Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][O:5][C:4](=O)[CH2:3]1.S(Cl)([Cl:10])=O.[CH3:12][OH:13]>>[CH3:12][O:13][C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[CH2:6][Cl:10]
Reactant: CO
Reactant: CC1COC(=O)C1
Reactant: O=S(Cl)Cl
Product: COC(=O)CC(C)CCl
Temperature: -10 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
4-Methyl-dihydro-furan-2-one (4 g, 39.95 mmol) was dissolved in MeOH (10 ml) and the solution was cooled to −10° C. Thionyl chloride (3.6 ml, 49.9 mmol) was added dropwise. The mixture was stirred at −10° C. for 2 hrs and hereafter for 16 hrs at room temperature. The mixture was concentrated in vacuo to give crude 4-Chloro-3-methyl-butyric acid methyl ester (4 g, 87%) which was used in the next step without further purification.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[CH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH3:36][S:33]([C:30]1[CH:29]=[CH:28][C:27]([C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[CH:32][CH:31]=1)(=[O:34])=[O:35]
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3[nH]2)cc1
Yield: 7.9 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.45 g, 8.6 mmol) in ethanol (8 mL), tetrahydrofuran (8 mL) and an aqueous sodium hydroxide solution (10%, 3 mL) was heated at 50° C. for 2 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (260 mg, 78%) which was used in the next step without further purification: LC/MS m/e calcd for C21H22N2O3S [M+H]+ 383.49, observed 383.4.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17]C=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>>[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:3]=1[CH2:2][C:1]([OH:9])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(O)Cc1ccc([N+](=O)[O-])cc1Cl
Yield: 87.2 %

Procedure:
The title compound was prepared using the method of example 110, starting with diethyl malonate (Aldrich, 30.5 mL, 200 mmol), 3,4-dichloronitrobenzene (Aldrich, 19.2 g, 100 mmol), cesium carbonate (Aldrich, 81.5 g, 250 mmol) and 150 mL of aqueous 6N HCl solution. 18.8 g (87%) of compound 111 was obtained as pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[CH:13]([N:16]([CH:19]([CH3:21])C)[CH2:17]C)([CH3:15])C.C1C[O:25]CC1.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]([C:17]([N:16]1[CH2:13][CH2:15][CH2:21][CH2:19]1)=[O:25])[CH2:5][C:6](=[O:12])[NH:7]2
Reactant: C1CCOC1
Reactant: O=C1CNc2c(F)cccc2N1
Reactant: CCN(C(C)C)C(C)C
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1CN(C(=O)N2CCCC2)c2c(F)cccc2N1
Reaction time: 2 h

Procedure:
To 1.20 g of 5-fluoro-1,2,3,4-tetrahydroquinoxalin-2-one (EXAMPLE 24), 1.26 ml of diisopropylethylamine, and 15 ml of THF at 0° is added 6.0 ml of 1.2M phosgene in toluene. The ice bath is removed and the reaction is stirred for 2 h, at which time an additional 0.2 ml of diisopropylethylamine and 1.0 ml of phosgene solution are added. After an hour, 1.26 ml of diisopropylethylamine and 0.60 ml of pyrrolidine are added and the reaction is stored in the freezer over the weekend. The reaction is then partitioned between ethyl acetate and aq. sodium bicarbonate and saline. The organic layers are dried over magnesium sulfate and concentrated and the crude product is chromatographed on silica gel (250 ml) using ethyl acetate/dichloromethane (30/70) to give 1.47 g of product. Recrystallization from ethyl acetate/ethyl ether/hexane gives product in two crops; mp 186.5°-187.5°; MS (m/z) at 263; IR (mineral oil) 1692, 1658, 1407, 1604, 1623 cm-1 ; NMR (CDCl3) 1.85, 3.28, 4.27, 6.68, 6.82, 7.04, 8.41 δ.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>O1CCCC1.O.CCOCC>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:29])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccnc4)c3C2=O)C(=O)N1
Yield: 79.3 %

Procedure:
A stirred mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.09 g, 4.0 mmol) and nicotinoyl chloride hydrochloride (1.42 g, 8.0 mmol) in tetrahydrofuran (60 ml) was heated to reflux for 22 h. The suspension was filtered and washed with tetrahydrofuran (20 ml) and ether (10 ml) to yield a white solid. The solid was slurried in pH 7 buffer (40 ml) and ether (30 ml) for 1 h. The suspension was filtered and washed with water (20 ml) and ether (20 ml) to N-[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]-3-pyridylcarboxamide as a white solid (1.2 g, 79% yield): mp, 176-178° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H, CHH), 2.49-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.3, 12.5 Hz, 1H, NCH), 7.64 (dd, J=4.9, 7.9 Hz, 1H, Ar), 7.71 (d, J=7.3 Hz, 1H, Ar), 7.92 (t, J=7.8 Hz, 1H, Ar), 8.29-8.34 (m, 1H, Ar), 8.45 (d, J=8.2 Hz, 1H, Ar), 8.83 (dd, J=1.2, 4.8 Hz, 1H, Ar), 9.15 (d, J=1.7 Hz, 1H, Ar), 10.55 (s, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 49.00, 119.06, 119.34, 123.91, 127.36, 129.17, 131.55, 135.24, 135.94, 136.20, 148.47, 152.95, 163.85, 166.59, 167.54, 169.69, 172.72; Anal Calcd for C19H14N4O5+0.13H2O: C, 59.95; H, 3.78; N, 14.72; H2O, 0.62. Found: C, 59.83; H, 3.66; N, 14.68; H2O, 0.64.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[OH2:16]>>[F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]([C:11]([OH:10])=[O:12])[C:7]=1[C:8]([OH:16])=[O:9]
Reactant: O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Product: O=C(O)c1c(F)c(F)c(F)c(F)c1C(=O)O
Yield: 82 %

Procedure:
After mixing 110 g (0.5 mol) of tetrafluorophthalic anhydride and 150 ml of water, the mixture was refluxed for about one hour. After cooling the reaction mixture, crystals deposited were collected by filtration and dried to provide 97.6 g (yield 82%) of tetrafluorophthalic acid as white crystals. If necessary, the crystals could be further purified by recrystallization from an aqueous 6N hydrochloric acid solution.
Reaction SMILES: [F:1][C:2]([F:14])([C:7]1[N:8]=[CH:9][NH:10][C:11](=[O:13])[CH:12]=1)[C:3]([F:6])([F:5])[F:4].[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:12]1[C:11](=[O:13])[NH:10][CH:9]=[N:8][C:7]=1[C:2]([F:1])([F:14])[C:3]([F:6])([F:5])[F:4]
Reactant: O=c1cc(C(F)(F)C(F)(F)F)nc[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc(C(F)(F)C(F)(F)F)c1Cl
Temperature: 25 °C

Procedure:
A solution of 4-pentafluoroethylpyrimidin-6-one (0.4 g) and N-chlorosuccinimide (0.27 g) in dry dimethylformamide (5 ml) was heated to 80° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was poured into water, and extracted into ethyl acetate. The organic layer was dried, over anhydrous magnesium sulphate, filtered, and evaporation of the solvent under reduced pressure gave a brown oil. Recrystallisation from water gave 5-chloro-4-pentafluoroethylpyrimidin-6-one
Reaction SMILES: NC1C=CC(O[CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=CC=1.[CH2:22]([N:26]1[CH:30]=[C:29]([C:31]2[S:35][CH:34]=[C:33]([C:36]([OH:38])=O)[CH:32]=2)[CH:28]=[N:27]1)[CH:23]([CH3:25])[CH3:24].C(OC([N:49]1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[CH2:22]([N:26]1[CH:30]=[C:29]([C:31]2[S:35][CH:34]=[C:33]([C:36]([NH:49][C@@H:7]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]3)=[O:38])[CH:32]=2)[CH:28]=[N:27]1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Cn1cc(-c2cc(C(=O)O)cs2)cn1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Product: CC(C)Cn1cc(-c2cc(C(=O)N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)cs2)cn1

Procedure:
The title compound was prepared as described in Example 1A, substituting (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 5-(1-isobutyl-1H-pyrazol-4-yl)thiophene-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: C(OC(=O)[N:7]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)[C:8]1[C:9]2[N:10]([CH:23]=[CH:24][N:25]=2)[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:12][N:13]=1)(C)(C)C.Br[C:40]1[CH:45]=[C:44]([CH3:46])[N:43]=[C:42]([O:47][Si](C(C)(C)C)(C)C)[CH:41]=1.CC([O-])=O.[K+]>O1CCOCC1>[CH3:46][C:44]1[NH:43][C:42](=[O:47])[CH:41]=[C:40]([C:11]2[N:10]3[CH:23]=[CH:24][N:25]=[C:9]3[C:8]([NH:7][C:26]3[CH:27]=[CH:28][C:29]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:13][CH:12]=2)[CH:45]=1
Reactant: Cc1cc(Br)cc(O[Si](C)(C)C(C)(C)C)n1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(B2OC(C)(C)C(C)(C)O2)n2ccnc12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Half of the solution prepared in Step 3 and 4-bromo-2-(tert-butyldimethylsilyloxy)-6-methylpyridine (30 mg, 0.10 mmol) are mixed and diluted with dioxane (0.15 mL). KOAc (15 mg, 0.15 mmol) and Pd(dppf)Cl2DCM (2 mg, 0.0025 mmol) are added and the system is flushed with N2 and heated at 80° C. for 2.5 h. The mixture is cooled to rt, diluted with DCM (5 mL) and MeOH (1 mL) and filtered through celite. The solvents are evaporated, the residue is suspended in DCM (2 mL) and TFA (0.5 mL) is added, causing the solid to dissolve. The solution is stirred at rt overnight and the solvents are then evaporated. The residue is purified by preparative HPLC to afford the title compound as a yellow solid. LCMS: Rt=0.84 min (100%), m/z (ESI) 403 (M+H)+.
Reaction SMILES: ClS(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].C(OCC)(=O)C>CCCCCC>[F:6][C:7]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:10]=[C:9]2[C:8]=1[C:19](=[O:21])[CH2:18][CH2:17]2
Reactant: O=C(O)CCc1ccc(C(F)(F)F)c(F)c1
Agent: O=S(=O)(O)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(C(F)(F)F)c(F)c21
Temperature: 0 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Chlorosulfonic acid (12.6 mL) was added to a stirred solution of 3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid (I-77b: 1.0 g, 4.2707 mmol). The resulting mixture was stirred for 5 hours at 0° C. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was quenched with ice water and extracted with chloroform (2×150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (5% ethyl acetate in hexane), afforded 550 mg of the product (58.9% yield).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O:14][B:15](OC(C)C)[O:16]C(C)C)(C)C.C([Li])CCC>C1COCC1>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([B:15]([OH:16])[OH:14])[C:7]1=2
Reactant: Brc1cccc2ccsc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2ccsc12
Temperature: -70 °C
Reaction time: 1 h
Yield: 75218.4 %

Procedure:
Combine 7-bromobenzo[b]thiophene (300 g, 1.41 mmol) and tri-isopropylborate (403.6 g, 2.15 mmol) in anhydrous THF (4 L) in a 12-L Morton flask fitted with a mechanical stirrer and cool under nitrogen in a dry-ice/acetone bath to −70° C. Add n-butyl lithium (1.6 M in hexane, 714 g, 1.68 mmol) dropwise at such a rate as to keep the internal temperature less than −67.5° C. After the addition is complete allow the reaction mixture to stir at this temperature for 1 h. Remove the cooling bath and slowly add 4 L of water, which causes the temperature to rise to about −5° C. Next, add concentrated HCl (75 mL) until the pH of the solution is about pH=2. Allow the slurry to stir for 1 h. Add sufficient 5 N aqueous NaOH to adjust the pH of the mixture to about pH=12 and transfer to a 22-L bottom-drop funnel Separate and save the lower aqueous layer. Dilute the upper organic layer with 4 L of methyl-tert-butyl ether and extract with 1 L of 5 N aqueous NaOH. Separate the aqueous layer, combine with the previous aqueous extract and place back in the separatory funnel Wash the aqueous layer with additional methyl-tert-butyl ether (4 L). Again, separate the aqueous layer and transfer to a 12-L, 3-neck round bottom flask fitted with a mechanical stirrer. Cool the solution to +5° C. with an ice-water bath. Add concentrated HCl slowly until the pH of the solution is about pH=2. Stir the mixture for 30 minutes and then filter off the resulting solid. Rinse the solid on the funnel twice with 2 L of water and allow to air-dry for 30 min. Place the solid in a vacuum oven at 50° C. and dry under vacuum overnight. The dried solid is slurried with 2 L of n-heptane for 30 min to remove the yellow color. Again filter off the solid, air-dry for 30 min and then vacuum-dry at 40° C. overnight to give the title compound (188.8 g, 75%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 7.86 (d, J=8 Hz, 1H), 7.49-7.57 (m, 2H), 7.30-7.39 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:30](O)[CH3:31]>>[CH2:30]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([NH:1][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1)[CH3:31]
Reactant: CCO
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1Nc1ccccc1
Reactant: BrCc1ccccc1
Product: CCOC(=O)c1cc(NCc2ccccc2)c(Nc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
A mixture of 3 -amino-4-anilino-5-sulphamyl-benzoic acid (2 g), benzyl bromide (3 g), and ethanol (50 ml 99.9%) was refluxed for 8 hours. After cooling, the ethyl-4-anilino-3-benzylamino-5-sulphamyl-benzoate crystallized and was collected by suction. After recrystallization from ethanol the melting point was 160°-161° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])(=O)[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].C(CC(O)C([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(O)=O.[C:33](OC(=O)C1C=CC=CC=1)(=[O:40])C1C=CC=CC=1.C([O-])(=O)C1C=CC=CC=1>>[CH3:3][C:2]1[C:33](=[O:40])[C:14]2[C:6](=[C:7]([C:8]([OH:10])=[O:9])[CH:11]=[CH:12][CH:13]=2)[O:5][C:1]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCC(=O)Oc1ccccc1C(=O)O
Reactant: O=C(O)CC(O)C(=O)c1ccccc1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc2c1=O

Procedure:
Thus, 2-propionyloxybenzoic acid is heated with anhydrous aluminum chloride in a Fries rearrangement and the resulting 3-carboxy-2-hydroxypropiophenone is heated with benzoic anhydride and alkali benzoate at 180° to 190° C. to afford 3-methylflavone-8-carboxylic acid derivatives.
Reaction SMILES: [F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].B(OC)(OC)OC.CSC.B.CO>C1COCC1>[F:1][C:2]1[C:10]([I:11])=[C:9]([CH3:12])[CH:8]=[CH:7][C:3]=1[CH:4]=[O:5]
Reactant: Cc1ccc(C(=O)O)c(F)c1I
Agent: B
Agent: COB(OC)OC
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1ccc(C=O)c(F)c1I
Reaction time: 0.25 h

Procedure:
To a solution of 2-fluoro-3-iodo-4-methylbenzoic acid (2.00 g, 7.1 mmol) in anhydrous THF (10 mL) was added trimethyl borate (0.80 mL, 7.1 mmol) at RT. The resulting mixture was stirred for 15 min, then cooled in an ice bath and treated with borane-dimethyl sulfide (6.4 mL of 2.0 M solution in THF, 12.8 mmol) slowly. The reaction mixture was stirred for 4 h at RT. Methanol (0.5 mL) was added dropwise at RT. After stirring for 30 min, the reaction mixture was concentrated under vacuum. The residue was diluted with of ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate followed by brine. The resulting organic solution was then dried over magnesium sulfate and concentrated under reduced pressure to give 2-fluoro-3-iodo-4-methylphenyl)methanol as an off-white amorphous solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][C:22]1[CH:26]=[C:25]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[NH:24][C:23]=1[CH:35]=O>N1CCCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:23]4[NH:24][C:25]([C:27]([N:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)=[O:28])=[CH:26][C:22]=4[CH3:21])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=O
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CCOCC2)[nH]c1C=C1C(=O)N(C)c2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 90 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (116 mg, 0.4 mmol), 3-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde (130 mg) and piperidine (1 drop) in ethanol (2 mL) was stirred at 90° C. for 2 hours. The reaction was diluted with water and the precipitate was collected by vacuum filtration, washed with water, ethyl acetate and hexane and dried to give 141 mg (74%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.42 (br s, 1H, NH), 9.29 (br s, 1H), 8.38 (s, 1H), 7.72 (m, 1H), 7.34-7.41 (m, 3H), 6.6 (s, 1H), 3.67 (m, 4H, 2×CH2), 3.65 (m, 4H, 2×CH2), 3.29 (s, 3H, CH3), 2.20 (s, 3H, CH3). MS 497 [M++1].
Reaction SMILES: C([Li])CCC.[CH:6](=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]>>[F:13][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[CH:18][C:19]=1[CH:6]([OH:12])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Fc1ccccc1F
Reactant: CCCCCC=O
Agent: [Li]CCCC
Product: CCCCCC(O)c1cccc(F)c1F

Procedure:
Quantities: n-butyllithium (31 cm3, 10.0M in hexanes, 0.31 mol), hexanal (31.5 g, 0.31 mol) and 1,2-difluorobenzene (35.5 g, 0.31 mol). The experimental procedure was as described in Example 16.
Reaction SMILES: OC[C@@H](N[C:11](=[O:25])[C@@:12]([CH3:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:27]>O1CCOCC1>[CH3:24][C@:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]([OH:25])=[O:27]
Reactant: O=S(=O)(O)O
Reactant: CC(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)CC[C@@](C)(C(=O)O)c1ccccc1
Yield: 97 %

Procedure:
To a solution of Example 39A (4.26 g, 12.55 mmol) in 1,4-dioxane (15 mL) was added 4M sulfuric acid (15 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo and partitioned between water and methylene chloride. The methylene chloride layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.70 g, 97%). 1H NMR (300 MHz, CDCl3): δ ppm 0.88 m, 6 H) 1.09 m, 2 H) 1.52 m, 4 H) 1.99 m, 2 H) 7.35 m, 5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([F:13])[CH:3]=1.CC1CCCN(C)C1(C)C.[Li].CN([CH:28]=[O:29])C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:28]=[O:29])=[C:4]([F:13])[C:5]([Si:9]([CH3:10])([CH3:12])[CH3:11])=[C:6]([F:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)c1c(F)cc(Cl)cc1F
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: C[Si](C)(C)c1c(F)cc(Cl)c(C=O)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A solution of 1-chloro-3,5-difluoro-4-trimethylsilylbenzene (1.5 g, 6.8 mmol) in THF (10 mL) was added to a solution of lithium tetramethylpiperdine (14 mmol) in THF (15 mL) at −75° C. The solution was stirred for 2 hours then DMF (1.5 g, 20 mmol) was added and the solution allowed to warm to ambient temperature. The reaction was quenched with a saturated solution of ammonium chloride (25 mL) and extracted with ethyl ether (2×25 mL) and the combined extracts dried (sodium sulfate) and concentrated. The residue was purified by chromatography (hexanes) to give 6-chloro-2,4-difluoro-3-trimethylsilylbenzaldehyde (1.4 g, 5.6 mmol): LC/MS (m/z=248).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[CH3:25])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CCOC(C)=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>[CH3:26][N:27]1[CH:31]=[C:30]([C:2]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:15][C:14]=4[CH3:25])[N:10]=[CH:11][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH:29]=[N:28]1
Reactant: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
To a solution of 8-chloro-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 113, 12 mg, 0.034 mmol) in 1,4-dioxane (2 mL) and water (1 mL) was added 1-methylpyrazole-4-boronic acid pinacol ester (14 mg, 0.068 mmol), cesium carbonate (17 mg, 0.051 mmol) and Pd(PPh3)4 (2 mg, 1.71 umol). The reaction mixture was heated to 100° C. under microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-15% MeOH in EtOAc to give the title compound (7 mg, 52%).
Reaction SMILES: [Na].[OH:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH3:12]>C(O)C>[CH2:11]([O:2][C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:12]
Reactant: Cc1ncccc1O
Reactant: CCBr
Agent: [Na]
Solvent: CCO
Product: CCOc1cccnc1C

Procedure:
Sodium metal (46.2 g) was dissolved in absolute ethanol (1 l) with stirring under nitrogen. 3-Hydroxy-2-methylpyridine (200 g prepared as described in C.A. 48, P4597 h) was added. The mixture was stirred at ambient temperature for 30 minutes and then a solution of bromoethane (150 ml) in absolute ethanol (100 ml) was added. The mixture was boiled under reflux for 5 hours then cooled and filtered. The filtrate was evaporated and the residue partitioned between dichloromethane and water. The organic layer was separated off and the aqueous layer extracted with dichloromethane. The combined organic extracts were dried and evaporated. The residue was distilled to give 3-ethoxy-2-methyl-pyridine b.p. 80°-84° C. (20 mmHg).