Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([C:16](=O)[C@H:17]([NH:25][CH:26]=O)[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.B(F)(F)F.CCOCC.B.C1COCC1.Cl>C1COCC1>[NH:1]1[C:9]2[C:4](=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]([NH:25][CH3:26])[CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:12][CH2:11]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=CN[C@H](Cc1ccccn1)C(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN[C@H](Cc1ccccn1)CN1CCN(c2cccc3[nH]ccc23)CC1
Temperature: 25 °C
Yield: 16.6 %

Procedure:
To a solution of (1R)-2-[4-(1H-indol-4-yl)piperazin-1-yl]-2-oxo-1-(pyridin-2-ylmethyl)ethylformamide (710 mg.; 1.9 mmol, from Example 19) in THF (10 mL) was added BF3.Et2O (0.47 mL; 3.8 mmol). The reaction mixture was heated to reflux, and treated, at reflux, with a 1M solution of BH3.THF in THF (19 mL; 19 mmol). Stirring was continued at reflux for 16 hours. The mixture was cooled to ambient temperature, cautiously treated with 5N aqueous HCl (20 mL), and heated to reflux for 4 hours. The mixture was cooled to ambient temperature and concentrated in vacuo to remove THF. The aqueous residue was washed with ether, and the ether layer discarded. The aqueous layer was rendered basic with 6N NaOH, and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo to afford the title compound as a white solid (110 mg.; 17%). MS (+) ESI [M+H]+ @ m/z 350.
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:13][CH3:14])=[N:6][C:7]([CH3:12])=[CH:8][C:9]=1[S:10][CH3:11])([O-])=O.O1CCOCC1.[H][H]>[Ni].CO>[NH2:1][C:4]1[C:5]([S:13][CH3:14])=[N:6][C:7]([CH3:12])=[CH:8][C:9]=1[S:10][CH3:11]
Reactant: CSc1cc(C)nc(SC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: C1COCCO1
Product: CSc1cc(C)nc(SC)c1N
Yield: 85 %

Procedure:
A mixture of 18.9 g (0.082 mol) 3-nitro-2,4-bis(methylthio)-6-methylpyridine and 18.9 g Raney nickel in 600 ml. 1,4-dioxane and 300 ml methanol was shaken with hydrogen (15 psi) in a Parr hydrogenation apparatus for 3.5 hours. The catalyst was filtered and the filtrate was concentrated to dryness in vacuo. The solid residue was chromatographed on silica gel (650 g), eluting with 9:1 hexane/ethyl acetate to yield 14.0 g. (85% yield) of the title compound as an off white solid.
Reaction SMILES: [C:1]1([C:18]([OH:20])=O)[C:14]2[CH2:13][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([C:15]([OH:17])=O)[C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C=O.S(Cl)(Cl)=O>[C:18]([C:1]1[C:14]2[CH2:13][C:12]3[C:7](=[C:8]([C:15](=[O:17])[C:1]4[CH:14]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)(=[O:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1cccc2c1Cc1cccc(C(=O)O)c1C2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cccc2c1Cc1cccc(C(=O)c3ccccc3)c1C2
Temperature: 60 °C
Reaction time: 18 h
Yield: 27 %

Procedure:
A solution of 9,10-dihydro anthracene-1,5-dicarboxylic acid (52, 1 g, 3.73 mmol) in 200 μl of dimethyl formamide and 20 ml of thionyl chloride was refluxed for 3 hours. The resulting solution was evaporated to dryness under vacuum, 60 ml of benzene added, and warmed to 60° C. to obtain a solution. This solution was slowly added to a 250 ml round bottom flask containing a mixture of AlCl3 and 20 ml of benzene. The resulting mixture was stirred for 18 hours at room temperature and poured into 100 ml of an ice/water mixture containing 10 ml of conc. HCl. The organic layer was separated and the aqueous layer was washed twice with 100 ml portions of benzene. After drying over Na2SO4, the combined organic extracts were dried under vacuum to yield a brown colored crude product. This was further purified by flash column chromatography to obtain a dark yellow, oily product (0.39 g, 27%) (According to NMR studies the product is 80+% pure). 1H NMR (300 MHz, CDCl3): δ 4.04 (s, 4H), 7.20-7.86 (m, 16H), 7.51 (d, 2H, J=6 Hz), 7.70 (d, 2H, J=6 Hz), 13.00 (broad s, 2H). 13C NMR (300 MHz, CDCl3): δ 33.95, 125.48, 126.98, 128.51, 128.55, 129.94, 130.30, 133.24, 135.74, 137.88, 197.15.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[C:24]([CH3:25])=[C:23]([CH3:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: NCCc1ccccc1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1C
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccccc3)c2c1C

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(isoxazol-5-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-phenethylamino-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccc(Cl)c(Cl)c4)CC3)nn2C(C)(C)C)cc1

Procedure:
99 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(3,4-dichlorophenyl)piperazine (51 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: C([O:5][C:6](=[O:52])[C:7]([O:10]/[N:11]=[C:12](/[C:39]1[N:40]=[C:41]([NH:44]C(OC(C)(C)C)=O)[S:42][CH:43]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([O-:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N+:34]([CH3:37])=[CH:33][C:32]=2[CH3:38])[N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:44][C:41]1[S:42][CH:43]=[C:39](/[C:12](=[N:11]/[O:10][C:7]([C:6]([OH:52])=[O:5])([CH3:9])[CH3:8])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([O-:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][N+:34]([CH3:37])=[CH:33][C:32]=3[CH3:38])[N:28]=[N:27]2)=[O:14])[N:40]=1
Reactant: Cc1c[n+](C)ccc1-c1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)[O-])nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c[n+](C)ccc1-c1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)C(=O)N2S(=O)(=O)[O-])nn1
Yield: 61.7 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(1,3-dimethylpyridin-1-ium-4-yl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxoazetidine-1-sulfonate (24 mg, 0.032 mmol), DCM (1.2 mL) and TFA (0.3 mL, 3.9 mmol). The crude residue was purified by reverse phase prep HPLC (T3, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (12 mg, 62%) as a white solid. LCMS: m/z=606.1 (M−1); 1H NMR (400 MHz, D2O): δ 8.65 (s, 1H), 8.57 (s, 1H), 8.49 (d, J=5.6 Hz, 1H), 8.27 (d, J=6.8 Hz, 1H), 6.74 (br s, 1H), 5.47 (d, J=5.2 Hz, 1H), 4.97-4.88 (m, 3H), 4.21 (s, 3H), 2.46 (s, 3H), 1.30 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26]O)[O:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(OP(OC2C=CC=CC=2)([N:76]=[N+:77]=[N-:78])=O)=CC=1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>O1CCCC1>[N:76]([CH2:26][C@@H:18]1[C@H:19]2[O:23][C:22]([CH3:24])([CH3:25])[O:21][C@H:20]2[C@H:16]([N:13]2[C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]4[CH:28]=[CH:29][C:30]([O:32][CH3:33])=[CH:31][C:3]=4[O:2][CH3:1])[C:8]=3[CH:15]=[CH:14]2)[O:17]1)=[N+:77]=[N-:78]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2O[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of ((3aR,4R,6R,6aR)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2.83 g, 6.20 mmol) and triphenylphosphine (2.28 g, 8.68 mmol) in dry tetrahydrofuran (32 mL) was cooled at 0° C. in an ice/water bath. Diisopropyl azodicarboxylate (1.71 mL, 8.68 mmol) was added dropwise, followed by a solution of diphenylphosphonic azide (1.87 mL, 8.68 mmol) in tetrahydrofuran (5.3 mL, 66 mmol). Upon addition of the DPPA solution, a white milky precipitate formed. After about 30 minutes, the reaction mixture was allowed to warm to room temperature and stir overnight. After 24 h, HPLC indicated that all the starting material had been consumed. The reaction mixture was concentrated to about ½ the original volume and purified by flash chromatography (175 g silica gel, 10-55% EA/hept) to yield the title compound (2.49 g, 83%) as a slightly yellow stiff foam: MS (ESI+) for C23H27N7O5 m/z 482.2 (M+H)+; (ESI−) for C23H27N7O5 m/z 480.1 (M+H)−, m/z 526.1 (M+CO2H)−; HPLC purity 97%.
Reaction SMILES: [C:1]([CH2:4][C:5]1[N:6]=[C:7]([S:10][C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[S:8][CH:9]=1)(O)=O.[CH2:17]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH2:20][CH3:21]>O1CCCC1>[CH3:15][C:11]([S:10][C:7]1[S:8][CH:9]=[C:5]([CH2:4][CH2:1][NH:26][C:25]2[CH:27]=[CH:28][C:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)[N:6]=1)([CH3:16])[C:12]([OH:14])=[O:13]
Reactant: CCCCCc1ccc(N)cc1
Reactant: CC(C)(Sc1nc(CC(=O)O)cs1)C(=O)O
Solvent: C1CCOC1
Product: CCCCCc1ccc(NCCc2csc(SC(C)(C)C(=O)O)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An operation similar to that of Example 520-1 was performed using 2-{[4-(carboxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid resin synthesized in Example 461-4 and 4-amylaniline (0.098 g) as starting materials. To the obtained resin were added tetrahydrofuran (2.0 mL) and 1 mol/L borane-tetrahydrofuran complex (2.0 mL), and the mixture was stirred at room temperature overnight. The resin was collected by filtration from the reaction mixture, washed once with tetrahydrofuran, twice with tetrahydrofuran/methanol=1:1 solution, and twice with methanol. Then, a solution (4.0 mL) of tetrahydrofuran-methanol-piperidine (1:1:2) was added to the resin, and the mixture was stirred at room temperature overnight. After completion of the reaction, the resin was collected by filtration, washed four times with tetrahydrofuran and twice with methanol, and vacuum dried to give the title pale-yellow resin (0.30 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[O:23][CH3:24].O>ClCCl>[Br:15][C:16]1[C:17]([O:23][CH3:24])=[CH:18][C:19]([F:22])=[C:20]([C:9]([C:8]2[CH:12]=[CH:13][CH:14]=[C:6]([F:5])[CH:7]=2)=[O:10])[CH:21]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1cc(F)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(F)c(C(=O)c2cccc(F)c2)cc1Br
Temperature: -60 °C

Procedure:
A total of 716 mg of aluminium chloride was suspended in 24.4 ml of dichloromethane and was then mixed with 0.65 ml of 3-fluorobenzoyl chloride and 1 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a under stirring at −60° C. The mixture was raised in temperature to room temperature over 2.5 hours and was stirred for further 3 hours. Water was added to the reaction mixture under ice-cooling, followed by extracting with diethyl ether. The resulting organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 856 mg of the title compound as white crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5]([Cl:14])=[N:6][C:7]2[N:8]([N:11]=[CH:12][CH:13]=2)[C:9]=1Cl.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[C:15]([N:19]1[C:9]2[N:8]3[N:11]=[CH:12][CH:13]=[C:7]3[N:6]=[C:5]([Cl:14])[C:4]=2[CH2:3][CH2:2]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: ClCCc1c(Cl)nc2ccnn2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)N1CCc2c(Cl)nc3ccnn3c21
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.6 %

Procedure:
In 70 ml of dimethylformamide were dissolved 12.50 g of 6-(2-chloroethyl)-5,7-dichloropyrazolo[1,5-a]pyrimidine, and 9.55 g of tert-butylamine and 11.47 g of triethylamine were added to the solution. The mixture was stirred for 2 days at room temperature. Excess amines and the solvent were distilled off under reduced pressure, and the residue was dissolved in chloroform. After the chloroform layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was treated with a chloroform-ether system to deposit crystals. The crystals were collected by filtration and recrystallized from ethanol to obtain 11.34 g (yield: 90.6%) of the intended product. White crystals.
Reaction SMILES: [H-].[Na+].C(O)C=C.[S:7]([CH2:16][CH2:17][C:18]([O:20]CC=C)=[O:19])[CH2:8][CH2:9][C:10]([O:12]CC=C)=O>CCOCC>[S:7]1[CH2:8][CH2:9][C:10](=[O:12])[CH:17]([C:18]([OH:20])=[O:19])[CH2:16]1
Reactant: C=CCOC(=O)CCSCCC(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: C=CCO
Solvent: CCOCC
Product: O=C(O)C1CSCCC1=O
Temperature: 25 °C
Yield: 83.1 %

Procedure:
To a mixture of sodium hydride (60% in oil, 1.6 g, 38.7 mmol) in 10 mL of dry ether at room temperature was added allyl alcohol (2.25 g, 38.7 mmol) in a dropwise manner. The resultant mixture was stirred for 15 min. A solution of 3,3'-thiodipropionic acid, diallyl ester (5.0 g, 19.3 mmol) in 10 mL ether was slowly added and the mixture refluxed for 5 h. The reaction was cooled to room temperature and then quenched with water and the pH adjusted to 4 with 1N HCl. The ether layer was separated and the aqueous layer was extracted with ether (2×100 mL). The combined etheral layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue purified by flash column chromatography on silica gel eluted with hexane:ether (9:1) to give 2.57 g of tetrahydrothiopyran-4-one-3-carboxylic acid, allyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=2)[CH2:18][CH2:17]1
Reactant: COCCN1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 125 °C
Reaction time: 24 h
Yield: 74.9 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (1.4 g, 8.1 mmol), 1-(2-methoxy-ethyl)-piperazine (2.0 g, 14.0 mmol) and anhydrous potassium carbonate (1.38 g, 10.0 mmol) in N,N-dimethylacetamide (3 ml) was stirred at 120-130° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (15 ml) and stirred vigorously. The resulting yellow brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (20 mL), filtered, washed with additional diethyl ether, dried to afford 5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-2-nitro-phenylamine (1.7 g, 75%) as a yellow brown powder.
Reaction SMILES: Br[C:2](=[CH2:14])[CH2:3][CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Mg].II.[F:18][C:19]1[CH:26]=[C:25]([F:27])[C:24]([C:28]2[CH:29]=[N:30][CH:31]=[N:32][CH:33]=2)=[CH:23][C:20]=1[CH:21]=[O:22]>C1COCC1.O>[Si:7]([O:6][CH2:5][CH2:4][CH2:3][C:2](=[CH2:14])[C:21]([C:20]1[CH:23]=[C:24]([C:28]2[CH:33]=[N:32][CH:31]=[N:30][CH:29]=2)[C:25]([F:27])=[CH:26][C:19]=1[F:18])=[O:22])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: O=Cc1cc(-c2cncnc2)c(F)cc1F
Reactant: C=C(Br)CCCO[Si](C)(C)C(C)(C)C
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: C=C(CCCO[Si](C)(C)C(C)(C)C)C(=O)c1cc(-c2cncnc2)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.99 %

Procedure:
A solution of ((4-bromopent-4-en-1-yl)oxy)(tert-butyl)dimethylsilane (prepared following the procedures of Rostami, Organic Letters, 2007), 9(4), 703-706) (3.30 g, 11.81 mmol) in THF (25 mL) was added to a flask filled with magnesium (0.574 g, 23.62 mmol) and iodine (0.092 g, 0.363 mmol), and the resulting dark brown suspension was stirred at rt for 15 min and then heated under reflux for 45 min. The color changed from brown to deep reddish and the color of iodine faded 10 min under reflux. Eventually, the color of the reaction mixture turned to grey. This regent was cooled to rt and then added to a suspension of 2,4-difluoro-5-(pyrimidin-5-yl)benzaldehyde (Preparation 15, 2 g, 9.08 mmol) in THF (14 mL), and the reaction mixture was stirred at rt for 12 h. Water was added and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in vacuo to give the crude product. The crude product was purified by silica gel chromatography eluting with 0-35% EtOAc/Hexane to give 5-((tert-butyldimethylsilyl)oxy)-1-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-2-methylenepentan-1-one (0.95 g, 2.270 mmol, 24.99% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ 9.27 (s, 1H), 8.93 (d, J=1.4 Hz, 2H), 7.59 (dd, J=8.2, 7.3 Hz, 1H), 7.20-7.03 (m, 1H), 6.04 (s, 1H), 5.78 (d, J=1.8 Hz, 1H), 3.70 (t, J=6.3 Hz, 2H), 2.62-2.41 (m, 2H), 1.85-1.70 (m, 2H), 0.93 (m, 9H), 0.09 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCCc1ccc2cnn(-c3ccc(F)cc3)c2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
A solution of 4-(1-(4-fluorophenyl)-1H-indazol-6-yl)butanoic acid (3, R1=4-Fluorophenyl) (13.86 g, 46.5 mmol) in DCM (225 mL) was treated with oxalyl dichloride (2M in DCM) (25.6 mL, 51.1 mmol). Two drops of DMF were added and the mixture was stirred for about 45 min at rt. A second portion of oxalyl dichloride (2M in DCM) (4.65 mL, 9.29 mmol) was added followed by 1 drop DMF. After about 15 min the solvent was removed under reduced pressure. The material was dissolved in DCM (225 mL) and the flask was fitted with a reflux condenser. Aluminum trichloride (8.2 g, 61.5 mmol) was added and the mixture was stirred for about 30 min. A second portion of aluminum trichloride (7.67 g, 57.5 mmol) was added to the mixture and stirring was continued for about 30 min. The reaction was quenched by slow addition of ice in small portions over about 30-45 min with vigorous stirring. After addition of about 50 g of ice, the biphasic mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with DCM (30 mL) and the combined organic solutions were washed with water (75 mL), 0.5 N aq. sodium hydroxide (100 mL) and brine (50 mL). The organic mixture was dried over MgSO4, filtered and concentrated under reduced pressure to a solid. The material was purified on silica gel (330 g) using a gradient of 0-15% EtOAc in DCM. Fractions containing >95% desired product were combined and concentrated under reduced pressure. Fractions containing desired product contaminated with the minor regioisomer [1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[g]indazol-9(6H)-one] were combined and concentrated under reduced pressure separately. The residue was purified on silica gel (80 g) using a gradient of 0-10% EtOAc in DCM. Fractions containing >95% desired product were combined with those from the first column and concentrated under reduced pressure to yield 1-(4-fluorophenyl)-7,8-dihydro-1H-benzo[f]indazol-5(6H)-one (4, R1=4-Fluorophenyl) (8.73 g, 67%); LC/MS, method 3, Rt=2.43 min, MS m/z 281 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.52 (d, J=0.9 Hz, 1H), 8.49 (s, 1H), 7.86-7.78 (m, 2H), 7.69 (s, 1H), 7.51-7.41 (m, 2H), 3.12-3.09 (m, 2H), 2.70-2.63 (m, 2H), 2.11-2.02 (m, 2H). Note: 1H NMR shows ˜4% minor regioisomer.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[NH:12][C:11]2=[O:21])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[NH2:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[N:12]([CH3:24])[C:11]2=[O:21])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)[nH]c1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Yield: 129.5 %

Procedure:
A solution of 7.5 grams (0.021 mole) of 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, 3.4 grams (0.025 mole) of potassium carbonate, and 3.5 grams (0.025 mole) of methyl iodide in 200 mL of acetone was stirred at ambient temperature for about 18 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in 200 mL of water. The mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 6.9 grams of crude product. The dark oil was combined with 7.0 grams of crude product prepared by a similar route to yield a total of 13.9 grams of crude product. The crude product was purified by column chromatography on silica gel, yielding 10.0 grams of title compound. The NMR spectrum was consistent with the proposed structure.