Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10](Cl)[CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>O1CCOCC1.O.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>[NH2:1][C:2]1[N:3]=[C:4]([NH2:13])[C:5]2[N:11]=[C:10]([C:23]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([Cl:20])[CH:22]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2nc(Cl)ccc2n1
Reactant: COc1ccc(B(O)O)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3nc(N)nc(N)c3n2)cc1Cl
Yield: 38.7 %

Procedure:
A suspension of 2,4-diamino-6-chloropyrido[3,2-d]pyrimidine (464 mg, 2.37 mmole), K2CO3 (1332 mg, 9.64 mmole), 3-chloro-4-methoxyphenyl boronic acid (907 mg, 4.86 mmole) in 1,4-dioxane (35.5 ml) and water (7 ml) was purged with a stream of nitrogen for 15 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (278 mg, 0.24 mmole) was added and the reaction mixture was heated at reflux under a N2 atmosphere for 4 hours. Upon cooling, the mixture was partitioned between CH2Cl2 and a saturated aqueous sodium bicarbonate solution. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by silica gel flash chromatography, using methanol and 1% Et3N in CH2Cl2 as eluent, gradually increasing the methanol concentrations from 5% to 10%, to afford the pure title compound (277 mg, yield 39%) which was characterized by its mass spectrum as follows: MS (m/z): 302 ([M+H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=3)=[C:9]([CH3:20])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:21]1[CH:22]=[CH:23][C:24]2N(O)N=[N:27][C:25]=2[CH:26]=1.NC1C=CC=CC=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:27][C:25]4[CH:26]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:17])=[CH:18][CH:19]=3)=[C:9]([CH3:20])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(C(=O)O)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Solvent: CN1CCOCC1
Product: Cc1sc2ncnc(N)c2c1-c1ccc(C(=O)Nc2ccccc2)cc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
A suspension of Example 66B (89 mg, 0.31 mmol) and HOBT (46 mg, 0.35 mmol) in DMF (4 mL) at room temperature was treated with aniline (0.029 mL, 0.31 mmol), NMM (0.086 mL, 0.78 mmol) and EDC.HCl (66 mg, 0.34 mmol), stirred overnight, and partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organic extracts ware washed with water, and brine, dried (Na2SO4), filtered, and concentrated to a volume of about 3 mL. The product was treated with hexanes and the resulting precipitate was collected by filtration to provide 84 mg (75%) of the desired product. MS(ESI(+)) m/e 361 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H); 8.30 (s, 1H); 8.12 (d, J=8.4 Hz, 2H); 7.80 (d, J=7.5 Hz, 2H); 7.58 (d, J=8.4 Hz, 2H); 7.37 (t, J=7.5 Hz, 2H); 7.12 (t, J=7.5 Hz, 1H); 2.32 (s, 3H); Anal. Calcd. for C20H16N4OS.0.1C4H8O2: C, 66.36; H, 4.59; N, 15.17. Found: 66.07; H, 4.76; N, 15.32.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+](C)([O-])=O.[CH3:9][N:10]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:20].ClC[CH:23]([O:26]C(CCl)CCl)CCl>C(Cl)Cl>[CH3:9][N:10]1[C:15]2[CH:16]=[C:17]([CH:23]=[O:26])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12][C:11]1=[O:20]
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: CN1C(=O)COc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CN1C(=O)COc2ccc(C=O)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
1 g of AlCl3 were suspended in 10 ml DCM, 0.5 ml of nitromethane were added to dissolve AlCl3, and the solution was cooled to 0° C. 4-Methyl-4H-benzo[1,4]oxazin-3-one (0.5 g, 3.06 mmol) dissolved in DCM was added to the above solution and stirred for 15 minutes at 0° C. To this solution was further added 0.36 ml of bis-chloromethyl-methylether in DCM. The reaction was stirred at 0° C. for 15 minutes and at room temperature for 3 h. The crude reaction mixture was then poured onto ice, the layers were separated and the organic phase was washed with NaHCO3 and brine. After drying over MgSO4 and filtration the solvent was evaporated, which afforded 0.43 g of crude product. The dark oil was purified by flash chromatography using EtOAc and cyclohexane as eluents, affording 0.2 g (37%) of 4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde as colourless solid.
Reaction SMILES: [Cl:1]/[CH:2]=[C:3](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl>CO>[ClH:1].[C:16]1(/[C:3](=[CH:2]\[Cl:1])/[CH2:4][NH2:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1C/C(=C/Cl)c1ccccc1
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: NC/C(=C/Cl)c1ccccc1
Yield: 99.7 %

Procedure:
(E)-1-Chloro-2-phenyl-3-phthalimidopropene (445 mg) is treated as described for the Z-isomer with hydrazine hydrate (85 mg) in methanol (6 ml). Hydrolysis with 50% aqueous hydrochloric acid gives (E)-2-phenyl-3-chloroallylamine hydrochloride (152 mg): colorless needles; m.p. 185°-186°;
Reaction SMILES: [CH3:1][N:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:3][CH:4]([OH:26])[CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:45][S:46](Cl)(=[O:48])=[O:47].O>C(OCC)C.ClCCl>[CH3:1][N:2]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:3][CH:4]([O:26][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:5][O:6][C:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCN(C)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN(C)CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OS(C)(=O)=O
Yield: 82.1 %

Procedure:
18 g (30 mmol) of 2a was dissolved in 100 ml of dry diethyl ether and 50 ml of dichloromethane. 6.84 g (60 mmol) of methanesulphonyl chloride in 50 ml of dichloromethane was added under stirring, and the mixture was refluxed for 5 hours. Water was then added, and the organic phase was decanted, dried and evaporated. The crude product was chromatographed (eluent as in Step 2), yielding 16.7 g of 3a (80%).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[F-:17].[K+].[F:19][C:20]([F:28])(S(F)(=O)=O)C([O-])=O>CN(C)C=O.[Cu]I>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([N+:14]([O-:16])=[O:15])=[C:2]2[C:20]([F:28])([F:17])[F:19])=[CH:7][CH:8]=1
Reactant: [F-]
Reactant: COc1ccc2ccc([N+](=O)[O-])c(I)c2c1
Reactant: O=C([O-])C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc([N+](=O)[O-])c(C(F)(F)F)c2c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
The mixture of 1-iodo-7-methoxy-2-nitronaphthalene (3.7 g, 11.24 mmol), CuI (2.3 g, 12.08 mmol) and KF (1 g, 17.24 mmol) in N,N-dimethylformamide (50 ml) was stirred for 0.5 h at 120° C. before the addition of 2,2-difluoro-2-(fluorosulfonyl)acetate (2.3 g, 11.97 mmol). The resulting solution was stirred for another 0.5 h at 120° C. and then quenched by water (300 ml). The crude product was extracted with dichloromethane (3×100 ml) and the organic fractions were combined and washed by brine (3×150 ml). The organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a residue, which was purified by silica gel column chromatography using 1%-10% ethyl acetate in petroleum ether to afford 7-methoxy-2-nitro-1-(trifluoromethyl)naphthalene as a off-white solid (2 g, 66%). 1H NMR (300 MHz, DMSO): δ 8.48 (d, J=8.7 Hz, 1H), 8.21 (d, J=9.3 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.56 (dd, J=9.0, 2.1 Hz, 1H), 7.41 (s, 1H), 3.96 (s, 3H).
Reaction SMILES: C12(COC3C=CC(C(N)=O)=CC=3C3C(OC)=NC=CC=3)CC3CC(CC(C3)C1)C2.[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:53][CH2:52]4)=[CH:49][C:45]([C:46]([NH2:48])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2.CS(Cl)(=O)=O.[O:60]1[CH2:64][CH2:63][CH:62]([S:65](Cl)(=[O:67])=[O:66])[CH2:61]1>>[C:30]12([CH2:40][O:41][C:42]3[C:50]([CH:51]4[CH2:52][CH2:53]4)=[CH:49][C:45]([C:46]([NH:48][S:65]([CH:62]4[CH2:63][CH2:64][O:60][CH2:61]4)(=[O:67])=[O:66])=[O:47])=[C:44]([F:54])[CH:43]=3)[CH2:37][CH:36]3[CH2:38][CH:32]([CH2:33][CH:34]([CH2:35]3)[CH2:39]1)[CH2:31]2
Reactant: O=S(=O)(Cl)C1CCOC1
Reactant: NC(=O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Agent: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: CS(=O)(=O)Cl
Product: O=C(NS(=O)(=O)C1CCOC1)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 38 step 4 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide with 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamide and to replace methanesulfonyl chloride with tetrahydrofuran-3-sulfonyl chloride, the title compound was obtained as a colorless solid (0.14 g, 28%): 1H NMR (300 MHz, CDCl3) δ8.72-8.60 (m, 1H), 7.60-7.53 (m, 1H), 6.63-6.53 (m, 1H), 4.62-4.48 (m, 1H), 4.33-4.23 (m, 1H), 4.16-3.82 (m, 3H), 3.56 (s, 2H), 2.58-2.44 (m, 1H), 2.42-2.26 (m, 1H), 2.10-1.99 (m, 4H), 1.84-1.66 (m, 12H), 1.00-0.89 (m, 2H), 0.70-0.61 (m, 2H); MS (ES+) m/z 478.1 (M+1).
Reaction SMILES: [I:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][CH2:18][OH:19]>CN(C=O)C>[I:1][C:2]1[C:7]([O:8][CH2:17][CH2:18][OH:19])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: OCCBr
Reactant: Cc1ccc(O)c(I)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCO)c(I)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
To a stirred mixture of 2-iodo-6-methylpyridin-3-ol (530 g, 2.25 mol), Cs2CO3 (876 g, 2.7 mol) and DMF (2.5 L) was added 2-bromo-ethanol (560 g, 4.51 mol) dropwise at 0° C. The mixture was stirred at 90° C. overnight. The reaction was cooled and the solvent was removed in vacuo. The residue was diluted with water (2 L) and the aqueous solution was extracted with CH2Cl2 (3×350 mL). The combined organic layers were washed with brine (2×150 mL), dried over anhydrous Na2SO4 and concentrated to afford 2-(2-iodo-6-methylpyridin-3-yloxy)ethanol (630 g) as a brown solid which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]2([CH3:14])[CH3:13].[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[CH2:21][I:22])([O-:17])=[O:16]>ClC1C=CC=CC=1Cl>[I-:22].[N+:15]([C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[CH2:21][N+:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([CH3:14])([CH3:13])[C:7]=1[CH3:12])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(CI)cc([N+](=O)[O-])c1
Reactant: COc1ccc2c(c1)C(C)(C)C(C)=N2
Solvent: Clc1ccccc1Cl
Product: COc1ccc2c(c1)C(C)(C)C(C)=[N+]2Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Product: [I-]
Temperature: 75 °C
Yield: 52.5 %

Procedure:
To 5-methoxy-2,3,3-trimethyl-3H-indole (1.90 g) was added 3,5-dinitrobenzyl iodide (4.62 g) and 1,2-dichlorobenzene (10 ml). The mixture was heated at 75° C. for 3 hours, during which time an orange solid separated. The mixture was then cooled in an ice bath and the solid fraction collected by filtration; it was washed sequentially with dichlorobenzene and diethyl ether and dried under vacuum to give the product (2.62 g).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][OH:28].[OH-].[Na+]>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10](/[C:12](/[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[N:27]\[OH:28])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(/C(=N/O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a suspension of 1h (210 mg, 0.59 mmol) in 10 mL ethanol was added an aqueous solution (2 mL) of hydroxylamine hydrochloride (127 mg, 1.83 mmol). Then 2 mL 1 N NaOH was added dropwise to the reaction mixture and the mixture was stirred at 55° C. for 3 h. After completion of the reaction, the residue was absorbed on silica gel and purified by column chromatography to give compounds 2e-cis (85 mg) and 2e-trans (50 mg). 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.35 (s, 1H), 7.91-7.89 (m, 2H), 7.50-7.44 (br, 3H), 6.85 (s, 2H), 3.73 (s, 6H), 3.70 (s, 3H). MS (ESI) m/z 393.1 (M+Na)+; 368.9 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[C:10]([OH:16])(=[O:15])[CH2:11]C(O)=O.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1)[CH2:11][C:10]([OH:16])=[O:15]
Reactant: [NH4+]
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Solvent: CCO
Product: NC(CC(=O)O)c1cccc(Br)c1
Temperature: 0 °C
Yield: 69.8 %

Procedure:
Step Z (1). A mixture of 200 grams (1.08 mol) of 3-bromobenzaldehyde, 112 grams (1.08 mol) of malonic acid, and 166.5 g (2.16 mol) of ammonium acetate was suspended in 1.125 liters of absolute ethanol. The mixture was mechanically stirred and brought to reflux temperature, whereupon the solution clarified. The mixture was kept at reflux for 16 h, and a precipitate formed. The mixture was chilled to 0° C., and the solid product was collected by filtration and washed with cold ethanol to yield 184 grams (70%) of 3-amino-3-(3-bromophenyl)propanoic acid as a white solid which was carried forward without further purification or analytical characterization.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[C:9]1(C)[CH:14]=CC(S(O)(=O)=O)=C[CH:10]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:10][C:9]1([CH3:14])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccccc2O1
Temperature: 25 °C
Yield: 37840.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 10.0 grams (0.091 mole) of catechol in 100 mL of toluene and 100 mL of acetone was stirred and 0.01 gram (catalyst) of para-toluenesulfonic acid was added in one portion. Upon completion of additon the reaction mixture was warmed to reflux where it was maintained during a 48 hour period. After this time the reaction mixture was cooled to ambient temperature, then it was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using petroleum ether as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 3.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[C:13]([O-])(O)=[O:14].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:10]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]([CH2:5]3)[CH:3]1[N:2]=[C:13]=[O:14])[CH2:9]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=C([O-])O
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: O=C=NC1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A vigorously stirred mixture of 2-aminoadamantane hydrochloride (5.01 g, 26.7 mmol), CH2Cl2 (50 mL) and satd aq NaHCO3 (50 mL) was cooled in an ice bath. After 15 min, solid triphosgene (2.64 g, 8.9 mmol) was added. The mixture was stirred in the ice bath for 30 min and the layers were separated. The aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure to afford the title compound (3.55 g, 75%) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[N+:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)([O-:32])=[O:31]>>[N+:30]([C:33]1[CH:38]=[C:37]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[C:3]=2[CH3:29])[CH:36]=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc([N+](=O)[O-])c1)OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (3-nitrophenyl)boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 59%. Melting point: 209-210° C. (ethyl acetate-hexane).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.S(Cl)(Cl)=O.[N:16]1([C:21]2[CH:22]=[C:23]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[N:16]1([C:21]2[CH:22]=[C:23]([NH:24][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([I:1])[CH:3]=3)[CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: Nc1cc(-n2ccnc2)cc(C(F)(F)F)c1
Reactant: Cc1ccc(C(=O)O)cc1I
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2cc(-n3ccnc3)cc(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.3 %

Procedure:
To 3-Iodo-4-methylbenzoic acid (3.07 g, 0.0117 mol) was added thionyl chloride (10 mL) and refluxed for 2 h. The excess thionyl chloride was carefully removed and the resulting acid chloride was dried in vacuo for 2 h. The residue was then dissolved in DCM (anhydrous, 25 mL) and cooled on ice. To the cooled solution was added 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline 5 (3.46 g, 0.0152 mol) in DCM followed by the dropwise addition of diisopropylethylamine (8.2 mL, 0.047 mol). This was stirred at ambient temperature for 21 h. The white solid that separated was filtered and washed with water and dried to provide 4.65 g of product. Additional product could be obtained from the filtrate following concentration and purification by silica gel flash chromatography in EtOAc/hexanes.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]#N)=[N:10][CH:11]=1)([CH3:3])[CH3:2].[OH-:14].[K+].[OH2:16].Cl>C(O)C>[CH:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:16])=[O:14])=[N:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)OCc1ccc(C#N)nc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CC(C)OCc1ccc(C(=O)O)nc1
Temperature: 25 °C

Procedure:
In a 25 mL round-bottom flask was place ethanol (4 mL) solution of 5-isopropoxymethyl-pyridine-2-carbonitrile (1 g, 5.7 mmol). A solution of KOH (1.6 g, 28.36 mmol) in ethanol (6 mL) was added. The mixture was refluxed overnight and cooled down to room temperature. The resulted gel like mixture was added H2O and acidified with 6 mL of 10% HCl. The aqueous solution was extracted with EtOAc. The organic extracts were dried and concentrated to give the crude 5-isopropoxymethyl-pyridine-2-carboxylic acid. The crude product was further purified by column chromatography using 20% MeOH/CH2Cl2. 1H NMR (CDCl3, 400MHz) δ 1.26 (d, 6H), 3.74 (m, 1H), 4.63 (s, 2H), 7.94 (d, 1H), 8.21 (m, 1H), 8.60 (s, 1H). Exact mass calculated for C10H13NO3 195.09, found 196.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:24]>CC(C)=O>[Cl:24][C:9]1[C:10]2[C:5](=[C:4]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]ncc2c1C#Cc1ccncc1
Solvent: CC(C)=O
Product: COc1ccc2c(Cl)nncc2c1C#Cc1ccncc1
Temperature: 85 °C
Yield: 62 %

Procedure:
A suspension under N2 of 6-methoxy-5-pyridin-4-ylethynyl-2H-phthalazin-1-one (2.26 g,), prepared as described in example 141, in POCl3 (40 ml) was heated for 3 hours at 85° C., then dried. The residue was taken up in a saturated NaHCO3 solution up to alkalinity, then filtered and extracted with ethyl acetate. The solid was dissolved in a CH2Cl2/CH3OH/ethyl acetate mixture, dried over Na2SO4 and filtered. The solution was joined to the previous organic phase and dried to give a residue which was taken up in acetone and filtered yielding 1.5 g of the title compound (yield: 62%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])=[CH:20][CH:19]=1.Cl>ClCCCl.O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:25]2([OH:32])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH2:22][C:21]3[CH:34]=[CH:35][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:24]2=[O:33])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Reactant: N#Cc1ccc(O)cc1F
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (8.00 g, 58.3 mmol) in 1,2-dichloroethane (500 mL) and tetrahydrofuran (50 mL) was added isopropylmagnesium chloride (29.2 mL, 2.0 M solution in tetrahydrofuran, 58.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h. 1-(4-methoxybenzyl)-1H-indole-2,3-dione (15.0 g, 56.1 mmol) was added and the reaction mixture was stirred at reflux for 156 h. The mixture was cooled to 0° C. and 10% w/v hydrochloric acid was added. The phases were separated and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford 2-fluoro-4-hydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (12.30 g, 54%): 1H NMR (300 MHz, DMSO-d6) δ 8.05 (d, J=9.0 Hz, 1H), 7.34-7.32 (m, 2H), 7.17-7.11 (m, 1H), 6.91-6.76 (m, 7H), 4.78 (ABq, 2H), 3.72 (s, 3H); MS (ES+) m/z 404.9 (M+1).