Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[O:11]1[CH:12]=[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH2:1][Br:13])[CH:9]=[N:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(-c2cnoc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: BrCc1cccc(-c2cnoc2)c1
Reaction time: 3 h
Yield: 76.2 %

Procedure:
185 mg of 4-(3-methylphenyl)isoxazole [see J. Heterocyclic Chem., 11, 51 (1974); and J. Chem. Soc., Perkin II, 1121 (1977)] was dissolved in 8 ml of carbon tetrachloride, and 206 mg of N-bromosuccinimide and a catalytic amount of benzoyl peroxide were added. The mixture was refluxed with stirring for 3 hours. The insoluble material was separated by filtration and the solvent was evaporated. The residue was purified by silica gel column chromatography Wakogel C-200, 30 g; eluting solvent: hexane/ethyl acetate=10/1 to give 210 mg (yield 76%) of the captioned compound as a colorless powder
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@@H:13]([OH:25])[CH2:14][P:15]([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(=[O:17])[OH:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:33])[O:30][CH2:31]Cl)[CH3:27]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:26]([O:28][C:29]([O:30][CH2:31][O:17][P:15]([CH2:14][CH:13]([OH:25])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])=[O:33])[CH3:27]
Reactant: O=C(NC[C@@H](O)CP(=O)(O)CC1CCCCC1)OCc1ccccc1
Reactant: CCOC(=O)OCCl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)OCOP(=O)(CC(O)CNC(=O)OCc1ccccc1)CC1CCCCC1
Yield: 23.2 %

Procedure:
To a solution of ((R)-3-benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (1.0 g, 2.71 mmol) and carbonic acid chloromethyl ester ethyl ester (1.13 g, 8.16 mmol) in toluene (60 mL) was added silver carbonate (2.26 g, 8.16 mmol). The reaction mixture was heated at reflux for 3 h. The reaction mixture was then filtered and was concentrated in vacuo. Purification by gradient flash chromatography (methanol/methylene chloride) on a 35 g RediSep disposable column gave (3-benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid ethoxycarbonyloxymethyl ester (300 mg, 0.63 mmol). 1H-NMR (CDCl3, 300 MHz): δ 7.35 (m, 5H), 5.65 (m, 2H), 5.45 (br s, 1H), 5.10 (s, 2H), 4.2 (m, 2H), 3.45 (dd, 1H), 3.20 (dd, 1H), 2.01-1.55 (m, 11H), 1.40-0.95 (m, 8H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:12]1([S:18][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCc2c(Br)cccc21
Reactant: Sc1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2c(Sc3ccccc3)cccc21

Procedure:
4-Bromo-1-indanone (0.30 g), thiophenol (0.15 mL), tris(dibenzylideneacetone)palladium(0) (0.13 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.082 g) and N,N-diisopropylethylamine (0.98 mL) are stirred in dioxane (1 mL) for 2 hours under microwave irradiation at 120° C. After removal of the solvent under vacuum the residue is purified by column chromatography (silica gel, cyclohexane:ethyl acetate 6:4) to give the desired material (0.34 g). LC (METHOD 5): tR=1.28 min; Mass spectrum: m/z=241 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[F-].[K+].[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][C:2]1([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)[CH:8]=2)[NH:3]1
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccsc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [F-]
Solvent: C1CCOC1
Product: CC1=CC(C)(C)Nc2ccc(-c3ccsc3)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
To a dry 50 mL round bottom flask charged with a mixture of trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester (0.50 g, 1.56 mmol), Pd(OAc)2 (0.035 g, 0.156 mmol), di-tert-butylbiphenylphosphine (DTBBPP) (0.093 g, 0.312 mmol), and KF (0.27 g, 4.67 mmol) suspended in THF (5 mL), was added 3-thiopheneboronic acid (0.30 g, 2.33 mmol). The flask was evacuated and flushed three times with argon and the reaction mixture was allowed to stir at room temperature for 2 days. The reaction mixture was filtered through diatomaceous earth and diluted with EtOAc (50 mL). The mixture was sequentially washed with water (10 mL), NaOH (1.0 M, 10 mL), and brine (10 mL). The organic phase was dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, 30% dichloromethane in hexanes) to give 2,2,4-trimethyl-6-thiophen-3-yl-1,2-dihydroquinoline (0.128 g, 32%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH2:11][CH:12](O[Si](C(C)(C)C)(C)C)[CH2:13][C:14](=O)[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27][C:28](=[O:33])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH:20]=[CH:19][CH:18]1[CH3:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:9](=[O:10])[CH:11]=[CH:12][CH:13]=[C:14]1[CH2:15][CH2:16][CH:17]1[CH:26]2[C:21](=[CH:22][CH:23]([CH3:34])[CH2:24][CH:25]2[O:27][C:28](=[O:33])[CH:29]([CH3:32])[CH2:30][CH3:31])[CH:20]=[CH:19][CH:18]1[CH3:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC(=O)CC(CC(=O)NCc3ccccc3)O[Si](C)(C)C(C)(C)C)C21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCc3cccc(=O)n3Cc3ccccc3)C21

Procedure:
To a stirred solution of 200 mg (0.32 mmol) 2-methyl-butyric acid 8-[6-benzylcarbamoyl-5-(tert.-butyl-dimethyl-silanyloxy)-3-oxo-hexyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester in 5 ml methylene chloride are added 0.3 g (2.6 mmol) trifluoroacetic acid. After 2 hours at room temperature the reaction mixture is quenched with saturated aqeous sodium bicarbonate. The aqueous phase is separated and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is evaporated. The residue is chromatographed over silica gel (hexane/ethyl acetate 7/3 to 2/3) affording the title compound as a white powder foam. MS (FAB) m/z 480 ([M+Li]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[CH2:36][CH2:35][C@@H:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[O:33][C:32]1=[O:45].[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[CH2:36][CH2:35][C@@H:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])[O:33][C:32]1=[O:45]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3CC[C@@H](c4ccccc4OC)OC3=O)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-c2ccc(C(=O)O)cc2C)cc1-c1ccc(C(F)(F)F)cc1CN1CC[C@@H](c2ccccc2OC)OC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methyl 4′-methoxy-2″-{[(6S)-6-(2-methoxyphenyl)-2-oxo-1,3-oxazinan-3-yl]methyl}-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (55.4 mg, 0.0358 mmol) in MeOH (1.5 mL) was added 4 M KOH solution (0.8 mL). The reaction was stirred at room temperature for 6 hours, and then quenched with 1 N HCl (5 mL) and diluted with EtOAc (15 mL). The aqueous layer was extracted with EtOAc (10 mL), and the combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by reverse-phase chromatography (C-18, 10 to 95% MeCN/water with 0.1% TFA) to afford 4′-methoxy-2″-{[(6S)-6-(2-methoxyphenyl)-2-oxo-1,3-oxazinan-3-yl]methyl}-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS=606.0 (M+1)+. 1H NMR (CDCl3, 500 MHz, rotamers present) δ 7.84-8.01 (m, 2H), 7.60-7.67 (m, 2H), 7.26-7.42 (m, 5H), 6.79-7.16 (m, 4H), 5.58 (dd, J=9.3, 2.7 Hz), 5.27 (dd, J=9.4, 2.6 Hz), 4.84 (d, J=14.9 Hz), 4.77 (d, J=15.6 Hz), 4.48-4.54 (m, 1H), 3.87 (s), 3.85 (s), 3.81 (s), 3.64 (s), 2.86-3.20 (m, 2H), 2.38 (s), 2.33 (s), 1.80-2.24 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[CH:10][C:9]=2[N+:21]([O-])=O)[CH2:3]1.O.[Cl-].[NH4+]>C(O)C.ClCCl.[Fe]>[F:24][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH2:13][CH2:14][O:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[N:11]=[CH:10][C:9]=2[NH2:21])[CH2:3]1
Reactant: C[Si](C)(C)COCCn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)COCCn1ncc(N)c1N1CCCC(F)(F)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a solution of 3,3-difluoro-1-(4-nitro-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-5-yl)piperidine (1.4 g, 3.86 mmol) in 20 mL of ethanol was added 40 mL of water, ammonium chloride (0.82 mg, 15.44 mmol), and iron powder (1.08 g, 19.3 mmol). The reaction mixture was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and filtered through a celite pad, rinsing with more dichloromethane. The filtrate was extracted twice with dichloromethane, then the combined organic extracts were dried over magnesium sulfate and concentrated to afford 1.2 g (93%) of 5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-amine. LCMS (ESI) m+H=333.1; 1H NMR (400 MHz, CDCl3) δ: 7.09 (s, 1H), 5.38 (m, 2H), 3.74 (m, 6H), 2.01 (s, 1H), 1.96 (s, 2H), 1.52 (m, 2H), 0.92 (m, 2H), 0 (s, 9H).
Reaction SMILES: [F:1][CH2:2][C@@H:3]([O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=O)[CH:4]=[CH2:5].Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO>[F:1][CH2:2][C@@H:3]([O:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[N:18][OH:19])[CH:4]=[CH2:5]
Reactant: C=C[C@@H](CF)OCC(=O)c1ccccc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C[C@@H](CF)OCC(=NO)c1ccccc1F
Temperature: 50 °C

Procedure:
(S)-2-((1-fluorobut-3-en-2-yl)oxy)-1-(2-fluorophenyl)ethanone (63.25 g, 279.59 mmol) was dissolved in anhydrous methanol (620 mL) and hydroxylamine hydrochloride (25.26 g, 363.47 mmol) and sodium acetate (34.40 g, 419.39 mmol) were added. The reaction mixture was heated to 50° C. for 90 min, then cooled to RT. It was then filtered through celite, washed with EtOAc (600 mL) and concentrated in vacuo. EtOAc (500 mL) was added to the crude product followed by water (600 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2×500 mL). The combined organic extracts were dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (10% to 50% EtOAc in hexanes) to afford the title compound as a clear oil. It exists as a mixture of geometric isomers (67.76 g, 100%). 1H-NMR (400 MHz, CDCl3) δ ppm 3.91-4.06 (m, 1H) 4.16-4.19 (m, 1H) 4.29 (d, J=5.56 Hz, 1H) 4.78 (d, J=0.76 Hz, 2H) 5.24-5.43 (m, 2H) 5.57-5.77 (m, 1H) 7.06-7.14 (m, 1H) 7.15-7.24 (m, 1H) 7.35-7.41 (m, 1H) 7.47 (td, J=7.45, 1.77 Hz, 1H) 9.24 (br. s, 1H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:18]([C@H:19]([CH3:27])[CH2:20][CH2:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:17][CH:16]=4)[C:10]1([CH3:38])[CH3:37])(C(C)(C)C)(C)C.Cl>C(O)C>[OH:8][C@H:9]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:28]([CH3:36])([CH2:29][CH2:30][C:31]=32)[C@@H:18]([C@H:19]([CH3:27])[CH2:20][CH2:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:17][CH:16]=4)[C:10]1([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Agent: Cl
Solvent: CCO
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3
Reaction time: 48 h
Yield: 81.1 %

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-cholesta-8,14-dien-24-one (0.1 g) is dissolved in 5 ml of ethanol, 0.2 ml of 6N hydrogen chloride is added and the mixture is stirred for 2 days. After aqueous work-up, column chromatography and crystallization from ethanol/-water, the title compound (64 mg) is obtained. 1H-NMR (CDCl3, 400 MHz): δ=5.35 (1H, s); 8.24 (1H, m); 2.62 (1H, m). MS: Calculated: 426.7. Found 426.3.
Reaction SMILES: [F:1][CH:2]([F:41])[N:3]1[C:7]2[C:8]([O:22][C@@H:23]([C@H:25]3[CH2:29][N:28]([C@@H](C4C=CC(OC)=CC=4)C)[C:27](=[O:40])[CH2:26]3)[CH3:24])=[N:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:11][C:6]=2[N:5]=[CH:4]1>C(O)(C(F)(F)F)=O>[F:41][CH:2]([F:1])[N:3]1[C:7]2[C:8]([O:22][C@@H:23]([C@H:25]3[CH2:29][NH:28][C:27](=[O:40])[CH2:26]3)[CH3:24])=[N:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(-c4ccc(OC)c(OC)c4)cc4ncn(C(F)F)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc3ncn(C(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)cc1OC
Temperature: 60 °C
Reaction time: 22 h

Procedure:
(R)-4-((R)-1-(3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.30 (max. 0.153 mmol) was dissolved in TFA (2 mL) and heated to 60° C. with stirring. After 22 h, the red solution was concentrated in vacuo and diluted with EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL). The phases were separated and the aqueous phase was extracted with EtOAc (20 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated onto 2 g silica gel. Purification by silica gel chromatography (0% to 2.5% to 5% MeOH in DCM) provided (R)-4-((R)-1-(3-(difluoromethyl)-6-(3,4-dimethoxyphenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3.02.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:17][CH3:18])=[C:14]([F:16])[CH:15]=2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:19][C:20]1[N:25]=[C:24]([S:26][CH3:27])[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=1.[F-].[Cs+]>O1CCOCC1.O.[Cu]I.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>[Cl:8][C:6]1[N:7]=[C:2]([C:22]2[CH:23]=[C:24]([S:26][CH3:27])[N:25]=[C:20]([CH3:19])[N:21]=2)[C:3]([NH:9][C:10]2[CH:11]=[N:12][C:13]([O:17][CH3:18])=[C:14]([F:16])[CH:15]=2)=[N:4][CH:5]=1
Reactant: COc1ncc(Nc2ncc(Cl)nc2Br)cc1F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(SC)nc(C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(Nc2ncc(Cl)nc2-c2cc(SC)nc(C)n2)cc1F
Temperature: 140 °C
Yield: 69.1 %

Procedure:
A glass microwave reaction vessel was charged with 3-bromo-5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)pyrazin-2-amine (216 mg, 0.648 mmol,), 2-methyl-4-(methylthio)-6-(tributylstannyl)pyrimidine (334 mg, 0.777 mmol), copper (I) iodide (25 mg, 0.130 mmol, Aldrich, St. Louis, Mo.), cesium fluoride (197 mg, 1.295 mmol, Alfa Aesar) and tetrakis(triphenylphosphine)palladium (74.8 mg, 0.065 mmol, Strem) in dioxane (3 mL). The reaction mixture was stirred and heated in a Emrys Optimizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 30 min. The reaction mixture was diluted with water (5 mL) and extracted with CH2Cl2 (2×30 mL). The combined organic extracts were washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography, eluting with 5% EtOAc/CH2Cl2 to give 5-chloro-N-(5-fluoro-6-methoxypyridin-3-yl)-3-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyrazin-2-amine (176 mg, 0.448 mmol, 69.2% yield). 1H NMR (300 MHz, CDCl3) δ 2.63 (s, 3H) 2.79 (s, 3H) 4.04 (s, 3H) 8.01-8.29 (m, 4H) 12.45 (s, 1H). m/z (ESI, +ve ion) 393.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>ClCCl>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Yield: 95 %

Procedure:
In a round-bottom flask, to a dichloromethane (125 mL) solution of 2-bromo-5-nitropyridine (5 g, 24.6 mmol), morpholine (5.4 mL, 61.5 mmol) was added. The reaction was refluxed for 4 hr, then cooled to room temperature. The solution was subsequently washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried (Na2SO4), filtered, and the solvent was removed in vacuo. 4-(5-Nitropyridin-2-yl)morpholine, a yellow solid, was obtained: 4.9 g (95% yield); 1H NMR (300 MHz, DMSO) δ 8.95 (d, J=2.7, 1H), 8.22 (dd, J=2.7, 9.6, 1H), 6.92 (d, J=9.6, 1H), 3.74-3.65 (m, 8H); LCMS (M+) m/z 210.34.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:19])([F:18])[F:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:17][C:16]([F:19])([F:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: FC(F)(F)CCCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCCCCCC(F)(F)F)cc1

Procedure:
To a suspension of 4-hydroxybenzaldehyde (488 mg, 4 mmol) and 6-bromo-1,1,1-trifluorohexane (657 mg, 3 mmol) in MeCN (10 mL) was added K2CO3 (829 mg, 6.00 mmol). The resulting mixture was reflux overnight. Insoluble material was filtered off and rinsed with MeCN. The combined filtrate was concentrated to afford a white solid. This white solid was partitioned between EtOAc and 1 N NaOH solution. The organic layer was separated, washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated to afford Intermediate 8A as a clear liquid. LCMS Anal. Calc'd for C13H15F3O2 260.10, found [M+H] 261.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.[ClH:10].[NH2:11]O>[Ni].CO>[ClH:10].[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][CH:4]([NH2:11])[CH2:3]1
Reactant: CC1(C)CCCC(=O)C1
Reactant: NO
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: CC1(C)CCCC(N)C1
Temperature: 60 °C

Procedure:
A 100 mL RBF was charged with 3,3-dimethylcyclohexanone (3.48 g, 27.6 mmol), hydroxylamine hydrochloride (2.01 g, 29.0 mmol), and 20 mL of MeOH. This mixture was heated to 60° C. for 1 h. To this solution was added Raney Nickel (approx 300 mg). This mixture was placed under a hydrogen atmosphere (1 atm) and heating was continued (60° C.) for 12 h. After that time, the solution was filtered, acidified with 1M HCl, and concentrated to give 3,3-dimethylcyclohexanamine HCl as an off-white solid. Step 2: A 20 mL vial was charged with (R)-3-(2-(tert-butylamino)-6-o-tolylquinolin-3-yl)-2-methylpropanoic acid (0.13 g, 0.33 mmol, prepared as in Example 8, Step 3-6), 3,3-dimethylcyclohexanaminium chloride (0.068 g, 0.42 mmol), TBTU (0.13 g, 0.42 mmol), and 2 mL of NMP. To this was added Hünig's base (0.11 g, 0.83 mmol). After stirring at RT for 2 h, the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried and concentrated to give an oil, which was purified via silica gel column chromatography to give the t-Bu protected amide intermediate. To this material, was added 3 mL of TFA and 3 mL of DCM. This mixture was heated at 40° C. for 12 h, then concentrated and purified by silica gel column chromatography (0-8% NH3/MeOH in CH2Cl2) to give (2R)-3-(2-amino-6-o-tolylquinolin-3-yl)-N-(3,3-dimethylcyclohexyl)-2-methylpropanamide as a white solid. MS (ESI, pos. ion) m/z: 430 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:26][CH2:25][N:24](C(OCC)=O)[CH2:23][CH2:22]2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11](=[O:20])[C:10]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N1CCN(c2cn(Cc3ccccc3)c3cc(OC)ccc3c2=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(=O)c(N3CCNCC3)cn(Cc3ccccc3)c2c1
Yield: 100.5 %

Procedure:
A mixture of the product of step (iv) (1.8 g), ethanol (40 ml) and 20% w/v aqueous potassium hydroxide solution (40 ml) was heated to reflux overnight, cooled and evaporated to dryness. The residue was partitioned between water and dichloromethane and the organic layer was separated, washed with brine, dried (MgSO4) and evaporated to yield 1-benzyl-3-(piperazin-1-yl)-7-methoxy-4-quinolone (1.5 g) as a yellow foam: NMR (CDCl3) δ 2.80 (1H, m), 3.20 (8H, m), 3.73 (3H, s), 5.28 (2H, s), 6.59 (1H, d), 6.88 (1H, dd), 7.15 (3H, m), 7.30 (3H, m), 8.41 (1H, d); m/Z 350 (N+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1(C)C=CC=CC=1.CO>[CH3:1][C:2]1[CH:13]=[CH:12][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:15])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc2cc(C(=O)O)oc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc2ccc(C)cc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 67.1 %

Procedure:
To a solution of 6-methylbenzofuran-2-carboxylic acid (11 g, 62.4 mmol) in 468 mL of toluene and 156 mL of MeOH was added 2N TMS-CHN2 (46.8 mL, 94 mmol) dropwise at room temperature. The reaction was stirred at room temperature for 6 hr. The reaction was then quenched by addition of acetic acid dropwise at 0° C. until the yellow color vanished, and gas evolution ceased. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography, 100% Heptane-10% Ethyl Acetate/90% Heptane, to give methyl 6-methylbenzofuran-2-carboxylate (7.96 g). 1H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 3.88 (s, 3H), 7.20 (dd, J=8.3, 1.0 Hz, 1H), 7.53 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.71 (d, J=1.0 Hz, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1>>[CH2:36]([O:35][C:33]([C:32]1[CH:38]=[CH:39][C:29]([NH:28]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:30][CH:31]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: CCOC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(OC)c(OC)cc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and ethyl 4-aminobenzoate