Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:20](=[O:22])=[O:21]>CCCCCC.O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)O
Reaction time: 0.25 h

Procedure:
While a mixture of 1.16 g of 3-(tert-butoxycarbonyl amino)pyridine and 25 ml of tetrahydrofuran was cooled in a dry ice-acetone bath, 8.5 ml of 1.65 M hexane solution of n-butyllithium was added so that the temperature of the reaction mixture did not exceed −60° C. The reaction mixture was stirred for 15 minutes. Cooling was stopped. Then, the reaction mixture was stirred until the temperature became 0° C. The reaction mixture was cooled in a dry ice-acetone bath again. After injection of carbon dioxide, cooling was stopped, and the reaction mixture was stirred at room temperature for two hours. After water was added, most of tetrahydrofuran and hexane was removed by concentration under reduced pressure. The residue was ice-cooled and 3N hydrochloric acid was added so as to adjust pH to about 3. Extraction with a mixture solvent (4:1) of ethyl acetate to tetrahydrofuran was carried out several times. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.53 g of 3-(tert-butoxycarbonyl amino)isonicotinic acid.
Reaction SMILES: C([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:12]2)C1C=CC=CC=1.[ClH:23].CO>[Pd]>[ClH:23].[F:22][C:19]1[CH:20]=[CH:21][C:16]([N:11]2[CH2:10][CH:9]3[NH:8][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(N2CC3CCC(C2)N3Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Fc1ccc(N2CC3CCC(C2)N3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
8-Benzyl-3-(4-fluoro-phenyl)-3,8-diaza-bicyclo[3.2.1]octane (2.7 g, 9.11 mmol) was dissolved in 1N hydrochloric acid/methanol (150 mL); 10% palladium on carbon (1.4 g) was then added under nitrogen. A hydrogenation was then carried out at 1 atmosphere for 2 hours. The reaction mixture was then filtered through Celite and concentrated to yield 3-(4-fluorophenyl)-3,8-diazabicyclo[3.2.1]octane, hydrochoride salt (2.2 g, 100%) as a white solid which had the following properties: Mp. 129-131° C.; 1H NMR CDCl3 δ: 9.69 (brd s, 1H), 7.07-6.95 (m, 2H), 6.90-6.80 (m, 2H), 4.05 (brd s, 2H), 3.49 (d, J=10.4 Hz, 2H), 3.08 (d, J=11.2 Hz, 2H), 2.00-1.84 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:16]([Si](C)(C)C)#[CH:17].C(N(CC)CC)C.[F-].[Cs+]>CN(C=O)C.CO.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.CCCCCC>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][NH:10][C:3]1[C:2]([C:16]#[CH:17])=[CH:7][N:6]=[C:5]([C:8]#[N:9])[N:4]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCCCCC
Product: C#Cc1cnc(C#N)nc1NCC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
5-Bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (7.58 mmol) and ethynyl-trimethyl-silane (22.74 mmol) in DMF (20 ml) are treated with triethylamine (38.0 mmol), copper (I) iodide (0.76 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.38 mmol) at room temperature. The mixture is stirred for 1.5 h at room temperature, poured into an ice water and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is dissolved in methanol (60 ml)—water (10 ml) and cesium fluoride (4.2 mmol) is added at room temperature and the mixture is stirred at room temperature for 5 min. The reaction mixture is evaporated, then water and CH2Cl2 are added. The organic layer is washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give the product in 76% yield. Rf=0.67 (n-hexane:AcOEt=2:1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[NH:22][CH:23]=[CH:24]4)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(Br)cnc32)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.4 %

Procedure:
To a stirred suspension of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.35 g, 0.73 mmol) and 1H-indol-5-ylboronic acid (0.14 mg, 0.88 mmol) in CH3CN (10 mL) was added 1 M Na2CO3 (10 mL) followed by bis(triphenylphosphine)palladium(II) dichloride (0.050 g, 0.071 mmol). The resulting mixture was stirred overnight at 60° C. After the mixture was evaporated to dryness in vacuo, it was dissolved in DMF (3 mL), absorbed onto Celite, and dried. The residue was purified via silica gel chromatography using CH2Cl2 as the eluent to obtain the title compound (0.26 g, 76%). 1H NMR (CDCl3, 300 MHz): δ 8.48 (d, J=2.1 Hz, 1H), 8.27 (bs, 1H), 8.26 (d, J=2.4 Hz, 1H), 8.08 (d, J=8.1 Hz), 7.85 (s, 1H), 7.81 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (dd, J=1.8, 8.4 Hz), 7.30 (m, 3H), 6.63 (m, 1H), 2.39 (s, 3H); MS ESI (m/z): 466.2/468.2 (M+1)+, calc. 465.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Cl[CH2:12][C:13]([N:15]([C:17]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)[CH3:16])=[O:14].N>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:17]2[N:15]([CH3:16])[C:13](=[O:14])[CH2:12][N:2]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[CH:27]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CN(C(=O)CCl)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: N
Solvent: CO
Product: CN1C(=O)CN=C(c2ccccc2)c2cc(Cl)ccc21
Yield: 96.09 %

Procedure:
A mixture of hexamethylenetetramine (17.5 g., 0.125 mol), methanol (135.5 ml) and 2(2-chloro-N-methylacetamido)-5-chlorobenzophenone (80.5 g., 0.25 mol) was saturated with ammonia. Heat the stirred mixture slowly to reflux with a steady stream of ammonia flowing through the mixture. During the course of the reaction ##STR5## was prepared. The product was not isolated. Hold at reflux for 6 hours. Stop the flow of ammonia and remove the solvent under vacuum. Take up the residue in a mixture of toluene (500 ml.) and hot water (500 ml). Separate the toluene phase and add to it, with stirring, 3N nitric acid (169 ml). The crystals which separate are filtered, wash with toluene (50 mls) and resuspended in a mixture of toluene (250 ml) and water (250 ml). Concentrated ammonia (30 ml) is added to pH 8. The toluene phase is separated, washed with water (250 ml) and then distilled to dryness in vacuo yielding 96.09% of 7-chloro-1-methyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, melting point 125° to 127° C.
Reaction SMILES: N(CC(O)=O)CC(O)=O.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[C:25]([N:32]([CH2:37][C:38]([OH:40])=[O:39])[CH2:33][C:34]([OH:36])=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.O.CCOC(C)=O>[C:25]([N:32]1[CH2:33][C:34](=[O:36])[O:40][C:38](=[O:39])[CH2:37]1)([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C(O)CNCC(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(=O)OC(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Iminodiacetic acid (5.0 g, 37.6 mmol) in THF-water (1:1, 100 ml) was treated with Na—HCO3 (12.6 g, 150 mmol) portion-wise over 15 minutes. Boc anhydride (9.85, 45.1 mmol) was added and the mixture was stirred at room temperature for 2 days. THF was removed by evaporation in vacuo and the aqueous solution was washed with ether (2×), acidified using conc. HCl to pH 1 under cooling with ice bath and extracted with AcOEt (3×). The organic phase was washed with brine, dried (Na2SO4) and evaporated in vacuo to yield 2.55 g (29%). Crude N-Boc-iminodiacetic acid (2.0 g, 8.6 mmol) was dissolved in AcOEt (100 ml), cooled to 0° C., and treated with triethylamine (2.43 ml, 17.4 mmol) and powdered triphosgene (0.84 g, 2.83 mmol). The suspension was stirred 15 minutes under cooling, and 15 minutes at room temperature. The solution was washed with brine, dried (MgSO4) and evaporated in vacuo to yield 17, 1.53 g (83%).
Reaction SMILES: ClC1C=C([C@H](CCN2CCC(N(C(=O)C(F)(F)F)CCNC(=O)C(F)(F)F)CC2)[CH2:10][N:11](C)[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=1Cl.FC(F)(F)C(N(CCNC(=O)C(F)(F)F)C1CCNCC1)=O.ClC1C=C(C(CC=O)CN(C)C(=O)C2C=CC=CC=2)C=CC=1Cl>>[CH3:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C[C@@H](CCN1CCC(N(CCNC(=O)C(F)(F)F)C(=O)C(F)(F)F)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: CN(CC(CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C(NCCN(C(=O)C(F)(F)F)C1CCNCC1)C(F)(F)F
Product: CNC(=O)c1ccccc1

Procedure:
(S)-N-[2-(3,4-Dichlorophenyl)-4-[4-[(2,2,2-trifluoro-acetyl)[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidino]-butyl]-N-methylbenzamide. Using the procedure of Example 1, replacing 4-(2-oxo-1,3-oxazolidin-3-yl)piperidine with 4-[(2,2,2-trifluoroacetyl)[2-(2,2,2-trifluoroacetylamino)ethyl]amino]piperidine, and N-[-2-(3,4-dichlorophenyl)-4-oxobutyl]-N-methylbenzamide with the (S)-enantiomer, the N-methylbenzamide was obtained as a viscous oil; MS: m/z=669(M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc(Br)cc3)cn2c1
Yield: 81.3 %

Procedure:
Dissolving 5 g (18 mmol) of 2,4′-dibromo acetophenone and 2.0 g (19 mmol) of 2-amino-5-picoline into 30 milliliter of ethanol, adding 2.9 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 4.2 g of 2-(4-bromo-phenyl)-6-methyl-imidazo [1,2-a] pyridine (yield: 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3([O:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]4[CH:30]=[CH:31][CH:32]=[C:21]34)[CH2:17][CH2:16]2)=[O:14])=[CH:7][C:4]=1[CH:5]=[O:6].[BH4-].[Na+]>CO>[OH:6][CH2:5][C:4]1[C:3]([O:2][CH3:1])=[CH:10][C:9]([O:11][CH3:12])=[C:8]([C:13]([N:15]2[CH2:16][CH2:17][C:18]3([O:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]4[CH:30]=[CH:31][CH:32]=[C:21]34)[CH2:19][CH2:20]2)=[O:14])[CH:7]=1
Reactant: COc1cc(OC)c(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(OC)c(C(=O)N2CCC3(CC2)Oc2ccccc2-n2cccc23)cc1CO
Reaction time: 0.25 h

Procedure:
2,4-Dimethoxy-5-(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbonyl)benzaldehyde (65 mg, 0.15 mmol) was suspended in MeOH (1 mL). NaBH4 (60 mg, 1.6 mmol) was added and the reaction mixture was allowed to stir for 15 minutes. The reaction mixture was filtered and was then purified by reverse phase preparative liquid chromatography utilizing a gradient of 20-99% methanol in water containing no modifier to give (5-(hydroxymethyl)-2,4-dimethoxyphenyl)(spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 434.2. found 435.5 (M+1)+; Retention time: 1.63 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:13]([O-])=O)=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CCOC(C)=O>C1COCC1.CO.[Pd]>[NH2:13][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cccc(OC)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.7 %

Procedure:
A suspension of compound 52 (26.2 g, 124 mmol) and Pd/C (10 wt. %, 6.0 g) in THF (400 mL) and MeOH (200 mL) was stirred under an atmosphere of H2 at room temperature for 18 hours. EtOAc (300 mL) was added to the mixture and filtered through a Celite pad. The filtrate was concentrated in vacuo to provide the crude product 53 (22.4 g, 99%) as colorless oil.
Reaction SMILES: [CH:1]1(O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: OC1CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=Cc2ccccc2C1

Procedure:
A 3-neck 500 mL round-bottomed flask fitted with a condenser and an addition funnel was charged with 2.62 g (0.11 mol) of Mg turnings and 20 mL of anhydrous diethyl ether. Slow addition of a solution of 25.10 g (0.09 mol) of 3,5-bis(trifluoromethyl) bromobenzene in diethyl ether (100 mL), followed by refluxing for 30 min, gave a brown-grey solution of the aryl Grignard reagent. The solution was cooled to room temperature (RT), filtered over a plug of Celite and evacuated to yield a brown oil. Toluene (40 mL) was added and the suspension cooled to 0° C. whereupon a solution of 2-indanone (9.22 g, 0.07 mol) in toluene (60 mL) was added dropwise to give a tan-brown slurry. This mixture was warmed to room temperature and stirred for an additional 3 hours. After cooling to 0° C. it was quenched with 150 mL of water, hexane (200 mL) added and the reaction mixture neutralized with 5 M HCl. The organic layer was separated, and the aqueous layer was extracted with two 50-mL portions of hexane. The combined organic layers were washed with two 50-mL portions of brine and dried over anhydrous magnesium sulfate. After filtration over Celite, the solvent was removed under vacuo yielding 21.5 g (89% based on 2-indanone) of 2-(bis-3,5-trifluoromethylphenyl) indanol as an off-white solid. 1H NMR (CDCl3, 23 C, 400 MHz): d 8.05 (s, 2H), 7.80 (s, 1H), 7.5-7.0 (M, 4H), 3.41 (m, 4H), 2.21 (s, 1H, OH). Under argon, this alcohol (21.5 g, 0.06 mol) and p-toluene-sulfonic acid monohydrate (800 mg) were dissolved in toluene (250 mL) and the solution was heated to reflux for 6 hours to afford 14.4 g, (70%) of 2-(bis-3,5(trifluoromethyl)-phenyl) indene upon recrystallization from diethyl ether/hexane at −18 C. 1H NMR (CDCl3, 23° C., 400 MHz): d 8.01 (s, 2H), Arf), 7.75 (s, 1H, Arf), 7.52 (d, J=7 Hz, 1H), 7.47 (d, J=7 Hz, 1H), 7.43 (s, 1H), 7.33 (dd, 2J=7 Hz, 1H), 7.27 (dd, 2J=7 Hz, 1H), 2.83 (s, 2H). 13C NMR (CDCl3, 23 C, 100 MHz): L144.3 (s), 143.1 (s), 138.0 (s), 132.1 (q, 2JC—F=33 Hz), 130.1 (d, JC—H=167 Hz), 127.0 (dd), JC—H=160 Hz, 2JC—H=7 Hz), 126.0 (dd, JC—H=159 Hz, 2JC—H=7 Hz)m 125.2 (brd, JC—H=162 Hz), 123.9 (dd, JC—H=156 Hz, 2JC—H=9 Hz), 123.4 (q, JC—F=273 Hz, CF3), 121.8 (dd, Jc-H=160 Hz, 2JC—H=8 Hz), 120.6 (brd, JC—H=167 Hz), 38.9 (td, JC—H=127 Hz, JC—H=7 Hz, CH2). C,H analysis: Anal. Found (Calcd): C, 62.45 (62-20); H 3.01 (3.07).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[CH:4][CH:3]=1.[B:12](OC(C)C)([O:17]C(C)C)[O:13]C(C)C.C([Li])CCC.Cl>O1CCCC1.O>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([B:12]([OH:17])[OH:13])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-bromo-4-(difluoromethoxy)-benzene (1.18 g) and triisopropyl borate (1.34 ml) in tetra-hydrofuran (6 ml) was added dropwise n-butyl lithium (1.58 M hexane solution, 3.68 ml) at −78° C. over 10 minutes under argon atmosphere, then the reaction mixture was allowed to warm to room temperature. After being starred at room temperature for 3 hours, the mixture was cooled to 0° C., and thereto were added a 6 N aqueous hydrochloric acid solution and water. The resultant mixture was extracted with ethyl acetate (30 ml) twice, and the combined organic layer was washed with brine (10 ml), dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residual solid was triturated with cold hexane to give the titled compound as a colorless solid. 1H-NMR (DMSO-d6) δ 7.12 (d, J=8.4 Hz, 2H), 7.27 (t, J=74.1 Hz, 1H), 7.83 (d, J=8.6 Hz, 2H), 8.08 (br-s, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.C(OC(C1C(C2C=CC(F)=CC=2)=NOC=1)=O)C>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1conc1-c1ccc(Cl)cc1
Agent: CCOC(=O)c1conc1-c1ccc(F)cc1
Product: O=C(O)c1conc1-c1ccc(Cl)cc1
Yield: 100.1 %

Procedure:
As described for example 13d, 3-(4-chloro-phenyl)-isoxazole-4-carboxylic acid ethyl ester (57.0 g, 226.5 mmol) was converted, instead of 3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid ethyl ester, to the title compound (50.7 g, 92%) which was obtained as a light yellow solid. MS: m/e=222.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CO.[Ni]>[NH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3](=[O:12])[N:4]([CH3:11])[CH:5]=1
Reactant: Cn1cc([N+](=O)[O-])cc(Cl)c1=O
Agent: [Ni]
Solvent: CO
Product: Cn1cc(N)cc(Cl)c1=O
Temperature: 25 °C
Reaction time: 97 h

Procedure:
Ra—Ni (EtOH) (230 mmol) was added to a solution of 3-chloro-1-methyl-5-nitro-1H-pyridin-2-one (Step E6) (136 mmol) in MeOH (400 mL) and the mixture was stirred at rt under a hydrogen atmosphere for 97 h. The reaction mixture was filtered over celite and concentrated. The product was purified by flash chromatography to afford the title compound as a black solid. ESI-MS: tR=0.33 min, [M+H]+ 159/161 (LC-MS 1); TLC: Rf=0.28 (9:1 CH2Cl2/MeOH).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][CH2:49][OH:50])[CH:46]=2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2.C(O)(C(F)(F)F)=O.N.CO>>[OH:50][CH2:49][CH2:48][CH2:47][N:45]1[CH:46]=[C:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=4[O:28][CH3:29])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH:43]=[N:44]1
Reactant: CN1Cc2c(-c3cnn(CCCO)c3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 105 °C
Reaction time: 0.75 h

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (897 mg, 1.98 mmol) and 7-amino-4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 289A, 633.5 mg, 2.212 mmol). in TFE (12 mL) was charged with TFA (654.2 mg, 5.737 mmol) and irradiated by microwave heating [Biotage, 105° C.] for 1 h. The reaction mixture was transferred to a round bottom flask and concentrated in vacuo. The residue was dissolved in MeOH (unmeasured amount), cooled to 0° C., and charged with 7.0 M of NH3 in MeOH (5 mL, 40 mmol). After stirring from 0° C. to rt over 1 h 45 min, the suspension was concentrated in vacuo and the crude product purified using a Teledyne/ISCO Combiflash system eluting with a solvent system of 0-10% MeOH:CH2Cl2 to afford the title material as a white solid, 1.1017 g (78%). 1H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 9.12 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 8.06-8.63 (m, 1H), 7.96 (s, 1H), 7.70 (d, J=8.84 Hz, 1H), 7.41 (d, J=7.07 Hz, 1H), 7.10 (br. t, J=2.00 Hz, 1H), 6.96 (br td, J=2.30, 8.00 Hz, 1H), 4.53-4.67 (m, 3H), 4.21 (t, J=7.20 Hz, 2H), 4.00 (qd, J=7.06, 8.12 Hz, 4H), 3.74 (s, 3H), 3.43 (q, J=6.06 Hz, 2H), 3.36 (d, J=19.96 Hz, 2H), 3.11 (s, 3H), 1.97 (quin, J=6.63 Hz, 2H), 1.17 (t, J=6.95 Hz, 6H). MS (ES+): m/z 704.23 (100) [MH+]. HPLC: tR=3.73 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]([C:10]#[N:11])([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
3,4-Dichlorophenylacetonitrile (10 g, 53.75 mmol) was stirred mechanically in THF (50 mL) at -78° C. and treated dropwise with sodium bis-(trimethylsilyl)amide (108 mL, 1 M; 2 eq.). The reaction slurry was allowed to warm to 20° C. and stirred for 3 hours. The solution was cooled to -78° C. and the slurry was treated with ethyl bromoacetate (12 mL, 107 mmol, 2 eq.). The slurry was again allowed to warm to 20° C. and stirred 18 hours. The slurry was dissolved in ethyl ether and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (400 g) with 20% ethyl acetate to give 15.85 g (82%) of the title compound.