Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1.C(N(C(C)C)CC)(C)C.[CH3:64][C:65]1[O:69][N:68]=[C:67]([C:70](O)=[O:71])[CH:66]=1>C(Cl)Cl>[Cl:27][C:28]1[C:29]([F:54])=[C:30]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[C:42]([O:45][CH:46]4[CH2:47][CH2:48][N:49]([C:70]([C:67]5[CH:66]=[C:65]([CH3:64])[O:69][N:68]=5)=[O:71])[CH2:50][CH2:51]4)[CH:43]=3)[N:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: Cc1cc(C(=O)O)no1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)c2cc(C)on2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.6 %

Procedure:
HATU (0.31 g) was added to a solution of N-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride (300 mg), diisopropylethylamine (0.45 ml) and 5-methyl-3-isoxazolecarboxylic acid (0.127 g) in methylene chloride (9 ml). The resulting mixture was stirred at room temperature for 2.5 hrs. Methylene chloride (20 ml) was added and the organics washed with aqueous sodium hydroxide (2M, 30 ml) and water (30 ml). The crudes were then purified by flash column chromatography eluting with methanol/methylene chloride (2.5/97.5). Fractions containing the desired product were evaporated to a white foam which was triturated with diethyl ether (20 ml) to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-({1-[(5-methylisoxazol-3-yl)carbonyl]piperidin-4-yl}oxy)quinazolin-4-amine as a white solid (0.115 g). 1H NMR Spectrum: (DMSO d6 373K) 1.87 (m, 2H), 2.08 (m, 2H), 2.48 (s, 3H), 3.61 (m, 2H), 3.89 (m, 2H), 3.96 (s, 3H), 4.80 (m, 1H), 6.40 (s, 1H), 7.22 (m, 1H), 7.22 (s, 1H), 7.42 (m, 1H), 7.59 (m, 1H), 7.90 (s, 1H), 8.39 (s, 1H), 9.26 (br s, 1H); Mass Spectrum: (M+H)+ 512.
Reaction SMILES: O.C([O:9][C:10](=[O:26])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:25])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1>[Pd].CO>[C:19]1([CH2:18][CH2:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([OH:26])=[O:9])=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.9 %

Procedure:
10% Pd-C (3.00 g) was added to a 1% water-containing methanol solution (200 ml) of N-(3-phenylpropionyl)-L-proline benzyl ester (25.59 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. After the catalyst was filtered off, the filtrate was concentrated to obtain 18.93 g of N-(3-phenylpropionyl)-L-proline.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](O)=O)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:21][CH2:22][C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([OH:27])[CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[O:27][C:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([CH2:24][CH2:25][CH3:26])[CH2:22][N:21]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1c(-c2ccccc2)nc2ccccc2c1C(=O)O
Reactant: CCCC(O)(CN)c1ccccc1
Product: CCCC1(c2ccccc2)CN=C(c2c(C)c(-c3ccccc3)nc3ccccc23)O1

Procedure:
Following essentially the procedure of Example 39, (3-methy-2-phenylquinolin-4-yl)carboxylic acid and 1-amino-2-phenyl-2-pentanol are converted to the titled compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1.[F-:16].[Cs+]>CS(C)=O.O>[F:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([O:14][CH3:15])=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1ccc2c(Cl)ncc(OC)c2c1
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2c(F)ncc(OC)c2c1
Temperature: 145 °C
Yield: 20.1 %

Procedure:
To a solution of 1-chloro-4,6-dimethoxyisoquinoline (1.5 g, 6.71 mmol) in DMSO (15 ml) was added cesium fluoride (4 g, 26.8 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (280 mg, 20.15%) as white solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.99-7.97 (d, J=8 Hz, 1H), 7.44-7.39 (m, 2H), 7.27-7.11 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H); 19F NMR: δ ppm −79.32 (1 F); MS: MS m/z 208.0 (M++1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[N:19]1([C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:2]3[C:11]4[C:6](=[CH:7][C:8]5[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=5[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:26][CH:27]=2)[CH2:20][CH2:21][CH2:16][CH2:17][CH2:18]1
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: Clc1ccnc2cc3ccccc3cc12
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc2cc3c(Nc4ccc(N5CCCCC5)cc4)ccnc3cc2c1
Yield: 84.9 %

Procedure:
4-Chlorobenzo[g]quinoline (7b) (50 mg, 0.23 mmol), 4-(1-piperidino) aniline (50 mg, 1.2 equivalents), bis(1,5-cyclooctadiene)nickel(O) (Ni(COD)2 1.5 mg, 0.02 equivalents), 1,1′-bis(diphenylphosphino)ferrocene (DPPF, 5 mg, 0.04 equivalents) and sodium t-butoxide (31 mg, 1.4 equiv) in 2.5 mL of dry toluene were refluxed under a 5 nitrogen atmosphere until observed complete by TLC. The mixture was concentrated in vacuo and purified by flash chromatography (gradient: 50:50:2 to 60:40:2 hexane: EtOAc:Et3N) to provide 69 mg of clean N-[4-(1-piperidinyl)phenyl]benzo[g]quinolin-4-amine (8), 85% yield.
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:4]=[C:5](/[CH:23]=[C:24](\[F:35])/[C:25]([NH:27][O:28]C2CCCCO2)=[O:26])[CH:6]=[N:7][C:8]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:11]1.CCOC(C)=O>CCO>[ClH:2].[ClH:1].[Cl:2][C:3]1[CH:4]=[C:5](/[CH:23]=[C:24](\[F:35])/[C:25]([NH:27][OH:28])=[O:26])[CH:6]=[N:7][C:8]=1[NH:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:11]1
Reactant: O=C(NOC1CCCCO1)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(NO)/C(F)=C/c1cnc(N[C@@H]2CCCN(CC3CCCCC3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2M ethanolic hydrogen chloride (2.0 mL) was added to the solution of (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.5 g) in EtOH (5 ml) and the mixture was stirred at ambient temperature for 3 hrs. To the reaction mixture was added AcOEt and isolated precipitate was collected by filtration to give (2Z)-3-(5-chloro-6-{[(3R)-1-(cyclohexylmethyl)-3-piperidinyl]amino}-3-pyridinyl)-2-fluoro-N-hydroxyacrylamide dihydrochloride (0.28 g),
Reaction SMILES: S(=O)(=O)(O)O.C([NH:13][C:14]1[CH:19]=[C:18]([C:20]2[S:24][C:23]([CH2:25][CH3:26])=[N:22][C:21]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:17]=[CH:16][N:15]=1)C1C=CC=CC=1.[OH-].[Na+]>>[CH2:25]([C:23]1[S:24][C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:13])[CH:19]=2)=[C:21]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[N:22]=1)[CH3:26]
Reactant: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(NCc3ccccc3)c2)s1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(-c2ccc(F)cc2)c(-c2ccnc(N)c2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
With ice cooling, 23 ml of conc. sulphuric acid are added to 4.75 g (10.9 mmol) of N-benzyl-4-[2-ethyl-4-(4-fluorophenyl)-1,3-thiazol-5-yl]pyridine-2-amine, and the reaction mixture is stirred at room temperature for 30 min. The reaction mixture is stirred into 100 ml of ice-water, the pH is adjusted to 10 using concentrated aqueous sodium hydroxide solution and the mixture is extracted with dichloromethane (3×100 ml). The combined organic phases are dried over MgSO4 and freed from the solvent under reduced pressure. The residue is triturated with MTBE and filtered off. The product obtained is 2.80 g (82%) of a beige solid; log P (pH2.7): 1.29 with MS (ESI): 300.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:4][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[C:6]=1[NH2:7].[CH2:22](C([Sn])=C(CCCC)CCCC)[CH2:23]CC>C1(C)C=CC=CC=1.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>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:3]2[C:2]([CH:22]=[CH2:23])=[C:6]([NH2:7])[N:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH3:14])[N:4]=2)=[CH:16][CH:17]=1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Cc1ccccc1-n1nc(-c2ccc(F)cc2)c(Br)c1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(-c2ccc(F)cc2)nn(-c2ccccc2C)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a solution of 4-bromo-3-(4-fluorophenyl)-1-(2-methylphenyl)-1H-pyrazol-5-amine (200 mg, 0.58 mmol) in toluene (10 mL) was added tributylvinyl tin (0.33 mL, 366 mg, 1.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol). The reaction mixture was heated to reflux and stirred for 16 h. After cooling to rt, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL), washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. Silica gel flash chromatography of the residue using 10% EtOAc/Hex afforded 3-(4-fluorophenyl)-1-(2-methylphenyl)-4-vinyl-1H-pyrazol-5-amine (87 mg, 51%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>N1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:22]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[O:28])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(O)C=CC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Reaction time: 8 h
Yield: 50.5 %

Procedure:
A solution of 5-chloro-3-(4-hydroxypiperidinocarbonylmetyl)benzothiazolin-2-one (3.2 g) in dry pyridine (2.5 ml) and dry tetrahydrofuran (50 ml) was cooled, to which a solution of maleic anhydride (1.0 g) in dry tetrahydrofuran (5 ml) was gradually dropwise added under stirring. The mixture was refluxed for two hours and then left overnight. The solvent was evaporated off under vacuum from the reaction mixture, and the residue was dissolved in 5% aqueous sodium bicarbonate (20 ml). The solution was cooled and adjusted to pH 2 with 1% hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and then subjected to chromatography on silica gel eluting with ethanol/benzene (1:1). The solvent was evaporated off under vacuum from the eluate at below 50° C. The residue was recrystallized from isopropyl alcohol to yield the title compound as colorless crystals (2.1 g). m.p. 197°-198° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(F)(F)F)cc1Cl
Yield: 1.5 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2-chloro-4-(trifluoromethyl)phenylboronic acid (available from Combi-Blocks Inc.; 100 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′-chloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-trifluoromethyl-biphenyl-2-carboxylic acid (2 mg, 2%). LCMS analysis indicated that the material was ˜100% pure, as measured by UV at 214 nm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH:12]([OH:35])[C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])[C:4]=12)#[CH:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([C:12]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=3[F:19])=[O:35])[C:4]=12)#[CH:2]
Reactant: C#Cc1ccnc2[nH]cc(C(O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.1 %

Procedure:
To N-{3-[(4-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide (8, 0.146 g, 0.288 mmol) dissolved in 15 mL of tetrahydrofuran, Dess-Martin periodinane (0.122 g, 0.288 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer separated and washed with brine, then dried over magnesium sulfate and filtered. The filtrate was concentrated under vacuum and the resulting material was purified by silica gel column chromatography, eluting with 0 to 30% ethyl acetate and hexane. The appropriate fractions were combined and the solvent removed under vacuum, and this material was further purified by silica gel column chromatography, eluting with 0 to 15% ethyl acetate and hexane. The appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (P-0001, 121 mg). MS (ESI) [M+H+]+=506.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[F:14].[O:15]1CCC[CH2:16]1.[Li]CCCC>CN(C)C=O>[F:14][C:3]1[C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:16]=[O:15]
Reactant: C1CCOC1
Reactant: COc1ccc(Br)c(F)c1C(F)(F)F
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: COc1ccc(C=O)c(F)c1C(F)(F)F
Temperature: -78 °C

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzene (380 mg, 1.39 mmol, 1.00 equiv), tetrahydrofuran (5.0 mL). This was followed by the addition of n-BuLi (2.5M) (0.62 mL, 1.10 equiv) dropwise with stirring at −78° C. The mixture was stirred for 1 h at −78° C. To this was added N,N-dimethylformamide (1.0 mL) and the resulting solution was stirred for 30 min at −78° C. in a liquid nitrogen bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 2 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined and dried in an oven under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4). This resulted in 0.140 g (45%) of 2-fluoro-4-methoxy-3-(trifluoromethyl)benzaldehyde as a light yellow solid. Mass spectrum (GC, m/z): Calcd. for C9H6F4O2, 222.0 (M). found 222.0.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:15]=[C:14]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Yield: 76.4 %

Procedure:
A mixture of 1-(7-ethoxycarbonylheptyl)-2,4,5-triphenyl-imidazole (13.6 g), 2N aqueous sodium hydroxide (300 ml) and ethanol (200 ml) was heated at reflux for 2.5 h. The ethanol was removed in vacuo and the reaction mixture was acidified with 2N aqueous hydrochloric acid. The aqueous solution was extracted with ethyl acetate (4×200 ml) and the organic extracts were combined, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from ethanol gave 1-(7-carboxyheptyl)-2,4,5-triphenylimidazole (9.77 g, 76.4%) as a white solid, m.p. 162°; Found C, 79.43; H, 6.93; N, 6.36%; C29H30N2O2 requires: C, 79.42; H, 6.90; N, 6.39%.
Reaction SMILES: C([C@](C(O)=O)(O)[C@](C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1.[C:31]1([C:37]2([CH2:42][CH2:43][OH:44])[CH2:41][CH2:40][NH:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:59]([N:62]2[CH:66]=[N:65][N:64]=[N:63]2)=[CH:58][C:54]=1[C:55](Cl)=[O:56]>C(OCC)(=O)C.O>[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:59]([N:62]2[CH:66]=[N:65][N:64]=[N:63]2)=[CH:58][C:54]=1[C:55]([N:39]1[CH2:40][CH2:41][C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([CH2:42][CH2:43][OH:44])[CH2:38]1)=[O:56]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)Cl
Reactant: OCCC1(c2ccccc2)CCNC1
Agent: COc1ccc(C(=O)[C@@](O)(C(=O)O)[C@](O)(C(=O)O)C(=O)c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCO)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Combine (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt (56.0 g, 92.1 mmol), sodium carbonate (19.5 g, 184 mmol) in ethyl acetate (2 L) and water (2 L). Cool to about 0° C. in an ice bath. After 30 minutes, slowly add portionwise 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (92.1 mmol). After the addition is complete, warm to ambient temperature. After 1 hour, dilute the reaction mixture ethyl acetate and extract with water, 1M aqueous hydrochloric acid solution, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound. Rf =0.48 (9/1 dichloromethane/methanol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].CCN(CC)CC.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:30][C:29]1[CH:31]=[CH:32][C:26]([S:23]([O:1][CH2:2][CH2:3][CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCN2C(=O)c3ccccc3C2=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
To a solution of 2-(3-hydroxypropyl) isoindoline-1,3-dione (1.8 g, 8.77 mmol) in CH2Cl2 (30 mL, 3 mL/mmol) was added Et3N (2 mL, 13.1 mmol). After stirring for 10 min at 0° C., tosylchloride (2 g, 10.5 mmol) was added and the reaction was stirred for 12 h at RT. The reaction was quenched with water and extracted with CH2Cl2 (2×50 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-(1,3-dioxoisoindolin-2-yl)propyl 4-methylbenzenesulfonate (3 mg, 96%). Observed mass (M+1): 360.1.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]([F:34])([F:33])[C:17]([C:19]1[S:23][C:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])=[CH:21][CH:20]=1)=[O:18]>C(O)=O>[F:34][C:16]([F:15])([F:33])[C:17]([C:19]1[S:23][C:22]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)[CH2:6][CH2:5]2)=[O:28])=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Solvent: O=CO
Product: N#Cc1ccc(N2CCN(C(=O)c3cccc(-c4ccc(C(=O)C(F)(F)F)s4)c3)CC2)nc1
Yield: 32 %

Procedure:
This compound was synthesized from 6-(piperazin-1-yl)nicotinonitrile and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described for example 37 step 3 (60 mg, yield 32%). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J=2.1 Hz, 1H), 8.19-8.17 (dd, J=4.0 Hz, J=1.5 Hz, 1H), 8.00-7.89 (m, 4H), 7.64-7.61 (m, 1H), 7.57-7.55 (m, 1H), 6.96-6.94 (t, J=9.2 Hz, 1H), 3.82-3.74 (m, 6H), 3.47 (m, 2H). MS (ESI) m/z: Calculated for C23H17F3N4O2S: 470.10. found: 515.6 (M+HCOOH)−
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[CH3:17])[N:7]=[C:6]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]1[CH3:24])[N:5]=2.[NH:25]1[CH:29]=[CH:28][C:27](B(O)O)=[N:26]1.CCN(CC)CC>C(COC)OC.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:24][C@H:19]1[CH2:20][O:21][CH2:22][CH2:23][N:18]1[C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([C:29]3[CH:28]=[CH:27][NH:26][N:25]=3)[NH:3]2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:7]=1
Reactant: OB(O)c1cc[nH]n1
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]c(Br)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]c(-c3cc[nH]n3)nc12
Temperature: 85 °C
Yield: 39.2 %

Procedure:
8-Bromo-2-((S)-3-methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (50 mg, 126 μmol) was dissolved in dimethoxyethane (2 mL) and water (0.2 mL), followed by addition of 1H-pyrazole-3-ylboronic acid (21.1 mg, 189 μmol), PdCl2(dppf) (9.21 mg, 13 μmol) and NEt3 (53 μl, 378 μmol) under argon. The reaction mixture was heated to 85° C. for 23 hours. The reaction mixture was then diluted with EtOAc, the organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (12 g SiO2, EtOAc) to give the product (19 mg, 39% yield).