C:30]=2[CH:35]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c(Br)c1)C(F)(F)F
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)c(Br)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
Pyridine (1.5 equiv) was added dropwise to the cooled suspension of the crude 2-bromo-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (24 g, 0.06 mol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (1.2 eq) in acetonitrile (300 ml) at 0° C. over 10 min. The r×n mix was stirred overnight. The solid was filtered and washed with EtOAc. The filtrate was washed with, H2O, brine, dried over MgSO4, filtered, and concentrated to dryness to give crude N-(3-bromo-4-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)sulfamoyl)phenyl)-2,2,2-trifluoroacetamide which was purified by flash chromatography on silica gel. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.6 (s, 1H), 10.56 (s, 1H), 9.20 (s, 1H), 8.12 (d, J=1.9 Hz, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.79 (dd, J=2.0, 8.6 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 7.20 (dd, J=1.9, 8.3 Hz, 1H), 4.85 (s, 2H). MS (ESI) m/z=479 (M+1).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1>C1C=CC=CC=1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(Cc1ccc(Br)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of aluminum chloride (2.64 g, 19.8 mmol) in dry benzene (40 ml) was added a solution of 4-bromophenylacetyl chloride (4.63 g, 19.8 mmol) in 15 ml benzene over a period of 25 minutes under nitrogen. The resulting dark yellow solution was refluxed for six hours, and cooled to room temperature. Ice water (100 ml) was added, and the layers separated. The aqueous layer was extracted with benzene (1×50 ml). The combined organic portions were washed with water (2×60 ml), 10% NaOH (1×60 ml), water (1×60 ml), and brine (1×60 ml), and dried over magnesium sulfate. After filtration, concentration of the filtrate in vacuo afforded the ketone as 5.06 g of a white microcrystalline solid (93% yield). NMR indicated good purity. A portion was recrystallized from boiling petroleum ether/ethanol to give the ketone as colorless plates: m.p. 147.5-149.0° C. (lit. m.p. 146-147° C.; Huttel, R. et al., J. Chem. Ber. 93:1433 (1960)); 1H NMR δ8.02 (d, J=7.1 Hz, 2H), 7.63-7.46 (m, SH), 7.16 (d, J=8.3, 2H), 4.27 (s, 2H).