Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.O.[OH-].[Na+].[N+:15]([O-])([OH:17])=[O:16]>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:15]([O-:17])=[O:16])=[C:5]([CH2:9][CH2:10][NH2:11])[CH:4]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(CCN)c1
Reaction time: 3 h
Yield: 21 %

Procedure:
To a solution of 2-(3-methoxyphenyl)ethylamine (1.51 g) in chloroform (30 ml), fuming nitric acid (specific gravity=1.52; 0.84 ml) and sulfuric acid (1.07 ml) were successively added dropwise under ice cooling and stirred under ice cooling for 3 h. Water and 2 N aqueous sodium hydroxide solution were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=9:1) to give 400 mg of the titled compound (yield, 21%)
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:22](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:22])[CH:9]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(NCc2ccccc2)C1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(Cc1ccccc1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 425.9 %

Procedure:
A solution of tert-butyl 3-(benzylamino)azetidine-1-carboxylate (13a) (0.55 gm, 2.09 mmol) in DMF was added methyl iodide (0.26 ml, 4.18 mmol) and cesium carbonate (1.36 gm, 4.18 mmol). The resultant reaction mixture was then warmed to 60° C. and stirred for 2 h. The reaction mixture was then diluted with ethyl acetate (100 ml), washed with water (3×25 ml), brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by column chromatography to give compound (13b) (2.46 gm, 72%). 1H NMR (400 MHz, CDCl3) δ: 1.40 (s, 9H), 3.40 (m, 5H), 4.00 (m, 2H), 4.20 (m, 2H), 5.2 (m, 1H), 7.50 (m, 3H), 7.70 (d, 2H); MS: m/z 277.10 (M+1)+.
Reaction SMILES: CS(O[C@H:6]1[C@@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=2)[CH2:9][N:8]([CH3:20])[CH2:7]1)(=O)=O.CN(C=O)C.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[N:26]([C@H:6]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=2)[CH2:9][N:8]([CH3:20])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CN1C[C@H](Oc2ccc(Cl)c(F)c2)[C@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C[C@@H](N=[N+]=[N-])[C@H](Oc2ccc(Cl)c(F)c2)C1
Temperature: 90 °C
Yield: 89.4 %

Procedure:
To a solution of 424 (400 mg, 1.24 mmol) and DMF (2.0 mL) was added sodium azide (0.806 g, 12.4 mmol). The mixture was heated at 90° C. overnight. The mixture was cooled, diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with water (3×30 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 300 mg of trans-(±)-3-azido-4-(4-chloro-3-fluorophenoxy)-1-methylpyrrolidine (426) which was used for next step without further purification: LC-MS (ESI) m/z 271 (M+H).
Reaction SMILES: [CH2:1]([Li])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][N-:8][CH3:9].[CH3:10][N-:11][CH3:12].C[N-]C.C[N-]C.[Ti+4:19]>CCCCC>[CH3:7][N-:8][CH3:9].[CH3:10][N-:11][CH3:12].[CH2:1]([Ti+2:19][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [Ti+4]
Reactant: [Li]CC(C)(C)C
Agent: C[N-]C
Solvent: CCCCC
Product: CC(C)(C)C[Ti+2]CC(C)(C)C
Yield: 86.4 %

Procedure:
A solution of 4.87 g of neopentyllithium in pentane was added to a solution of 7.0 g of titanium tetrakis(dimethylamide) in pentane with stirring. Lithium dimethylamide precipitated rapidly. The total amount of pentane in the reaction mixture was about 50-100 ml. After being stirred for one hour the mixture was filtered, and pentane was evaporated from the filtrate to give 7.5 g (86%) of dineopentyltitanium bis(dimethylamide) as an air-sensitive yellow oil. Nmr C6D6 : δ (NMe) 3.23, δ (CMe3) 1.05 ppm downfield from tetramethylsilane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccccc1Br
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1Br
Yield: 99.2 %

Procedure:
A solution of 2-bromophenol (5 mL, 47 mmol), imidazole (8 g, 118 mmol) and tert-butyldimethylsilyl chloride (8.6 g, 57 mmol) in DMF (50 mL) was stirred at rt overnight. The reaction was treated with water (150 mL) and extracted with Et2O (4×25 mL). The organic phase was washed with 50% aq lithium chloride solution twice, dried over MgSO4 and filtered. The solvent was evaporated and the crude product was purified by filtration through silica gel, washing with 1:1 EtOAc/hexanes to afford bromo-2-[(tert-butyl)dimethylsiloxy]benzene (13.4 g, 99%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43]([OH:45])=O)=[C:35]2[CH:34]=[N:33]1.[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([NH2:58])=[N:56][CH:57]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[C:36]2=[N:37][CH:38]=[N:39][C:40]([O:41][C@@H:42]([CH2:46][O:47][CH:48]([CH3:50])[CH3:49])[C:43]([NH:58][C:55]3[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=3)=[O:45])=[C:35]2[CH:34]=[N:33]1
Reactant: CC(C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)O
Reactant: Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (333 mg, 0.88 mmol) was added to (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxypropanoic acid D2 (300 mg, 0.80 mmol), 5-methylpyridin-2-amine (95 mg, 0.88 mmol) and N-ethyldiisopropylamine (0.153 mL, 0.88 mmol) in DCM (15 mL) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM (25 mL) and washed with saturated brine (20 mL). The aqueous layer was re-extracted with DCM (30 mL). The combined organics were evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (175 mg, 47.1%), 10% ee. 143 mg of this material was further purified by chiral preparative HPLC on Chiralcel OJ (50 mm×20 μm), eluent isohexane/EtOH/MeOH 70/15/15 to afford (2S)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-3-isopropoxy-N-(5-methylpyridin-2-yl)propanamide (56 mg, >99% ee which eluted after the R enantiomer).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[CH:15][C:14]=3[Cl:27])[C:8]2=[O:28])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[C:35]1(=[O:39])[O:38][CH2:37][CH2:36]1>C1COCC1>[Cl:19][C:18]1[CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:37][CH2:36][C:35]([OH:39])=[O:38])=[CH:22][CH:21]=2)[CH:15]=[C:14]([Cl:27])[C:13]=1[CH2:12][CH:9]1[CH2:10][CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:28]
Reactant: O=C1C(Cc2c(Cl)cc(-c3ccc(O)cc3)cc2Cl)CCN1C1CCCCC1
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)CCOc1ccc(-c2cc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 11.3 %

Procedure:
Treat a solution of 1-cyclohexyl-3-(3,5-dichloro-4′-hydroxy-biphenyl-4-ylmethyl)-pyrrolidin-2-one (55) (0.20 g, 0.47 mmol) in THF (3 mL) with a 1 molar solution of potassium tert-butoxide in THF (0.50 mL, 0.49 mmol) and stir for 5 minutes at room temperature. Add dropwise a solution of beta-propiolactone (0.038 g, 0.527 mmol) in THF (3 mL) and stir the reaction at room temperature for 16 hours under N2. Quench the reaction with 1 N HCl, extract with ethyl acetate and water, dry the organic layer (Na2SO4) and purify by normal phase chromatography (30 to 100% gradient of ethyl acetate in hexanes) to afford 26 mg (11%) of the title compound: LC-MS (ES+) m/z=exact mass calcd for C26H29Cl2NO4 489, found 490 and 492 (M+1 and M+3, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([O:9]C)=[O:8])(=[O:3])[CH3:2].I[Si](C)(C)C.O.C>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]([CH3:12])([CH3:11])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)C(C)(C)COC(C)=O
Agent: C[Si](C)(C)I
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 40.7 %

Procedure:
To a stirred solution of 4.0 grams (0.023 mole) of methyl 3-acetoxy-2,2-dimethylpropionate in 50 ml of carbon tetrachloride under an argon atmosphere was added slowly via a syringe 9.2 grams (0.046 mole) of iodotrimethylsilane. Upon completion of addition the reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was then heated at 50° for 1.5 hours, and at 65° for 18 hours. Nuclear magnetic resonance spectroscopy indicated the reaction had not gone to completion. The reaction mixture was heated at 65° for six days, then poured into 100 ml water. The mixture was stirred for 20 minutes and the carbon tetrachloride layer separated. The water layer was extracted with three portions of 50 ml each of methylene chloride. The methylene chloride extracts and the carbon tetrachloride layer were combined. The combination was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a semi-solid residue. The semi-solid was dissolved in hot ethyl acetate and treated with decolorizing charcoal. The mixture was filtered and the filtrate concentrated under reduced pressure to give a solid residue. The solid was recrystallized from hexane to give 1.5 grams of 3-acetoxy-2,2-dimethylpropionic acid; mp 56°-59°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14]C)[CH:8]=2)=[O:4].[H-].[Na+].I[CH3:19].O>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2ccc(O)cc2n1C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
To a solution of 6-methoxy-1H-indole-2-carboxylic acid methyl ester (11.57 g, 56.38 mmol) in N,N-dimethylformamide (DMF) (100 mL) was added 60% sodium hydride in oil (2.93 g, 73.29 mmol) under ice cooling. After the mixture was stirred for 15 minutes, iodomethane (3.86 mL, 62.02 mmol) was added and the mixture was stirred at the same temperature for 1 hour. To the mixture were added water and diethyl ether (Et2O), and then resulting precipitate was collected by filtration. The white precipitate was dissolved in dichloromethane (200 mL), and to the solution was added dropwise boron tribromide dichloromethane solution (100 mL) while ice cooling under an argon atmosphere. The reaction mixture was stirred at the same temperature for 1 hour, and then quenched with methanol (MeOH). The solvent was evaporated in vacuo, and water was added to the residue. The aqueous mixture was extracted with ethyl acetate (AcOEt). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give 10.19 g of the title compound as a brown powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:16](=[O:34])[C:17]([NH:19][C:20]1[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([O:31]CC)=[O:30])=[CH:23]3)=[O:18])=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>N1C=CC=CC=1>[O:34]=[C:16]([NH:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)[C:17]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([C:29]([OH:31])=[O:30])=[CH:23]2)=[O:18]
Reactant: CCOC(=O)c1cc2cc(NC(=O)C(=O)Nc3ccc4[nH]c(C(=O)OCC)cc4c3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]c(C(=O)O)cc2c1)C(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
5,5'-[(1,2-dioxo-1,2-ethanediyl)diimino]bis-1H-indole-2-carboxylic acid diethyl ester (220 mg, 0.48 mM) is suspended in pyridine (9 mL) and treated with 1N NaOH (1.5 mL). The milky mixture is heated to 60° C. under nitrogen. After 24 hrs N NaOH again added (1 mL) and the reaction heated another 3 hrs. The reaction is then neutralized by the addition of 1N HCl (2.5 mL) and concentrated to one-half volume at less than 20 torr. The residue is then treated with 1N HCl (50 mL) and centrifuged giving a residual slightly pink solid. This is is washed with water, centrifuged, and dried in the vacuum oven leaving the product 5,5'-[(1,2-dioxo-1,2-ethanediyl)diimino]bis-1H-indole-2-carboxylic acid (148 mg).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2C=CC=CC=2N=N1.Cl.[N:26]1([CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3([C:48]([OH:50])=O)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.Cl.CN.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:12][NH:8][C:48]([C:42]1([C:39]2[CH:40]=[CH:41][C:36]([O:35][CH2:34][CH2:33][CH2:32][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:37][CH:38]=2)[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:50]
Reactant: O=C(O)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)C1(c2ccc(OCCCN3CCOCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (640 mg, 1.7 mmol) was added to a solution of 4-[4-(3-Morpholin-4-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carboxylic acid hydrochloride (500 mg, 1.3 mmol), methylamine hydrogen chloride (130 mg, 1.9 mmol) and Hunig's base (790 μL, 4.5 mmol) in N,N-dimethylformamide (5 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was partitioned between 2M NaOH solution (20 mL) and DCM (2×20 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume) to provide the title compound (355 mg, 76%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 1.93-2.00 (m, 2H), 2.01-2.08 (m, 2H), 2.37-2.40 (m, 2H), 2.48 (m, 4H), 2.50 (t, 2H), 2.70 (d, 3H), 3.67-3.80 (m, 8H), 4.02 (t, 2H), 6.88 (d, 2H), 7.22 (d, 2H). LRMS APCI+ m/z 363 [MH]+.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][C:7]=1[CH3:8].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:78]([NH2:82])([CH3:81])([CH3:80])[CH3:79]>C(OCC)(=O)C.CN(C)C=O>[C:78]([NH:82][C:12]([C:11]1[C:4]2[C:5](=[N:6][C:7]([CH3:8])=[C:2]([Br:1])[N:3]=2)[N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=1)=[O:14])([CH3:81])([CH3:80])[CH3:79]
Reactant: Cc1nc2c(nc1Br)c(C(=O)O)cn2COCC[Si](C)(C)C
Reactant: CC(C)(C)N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc2c(nc1Br)c(C(=O)NC(C)(C)C)cn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A mixture of 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.16 g, 3 mmol), HBTU [1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide, hexafluorophosphate(1-) (1:1) (1.48 g, 3.9 mmol), N,N-dimethylformamide (12 mL) and triethylamine (0.61 g, 6 mmol) was stirred at room temperature for 1 h, and then tert-butylamine (0.63 mL, 6 mmol) was added. The mixture was stirred an additional hour and then diluted with ethyl acetate, washed once with 0.5 M sodium carbonate, twice with water, once with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, 20% ethyl acetate in hexanes) gave 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (1.22 g, 92%) as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.09 (s, 9H), 0.83 (t, J=8.2 Hz, 2H), 1.43 (s, 9H), 2.71 (s, 3H), 3.54 (t, J=8.2 Hz, 2H), 5.64 (s, 2H), 7.64 (s, 1H), 8.49 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([C:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])([CH3:12])[CH3:11].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[O:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Cc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(C)C(=O)C(=Cc1ccc(F)cc1)c1ccccc1

Procedure:
31 g (0.25 mol) of 4-fluorobenzaldehyde, 40.6 g (0.25 mol) of benzyl isopropyl ketone, 2.5 ml of piperidine and 1.75 ml of glacial acetic acid are boiled in a water separator for 20 hours in 200 ml of toluene. After removing the solvent, the residue is distilled through a 20 cm Vigreux column.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5](O)=[CH:4][C:3]=1[F:10].BrC1C=C(F)C(Cl)=C(F)C=1.C(OO)(C)(C)C.OO.ClC1C(F)=CC=CC=1F.FC1C=CC=C(F)C=1[NH2:41]>Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:41])=[CH:4][C:3]=1[F:10]
Reactant: Oc1cc(F)c(Cl)c(F)c1
Reactant: Nc1c(F)cccc1F
Agent: CC(C)(C)OO
Agent: Cl
Agent: Fc1cc(Br)cc(F)c1Cl
Product: Nc1cc(F)c(Cl)c(F)c1

Procedure:
Compound (250) can be prepared in the same manner as in Preparation Example 240, except for replacing compound (P102) with 4-chloro-3,5-difluorophenol. The 4-chloro-3,5-difluorophenol can be prepared by reacting a Grignard reagent prepared from 1-bromo-4-chloro-3,5-difluorobenzene with t-butyl hydroperoxide or converting the same Grignard reagent to a boric ester, and oxidizing the product with hydrogen peroxide under a basic condition. It is also prepared by nitrating 2-chloro-1,3-difluorobenzene (obtainable by decomposing a diazonium salt of 2,6-difluoroaniline in the presence of cuprous chloride or in hydrochloric acid), reducing the nitro-compound to obtain 4-chloro-3,5-difluoroaniline, and decomposing its diazonium salt in sulfuric acid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:18][C:19]([NH2:21])=[NH:20]>C(OCCO)C>[NH2:20][C:19]1[N:21]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([N+:10]([O-:12])=[O:11])[C:6]=2[CH3:13])[N:18]=1
Reactant: Cc1c([N+](=O)[O-])ccc(Cl)c1C#N
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CCOCCO
Product: Cc1c([N+](=O)[O-])ccc2nc(N)nc(N)c12
Yield: 82.7 %

Procedure:
Under a nitrogen atmosphere, a stirred solution 29.5 grams (0.150 mole) of 2-chloro-6-methyl-5-nitrobenzonitrile and 54.0 grams (0.300 mole) of guanidine carbonate in 1500 mL of 2-ethoxyethanol was heated at reflux during a 3.5 hour period. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was stirred with 300 mL of water, and the resultant solid was collected by filtration. The solid was washed with 50 mL of water and dried under reduced pressure, yielding 27.2 grams of 2,4-diamino-5-methyl-6-nitroquinazoline. The NMR spectrum was consistent with the proposed structure. The reaction was repeated again.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][CH:3]=1.[S-:16][C:17]#[N:18].[NH4+].BrBr>C(O)(=O)C>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:17]([NH2:18])[S:16][C:3]=2[CH:4]=1
Reactant: Nc1ccc(CCc2ccccn2)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(CCc3ccccn3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A mixture of 2-[2-(4-aminophenyl)ethyl]pyridine (5.94 g) and ammonium thiocyanate (4.56 g) in acetic acid (50 ml) was stirred at ambient temperature for one hour. A solution of bromine (4.8 g) in acetic acid (5 ml) was dropwise added to the above mixture at 18° to 23° C. under stirring and the resultant mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in a mixture of ethyl acetate and water. The solution was acidified to pH 1.0 with hydrochloric acid. The separated aqueous layer was adjusted to pH 7.5 with aqueous 20% potassium carbonate and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from ethyl acetate to give 6-[2-(2-pyridyl)ethyl]-2-aminobenzothiazole (4.8 g).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][C:20]1[CH:34]=[CH:33][C:23]([CH:24]([OH:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:22][C:21]=1[O:35][CH3:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[CH:34]=[CH:33][C:23]([C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:32])=[CH:22][C:21]=1[O:35][CH3:36])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cc(C(O)c2ccccc2F)ccc1OCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COc1cc(C(=O)c2ccccc2F)ccc1OCc1ccccc1
Reaction time: 3 h

Procedure:
69.8 g of 4-(benzyloxy)-2'-fluoro-3-methoxybenzhydrol (dissolved in 600 ml of methylene chloride) are treated within 30 minutes at 20° with 45.3 g of pyridinium chlorochromate and stirred at 20° for 3 hours. The precipitate formed is subsequently filtered and washed with methylene chloride. The filtrate is evaporated and the residue is filtered on 100 g of silica gel with ether. After recrystallization from ether, there is obtained 4-(benzyloxy)-2'-fluoro-3-methoxybenzophenone of m.p. 118°-120°.